Nutritional interventions for reducing morbidity and mortality in people with HIV

  • Review
  • Intervention

Authors

  • Liesl Grobler,

    Corresponding author
    1. South African Medical Research Council, South African Cochrane Centre, Tygerberg, Western Cape, South Africa
    2. Stellenbosch University, Centre for Evidence-based Health Care, Cape Town, Western Cape, South Africa
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  • Nandi Siegfried,

    1. University of Cape Town, Department of Psychiatry and Mental Health, Faculty of Health Sciences, Cape Town, South Africa
    2. University of California, San Francisco, Department of Epidemiology and Biostatistics, San Francisco, California, USA
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  • Marianne E Visser,

    1. Stellenbosch University, Division of Human Nutrition, Faculty of Medicine and Health Sciences, Tygerberg, South Africa
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  • Sarah SN Mahlungulu,

    1. Eastern Cape Department of Health, Lilitha College of Nursing, Lusikisiki, Eastern Cape, South Africa
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  • Jimmy Volmink

    1. South African Medical Research Council, South African Cochrane Centre, Tygerberg, Western Cape, South Africa
    2. Stellenbosch University, Faculty of Medicine and Health Sciences, Tygerberg, South Africa
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Abstract

Background

Adequate nutrition is important for optimal immune and metabolic function. Dietary support may, therefore, improve clinical outcomes in HIV-infected individuals by reducing the incidence of HIV-associated complications and attenuating progression of HIV disease, improving quality of life and ultimately reducing disease-related mortality.

Objectives

To evaluate the effectiveness of various macronutrient interventions, given orally, in reducing morbidity and mortality in adults and children living with HIV infection.

Search methods

We searched CENTRAL (up to August 2011), MEDLINE (1966 to August 2011), EMBASE (1988 to August 2011), LILACS (up to February 2012), and Gateway (March 2006-February 2010). We also scanned reference lists of articles and contacted authors of relevant studies and other researchers.

Selection criteria

Randomised controlled trials evaluating the effectiveness of macronutrient interventions compared with no nutritional supplements or placebo in the management of adults and children infected with HIV.

Data collection and analysis

Three reviewers independently applied study selection criteria, assessed study quality, and extracted data. Effects were assessed using mean difference and 95% confidence intervals. Homogenous studies were combined wherever it was clinically meaningful to do so and a meta-analysis using the random effects model was conducted.

Main results

Fourteen trials (including 1725 HIV positive adults and 271 HIV positive children), were included in this review. Neither supplementary food nor daily supplement of Spirulina significantly altered the risk of death compared with no supplement or placebo in malnourished, ART naive adult participants in the two studies which reported on this outcome. A nutritional supplement enhanced with protein did not significantly alter the risk of death compared to standard nutritional care in children with prolonged diarrhoea. Supplementation with macronutrient formulas given to provide protein and/or energy and fortified with micronutrients, in conjunction with nutrition counselling, significantly improved energy intake (3 trials; n=131; MD 393.57 kcal/day; 95% CI: 224.66 to 562.47;p<0.00001) and protein intake (2 trials; n=81; MD 23.5 g/day; 95% CI: 12.68, 34.01; p<0.00001) compared with no nutritional supplementation or nutrition counselling alone in adult participants with weight loss. In general supplementation with specific macronutrients such as amino acids, whey protein concentration or Spirulina did not significantly alter clinical, anthropometric or immunological outcomes compared with placebo in HIV-infected adults and children.

Authors' conclusions

Given the current evidence base, which is limited to fourteen relatively small trials all evaluating different macronutrient supplements in different populations at different stages of HIV infection and with varying treatment status, no firm conclusions can be drawn about the effects of macronutrient supplementation on morbidity and mortality in people living with HIV. It is, however, promising to see more studies being conducted in low-income countries, and particularly in children, where macronutrient supplementation both pre-antiretroviral treatment and in conjunction with antiretroviral treatment might prove to be beneficial.

Résumé scientifique

Interventions nutritionnelles pour réduire la morbidité et la mortalité chez les personnes atteintes du VIH

Contexte

Une nutrition adéquate est importante pour des fonctions immunitaire et métabolique optimales. Un suivi diététique pourrait donc améliorer les critères d'évaluation cliniques chez les individus infectés par le VIH en réduisant l'incidence des complications associées au VIH et atténuant la progression du VIH, en améliorant la qualité de vie et, enfin, en réduisant la mortalité liée à la maladie.

Objectifs

Evaluer l'efficacité de diverses interventions de macro-nutriments, administrés par voie orale, pour réduire la morbidité et la mortalité chez les adultes et les enfants atteints du VIH.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans CENTRAL (jusqu'à août 2011), MEDLINE (de 1966 à août 2011), EMBASE (de 1988 à août 2011), LILACS (jusqu'à février 2012), et Gateway (mars 2006-février 2010). Nous avons également passé au crible des listes bibliographiques d'articles et avons contacté les auteurs des études pertinentes et d'autres chercheurs.

Critères de sélection

Les essais contrôlés randomisés évaluant l'efficacité d'interventions de macro-nutriments comparé à l'absence de suppléments nutritionnels ou à un placebo dans la prise en charge des adultes et des enfants atteints du VIH.

Recueil et analyse des données

Trois évaluateurs ont appliqué les critères de sélection des études, évalué la qualité des études et extrait des données de façon indépendante. Les effets ont été évalués en utilisant la différence moyenne et des intervalles de confiance à 95 %. Les études homogènes ont été combinées lorsque cela était cliniquement pertinent et une méta-analyse utilisant le modèle à effets aléatoires a été réalisée.

Résultats principaux

Quatorze essais (portant sur 1 725 adultes séropositifs et 271 enfants séropositifs au VIH) ont été inclus dans cette revue. Ni des compléments alimentaires ni un supplément quotidien en spiruline n'ont modifié significativement le risque de décès comparé à l'absence de supplément ou à un placebo chez des participants adultes dénutris, jamais traités aux antirétroviraux, dans les deux études qui ont indiqué ce critère de jugement. Un supplément nutritionnel riche en protéines n'a pas modifié significativement le risque de décès comparé aux soins nutritionnels standard chez les enfants atteints de diarrhée prolongée. Une supplémentation par des formules de macro-nutriments administrées pour fournir des protéines et/ou de l'énergie et enrichies en micro-nutriments, en combinaison avec des conseils nutritionnels, a amélioré significativement l'apport en énergie (3 essais ; n=131 ; DM 393,57 kcal/jour ; IC à 95 % : 224,66 à 562,47 ; p<0,00001) et apport en protéines (2 essais ; n=81 ; DM 23,5 g/jour ; IC à 95 % : 12,68, 34,01 ; p<0,00001) comparé à l'absence de supplémentation nutritionnelle ou à des conseils nutritionnels seuls chez des participants adultes présentant une perte de poids. Dans la supplémentation générale avec des macro-nutriments spécifiques, tels que des acides aminés, la concentration en protéine de lactosérum ou la spiruline n'ont pas modifié significativement les critères de jugement cliniques, anthropométriques ou immunologiques comparé à un placebo chez des adultes et des enfants atteints du VIH.

Conclusions des auteurs

Etant donné la base de preuves actuelle, qui se limite à quatorze essais, de taille relativement petite, évaluant tous des suppléments de macro-nutriments différents dans des populations différentes à des stades différents de l'infection au VIH et avec des statuts de traitement divers, aucune conclusion définitive n'a pu être établie quant aux effets de la supplémentation en macro-nutriments sur la morbidité et la mortalité chez les personnes atteintes du VIH. Il est toutefois prometteur de voir que des études supplémentaires sont en train d'être réalisées dans des pays à faible revenu, et en particulier chez l'enfant, où une supplémentation en macro-nutriments tant avant le traitement antirétroviral qu'en association avec le traitement antirétroviral pourrait se révéler bénéfique.

Resumo

Intervenções nutricionais para reduzir a morbidade e a mortalidade em pessoas com HIV

Introdução

Uma nutrição adequada é importante para o funcionamento ideal do sistema imunológico e metabólico. O suporte nutricional pode, portanto, melhorar os desfechos clínicos em indivíduos infectados pelo HIV, reduzindo a incidência de complicações associadas ao HIV, atenuando a progressão da doença, melhorando a qualidade de vida e, em última instância, reduzindo a mortalidade relacionada à doença.

Objetivos

Avaliar a efetividade das diversas intervenções com macronutrientes, administrados por via oral, na redução da morbidade e da mortalidade em adultos e crianças que vivem com HIV.

Métodos de busca

Nós pesquisamos as seguintes bases de dados: CENTRAL (até agosto de 2011), MEDLINE (de 1966 a agosto de 2011), EMBASE (de 1988 a agosto de 2011), LILACS (até fevereiro de 2012) e Gateway (de março de 2006 a fevereiro de 2010). Também pesquisamos as listas de referências dos artigos e contatamos os autores de estudos relevantes e outros pesquisadores da área.

Critério de seleção

Ensaios clínicos randomizados que avaliaram a efetividade das intervenções com macronutrientes comparadas com a não utilização de suplemento nutricional ou com placebo no manejo de adultos e crianças infectados pelo HIV.

Coleta dos dados e análises

Três revisores, de modo independente, selecionaram os estudos, avaliaram sua qualidade e extraíram os dados. Os efeitos foram avaliados utilizando-se a diferença de médias e intervalos de confiança de 95% (95% CI). Os estudos semelhantes foram combinados sempre que isso fosse clinicamente relevante, e foi realizada metanálise usando o modelo de efeito randômico .

Principais resultados

Quatorze estudos (totalizando 1.725 adultos e 271 crianças HIV-positivos) foram incluídos nesta revisão. Entre os participantes adultos, desnutridos e virgens de tratamento antirretroviral, nem a alimentação suplementar, nem a suplementação diária com espirulina mudaram significativamente o risco de morte, em comparação com a não utilização de suplemento nutricional ou com placebo, nos dois estudos que relataram este desfecho. O uso de umsuplemento nutricional enriquecido com proteínas não alterou significativamente o risco de morte em comparação com o cuidado nutricional habitual em crianças com diarreia prolongada. Em adultos com perda de peso, a suplementação com fórmulas de macronutrientes,administradas para fornecer proteína e/ou calorias e enriquecidas com micronutrientes, juntamente com aconselhamento nutricional, melhorou significativamente a ingestão de calorias(3 estudos; n = 131; diferença média, MD, 393,57 kcal/dia; 95% CI: 224,66-562,47; p <0,00001) ea ingestão de proteína (2 estudos; n = 81; MD 23,5g/dia; 95% CI: 12,68 - 34,01; p <0,00001) em comparação com nenhuma suplementação nutricional ou somente com aconselhamento nutricional. Em adultos e em crianças infectados pelo HIV, de uma forma geral, a suplementação com macronutrientes específicos, tais como aminoácidos, concentrado proteico de soro de leite ou espirulina, não modificou significativamente os desfechos clínicos, antropométricos ou imunológicos.

Conclusão dos autores

Considerando a evidência atual, que é limitada a 14 estudos relativamente pequenos, todos avaliando diferentes suplementos de macronutrientes, em diferentes populações, em diferentes fases da infecção pelo HIV e, com diferentes status de tratamento, não se pode tirar conclusões definitivas sobre os efeitos da suplementação de macronutrientes na morbidade e mortalidade em pessoas vivendo com HIV. É, no entanto, promissor ver mais estudos sendo realizados em países de baixa renda e, particularmente, com crianças, nas quais a suplementação de macronutrientes, tanto no tratamento pré-antirretroviral quanto em conjunto com o tratamento antirretroviral, pode provar ser benéfica.

Notas de tradução

Tradução do Centro Cochrane do Brasil (Machline Paim Paganella)

アブストラクト

HIV感染者の罹患率および死亡率低下のための栄養療法

背景

十分な栄養摂取は最適な免疫・代謝機能を得る上で重要である。したがって、栄養補充はHIV関連合併症の罹患率を減少させ、HIV疾患の進行を遅らせることでHIV感染者の臨床アウトカムを改善するとともに、QOLを向上させ、最終的には疾患関連死亡率の低下をもたらす可能性がある。

目的

HIV感染成人および小児にさまざまな主要栄養素補充介入を経口で実施したときの罹病率および死亡率の低下効果を評価すること。

検索戦略

CENTRAL(2011年8月まで)、MEDLINE(1966~2011年8月)、EMBASE(1988年~2011年8月)、LILACS(2012年2月まで)およびGateway(2006年3月~2010年2月)を検索した。また、論文の参考文献リストを精査し、関連する研究の著者およびその他の研究者に連絡を取った。

選択基準

HIV感染成人および小児の管理における主要栄養素補充介入の有効性を、栄養補充を実施しない場合またはプラセボと比較したランダム化比較試験(RCT)。

データ収集と分析

3名のレビューアが独立して研究選択基準を用い、研究の質を評価し、データを抽出した。平均差(MD)および95%信頼区間を用いて効果を評価した。類似した研究は臨床的意義があれば統合し、ランダム効果を用いたメタアナリシスを実施した。

主な結果

14件の試験(HIV陽性の成人1725例および小児271例)を本レビューの対象とした。死亡リスクの低下をアウトカムとして報告した2件では、栄養不良で抗レトロウイルス剤療法による治療歴のない成人参加者において、栄養剤の摂取およびスピルリナの連日補充のいずれも、栄養補充を実施しない場合またはプラセボと比較して死亡リスクを有意に改善しなかった。長期下痢の小児では、蛋白を強化した栄養剤は標準的な栄養療法と比較して死亡リスクを有意に改善しなかった。体重減少がみられる成人参加者では、蛋白やエネルギーの供給を目的とし主要栄養素を強化した栄養補助剤の補充を栄養指導と併用した場合、栄養補充を行わなかった場合や栄養指導のみを実施した場合と比較して、エネルギー摂取量(3試験、131例、MD:393.57 kcal/日、95% CI:224.66~562.47;p<0.00001)および蛋白摂取量(2試験、81例、MD:23.5 g/日、95% CI:12.68~34.01、p<0.00001)が有意に改善された。全体として、HIV感染成人および小児に対するアミノ酸、乳清蛋白濃縮物またはスピルリナなどの特定の主要栄養素の補充は、プラセボと比較して臨床、人体計測および免疫学的アウトカムを有意に改善しなかった。

著者の結論

現時点のエビデンスの根拠は、いずれもHIV感染のステージや治療状況の異なるさまざまな集団を対象に異なる主要栄養素補充療法を評価した、比較的小規模の試験14件に限られている。そのため、HIV感染者の罹病率および死亡率に対する主要栄養素補充療法の効果について確固たる結論を出すことはできない。しかしながら、低所得国で特に小児を対象に実施中のその他の研究では、抗レトロウイルス療法実施前および抗レトロウイルス療法との併用のどちらにおいても、主要栄養素補充療法の有益性が立証される可能性があり、これらの研究の結果が待たれる。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2015.12.30]
《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。

Plain language summary

Nutritional interventions for reducing morbidity and mortality in people with HIV

Achieving and maintaining optimal nutrition is considered an important adjunct in the clinical care of patients infected with HIV, as good nutrition can improve an individual's immune function, limit disease-specific complications, and improve quality of life and survival. We sought to determine whether macronutrient interventions, either given to provide protein and/or energy or test the effect of specific macronutrients (i.e. ch as amino acids, whey protein concentrate or Spirulina), given orally, influence morbidity and mortality in adults and children living with HIV infection. Our review, based on fourteen small trials, evaluating different macronutrient supplements, found limited evidence that balanced macronutrient formulas increase protein and energy intake. However, we found no evidence that such supplementation translates into reductions in disease progression or HIV-related complications, such as opportunistic infections or death.

Résumé simplifié

Interventions nutritionnelles pour réduire la morbidité et la mortalité chez les personnes atteintes du VIH

Le fait de parvenir et de maintenir une nutrition optimale est considéré comme un traitement d'appoint important dans les soins cliniques des patients infectés par le VIH, car une bonne nutrition peut améliorer la fonction immunitaire d'un individu, limiter les complications spécifiques de la maladie et améliorer la qualité de vie et la survie. Nous avons cherché à déterminer si des interventions de macro-nutriments, soit proposées pour fournir des protéines et/ou de l'énergie soit pour tester l'effet de macro-nutriments spécifiques (tels que des acides aminés, un concentré de protéines de lactosérum ou de la spiruline), administrés oralement, influencent la morbidité et la mortalité chez les adultes et les enfants atteints du VIH. Notre revue, basée sur quatorze essais de petite taille, évaluant différents suppléments en macro-nutriments, n'a trouvé que peu de preuves montrant que des formules de macro-nutriments équilibrées augmentaient l'apport en protéines et en énergie. Cependant, nous n'avons trouvé aucune preuve indiquant qu'une telle supplémentation se traduisait par des réductions de la progression de la maladie ou des complications liées au VIH, telles que les infections opportunistes ou le décès.

Notes de traduction

Traduit par: French Cochrane Centre 1st March, 2013
Traduction financée par: Pour la France : Ministère de la Santé. Pour le Canada : Instituts de recherche en santé du Canada, ministère de la Santé du Québec, Fonds de recherche de Québec-Santé et Institut national d'excellence en santé et en services sociaux.

Resumo para leigos

Intervenções nutricionais para reduzir a morbidade e a mortalidade em pessoas com HIV

Alcançar e manter uma nutrição adequada são considerados importantes aliados no tratamento de pacientes infectados pelo HIV. Sabe-se que uma boa alimentação pode melhorar a imunidade de um indivíduo, diminuir complicações específicas da doença e melhorar a qualidade de vida e a sobrevida. Nós procuramos descobrir se as intervenções com macronutrientes administrados por via oral, para fornecer proteína e/ou calorias ou para testar o efeito de macronutrientes específicos (isto é, como aminoácidos, concentrado proteico de soro de leite ou espirulina, uma alga com alto conteúdo de proteínas), influenciam a morbidade e a mortalidade em adultos e crianças infectados pelo HIV. Nossa revisão, baseada em 14 pequenos estudos, avaliando diferentes suplementos de macronutrientes, encontrou evidência limitada de que as fórmulas de macronutrientes equilibradas aumentam a ingestão de proteínas e calorias. No entanto, nós não encontramos nenhuma evidência de que tal suplementação leve à diminuição da progressão da doença ou de complicações relacionadas com o HIV, tais como infecções oportunistas ou morte.

Notas de tradução

Tradução do Centro Cochrane do Brasil (Machline Paim Paganella)

平易な要約

HIV感染者の罹患率および死亡率低下のための栄養療法

良好な栄養状態は免疫機能を高め、疾患特有の合併症の発現を抑え、QOLおよび生存率を改善するため、最適な栄養状態を達成してこれを維持することは、HIV感染患者の臨床ケアにおいて重要な補助治療となる。 蛋白やエネルギーの供給または特定の主要栄養素(アミノ酸、乳清蛋白濃縮物またはスピルリナなど)の効果を調べることを目的として実施した経口による主要栄養素補充介入が、HIV感染成人および小児の罹病率や死亡率に効果を及ぼすかどうかを確認することを試みた。本レビューでは、異なる主要栄養素補充療法を評価した14件の小規模試験に基づき、バランスのとれた主要栄養素補助剤が蛋白およびエネルギー摂取量を増加させるという限られたエビデンスが得られた。しかし、こうした補充療法が疾患進行や日和見感染または死亡などのHIV関連合併症の減少につながるというエビデンスは得られなかった。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2015.12.30]
《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。

Summary of findings(Explanation)

Summary of findings for the main comparison. Balanced nutritional supplement compared to counselling or nutritional placebo in patients with weight loss for reducing morbidity and mortality in people with HIV
  1. 1 All three trial reports were unclear regarding randomisation and selection bias may be present. The trials were not blinded for participants and personnel possibly leading to performance bias. Blinding was not clearly reported for outcome assessment and detection bias may be present. Attrition was high in the Berneis trial at 16%.
    2 The trials are relatively small with Berneis only having 15 participants. This could lead to imprecision
    3 Trial reports were unclear regarding randomisation and selection bias may be present. The trials were not blinded for participants and personnel possibly leading to performance bias. Blinding was not clearly reported for outcome assessment and detection bias may be present. Attrition was high in the Berneis trial at 16%.
    4 Both are small trials, Berneis only has 15 participants so results are likely to be imprecise.
    5 The meta-analysis included combining mean change scores from baseline to study endpoint (Schwenk and Rabeneck)and actual mean weight measurements at study endpoint (Berneis and De Luis) as described in the Cochrane Review Handbook. No mean weights in the control groups were reported for the two trials in which change scores were provided and the range reported here only reflects that of the Berneis and De Luis trials.
    6 All four trial reports were unclear regarding randomisation and selection bias may be present. The trials were not blinded for participants and personnel possibly leading to performance bias. Blinding was not clearly reported for outcome assessment and detection bias may be present. Attrition was high in the Berneis trial at 16% and in Rabeneck at 24%. Attrition bias is likely.
    7 As all the sample sizes are small, Imprecision is likely in the indiviudal trials. This is reduced by the meta-analysis.
    8 The meta-analysis included combining mean change scores from baseline to study endpoint and actual mean measurements at study endpoint as described in the Cochrane Review Handbook. No fat free mass in % TBW was reported in the control group for Rabeneck and so we included the change score instead. In Schwenk it is not clear that the data presented are % TBW as they reflect the Area under the Curve. However the trial adds very little weight (0.6%) so we retained it in the analysis.
    9 The De Luis trial did not report change scores and so the actual mean weights are reported. In the control group this was 57.6kg
    10 Berneis is a small trial with 15 participants leading to imprecision. As there is only one other trial in the meta-analysis imprecision is likely.
    11 Results are for one trial only with a high risk of selection, performance, and detection bias.
    12 Results are from one trial only and as the sample size is small imprecision is likely.

Balanced nutritional supplement compared to counselling or nutritional placebo in patients with weight loss for reducing morbidity and mortality in people with HIV
Patient or population: patients with reducing morbidity and mortality in people with HIV
Settings:
Intervention: Balanced nutritional supplement
Comparison: counselling or nutritional placebo in patients with weight loss
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Counselling or nutritional placebo in patients with weight lossBalanced nutritional supplement
Energy intake (kcal/day)
Follow-up: 6 to 12 weeks
The mean energy intake (kcal/day) ranged across control groups from
1,777 to 2,412 kcal/day
The mean energy intake (kcal/day) in the intervention groups was
393.57 higher
(224.66 to 562.47 higher)
 131
(3 studies)
⊕⊕⊝⊝
low 1,2
 
Protein intake (g/day)
Follow-up: 6 to 12 weeks
The mean protein intake (g/day) ranged across control groups from
79 to 81 g/day
The mean protein intake (g/day) in the intervention groups was
23.35 higher
(12.68 to 34.01 higher)
 81
(2 studies)
⊕⊕⊝⊝
low 3,4
 
Body weight
Follow-up: 6 - 12 weeks
The mean body weight ranged across control groups from
71.8 to 73.3 kg 5
The mean body weight in the intervention groups was
0.17 lower
(1.1 lower to 0.75 higher)
 233
(4 studies)
⊕⊕⊕⊝
moderate 6,7
 
Fat mass measured in % of TBW
Follow-up: 6 to 12 weeks
The mean fat mass measured in % of tbw ranged across control groups from
8.5 to 15.5 % 8
The mean fat mass measured in % of tbw in the intervention groups was
1.14 lower
(2.58 lower to 0.29 higher)
 233
(4 studies)
⊕⊕⊕⊝
moderate 6,7
 
Fat free mass
Follow-up: 6 to 12 weeks
The mean fat free mass ranged across control groups from
-0.3 to 3.8 Change in fat free mass in kg 9
The mean fat free mass in the intervention groups was
0.37 lower
(2.77 lower to 2.03 higher)
 218
(3 studies)
⊕⊕⊝⊝
low 1,2
 
CD4
Follow-up: mean 12 weeks
The mean cd4 ranged across control groups from
311 to 559 Cells/mm3
The mean cd4 in the intervention groups was
114.48 lower
(233.2 lower to 4.23 higher)
 81
(2 studies)
⊕⊕⊝⊝
low 3,10
 
Viral load (log10 copies/ml)
Follow-up: mean 12 weeks
 The mean viral load (log10 copies/ml) in the intervention groups was
3.71 lower
(12.16 lower to 4.74 higher)
 66
(1 study)
⊕⊝⊝⊝
very low 11,12
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

HIV/AIDS and macronutrient deficiency

Adequate nutrition is critical for optimal immune function. Dietary therapy is therefore regarded as an important adjunct in the clinical care of patients infected with HIV. It is believed that achieving and maintaining optimal nutrition will improve the individual's immune function, reduce the incidence of complications associated with HIV infection, attenuate the progression of HIV infection, improve quality of life, and ultimately reduce mortality associated with the disease (de Pee 2010; Hsu 2005).

People living with HIV are at great risk of nutritional disorders. This is the case in both untreated (i.e. not receiving antiretroviral therapy (ART)) and treated (i.e. receiving some form of ART) HIV-infected individuals. Furthermore, HIV infection is most prevalent in parts of the world where food security is compromised. Populations at high risk of HIV infection may lack appropriate nourishment prior to infection by HIV. Starvation and undernourishment severely compromise the immune system thereby increasing both susceptibility to HIV infection and progression of HIV/AIDS. (Scrimshaw 1997; Anabwani 2005; Schaible 2007).  

Untreated HIV infection is characterised by increased resting energy expenditure (REE, Kosmiski 2011), decreased appetite, decreased intake and digestion of food and decreased absorption of nutrients (Koethe 2010). HIV-infected individuals receiving antiretroviral therapy may experience the adverse effects of antiretroviral drugs such as nausea and insomnia, which also have a negative impact on nutrient status. Poor nutrient status may in turn exacerbate these adverse effects, in part by increased drug toxicity (Ammassari 2001; WHO 2004; Hardon 2007).

As a result of the increased REE in untreated HIV infection, both fat and protein stores are oxidised to fuel the body's energy requirements (Macallan 1995a; Batterham 2001; Kosmiski 2011). Whole-body protein turnover is up to 25% higher in untreated HIV-infected individuals than in HIV-negative controls (Macallan 1995b) and fat stores are replenished more readily than protein stores even when nutrition is adequate (Kotler 1999). The resultant loss of body protein could further compromise the immune system of the HIV-infected individual (Schaible 2007).

HIV-associated weight loss and wasting are independent contributing factors to poor clinical outcomes in people living with HIV/AIDS (Wheeler 1998; Kotler 1989). In most cases, acute weight-loss episodes are associated with secondary infections (Macallan 1993). Once the secondary infections are successfully treated and energy intake is increased sufficiently, patients are able to regain weight and remain weight-stable (Macallan 1998). Instances of chronic weight loss are normally associated with secondary gastrointestinal infections and subsequent malabsorption (Macallan 1993).

Weight loss and low Body Mass Index (BMI < 17kg.m-2), a proxy for poor nutritional status, are independent predictors of mortality, particularly in resource-limited settings (Marazzi 2008; Liu 2011). This remains true despite the introduction of ART. In a recent study, Liu 2011 found that HIV-infected patients with low BMI (BMI<17kg.m-2) had a significantly higher risk of early mortality (death within 3 months) following the initiation of ART. Of the patients who survived the first 3 months of ART, those who experienced weight loss had a higher risk of subsequent death compared to those who were weight stable during this period.

Description of the intervention

Macronutrients and macronutrient interventions

Macronutrients are variably defined but are classically understood to be essential nutrients that are required by the body in relatively large amounts. Dorland’s Illustrated Medical Dictionary defines macronutrients as carbohydrates, fats and proteins and states that: ‘minerals necessary in relatively large amounts (for example Calcium, Chloride, Magnesium, Phosphorus, Potassium and Sulphur) are sometimes included and sometimes excluded.’ (Dorland 2007).

Macronutrient interventions

In this review, a macronutrient intervention could be any intervention given to provide protein and/or energy, ie through carbohydrates and/or fat, by replacing or supplementing the normal diet (for example, high or low fat/carbohydrate/protein diets). Macronutrient interventions can also include dietary supplements not given specifically to provide energy but rather to test the effectiveness of specific nutritional elements (for example, amino acids, whey protein concentrate and Spirulina). Macronutrient interventions may be delivered in liquid, powder or tablet formulation. In resource-scare regions where malnutrition is prevalent, food programmes deliver replacement food or foodstuffs in addition to local staple foods in the form of 1) high-energy ready-to-use therapeutic foods, 2) corn-soya blends, or 3) fortified blended foods, ready-to-use foods, high-energy biscuits and compressed food bars (World Food Programme; Koethe 2009). Macronutrient supplements may be fortified with micronutrients in the form of vitamins and trace elements. An existing Cochrane review, revised in 2010, has summarised the effects of micronutrient supplementation in people with HIV/AIDS (Irlam 2010).

Why it is important to do this review

People living with HIV are at great risk of nutritional disorders. Adequate nutrition is critical for optimal immune function. Dietary therapy is, therefore, an important adjunct in the clinical care of patients infected with HIV.

HIV infection is most prevalent in parts of the world where food security is compromised. Populations at high risk of HIV infection may lack appropriate nourishment prior to infection by HIV. Starvation and undernourishment severely compromises the immune system thereby increasing susceptibility to HIV infection and progression of the disease (Anabwani 2005). Poor nutrient status in HIV-infected individuals is an independent predictor of mortality in both untreated and treated individuals with HIV (Marazzi 2008; Koethe 2010; Liu 2011).   

The World Health Organization is currently updating the guidelines for nutritional interventions. Current guidelines for HIV-specific populations are based on an appraisal of the evidence conducted in 2003 and a consultative meeting in 2005. A review of all the evidence conducted on searches as up-to-date as feasible, is desirable when informing guidelines. This 2011 review update seeks to provide a comprehensive summary of the current evidence for macronutrient supplementation in HIV-infected individuals.

Objectives

The objective of this review was to evaluate the effectiveness of various macronutrient interventions in reducing morbidity and mortality in adults and children living with HIV infection.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) evaluating the effectiveness of various macronutrient interventions in the management of individuals living with HIV/AIDS were considered. Studies were included regardless of the setting in which they were carried out.

Types of participants

Studies involving adults and children with HIV/AIDS were included in the review. Studies involving HIV-infected pregnant women were excluded from the review. Studies involving participants with TB/HIV co-infection were included if the randomisation of the participants was stratified according to HIV infection status.

Types of interventions

Experimental

In this review, a macronutrient intervention could be any intervention given to provide protein and/or energy, ie through carbohydrates and/or fat, by replacing or supplementing the normal diet (for example, high or low fat/carbohydrate/protein diets). Macronutrient interventions could also include dietary supplements not given specifically to provide energy but rather to test the effectiveness of specific nutritional elements (for example, amino acids, whey protein concentrate and Spirulina). In this instance, only interventions providing 1g or more of the specific macronutrient element were included in the review. Only macronutrient interventions administered orally and for four weeks or longer were included in the review.

Control

The control groups could include usual diet, no macronutrient supplementation, dietary counselling or non-nutritive placebo.

Studies assessing the effects of total parenteral or enteral nutritional interventions administered via tube feeding were excluded from this review. Macronutrient interventions fortified with micronutrients were included in the review. However, trials evaluating micronutrient supplements alone in people with HIV infection were excluded, as they form part of an existing Cochrane review (Irlam 2010). Studies assessing nutritional interventions for reducing HAART-related co-morbidities in HIV-infected people were also excluded as these studies would form part of another Cochrane protocol (Marti-Carvajal 2010)

Randomised controlled trials comparing the effectiveness of two or more macronutrient interventions (i.e. studies which did not have a control group that received no macronutrient supplementation, dietary counselling or non-nutritive placebo) in HIV-infected individuals were not included in review, however, data from these studies was included in Table 1.

Table 1. Characteristics of comparative studies
Study IDBakeine 1997 (Abstract)
Methods

COUNTRY:

Uganda

SETTING:

Joint Clinical Research Centre, Kampala

FOLLOW UP:

At days1 and 56 weight, triceps skinfold, serum albumin and CD4 cell count were evalulated

Participants

INCLUSION CRITERIA:

Early stage (CDC stage I-III), largely asymptomatic HIV-infected patients

EXCLUSION CRITERIA

Number randomised: 22 (7 males, 15 females)

Mean age at baseline: 31±12 years

InterventionIn addition to normal diet patients received daily a 4.2 MJ supplement of either Nutrifil (Nutrifil is cow’s- milk-based, is highly digestible and contains a wide range of micronutrients. It consists of 150g protein, 110g fat, 650g carbohydrate/kg) or Cornsoy blend (160g protein, 60g fat, 660g carbohydrate/kg) for 8 weeks.
Outcomes

                                                                Nutrifil-supplemented group (n 11)                  CSB-supplemented group (n 11)

                                                                                                                                                                            

                                                                      Day 1                    Day 56                              Day 1                          Day 56             

                                                                Mean         SE           Mean       SE                Mean              SE            Mean         SE

                                                                                                                                                                                    

Body weight (kg)                                 53.4           2.9         55.5**     3.0                 60.4                3.3           61.3*        3.5

TSFT (mm)                                           11.6           1.4         14.7**     1.9                 11.8                2.4           13.3*         2.5

Serum albumin (g/L)                           37.6           1.3         41.8**     1.0                 37.2             1.0         40.2*             1.2      

CD4/ mm3                                            423            81          400            81               456                  97           328*          45

Significantly different from day 1,  same group:   *P < 0.05,   **P < 0.005, ( paired tests).

The mean increase in the Nutrifil group (2.14 (SE 0.6) kg) was greater than that in the CSB group (0.98 (SE 0.5) kg). Increments in TSFT and serum albumin were also seen in both groups with increases again being greater in the Nutrifil group. Mean CD4 cell counts decreased in the CSB group but remained unchanged in the Nutrifil group. Weight change was positively correlated to changes in the CD4 cell count in the Nutrifil group (r  0.66  P < 0.05), but not in the CSB group (r 0.03, NS). Furthermore, five patients (45%) in the Nutrifil group experienced a rise in CD4 cell count at the end of the study, compared with two (18%) in the CSB group.

Risk of bias 
Study IDCharlin 2002 (Full text)
Methods

COUNTRY:

Chile

SETTING:

AIDS wards in the Jose Joaquin Aguirre and San Juan de Dios Hospitals in Santiago, Chile.

DURATION OF RECRUITMENT:

Not specified

DURATION OF TRIAL:

September 1994-August 1995

FOLLOW-UP:

At baseline, 45th and 90th day of trial height, weight and skinfold measurements (to determine fat mass and fat free mass) and CD4 and CD8 cell count were assessed. 24 hour urinary ureic nitrogen was determined as well as Resting Energy Expenditure. Nutritional intake was recorded using 24-hour recall taken on three alternate days before beginning of study and during the supplementation period. Systemic signs and symptoms were recorded each day.

ETHICS:
Not reported on in the trial
TRIAL REGISTRATION:
FUNDING:

Study supported from a grant from research project FONDECYT 1940507 and collaboration from Davis Laboratories, Braun Co, Chile

Participants

INCLUSION CRITERIA:

HIV-infected outpatients

EXCLUSION CRITERIA:

Not specified

Participants enrolled: 46
Participants randomised: 46
Mean age at baseline: 37 ± 12 years
Sex at baseline: 4 females; 42 males
Mean BMI at baseline: 18.5±1.4 kg.m-2 (group 1); 18.6±1.2 kg.m-2 (group 2)

Stage of HIV: 11 patients category A or B; 35 patients category C (AIDS) according to Centre for Disease Control guidelines, 1992

ARV therapy status: 11 patients on zidovudine therapy in group 1; 12 patients on zidovudine therapy in group 2

At baseline energy intake was greater in group 1 (34.2±8.8 kcal/kg/d) than group 2 (27.2±7.5 kcal/kg/d).

Intervention

Group 1:

Patients received polymetric diet during first 45 days then regular food for 45 days. Polymetric diet consisted of powdered drink containing 103kcal, 3.6g protein (sodium and calcium caseinate: 14% contribution to total energy), 13.0g carbohydrates (maltodextrins) and 4g fats (sunflower seed oil and coconut oil) per 10 dl. This formula provides the US-RDA requirements for adults of vitamins and micronutrients with 200 dl per day. Regular food consisted of cereals, diary products, eggs albumin˜15% of protein contribution to total energy.

Group 2:

Patients received regular food for 45 days then polymetric diet for 45 days.

Outcomes

Mortality: 3 patients died in Group 1; 8 patients died in Group 2 in the first 45 days of the trial

Significant increase in weight, BMI and fat-free mass (FFM) was observed in both groups. An increase in fat mass was observed in Group 2. No significant differences were noted in plasma albumin, CD4 and CD8 cell count. Energy intake increased in both groups. with a significant increase noted in group 2 between the 45th day to the 90th day.

Risk of bias

Random sequence generation (selection bias): Unclear risk - Method not reported.
Allocation concealment (selection bias): Unclear risk - Method not described in report.
Blinding of participants and personnel (performance bias): High risk - Participants could not be blinded as the appearance was different between the supplements.

Blinding of outcome assessment (detection bias): Unclear risk - It is not clear if the outcome assessors were blinded.
Incomplete outcome data (attrition bias): 11/46 patients died (24% attrition)
Selective reporting (reporting bias): Unclear risk - Protocol not obtained.

Study IDChlebowski 1993 (Abstract)
Methods

COUNTRY:

USA

FOLLOW UP:

Parameters evaluated at 0 (baseline), 3, and 6 mo included adherence, weight change, anthropometric measurements, serum biochemical indices, gastrointestinal symptoms, physical performance, and intercurrent health events (including hospitalizations).

Participants

INCLUSION CRITERIA:

HIV-infected, early stage, relatively asymptomatic patients

EXCLUSION CRITERIA

Number randomised: 80

Intervention

INTERVENTION:

Received 2-3 8 oz cans of ready-to-feed peptide-based enteral formula consisting of 18.7% protein, 65.5% carbohydrate, 15.8% fat and 1.28 kcal/ml per day for 6 months (NEF)

CONTROL:

Received 2-3 8oz cans of standard enteral formula consisting of 14% protein, 55% carbohydrate, 31% fat, 1.06 kcal/ml per day for 6 months (SEF).

Outcomes56 patients completed the study. Those supplemented with NEF maintained their body weight significantly (p = 0.04) better, had significantly (p = 0.03) more stable triceps skin-fold measurements, and had significantly (p = 0.04) lower blood urea nitrogen than patients consuming the SEF supplement. Consumption of the NEF supplement was also associated with significantly reduced hospitalizations during the 3- to 6-mo evaluation period (p = 0.02). The NEF supplement was well tolerated and did not result in untoward clinical effects. These data suggest that supplemental use of an NEF provides superior nutritional management compared with an SEF for patients with early-stage HIV infection.
Risk of biasAttrition rate: 24/80 loss to follow up
Study IDComi 1996 (Abstract)
Methods

COUNTRY:

Italy

FOLLOW UP:

Nutritional status was evaluated by anthropometric parameters, hematological indexes, and by tetrapolar bioelectrical impedance analysis (BIA), before and after one month of diet.

Participants

INCLUSION CRITERIA:

AIDS patients (CDC stage IV CI)

Number randomised: 50 (36 males; 14 females)

InterventionGroup A: treated with normocaloric (35Kcal/kg usual weight), normoproteic (1g/kg usual weight) diet for 1 month;
Group B: treated with an hypercaloric (40Kcal/kg of usual weight), hyperproteic (2g/kg usual weight) dietetic regimen for 1 month.
OutcomesGroup A: Statistical significant increase in Body Weight (pre: 59.9±9.9kg; post: 61.2±9.7, p<0.001), BMI (pre: 20.5±3.0, post: 21.0±2.9, p<0.001) and Total Cholesterol (pre:144.3±39.5, post: 162.5±62.8, p<0.04), Triceps skinfold and Mid arm muscle area increased but not significantly. Group B: Significant increase in body weight (pre: 59.1±9.9, post: 60.4±10.4, p<0.001), BMI (pre: 20.3±3.0, post: 20.7±3.0, p<0.001), Tricep skinfold (pre: 6.8±4.1, post: 7.4±4.2, p<0.009), mid arm muscle area (pre: 41.4±11.8, post: 42.9±11.5, p<0.002), HDL Cholesterol (pre: 31.8±10.1, post: 37.8±12.1, p<0.001).
Risk of bias

Random sequence generation:

Allocation concealment:

Study IDde Luis 2010
Methods

COUNTRY

Spain

SETTING

Not reported

DURATION OF TRIAL

Not reported
FOLLOW UP

At baseline and 3 months: prospective serial assessment of nutritional status, nutrient intake (24 hour food recall), GI symptoms, anthropometry, intercurrent health events, blood chemistry, liver function and plasma fatty acids

ETHICS

Written informed consent received. Ethics and regulatory approval not reported.

Participants

INCLUSION CRITERIA

  • HIV-infected patients (30-60 years old)

  • Previous weight loss (>5% in previous 3 months)

  • Absence of chronic febrile illness

  • Absence of severe GI symptoms (diarrhoea for >30 days or >3 times per day)

  • adequate liver and kidney function

  • Remain on HAART treatment for 3 months prior to and for duration of tria

Number enrolled: 33

Number randomised: 30

Mean age at baseline:41.6±8.4 years in ENSURE group; 42.1±4.8 years in PROSURE group

Mean BMI at baseline:19.2±0.9 kg.m-2 in ENSURE group; 18.8±2.2 kg.m-2 in PROSURE group

All patients receiving HAART therapy

CDC class A-B (%):54.7% in ENSURE group; 55.7% in PROSURE group

CDC class C (AIDS, %):53.3% in ENSURE group; 60% in PROSURE group

Intervention

INTERVENTION

2 can of PROSURE per day (236 ml per can) containing:

  • Caloric density (Kcal/ml): 1.2

  • Protein (g/l): 66 (21.6%)

  • Fat (g/l): 25.6 (18.8%)

  • Carbohydrate (g/l): 183 (59.6%)

  • Dietary fibre (g/l): 20.4

  • n-3 fatty acids (mg/l): 6.29

Dietary counselling also provided

CONTROL

2 cans of ENSURE per day (236 ml per day) containing:

  • Caloric density (Kcal/ml): 1.06

  • Protein (g/l): 37.2 (14%)

  • Fat (g/l): 37.2 (31.5%)

  • Carbohydrate (g/l): 145 (54.5%)

  • Dietary fibre (g/l): 0

  • n-3 fatty acids (mg/l): 0

Dietary counselling also provided

ADHERENCE:

Patient reported

OutcomeOutcomes were not clearly delineated into primary and secondary. Although reported that study powered to detect 4% change in body weight. Total calorie and protein consumption were similar in both groups at 3 months with a significant increase in each group for both calorie (ENSURE: 18.8% increase; PROSURE: 19% increase) and protein intakes (ENSURE:18.5% increase, PROSURE:18.4% increase). Significant and sustained increase in weight due to increase in fat-free mass in ENSURE group and increase in both fat-free mass and fat mass in PROSURE group. No hospitalisations or adverse events reported or observed throughout trial.
Risk of biasRandom sequence generation (selection bias): Unclear risk - Not reported.
Allocation concealment (selection bias): Unclear risk - Not reported.
Blinding of participants and personnel (performance bias): Unclear risk - Not reported for participants and personnel
Blinding of outcome assessment (detection bias): Unclear risk - Not reported for outcome assessors
Incomplete outcome data (attrition bias): Low risk - All randomised participants completed trial
Selective reporting (reporting bias): Unclear risk - Protocol not obtained
Study IDde Luis Roman 2001
Method

COUNTRY:

Spain

SETTING:

Not reported

DURATION OF TRIAL:

Not reported

FOLLOW UP:

At baseline and 3 months: prospective serial assessment of nutritional status, nutrient intake (24 hour food recall), GI symptoms, anthropometry, intercurrent health events, blood chemistry, liver function and plasma fatty acids

ETHICS:

Patients provided informed consent (not sure if written or oral). Ethics or regulatory approval not specified in the report

Participants

INCLUSION CRITERIA:

  • HIV-infected patients aged between 18-60 years with or without AIDS defining illness

  • Absence of chronic febrile illness

  • Weight stable

  • Absence of severe GI symptoms (diarrhoea for >30 days or >3 times per day)

  • adequate liver and kidney function

  • Remain on HAART treatment for 3 months prior to and for duration of trial

Number enrolled: 91

Number randomised: 74

Percentage male at baseline: 77.6% in ENSURE group; 78.6% in ADVERA group

Mean age at baseline:37.9±10 years in ENSURE group; 38.9±8.8 years in ADVERA group

Mean BMI at baseline:22±2.8 kg.m-2 in ENSURE group; 21±2.8 kg.m-2 in ADVERA group

All patients receiving HAART therapy

Mean CD4 count at baseline (count/ul): 454±271 in ENSURE group; 561±369 in ADVERA group

CDC class A-B (%):57.2% in ENSURE group; 51.1% in ADVERA group

CDC class C (AIDS, %):42.8% in ENSURE group; 48.9% in ADVERA group

Intervention

INTERVENTION

3 can of ADVERA (enterotropic peptide-based enteral formula with n-3 fatty acids) per day (236 ml per can) containing:

  • Caloric density (Kcal/ml): 1.28

  • Protein (g/l): 60 (18.7%)

  • Fat (g/l): 22.8 (15.8%)

  • Carbohydrate (g/l): 215.8 (65.5%)

  • Dietary fibre (g/l): 8.9

  • n-3 fatty acids (mg/l): 9.46

Dietary counselling also provided

CONTROL

3 cans of ENSURE per day (236 ml per day) containing:

  • Caloric density (Kcal/ml): 1.06

  • Protein (g/l): 37.2 (14%)

  • Fat (g/l): 37.2 (31.5%)

  • Carbohydrate (g/l): 145 (54.5%)

  • Dietary fibre (g/l): 0

  • n-3 fatty acids (mg/l): 0

Dietary counselling also provided

ADHERENCE:

Patient reported

Outcome
  • Treatments with both supplements resulted in a significant and sustained increase in weight (3.2% in ENSURE group and 3.1% in ADVERA group). This increase was mostly due to fat mass (12.8% in ENSURE group and 7.5% in ADVERA group).

  • Total body water and fat-free mass remained unchanged

  • CD4 counts remained stable in the ENSURE group, while a significant increase was detected in the ADVERA group from baseline to 3 months (576±403 vs. 642±394 cells per mm3, P<0.05). At 3 months, the ADVERA group had a significantly higher CD4 count compared with the ENSURE group.

  • The supplemented group had fewer hospitalizations than the standard group, but no statistical differences were found.

  • No side effects to the supplements were reported

Risk of biasRandom sequence generation (selection bias): Unclear risk - Not reported.
Allocation concealment (selection bias): Unclear risk - Not reported.
Blinding of participants and personnel (performance bias): Unclear risk - Not reported for participants and personnel
Blinding of outcome assessment (detection bias): Unclear risk - Not reported for outcome assessors
Incomplete outcome data (attrition bias): Low risk - All randomised participants completed trial
Selective reporting (reporting bias): Unclear risk - Protocol not obtained
Study IDGibert 1999
Methods

COUNTRY:

USA

SETTING:

14 administrative units comprising 55 clinics and physician offices

DURATION OF RECRUITMENT:

Jul 1996 - December 1997

DURATION OF TRIAL:

Jul 1996 - April 1998 (22 months: end of trial estimated to be four months after last recruitment)

FOLLOW-UP:

At baseline, two month and four month visits: height and weight measured with standardized procedures using calibrated scales; body composition calculated using BIA-101Q analyzer and Body cell mass (BCM) and total body fat (TBF) recorded.

At 2 and 4 month visits, 24 hour dietary recall assessed using Minnesota Nutrition Data System NDS-93 and questionnaire administered regarding aerobic and muscle-building activities.

ETHICS:
Institutional review board approval was obtained at each unit.
TRIAL REGISTRATION:
FUNDING:
National Institute of Allergy and Infectious Disease and Nestle Clinical Nutrition

Participants

INCLUSION CRITERIA:

  • HIV-infected adults >= 13 years

  • CD4 < 200 cells/mm3

  • Karnofsky scale >= 60

  • Stable weight (loss of no more than loss of 5% body weight recorded in 3 to 6 months prior to trial)

  • Serum creatinine level of <=2.5mg/dL

  • Total bilirubin =< 3mg/dL

EXCLUSION CRITERIA:

  • Active opportunistic infection

  • Malignancy or Diabetes Mellitus

  • History of phenylketonuria

  • Appetite stimulants

  • Anabolic steroids

  • Caloric supplements

  • Pregnant or breastfeeding

  • BMI >= 29kg/m

Participants enrolled: 536
Participants randomised: 536
Mean age at baseline: 40.8 (SD: +/- 8.4 years) in the Peptamen intervention group; 39.7 years (SD: +/- 8.4 years) in the NuBasics intervention group; 39.9 years (SD: +/- 8.2 years) in the control multivitamin group
Sex at baseline: 12.9% women in the Peptamen intervention group; 12.8% women in the NuBasic intervention group; 10.6% in the control group
No significant differences in baseline criteria observed.

Intervention

INTERVENTION:

Peptamen caloric supplement, each 250ml fluid contained 250kcal comprising:

  • 10g whey protein (16% kcal)

  • 9.8g fat with 6.75g medium-chain triglycerides (33% kcal

The supplementation was a fluid and 250ml was taken twice daily

INTERVENTION:

NuBasics caloric supplement, each 250ml fluid contained 250kcal comprising:

  • 8.75g whey protein

  • 9.2g fat

The supplementation was a fluid, bar or coffee and 500kcal was required daily.

CONTROL:
A daily multivitamin and mineral supplement. Form not reported.
DURATION:
Four months
CO-INTERVENTIONS:
None reported.
COMPLIANCE:
Participants reported the amount of supplement consumed in the previous week to visit based on a 24 hour dietary recall. 69% was consumed in the NuBasics group and 62% in the Peptamen group using this method. However, on case-report post the study, adherence was reported as 82% in the NuBasic group and 65% in the Peptamen group.

OutcomesThis three-armed trial compared two formulations of caloric supplements: Peptamen comprised peptides and medium-chain triglycerides (MCT) and NuBasics comprised whole protein and long-chain triglylcerides (LCT), in patients with stable weights (no more than 5% weight loss in three to six months prior to trial). These supplements were compared with each other and with a control group of multivitamins and mineral supplementation. Both the intervention groups received the same multivitamins and mineral supplementation as the control group. Mortality was low in all three groups: one in the Peptamen group, four in the NuBasics group and three in the control group. Disease progression was also measured. For the combined outcome of disease progression or death, the authors report the raw data. In the Peptamen group, four participants progressed or died, 14 progressed or died in the NuBasics group and 12 progressed or died in the control group. We analysed the difference between the Peptamen and control groups in REVMAN and found that participants in the Peptamen group were not statistically significantly less likely to die or progress than those in the control group (RR = 0.34; 95% CI: 0.11, 1.02; p = 0.05). See Analysis 4.1

The trial reports means and standard errors for percentage change for outcomes and not the actual weight change itself. We report the outcomes as reported by the authors in the text. For mean percentage changes in body weight, there were no statistically significant differences between the three groups with a mean % change of 0.8% in the Peptamen group, 1.1% in the NuBasics group and 0.7% in the multivitamin groups. Using analysis of variance the authors report a p value of 0.74 between the groups. Mean percentage change in body cell mass (BCM) at study endpoint was not statistically significant between groups using analysis of variance (p = 0.63). The mean percentage BCM was 0.7% in the Peptamen group, 1.2% in the NuBasics group and 0.6% in the control group.

Mean daily caloric intake was statistically significantly higher in the Peptamen and NuBasics groups when compared with the multivitamin control group respectively. Participants in the Peptamen group had a mean intake 325 kilocalories more than those in the control group (MD: 325.00; 95% CI: 79.66, 570.34; p = 0.009). See Analysis 4.2. Participants in the NuBasics group had a mean intake 238 kilocalories more than those in the control group (MD: 238; 95% CI: 11.58, 464.42; p = 0.04). See Analysis 4.3. There was no statistically significant difference in intake between the Peptamen and NuBasics groups (MD: 87.00; 95% CI: -142.89, 316.89; p = 0.46). See Analysis 4.4.

More participants in the Peptamen group (22%) discontinued the trial compared with those receiving NuBasics (7%). One third of the participants discontinuing in the Peptamen group did so because of diarrhoea and nausea. In the NuBasics group none stopped due to side effects. In the control group 5% stopped and a quarter of these did so for reasons of nausea, vomiting, diarrhoea or constipation.
Risk of biasRandom sequence generation (selection bias):Unclear risk - Random blocks of permutation of sizes 3 to 6 with equal probability stratified by unit. Actual method not reported
Allocation concealment (selection bias): Low risk - Allocated by telephone to Central Statistical Center
Blinding of participants and personnel (performance bias): High risk - No blinding of participants and not reported for personnel
Blinding of outcome assessment (detection bias): High risk - Measurements were done by investigators using scales so could be influenced by knowledge of treatment assignment
Incomplete outcome data (attrition bias): Low risk - Attrition in Peptamen = 9/178 (5%); in NuBasics = 8/179 (4.5%); in control = 15/179 (8.4%)
Selective reporting (reporting bias)Unclear risk: Protocol not available.
Study IDHellerstein 1994 (Abstract)
Methods

COUNTRY:

USA

FOLLOW UP:

Nutrient intake, body composition, GI symptoms, nutritional status and AIDS specific surrogate markers were assessed at 6 weeks, 6 months and 12 months

ParticipantsPatients with AIDS or HIV-associated weight loss (13.2±4.2% body wt)
Interventions

Whole protein formula in the form of 2 8oz cans per day for 1 year (WP group)

Peptide-based formula in the form of 2 8oz cans per day for 1 year (PB group)

OutcomesBoth formulas were well-tolerated and there were no adverse effects on GI function or related symptoms. Evaluation of food and formula intake at 6 months revealed an increased intake of calories and protein in both groups. This occurred through supplement intake (500-600 kcal/day and 17-28g protein/day) which resulted in some decrease in spontaneous food intake (196-382 kcal/day and 5.6-14.45 protein/day). The net increase was approximately 400 kcal/day. REE was elevated compared to normal (110% predicted) at baseline & did not change during supplementation. The response of fat free mass (FFM) at 6 wks was significantly correlated (r2 = -0.42, p < 0.01) with baseline hepatic fat synthesis (an index of cytokine presence and metabolic dysregulation). A majority of patients maintained their entrance body weight as only 20% experienced reductions of 2.2 kg or greater. When considering all data from the 1 yr follow up, the risk of a > or = 50% drop from baseline in the CD4 count was 7.4 times greater in the WP than the PB group (p < 0.01). In conclusion, total intake of nutrients increased even after reduction of voluntary food intake was considered. This increased macro and micro nutrient intake resulted in apparent weight maintenance without untoward GI symptom or function. Specific dietary management with the PB formula may provide added clinical benefit based on the CD4 analyses.
Risk of bias 
Study IDMendez 1998
Methods

COUNTRY:

USA

SETTING:

Seven community research sites

FOLLOW UP:

Weight and body composition by single frequency bioimpedance analysis were measured monthly for 6 months

Participants

INCLUSION CRITERIA:

Clinically-stable, HIV-infected subjects with CD4+ lymphocytes below 100 cells/mm3

Number randomised: 119

InterventionsFormula containing long chain triglycerides (LCT) vs formula containing medium chain triglycerides (MCT). Subjects were prescribed three cans of coded formulae to take daily as a supplement to their usual diet, for six months.
OutcomesThe two groups were similar at baseline. Dropout rates were high in both groups over the six month follow up. Both groups gained weight, on average, during the study. The LCT group gained significantly more weight than the MCT group (0.63 vs 0.13 kg/month, p = 0.016). In contrast, gains in body cell mass were small and similar in the two groups (0.08 vs 0.06 kg/month, p = 0.655). Subjects who dropped out before the four month follow up were more likely to have lost body cell mass during months 1-3 than those who continued on study.
Risk of bias 
Study IDNdekha 2009 (Full text)
Methods

COUNTRY:
Malawi
SETTING:
Antiretroviral therapy clinic at Queen Elizabeth Central Hospital in Blantyre
DURATION OF RECRUITMENT:
Jan 2006 - Jan 2007 (estimated)
DURATION OF TRIAL:
Jan 2006 - Apr 2007 (16 months)
FOLLOW-UP:
At baseline, physician examination was conducted, Quality of Life questionnaire was administered and demographic data, clinical status, and anthropometric measurements, including and bioelectrical impedance analysis, were collected.
At 2 weeks, 6 weeks, 10 weeks and 14 weeks clinic visits included all of the above measurements and procedures. A four-item validated adherence questionnaire was conducted at each visit after enrolment to assess adherence to ART.
Blood samples collected at baseline and 14 weeks.

ETHICS:
College of Medicine research and ethics committee, University of Malawi; Human studies committee of Washington School of Medicine; Committee for research on human subjects at University of Witwatersrand
TRIAL REGISTRATION:
Registered on Current Controlled Trials ISRCTN67515515
FUNDING:
USAID Food and Nutrition Technical Assistance Project of the Academy for Educational Development and AIDS Care Research in Africa

Participants

INCLUSION CRITERIA:

  • HIV-infected adults > 18 years

  • Met criteria for antiretroviral therapy according to Malawian national HIV treatment guidelines (WHO clinical Stage III or IV or CD4 < 250 cells/mm3)

  • BMI < 18.5

EXCLUSION CRITERIA:

  • Pregnancy or lactation

  • Participation in another supplementary feeding programme

Participants enrolled: 491
Participants randomised: 491
Mea age at baseline: 36 years (SD: +/- 11 years) in the intervention group; 36 years (SD: +/- 12 years) in the control group
Sex at baseline: 62% women in the intervention group; 58% women in the control group
No significant differences in baseline criteria observed.

Intervention

INTERVENTION:

Fortified spread 245g/day containing:

  • 35.5g protein

  • 91g fat

  • 5694kJ energy

Varied micronutrients including vitamins and trace elements

The spread was peanut-based and was provided in 245g plastic bottles and one bottle was consumed daily.

CONTROL:

Corn-soy blended flour 374g/day containing:

  • 50g protein

  • 26.2g fat

  • 5694kJ energy

Varied micronutrients including vitamins and trace elements
The same level of energy was provided in both supplements and was 50% of the daily estimated average energy requirements based on WHO guidelines that take into account that HIV-infected people require 30% more energy than healthy people. The amounts of micronutrients differed between the supplements but in neither were the amounts in excess of the estimated average requirement.
DURATION:
Taken daily for 14 weeks
COMPLIANCE:
Not clearly reported but in focus groups of 42 participants in the intervention group and 53 in the corn-soy group following the trial , the supplementation was reported to be highly appreciated and shared with family. Corn-soy blend was more likely to be shared as required preparation.

OutcomesAll participants had a BMI < 18.5 at study entry. The trial reported mortality data. Overall 131 participants died with those in the fortified spread being no more likely to die than those in the corn-soy blend group (RR 1.05; 95% CI: 0.78, 1.41; p = 0.74). See Analysis 7.1. Although 95% Confidence Intervals were reported, no p values were provided. We recalculated the analyses in REVMAN and report these. Participants in the fortified spread group gained significantly more weight than those in the corn-soy blend group (MD: 1.3kg; 95%CI: 0.52, 2.08; p = 0.001), had a greater gain in fat-free body mass (MD: 0.70kg; 95% CI: 0.15, 1.25; p = 0.01) and in mid-upper arm circumference (MD: 0.60cm; 95% CI: 0.27, 0.93; p = 0.0003). See Analysis 7.2; Analysis 7.4; Analysis 7.5. Change in BMI was also statistically significantly greater in the fortified spread group compared with the corn-soy blend group (MD: 0.6kg; 95% CI: 0.3 to 0.9; p < 0.0001). See Analysis 7.3.

Change in mean CD4 count at study endpoint was not statistically significantly different between the groups. See Analysis 7.7. The authors report that viral load and quality of life also did not differ significantly between groups. The authors conducted further analyses stratifying the outcomes by diet quality on enrolment and the type of supplement. Neither of the supplements affected any of the three dietary subgroups differently. Adverse effects were not reported.
Risk of biasRandom sequence generation (selection bias): Unclear risk - Method not clearly reported. Reported as blocks of 50 numbers
Allocation concealment (selection bias): Low risk - Allocation done using sealed, unmarked, opaque envelopes which were opened in an area separate from the research and treatment room. Envelopes contained a unique number from 1 to 500 and staff member then matched the number with the food supplement.
Blinding of participants and personnel (performance bias): High risk - Participants could not be blinded as the appearance was different between the supplements. The personnel were blinded.
Blinding of outcome assessment (detection bias): Low risk - The personnel, including clinicians and nutritionist, were blinded
Incomplete outcome data (attrition bias): High risk - For the primary outcome of BMI and fat-free body mass, attrition was high due to the high number of deaths: Intervention: 89/245 (32.7%); control: 80/246 (32.5%). For other outcomes, such as death, the attrition would have less potential for bias.
Selective reporting (reporting bias): Unclear risk - Protocol not obtained.
Study IDPichard 1998
Methods

COUNTRY:
Switzerland
SETTING:
Outpatient, University Hospital, Geneva
DURATION OF RECRUITMENT:
Not reported
DURATION OF TRIAL:
Not reported
FOLLOW-UP:
At enrolment and at monthly visits, a clinical examination was done with weight to nearest 50g, height, and BMI calculated.
At baseline, 3 months, 6 months and 12 months, bloods were taken for total leucocytes, CD4 and CD8, p24 antigen, and beta2 microglobulin.
At baseline, 3 months and 6 months, the French language validated self-applied questionnaire derived from the Medical Outcome Study 36-item short form health survey, was administered.
Food intake was monitored by a standard 3-day calorie count food intake questionnaire.

ETHICS:
Ethics Committee of Department of Medicine at Geneva University Hospital
TRIAL REGISTRATION:
Could not locate trial protocol.
FUNDING:
Sponsorship by Sandoz Nutrition, Bern, Switzerland

Participants

INCLUSION CRITERIA:

  • HIV-infected adults (adult not defined so assumed to be > 18 years)

  • CD4 >= 100 X 106/L

EXCLUSION CRITERIA:

  • Change in antiretroviral therapy in 8 weeks prior to the trial

  • Symptomatic neuropathy or myopathy

  • Neoplasia

  • Endocrine disorders

  • Diabetes Mellitus

  • Treatment for hypo- or hyperthyroidism

  • Renal failure

  • Liver cirrhosis

  • GIT resection

  • Psychiatric disorders

  • Active intravenous use

Participants randomised: 64
Baseline characteristics only reported for 55 participants who completed the study.
Mean age at baseline: 36.7 years +/- SEM: 1.6 years in the Arginine group; 32.6 years +/- 1.8 years in the control group
Sex at baseline: 4/27 (14.8%) women in the intervention group; 7/28 (25%) women in the control group
No significant differences in baseline characteristics were observed.

Intervention

INTERVENTION:

Enriched omega-3 fatty acid supplementation containing 606kcal comprising:

  • 33g protein (22% of total energy content)

  • 26g casein

  • 7.4g arginine

  • 16.8g fat (25% of total energy content)

  • 4g essential fatty acids

  • 2.4g omega-6 fatty acid

  • 1.7g omega-3 fatty acid

  • 80.4g carbohydrates (53% of total energy content)

  • 10g dietary fibre

The supplementation was taken as two servings daily of 76g powder) for 6 months.

CONTROL:

Standard supplementation containing 606kcal comprising:

  • 26 protein (17% of total energy content)

  • 26g casein

  • 16.8g fat (25% of total energy content)

  • 2.4g essential fatty acids

  • 2.4g omega-6 fatty acid

  • 0.1 omega-3 fatty acid

  • 0.12g alpha-linoleic acid

  • 88.0g carbohydrates (58% of total energy content)

  • 10g dietary fibre

The supplementation was taken as two servings daily of 76g powder for 6 months.
COMPLIANCE:
Compliance reported as percentage of patients completing the trial: 70% completed the trial.

Outcomes

PRIMARY OUTCOMES:

Primary outcomes not clearly reported in the text. Protein intake and weight gain reported prominently. In the abstract main outcome measures listed include:

  • Disease progression measured by AIDS-defining events

  • CD4 and CD8 counts

  • Viraemia

  • Tumour necrosis factor soluble receptors

  • Nutritional status determined by anthropometric, bioelectrical impedance and dietetic assessment

SECONDARY OUTCOMES:
Change in fat mass
Total energy intake
ADVERSE EVENTS:
Tolerance and appetite and gastrointestinal symptoms recorded using standard questionnaire.

RESULTS:

Fifty-five patients completed the protocol. Compliance with and tolerance of oral nutritional supplement during the 6-month period was excellent. In both groups of patients the following were found: total energy intake was transiently increased and then returned to baseline level; nitrogen/energy intake ratio was increased throughout the study; gain of body weight and fat mass were approximately 2 and 1kg, respectively, over 6 months, and were similar in both groups. In addition, CD4 and CD8 lymphocyte counts, viraemia, tumour necrosis factor soluble receptors remained statistically unchanged and were similar in both groups. Enrichment of an oral nutritive supplement with arginine and omega-3 fatty acids did not improve immunological parameters. However, body weight increased in both groups

Risk of biasRandom sequence generation (selection bias): Unclear risk - Not reported.
Allocation concealment (selection bias): Unclear risk - Not reported.
Blinding of participants and personnel (performance bias): Unclear risk - Reported as 'double-blind' but not stated clearly for participants and personnel
Blinding of outcome assessment (detection bias): Unclear risk - Reported as 'double-blind' but not stated clearly for outcome assessors
Incomplete outcome data (attrition bias): High risk - Attrition was high: 5/32 (29.1%) in the Arginine group; 4/32 (24.3%) in the standard group
Selective reporting (reporting bias): Unclear risk - Protocol not obtained.
Study IDPrayGod 2011
Methods

COUNTRY:

Tanzania
SETTING:
Four TB clinics in Mwanza city, under the Tanzanian National TB and Leprosy Programme (NTLP)
DURATION OF TRIAL:

April 2006-March 2009
FOLLOW-UP:

Weight, arm fat area, arm muscle area and hand grip strength assessed at 2 months and 5 months

ETHICS:
Based on guidelines according to Declaration of Helsinki. National Medical Research Coordinating Committee of the National Institue of medical Research in Tanzania and approval from the Danish National Committee on Biomedical Research Ethics. Written informed consent obtained from all patients.
TRIAL REGISTRATION:
ClinicalTrials.gov identifier: NCT00311298
FUNDING:

The Danish Council for Independant Research, Danida and the University of
Copenhagen

Participants

INCLUSION CRITERIA:

New or relapse PTB/HIV-co-infected patients older than 15 years and residents of Mwanza City

EXCLUSION CRITERIA:

  • Extra-pulmonary TB

  • pregnancy

  • Terminal illness

Number randomised:377

Number included in analyses:166 (2 months); 151 (5 months)

Mean age at baseline: 34.7±10.3 years in energy-protein group; 36.2±9.5 years in control group

Sex ratio (M/F) at baseline: 95 males: 94 females in energy-protein group; 95 males: 93 females in control group

Mean BMI at baseline: 18.7±2.9 kg.m-2 in energy-protein group; 18.5±2.8 kg.m-2 in control group

Intervention

INTERVENTION:

Intervention group received 6 daily energy-protein biscuits for the first 60 days of treatment, of which one contained the additional micronutrients. Energy-protein biscuit contained 4.5 g protein, 615 kilojoules energy, 120 mg phosphorous, 120 mg calcium, 36 mg magnesium, 70 mg sodium, 150 mg potassium, and traces <1 mg of iron and zinc. Energy-protein biscuit with additional micronutrients contained all of the above plus 1.5 mg vitamin A, 20 mg thiamin, 20 mg riboflavin, 25 mg vitamin B6, 50 μg vitamin B12, 0.8 mg folic acid, 40 mg niacin, 200 mg vitamin C, 60 mg vitamin E, 5 μg vitamin D, 0.2 mg selenium, 5 mg copper, 30 mg zinc.

CONTROL:

The control group received one daily energy-protein biscuit with additional micronutrients.

ADHERENCE:

Either by direct observation or use of a log book recording intake of supplement

OutcomesIn energy-protein group: 37/189 lost to follow up and in control group: 35/188 lost to follow up. There were no effects on any outcome at 2 months, but energy–protein supplementation was associated with a 1·3 (95% CI 20·1, 2·8) kg marginally significant gain in handgrip strength at 5 months. At 2 months, there was an interaction between energy–protein supplementation and CD4 count level for weight (Pinteraction =0·03), which was explained by a 1·9 kg (95% CI 0·1, 3·7; P¼0·04) higher weight gain among patients with CD4 counts of 350 cells/ml or higher, and the lack of effect among those who had CD4 counts below 350 cells/ml (20·2 kg; 95% CI 21·3, 0·8; P¼0·66). Similarly, at 5 months, energy–protein supplementation led to a 2·3 (95% CI 0·6, 4·1) kg higher handgrip strength gain among patients with CD4 counts<350 cells/ml, but not in those with high CD4 counts (Pinteraction =0·04). In conclusion, energy–protein supplementation to PTB/HIV-co-infected patients had no overall effects on weight and body composition, but was associated with marginally significant gain in handgrip strength. More
research is needed to develop an effective supplement, before it is recommended to TB programmes.
Risk of BiasRandom sequence generation (selection bias): Low risk 'Computer-generated randomisation sequence, using permuted blocks of ten'
Allocation concealment (selection bias): Low risk 'The allocation sequence was used by designated research staff to sequentially arrange and label supplement packs with identity numbers ranging from 1 to 500. During the study the randomisation sequence and code were kept in a safe cabinet only accessible by designated research staff. Recruitment was done by clinic staff. The same designated research staff not employed at the study clinics assigned an identity number to the recruited patient and sent the corresponding nutritional pack to the respective clinic'.
Blinding (performance bias and detection bias): High risk Blinding was not possible due to the nature of the intervention
Incomplete outcome data (attrition bias): Low risk At 2 and 5 months, 12.2% and 19.1% of patients were lost to follow-up. However, the proportions lost to follow-up were similar across the intervention and control arms of the study.
Selective reporting (reporting bias): Unclear risk. Trial protocol not retrieved. Deaths and cure are not reported.
Study IDSattler 2008
Methods

COUNTRY:
USA and Puerto Rico
SETTING:
15 Adults AIDS Clinical Trials Group (ACTG) ambulatory research sites based at tertiary hospitals
DURATION OF RECRUITMENT:
Feb 1999 - Dec 1999
DURATION OF TRIAL:
13 months (estimated from final recruitment month plus12 weeks follow-up)
FOLLOW-UP:
At baseline, physician examination and outcome data collected, including anthropometric measurements with weight measured using a calibrated scale.
At 6 weeks, above repeated and three-day dietary diary administered by dietician.
At 12 weeks, above repeated and three-day dietary diary administered by dietician.
Routine overnight fasting bloods taken at all three follow-up visits

ETHICS:
Approved by the Instititional Review Board at each ACTG site.
FUNDING:
Funded by National Institute of Allergy and Infectious Diseases through ACTG 01 grant.
Biomune Systems Inc provided whey protein and control supplement

Participants

INCLUSION CRITERIA:

  • HIV-infected adults

  • Stable weight loss > 3% over course of HIV infection, but no change in weight in two months prior to enrollment

  • HIV RNA concentration <5000 copies/ml

  • HAART or no HAART

EXCLUSION CRITERIA:

  • Opportunistic infections

  • Malabsorption

Participants enrolled: 66
Participants randomised: 59
Median age at baseline: 41 years (range: 31- 66) in the intervention group; 41 years (26-58) in the control group
Sex at baseline: 26:3 men:women in the intervention group; 26:4 men: women in the control group
No significant differences in baseline criteria observed.

Intervention

INTERVENTION:

High protein supplement 280kcal serving containing:

  • 40g whey protein

  • 20.5g carbohydate

  • 4g fat

CONTROL:

Isocaloric supplement 280kcal serving containing:

  • 0.6g casein (protein)

  • 60.8g carbohydrate

  • 4g fat

Control had same texture, appearance and taste as intervention.
DURATION:
Taken orally twice a day between meals for 12 weeks
COMPLIANCE:
Not clearly reported but one participant in intervention group stopped due to disliking the taste

OutcomesIn Sattler 2008 all analyses were performed using the WiIcoxon rank sum test for non-normally distributed data. The report also provided means and standard deviations and these were entered into REVMAN for calculations. We report the REVMAN calculations and the Wilcoxon rank sum test data as reported by the authors which are likely to be more accurate if there was a lack of a normal distribution for the outcomes. For daily energy intake, there was no statistically significant difference in the mean change in intake from baseline to week 12 between the whey protein and placebo groups (REVMAN: MD: -6.00; 95% CI: -637.57, 625.57; p = 0.99). See Analysis 6.1. The authors’ analysis report a non-significant p = 0.12. For daily protein intake, participants in the whey protein group had a statistically significantly greater intake than the placebo group (REVMAN: MD: 1.17g/kg/day; 95% CI: 0.80, 1.54; p < 0.00001). SeeAnalysis 6.2. This was also significant when analysed using the Wilcoxon rank sum test (reported p < 0.01).

For mean change in weight, total lean body mass and fat mass from baseline to week 12, there were no statistically significant differences either by REVMAN analysis or reported Wilcoxon rank sum test. See Analysis 6.3; Analysis 6.4; and Analysis 6.5. The authors do not provide final or changes in BMI but conducted an analysis correlating baseline BMI to changes in weight in either group and found no correlation (reported Spearman correlation: whey protein: -0.18; p = 0.36; placebo: 0.32; p = 0.12)

Mean change in triglycerides was statistically significantly lower in the whey protein group compared with placebo at week 12 (MD: -55.00; 95% CI: -102.62, -7.38; p = 0.02). See Analysis 6.6. This was also found to be significant when using the Wilcoxon rank sum test (reported p = 0.03). For mean change in CD4 count the authors conducted a Wilcoxon rank sum test and showed a statistically significant increase in the CD4 count in the whey protein group compared with placebo (reported p = 0.03). In analysis in REVMAN the result was not statistically significant at p = 0.22. See Analysis 6.7. Given that CD4 counts are known to be non-normally distributed it is likely the authors’ use of Wilcoxon rank sum test is more accurate.

No adverse effects were reported.
Risk of biasRandom sequence generation (selection bias): Unclear risk - Not reported.
Allocation concealment (selection bias): Unclear risk - Not reported.
Blinding of participants and personnel (performance bias): Low risk - Participants and personnel reported as blinded and control supplement had same texture, taste and appearance as intervention supplement
Blinding of outcome assessment (detection bias): Low risk - Personnel reported as blinded.
Incomplete outcome data (attrition bias): High risk - Attrition was high in the intervention group 12/29 (41%) at 12 weeks follow-up and less in the control group 6/30 (20%). The observations completed at 6 weeks were carried forward for analysis but the differential follow-up between the groups is a possible source of bias.
Selective reporting (reporting bias): Unclear risk - Protocol not obtained
Study IDSuttmann 1996
Methods

COUNTRY:
Germany
SETTING:
Outpatient clinic, not clearly stated, assume at the Medizinische Hochschule, Hannover
DURATION OF RECRUITMENT:
Not reported
DURATION OF TRIAL:
Not reported but cross-over trial of 8 months duration per participant
FOLLOW-UP:
At baseline and at monthly visits for 32 weeks, a clinical examination was done.
Every two months, weekly dietary records were obtained: the nutrient intake was determined by computer analysis of 7-day diet records
Anthropometry and bioelectrical impedance analysis and bloods were done monthly.

ETHICS:
Ethics Committee of Medizinische Hochsculle, Hannover, Germany
TRIAL REGISTRATION:
Could not locate trial protocol.
FUNDING:
Not reported.

Participants

INCLUSION CRITERIA:

  • HIV-infected adults > 18 years

  • Estimated survival > 8 months

  • Platelet count > 50,0000 /µL

  • No malignancies

  • No mycobacteriosis or cytomegalovirus

  • No intravenous drug use

  • No immune-modulating treatments

  • Stable medication for 1 month prior to study entry

Participants randomised: 10 cross-over
Baseline characteristics only reported for 55 participants who completed the study.
Mean age at baseline: 32.6 years +/- SEM: 1.8 years in the Arginine group; 36.7 years +/- 1.6 years in the control group
Sex at baseline: 7/27 (26%) women in the intervention group; 4/28 (14.3%) women in the control group
No signficant differences in baseline characteristics were observed.

Intervention

INTERVENTION:

Enriched arginine formula containing 500kcal comprising:

  • 27.9g protein

  • 21.7g casein

  • 6.2g arginine

  • 13.9g fat

  • 3.2g essential fatty acids

  • 1.9g n-6 fatty acids

  • 1.4g n-3 fatty acids

  • 1.8g Linolenic acid

  • 67g carbohydrates

The supplementation was taken as a daily liquid formula for 16 weeks and then crossed over to control formula for 16 weeks.

CONTROL:

Non-enriched formula containing 500kcal comprising:

  • 21.7g protein

  • 21.7g casein

  • 13.9g fat

  • 3.7g essential fatty acids

  • 3.6g n-6 fatty acids

  • 0.1g n-3 fatty acids

  • 3.6g Linolenic acid

  • 73.2 carbohydrates

The control supplementation was taken as a daily liquid formula for 16 weeks and then crossed over to the enriched formula for 16 weeks.
COMPLIANCE:
Mean intake of formula reported as 638 +/- 117 kcal/day for the intervention and 695 +/- 118 kcal/day with no statistically significant differences in intake between groups. (assume this measurement is taken from reported weekly dietary records)

OutcomesThere was no statistically significant difference in energy intake between the arginine-enriched formula group and the non-enriched formula groups (MD: -10kcal/day; 95% CI: -459.96, 439.96; p = 0.97). See Analysis 2.1. Body weight was significantly increased by a mean of 3.40kg and could be as much as 5.29kg or as little as 1.51kg (MD: 3.4; 95% CI: 1.51, 5.29; p < 0.0004). Authors state that no significant differences between groups for lean body mass and fat mass but the numerical data is not reported. The change in CD4 counts did not differ statistically significantly between the arginine-enriched formula group and the non-enriched formula group (MD: -50.00; 95% CI: -151.73, 51.71; p = 0.34). See Analysis 2.5. Viral load is not reported as an outcome. Adverse effects: a high temperature was reported by two patients (one in arginine-enriched formula group and one in the non-enriched formula group), and diarrhoea was reported by two patients (one in the arginine-enriched formula group and one in the non-enriched formula control group), but the authors state that the differences observed were not significant between the two periods.
Risk of biasRandom sequence generation (selection bias): Unclear risk - Cross-over trial but method of randomisation not reported.
Allocation concealment (selection bias): Unclear risk - Not reported.
Blinding of participants and personnel (performance bias): Unclear risk - Reported as 'double-blind' but not clearly specified.
Blinding of outcome assessment (detection bias): Unclear risk - Reported as 'double-blind' but not clearly specified.
Incomplete outcome data (attrition bias): Low risk - Nil. All participants remained in study
Selective reporting (reporting bias): Unclear risk - Trial protocol not located and cannot exclude selective reporting bias as primary outcomes not stated.

Types of outcome measures

Primary outcomes

  • All-cause mortality

  • Mortality related to HIV infection and other HIV-related conditions

  • Morbidity (frequency, types, and duration of episodes of opportunistic infections; incidence of AIDS as defined by each trial; hospital admissions; and other types of illnesses related to HIV infection as reported in each study)

Secondary outcomes

  • Disease progression according to WHO (WHO 2007) or CDC staging system as recorded in each study

  • Indices of viral load

  • Markers of immune response (absolute CD4+ T-lymphocyte count and CD4+ percent of total lymphocytes)

  • Nutritional status, including measurements such as body weight, body composition and lean body mass, body mass index (BMI), weight-for height and linear growth in children

  • Energy expenditure

  • Biochemical markers, such as serum albumin

  • Dietary intake and appetite

  • Functional outcomes such as child development, quality of life and level of physical activity

If studies reported on additional outcomes not listed above we also reported the data for these outcomes in the review. Adverse events were recorded when these were provided.

Search methods for identification of studies

See: Cochrane HIV/AIDS Group methods used in reviews.

See: Collaborative Review Group search strategy.

A comprehensive, unbiased search strategy was developed to ensure that as many relevant studies as possible were screened for inclusion in the review. An attempt was made to identify all relevant studies, regardless of language or publication status (published or unpublished, in press or in progress).

Electronic searches

  • Journal and trial databases

MEDLINE

A search of MEDLINE was conducted in February 2010 limited from January 2006 to January 2010 as the original review published review in 2007 included searches prior to and including 2006. We ran a final search on 24 August 2011 to ensure that the most recent trial reports were identified using the strategy outlined in Appendix 2: PUBMED search strategy.

EMBASE

The searches were conducted in February 2010 and a final revised search was conducted on the 26 August 2011 using the strategy outlined in Appendix 3: EMBASE search strategy

Cochrane Central Register of Controlled Trials (CENTRAL)
A search of the CENTRAL database of The Cochrane Library (2010), was conducted in February 2010 and a final revised search of Issue 3 The Cochrane Library (2011), on 26 August 2011 using the strategy in Appendix 4: Cochrane Library search strategy.  CENTRAL provides records marked either as RCTs or Systematic Reviews.

LILACS ( http://lilacs.bvsalud.org/en/ )

LILACS is an index of scientific and technical literature of Latin America and the Caribbean. We searched this database on 8 February 2012 using the following search terms: (HIV OR HIV/AIDS) AND (nutrition OR nutritional OR nutrient*) [all fields]

  • Conference databases

A search of the National Library of Medicine GATEWAY database which contains abstracts from the major HIV/AIDS conferences was done on 5 February 2010. However, no updated search of conference abstracts was done in 2011 as NLM Gateway is no longer maintained and updated.

  • Trial Registers

The trials registry www.clinicaltrials.gov was searched on 16 August 2011 using the search string: 

(nutrition therapy OR fortified food OR energy intake OR dietary fat OR dietary protein OR dietary carbohydrate OR macronutrient OR spirulina OR supplement OR amino acid OR fatty acid OR oil) AND HIV | Interventional Studies |

The search was limited to 1980 to ensure coverage throughout the period HIV has been documented.

Searching other resources

We were in close contact with individual researchers working in the field, and policymakers based in inter-governmental organizations.  We also checked the reference lists of all studies identified by the above methods and examined any systematic reviews, meta-analyses, or clinical guidelines we identified during the search process for references.

Data collection and analysis

Selection of studies

NS and LN read the titles, abstracts and descriptor terms of all downloaded material from the electronic searches to identify potentially eligible reports. Full text articles were obtained for all citations identified as potentially eligible and NS and LN inspected these to establish the relevance of the article according to the pre-specified criteria. Where there was any uncertainty as to the eligibility of the record, the full article was obtained.

NS and LN applied the inclusion criteria with studies reviewed for relevance based on study design, types of participants, interventions and outcome measures. All studies not meeting the inclusion criteria were excluded and the reasons for exclusion were stated in the table “Characteristics of Excluded Studies.”

Data extraction and management

NS, LG, SM and MV independently extracted data using a standardised electronic data extraction form. The following characteristics were extracted from each included trial:

  • Administrative details: Trial identification number; author(s); published or unpublished; year of publication; number of studies included in paper; year in which study was conducted; details of other relevant papers cited;

  • Details of the study: study design (Cochrane review, non-Cochrane systematic review, RCT); type, duration and completeness of follow-up; country and location of study (e.g. higher-income vs. lower-income country); informed consent and ethics approval;

  • Details of participants: presence of malnutrition, age, disease progression according to CD4 count or staging by WHO clinical stages, setting, sample size, relevant baseline characteristics including CD4 count and viral load;

  • Details of intervention and control group: type of supplements of macronutrient(s); dosage of macronutrient(s); form and formulation of macronutrient(s), additional co-interventions (such as ART, TB treatment or other management of opportunistic infections); fortification with micronutrients

  • Details of outcomes: all pre-specified outcomes and any additional outcomes reported in the study; adverse events and toxicity.

  • Details of quality assessment: type of quality assessment including use of the Risk of Bias tool.

  • Details of data analysis: numbers and reported statistics for each reported outcome

Where trials were reported in more than one reference, all the trial reports were used to extract data as comprehensively as possible. Discrepancies regarding extracted data were resolved by discussion and, if necessary, referred to an additional reviewer (JV).

Assessment of risk of bias in included studies

The components of each included trial were examined for risk of bias using a standard form. This included information on the sequence generation, allocation concealment, masking (participants, personnel and outcome assessor), incomplete outcome data, selective outcome reporting and other sources of bias. The methodological components of the trials were assessed and classified as adequate, inadequate or unclear as per the Cochrane Handbook for Systematic Reviews of Interventions ( Higgins 2008).

Sequence generation

Low risk: investigators described a random component in the sequence generation process such as the use of random number table, coin tossing, cards or envelops shuffling etc

High risk: investigators described a non-random component in the sequence generation process such as the use of odd or even date of birth, algorithm based on the day/date of birth, hospital or clinic record number

Unclear: insufficient information to permit judgment of the sequence generation process

Allocation concealment

Low risk: participants and the investigators enrolling participants cannot foresee assignment, e.g. central allocation; or sequentially numbered, opaque, sealed envelopes.

High risk: participants and investigators enrolling participants can foresee upcoming assignment, e.g. an open random allocation schedule (e.g. a list of random numbers); or envelopes were unsealed or non-­opaque or not sequentially numbered

Unclear: insufficient information to permit judgment of the allocation concealment or the method not described

Masking

Low risk: blinding of the participants, key study personnel and outcome assessor, and unlikely that the blinding could have been broken. Or lack of blinding unlikely to introduce bias. No blinding in the situation where non-blinding is not likely to introduce bias.

High risk: no blinding, incomplete blinding and the outcome is likely to be influenced by lack of blinding

Unclear: insufficient information to permit judgment of adequacy or otherwise of the blinding

Incomplete outcome data

Low risk: no missing outcome data, reasons for missing outcome data unlikely to be related to true outcome, or missing outcome data balanced in number across groups

High risk: reason for missing outcome data likely to be related to true outcome, with either imbalance in number across groups or reasons for missing data

Unclear: insufficient reporting of attrition or exclusions

To calculate attrition per group the denominators according to the intention-to-treat principle was used: participants were maintained in the groups into which they were randomized and the overall potential number of participants who could produce an outcome was used as the denominator.

Selective Reporting

Low risk: a protocol is available which clearly states the primary outcome as the same as in the final trial report

High risk: the primary outcome differs between the protocol and final trial report

Unclear: no trial protocol is available or there is insufficient reporting to determine if selective reporting is present

Other forms of bias

Low risk: there is no evidence of bias from other sources

High risk: there is potential bias present from other sources (e.g. early stopping of trial, fraudulent activity, extreme baseline imbalance or bias related to specific study design)

Unclear: insufficient information to permit judgment of adequacy or otherwise of other forms of bias

Measures of treatment effect

We used Review Manager 5.1 to calculate the risk ratio (RR) for dichotomous data, and the weighted mean difference (WMD) for continuous data, with 95% confidence intervals and we report these results below. Where this was not possible due to missing primary data, we report only the results as presented in the published studies. When units of measurement differed between trials we chose to use the SI unit and appropriate conversions were made.

Dealing with missing data

Where data was missing or unclear, we planned to contact authors where this was possible to do so. When percentages were provided without denominators these were back-calculated. If only standard errors or 95% confidence intervals were reported for means and no standard deviations, the standard deviations were calculated as follows:

SD = SEM x Square root of sample size

Assessment of heterogeneity

RCTs were first assessed for clinical heterogeneity by examining variability in the participants, interventions and outcomes. Where it was clinically meaningful to combine studies, we conducted a meta-analysis using the random effects model as we anticipated heterogeneity. We further assessed statistical heterogeneity in the meta-analysis study results using the Chi-square test for heterogeneity with a 10% level of significance as the cut-off. The impact of statistical heterogeneity was quantified using the I2 statistic (Higgins 2002). We used the following guidelines for the interpretation of the I2 values (Higgins 2011):

0% to 40%: might not be important;

30% to 60%: may represent moderate heterogeneity;

50% to 90%: may represent substantial heterogeneity;

75% to 100%: considerable heterogeneity.

Data synthesis

Where trials were sufficiently homogenous we combined the results of the trials using the random effects model as we anticipated some heterogeneity. Importantly, for changes in mean measurements, we combined the results if a mean change from baseline to end-point was recorded or if a final mean at the end-point of the study was recorded as described in the Cochrane Review Authors’ Handbook. When measurement time points and lengths of follow up differed between studies we combined these when we thought this was meaningful. Where appropriate we categorised studies into length of follow-up from less than 3 months (short term follow-up), 3 to 6 months (medium term follow-up) and 6-12 months (long term follow-up).

Subgroup analysis and investigation of heterogeneity

The pre-specified sub-groups to investigate for possible sources of heterogeneity across studies were:

  1. By disease progression: CD4< 200 vs. CD4 <350 vs. CD4 >350

  2. By disease progression: WHO HIV clinical stage 1-4 or CDC Stages 1-3

  3. By ART status: on ART vs. not eligible for ART vs. eligible but not on ART

  4. By age: 0-14 years of age vs. 14-19 years of age vs. 20 years and older

None of the included trials presented data in a format that allowed extraction of the above sub-groups, therefore we did not conduct sub-group analyses.

GRADE assessments

GRADEPro was used to create Summary of Findings tables for meta-analyses using the pre-specified outcomes. In determining the level of evidence for each outcome, both the efficacy results and the assessment of the risk of bias was integrated into a final assessment of the level of evidence and full details of the decision provided.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification; Characteristics of ongoing studies.

Results of the search

Electronic database
2010 Search of electronic journal and trial databases

The 2010 PUBMED search yielded 897 records of which 32 were identified as potentially eligible studies and the full texts obtained.

The 2010 EMBASE search yielded 528 records of which 18 were identified as potentially eligible and the full texts obtained.

The CLIB search yielded 333 records marked as RCT records of which 21 were identified as potentially eligible and the full texts obtained.

2011 Search of electronic journal and trial databases

The 2011 searches of PUBMED yielded 265 records, of EMBASE 152 records and of CLIB 42 records. These were de-duplicated electronically using PROCITE reference management software and 67 duplicate records were removed prior to manual checking.

Conference databases

The NLM GATEWAY search yielded 1503 records of which 89 were coded as Meeting Abstracts. We identified two of these abstract records for further assessment.

Trials Registries

The 2011 search of www.clinicaltrials.gov yielded 212 studies of which 28 were identified for further assessment.

Other sources

One included study was identified through discussion with an expert in the field. A further study was identified through the search conducted for the review entitled: Micronutient supplementation in children and adults with HIV infection. This study has been placed in the Studies awaiting assessment category.

A total of 33 full-text articles were obtained. We conducted eligibility assessments on each of these and identified a total of 6 references reporting on 6 RCTs eligible for inclusion. The reasons for exclusion for 25 studies are detailed in Figure 1. Two studies were categorised as awaiting assessment (see: Studies awaiting classification) and once further details are obtained, these studies may become eligible.

Figure 1.

Study flow diagram.

Included studies

We identified a total of six new RCTs to be included in the review in addition to the eight RCTs already included in the review, making a total of 14 RCTs. Full details for each of the trials are reported in the table: Characteristics of included studies.

Trial locations

Seven studies were conducted in high-income countries. Four studies were conducted in the USA (Clark 2000; Keithley 2002; Rabeneck 1998; Shabert 1999), two in Switzerland (Berneis 2000; Karsegard 2004) and one in Germany (Schwenk 1999). Four studies were conducted in African countries. One in South Africa (Rollins 2007), one in Kenya (FANTA-KEMRI study 2011), one in Burkina Faso (Simpore 2005), one in Central African Republic (Yamani 2010). One trial was conducted in Brazil (Moreno 2005) and another in India (Sudarsanam 2011). It is not clear where the study by de Luis 2003 (de Luis 2003) was conducted, although based on the address of the corresponding author it appears to be Spain. In general the trials were conducted in the out-patient (ambulatory) setting.

Trial participants

A total of 1725 adults and 271 children were included across the trials. All participants were infected with HIV. In six trials at least half or all of the participants received antiretroviral therapy (ART). In three of the four African studies none of the participants received ART. In seven studies the majority (>50%) or all participants were CDC category C (AIDS) or WHO Stage III/IV. More men participated in trials than women. Trials evaluated interventions in participants from diverse populations including those with normal weight, those with stable weight loss, and those with malnutrition. In one trial participants were TB/HIV co-infected (Sudarsanam 2011). In the remaining trials all participants were free of confirmed secondary infections or other signs and symptoms of infection, such as fever, chills, or persistent diarrhoea upon enrollment into the study. No trials were identified in pregnant or lactating women although two studies awaiting assessment may provide data on this population group when final results are available (Kindra 2011; van der Horst 2009).

Trial interventions and comparison groups

The interventions can be broadly classified as follows:

ADULTS
Macronutrient supplementation fortified with micronutrients given to provide protein and/or energy by replacing or supplementing usual diet plus nutrition counselling versus nutrition counselling or standard care
Macronutrient formulas fortified with micronutrients plus nutrition counselling versus nutrition counselling alone in participants with and without weight loss (five trials)
  • Four trials in participants with > 5% weight loss:

  1. Liquid supplement containing 600 kcal/day, 17% protein (whey), 59% carbohydrates, 26% fat, electrolytes, trace elements and micronutrients plus nutrition counselling versus nutrition counselling for 12 weeks (Berneis 2000).

  2. Liquid supplement containing 795 kcal/day, 14% protein, 54% carbohydrates, 32% fat, electrolytes, trace elements and micronutrients (ENSURE®) plus nutrition counselling versus nutrition counselling for 12 weeks (de Luis 2003).

  3. Specialized medium chain triglyceride (MCT) formula to provide additional 960 kcal/day over and above usual diet (Lipisorb® Liquid Nutrition: 17% protein, 48% carbohydrates, 35% fat) plus nutrition counselling versus nutrition counselling for 6 weeks (Rabeneck 1998).

  4. Range of fortified oral supplements providing 600 kcal/day in addition to usual diet plus nutrition counselling versus nutrition counselling for 8 weeks (Schwenk 1999)

  • One trial in participants with normal body weight assumed:

  1. 1-2 cans per day of standard oral formula (Ensure Plus®: 355 calories per can, 15% protein, 53% carbohydrates, 32% fat) plus nutrition counselling versus 1-2 cans per day of immune-enhancing oral formula (Advera®: 303 calories, 19% protein, 65% carbohydrates, 16% fat) plus nutrition counselling versus nutrition counselling for 1 year (Keithley 2002).

Supplementary food fortified with micronutrients plus nutrition counselling vs nutritional counselling alone in malnourished participants (two trials)
  • One trial in participants either initiating ART or not yet eligible for ART:

  1. ART (BMI<18.5 kg/m2) and pre-ART participants received either 300g per day of fortified blended food for 6 months plus nutrition counselling for 12 months or nutrition counselling alone for 12 months (FANTA-KEMRI study 2011)

  • One trial in participants with TB/HIV co-infection:

  1. A locally prepared cereal-lentil mixture providing 930 kcal/day plus multivitamin micronutrient supplement plus nutrition counselling versus nutrition counselling alone for 6 months (Sudarsanam 2011).

Specific macronutrient supplements versus placebo, no supplement or usual diet
  • Two trials in participants with weight loss or low BMI

  1. Participants received either amino acid mixture containing 14g arginine (free base), 14g glutamine and 3g β-hydroxy-β-methylbutyrate (HMB, calcium salt) plus citric acid (ph 4.5) or isocaloric placebo of bulk maltodextrin for 8 week(Clark 2000)

  2. ART naive participants received either 10g per day Spirulina or 10g per day placebo of green clay for 6 months (Yamani 2010)

  • Two trials in participants with normal or assumed normal weight

  1. 10g per day of L-ornithine alpha-ketoglutarate (OKG, 1.3g of nitrogen) and nutritional counselling versus isonitrogenous placebo plus nutrition counselling for 12 weeks (Karsegard 2004)

  2. Daily vitamin and mineral preparation plus L-glutamine (GLN) amino acid (400g/day) plus antioxidant nutrients (ascorbic acid 800mg/d, α-tocopherol 500 IU/d, β-carotene 27000IU/d, selenium 280ug/d and N-acetyl cysteine 2400mg/d) plus weekly nutrition counselling versus placebo of glycine plus weekly nutrition counselling for 12 weeks (Shabert 1999)

CHILDREN
Macronutrient supplements fortified with micronutrients given to provide protein and/or energy by replacing or supplementing usual diet versus no supplement or standard care
  • One trial in children with prolonged diarrhoea:

Enhanced diet: casein maltodextrin-based milk formula (AL110) until diarrhoea resolved and appetite re-established, thereafter, amount of milk formula modified to provide at least 150 kcal/kg/day containing ˜4.0–5.5 g protein/kg/day and 15% of calories as protein versus standard nutrition support: casein maltodextrin-based milk formula with 67 kcal/100mL offered at least four times per day and a maize porridge/pureed vegetable/oil diet with fermented milk offered at least four times per day. This diet provided at least 100-110 kcal/kg/day containing ˜2.2g protein/kg/day (9.5% of calories as protein) for 6 months (Rollins 2007).

Specific macronutrient supplements versus placebo, no supplement or usual diet
  • One trial in children with rapidly progressive HIV infection

Whey protein concentrate versus placebo of maltodextrin for 4 months (Moreno 2005).

  • One trial in undernourished children

Spirulina supplement plus traditional meals (millet, vegetables and fruit) versus traditional meals for 8 weeks (Simpore 2005).

Trial outcomes

None of the studies included in this review specifically aimed to assess the effects of macronutrient interventions on the all-cause or HIV-related mortality and/or morbidity we pre-specified as primary outcomes. Proxies of these outcomes, such as body weight, body composition, viral load, CD4 count, energy intake and quality of life were measured. Outcomes were not consistently reported across trials with some reports conducting analyses with means (normal distribution) and others reporting medians (non-normal distribution) for the same outcomes. In general, outcomes measured anthropometric and immunologic parameters rather than clinical symptoms. Although most trials reported on BMI in the baseline characteristics, few reported on it as an outcome of the trial.

Trial Methods

Trials were small with sample sizes ranging from 18 to 1057 with a mean sample size of 143. Follow-up ranged from six weeks to 12 months with more than half (8 out of 14 trials) including a follow-up of 12 weeks or less.

Risk of bias in included studies

Allocation

Random generation

Risk due to bias arising from the method of generation of the allocation sequence was low in six studies (Clark 2000; FANTA-KEMRI study 2011; Keithley 2002; Rollins 2007; Shabert 1999; Sudarsanam 2011). Five of the studies reported generating the sequence by computer and for the one study we obtained this information directly from the authors. The remaining nine studies did not report how the randomisation sequence was generated so the risk of bias was rated as unclear in these studies (See: Figure 2; Figure 3).

Figure 2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation concealment

Risk due to bias arising from the method of allocation concealment was rated as low in four studies (Keithley 2002; FANTA-KEMRI study 2011; Schwenk 1999; Sudarsanam 2011). The reported methods included central co-ordination of the allocation and use of sealed, unmarked, opaque envelopes. Allocation concealment was not reported in the remaining ten studies so the risk of bias was rated as unclear for those (See: Figure 2; Figure 3).

Blinding

Blinding of participants and personnel (performance bias)

Risk of bias arising from lack of blinding of participants and personnel was rated as low for three studies all of which reported using a placebo which was identical in appearance to the intervention (Clark 2000; Karsegard 2004; Shabert 1999). In two trials is was unclear if the participants or personnel were blinded (Moreno 2005; Yamani 2010). The remaining 9 trials all used controls which were not identical to the intervention or the intervention was such that it was not possible to blind the participants and personnel. The risk arising from this was rated as high for all 9 trials (See: Figure 2; Figure 3).

Blinding of outcome assessors (detection bias)

In two trials outcome assessment was clearly reported as blinded, or confirmed with the authors to be so, and detection bias was thus rated as low (Clark 2000; Shabert 1999). Blinding was unclear in 11 trials and the risk of detection bias was rated as unclear. In one trial detection bias was rated as high, as it was stated in the report that no steps were taken to blind the outcome assessors to the treatment assignments (Sudarsanam 2011)(See: Figure 2; Figure 3).

Incomplete outcome data

Risk of attrition bias was rated as low in three trials (de Luis 2003; Simpore 2005; Sudarsanam 2011). Risk of attrition bias was rated as high in nine trials in which attrition was greater than 10% overall and/or differentially distributed between the intervention and control groups (Clark 2000; FANTA-KEMRI study 2011; Karsegard 2004; Keithley 2002; Moreno 2005; Rabeneck 1998; Rollins 2007; Shabert 1999; Yamani 2010). Risk of attrition bias was unclear in the remaining two trials. In Schwenk 1999 overall attrition was moderate at 10%(5/50) but was differentially distributed between groups at 8% (2/26) in the intervention group and 13% (3/24) in the control group (Schwenk 1999). In Berneis 2000 overall attrition was high (16.7%) and no further information regarding group assignment is provided (Berneis 2000)(See: Figure 2; Figure 3).

Selective reporting

The trial protocols were not obtained for any of the trials and therefore the risk of bias due to selective reporting of outcomes was rated as unclear for all the trials (See: Figure 2; Figure 3).

Effects of interventions

See: Summary of findings for the main comparison Balanced nutritional supplement compared to counselling or nutritional placebo in patients with weight loss for reducing morbidity and mortality in people with HIV

We present the results of the trials conducted in adults followed by the results of the trials conducted in children. Where it was possible to combine the results of outcomes in a meta-analysis, we report on the meta-analysis of these outcomes. When meta-analysis was not possible, we provide reasons for this and report the results for each trial.

ADULTS

Macronutrient interventions, fortified with micronutrients, given to provide protein and/or energy by replacing or supplementing usual diet plus nutrition counselling versus nutrition counselling alone or standard care

MACRONUTRIENT FORMULAS FORTIFIED WITH MICRONUTRIENTS PLUS NUTRITION COUNSELLING VERSUS NUTRITION COUNSELLING ALONE IN PARTICIPANTS WITH AND WITHOUT WEIGHT LOSS

Five trials assessed the effects of macronutrient supplements given to provide protein and/or energy in conjunction with nutrition counselling compared to nutrition counselling alone in adequately nourished participant with or without weight loss (Berneis 2000; de Luis 2003; Keithley 2002; Rabeneck 1998; Schwenk 1999). All the interventions included micronutrients in varied percentages of the Recommended Daily Allowance (details from product web sites). This may be a possible confounder in the outcomes of these studies, as one cannot distinguish between the effect of the increased energy supply or that of the vitamins and minerals. Excluding the Keithley 2002 trial, all the participants entered the trials with a loss of body weight of more than 5% or a reduction in their BMI in the previous 6 months. As Keithley 2002 was a three-armed trial we report the comparisons between each of the two intervention groups and the control group.  

  • Clinical symptoms

Only Keithley 2002 reported on clinical symptoms but did not define the symptoms nor provide numerical data. The authors report that there were no significant differences between reported clinical symptoms among the two intervention groups and the nutritional counselling control group.

  • Energy intake

Meta-analysis of three trials (N = 131; Berneis 2000; de Luis 2003; Schwenk 1999) comparing balanced nutritional supplements (consisting of 50-60% carbohydrate, 15-30% protein and 20-30% fat aimed at improving energy intake by 600-960 kcal/day) with no nutritional supplements, showed significantly increased energy intake by 394kcal/day in the intervention arm (Mean Difference: 393.57kcal/day; 95%CI: 224.66, 562.47; p < 0.00001). See Analysis 1.1. The increase was statistically significant and could be as much as an increase of 562 kcal/day or as little as 225 kcal/day. There was little statistical heterogeneity between the trial results (Ҳ2 = 2.75; df = 2; p = 0.25) with the heterogeneity quantified by an I2 of 27%.

Although no p values were presented, Keithley 2002 reported no statistically significant differences in energy intake between the groups at any of the study visits. We calculated the mean difference, 95% CI and level of significance for energy intake at 12 months between each group. At 12 months there was no statistically significant difference in the mean energy intake between a) the Ensure Plus group (2236kcal/day, SD 1045) and the control group (1855 kcal/day, SD 991; mean difference: 381 kcal/day; 95%CI: -218.92,980.92; p=0.22); b) the Advera (Immune-enhancing formula) group (2461 kcal/day, SD 1019) and the control group (1855 kcal/day, SD 991; mean difference: 606 kcal/day; 95%CI: -17.30,1229.30; p=0.06); and c) the Ensure Plus group (2236kcal/day, SD 1045) and the Advera group (2461 kcal/day, SD 1019; mean difference:-225; 95%CI:-817.69, 367.69; p=0.46).

Rabeneck 1998 do not provide the numerical energy intake data but report that 56% of the group receiving the specialized MCT formula and 50% of the control group (nutritional counselling) achieved 80% or more of the energy target, defined as 960kcal/day greater than estimated total energy expenditure (p=0.56).

  • Protein intake

Meta-analysis of two trials (N = 81; Berneis 2000; de Luis 2003) showed supplementation with a liquid formula providing an additional 600-795 kcal/day and consisting of 14-17% protein, 55-60% carbohydrates and 26-32% fat, significantly increased daily protein intake compared with no supplements (Mean Difference: 23.25g/day; 95% CI: 12.68, 34.01; p < 0.00001). See Analysis 1.2. There was no statistical heterogeneity between results (Ҳ2 = 0.09; df = 1; p = 0.77) with the heterogeneity quantified by an I2 of 0%.

Keithley 2002; Rabeneck 1998 and Schwenk 1999 did not report protein intake.

  • BMI

One trial reported on BMI at baseline and at 6 and 12 months (Keithley 2002). Rabeneck 1998 did not provide data for BMI as an outcome despite recording the method of analysis used for it. In Keithley 2002 mean BMI at 12 months did not differ statistically significantly between the Ensure Plus group (Mean BMI: 24, SD 4 kg/m2) and the control group (Mean BMI: 27, SD 7 kg/m2; Mean Difference: -3, 95%CI: -6.5, 0.5; p=0.07); between the Advera group (Mean BMI: 26, SD 5 kg/m2) and the control group (Mean BMI: 27, SD 7 kg/m2; Mean Difference: -1, 95%CI: -4.8, 2.8; p=0.6) or between the Ensure Plus group (Mean BMI: 24, SD 4 kg/m2) and the Advera group (Mean BMI: 26, SD 5 kg/m2; Mean Difference: 2, 95%CI: 0.79, 4.79; p=0.17). Mean difference and p values were calculated in Review Manager.  

  • Body weight

A meta-analysis of 4 trials (N=233; Berneis 2000; de Luis 2003; Rabeneck 1998; Schwenk 1999) found no statistically significant difference in body weight between the supplemented group and those receiving nutrition counselling alone (Mean Difference: -0.17; 95% CI: -1.10, 0.75; p = 0.72). See Analysis 1.3. Statistical heterogeneity was quantified at 9% by the I2 and was not statistically significant (Ҳ2 = 3.30; df = 3; p = 0.35). For this outcome we combined both mean change from baseline to end-point data and actual mean body weight at the end-point of the study. Berneis 2000 reported that body weight did not change significantly from baseline in either group after 12 weeks and there was no significant difference between the groups at the study endpoint. After 6 weeks Rabeneck 1998 found no significant difference in body weight between the group receiving nutrition counselling and supplementation with a specialised MCT formula and those receiving nutrition counselling alone. Schwenk 1999 reported a similar increase in body weight in both groups after 8 weeks. de Luis 2003 was the only study to report a significant change in body weight in the supplemented group. Following 3 months of supplementation, de Luis 2003 reported a 2.75% (p<0.05) increase in body weight in the Ensure® group, with the weight gain mainly due to an increase in fat mass.

Keithley 2002 reported no statistically significant differences in body weight between the groups after 12 months, but did not present the p values. Using Review Manager we calculated the mean difference, 95%CI and p values between the groups at 12 months. At 12 months the mean body weight for the Ensure Plus group was 72kg (SD 17) while the mean body weight in the control group was 78kg (SD 23; mean difference: -6.0; 95%CI:-18.23, 6.23; p=0.32). The mean body weight for the Advera group (mean body weight=78kg, SD 13) and the control group (mean body weight=78kg, SD 23) were practically identical (Mean difference was 0, 95%CI: -11.74,11.74; p=1). Even though there was a 6 kg difference in mean body weight between the Ensure Plus group and the Advera group at 12 months this difference was not significant (Mean difference: 6; 95%CI: -2.57, 14.58; p=0.19).

  • Fat mass

A meta-analysis of four trials (N = 233; Berneis 2000; de Luis 2003; Rabeneck 1998; Schwenk 1999) showed no statistically significant difference in fat mass, measured as a percentage of total body weight, between the supplemented and non-supplemented groups (mean difference: -1.14%; 95% CI: -2.58, 0.29; p = 0.12). See Analysis 1.4. There was no statistical heterogeneity between results (Ҳ2 = 1.34; df = 3; p = 0.72) with the heterogeneity quantified by an I2 of 0%.

In Keithley 2002 body fat mass was presented in kg/m2. At 12 months the mean body fat mass in the Ensure Plus and in the Advera group was 9kgm2(SD 2), and in the control group it was 9kg/m2(SD 1). The authors report that there were no statistically significant differences between the groups but do not report the p values. Using Review Manager we calculated the following p values between the three groups at 12 months: mean fat mass in the Ensure Plus group versus the control group, p=1.0; mean fat mass in the Advera group compared to the control, p=1.0; mean fat value in the Ensure Plus group compared to the Advera group, p=1.0.

  • Fat free mass

In a meta-analysis of three trials (N = 218; de Luis 2003; Rabeneck 1998; Schwenk 1999) there was no statistically significant difference in fat free mass between the supplemented and the non-supplemented groups (MD: -0.37; 95% CI: -2.77, 2.03; p = 0.78). See Analysis 1.5. Statistical heterogeneity between results was not significant (Ҳ2 = 4.77; df = 2; p = 0.09) but was high with the heterogeneity quantified by an I2 of 58%.

Fat free mass was not reported in Keithley 2002 or in Berneis 2000.

  • CD4 cell count

A meta-analysis of the two trials which reported on this outcome (N = 81; Berneis 2000; de Luis 2003) showed no statistically significant difference in CD4 cell count between the supplemented and the non-supplemented groups (Mean Difference: -114.48; 95%CI: -233.20, 4.23; p = 0.06). See Analysis 1.6. Heterogeneity was not significant (Ҳ2 = 0.13; df = 1; p = 0.72) with the heterogeneity quantified by an I2 of 0%.

Keithley 2002 reported no significant difference in mean CD4 cell counts between the three groups at any of the time points. At 12 months the mean CD4 cell count in the Ensure Plus group was 471 cells/mm3 (SD 175), compared to the mean CD4 cell count in the Advera group (459 cells/mm3, SD 198; mean difference: 12; 95%CI: -96.15, 120.15; p=0.82) and the mean CD4 cell count in the control group (437 cells/mm3, SD 182; mean difference: 34; 95%CI: -71.93, 139.93; p=0.5). There was also no significant difference in the mean CD4 cell count between the Advera and the control group (459 cells/mm3, SD 198 vs 437 cells/mm3, SD 182; mean difference: -22; 95%CI: -139.76, 95.76; p=0.72) at 12 months.

Rabeneck 1998 reports that there was no significant change observed in CD4 counts between the groups (no data provided).

Schwenk 1999 did not report on CD4 counts.

  • Viral load

Only one of the five trials (de Luis 2003) reported on the change in viral load over the course of the trial. After 12 weeks no statistically significant difference was noted in HIV viral load (log10copies/ml) between the supplemented and non-supplemented groups (N=66 participants; Mean Difference: -3.71 log10copies/ml; 95% CI: -12.16, 4.74; p = 0.39) in this study.

  • Adverse effects

Adverse effects were poorly reported and in general, were related to tolerance rather than adverse effects. Keithley 2002 reports that no significant differences were found in acceptance and tolerance of the formulas. Rabeneck 1998 noted that one participant discontinued the supplement due to nausea and epigastric pain and one discontinued as he did not like the taste of the supplement.

SUPPLEMENTARY FOOD FORTIFIED WITH MICRONUTRIENTS PLUS NUTRITION COUNSELLING VS NUTRITIONAL COUNSELLING ALONE IN MALNOURISHED PARTICIPANTS

A study conducted in Kenya evaluated the impact of supplementary food on nutritional and clinical status, treatment progress and quality of life of malnourished HIV-infected adults on ART and pre-ART (i.e. HIV-infected adults who did not qualify for ART according to the Kenyan National HIV treatment protocol. ART was only provided to HIV-infected adults who met the WHO Stage IV disease criteria, or who had a CD4 count <200 cells/µl FANTA-KEMRI study 2011). This trial pre-dated the recommendation to commence ART at CD4 counts less than 350 cells/µl. The food products were distributed monthly, for six months or until subjects reach the exit criterion of BMI = 23 kg/m2, whichever occurred first, and participants were followed up for a year. The food product was a blend of maize, soya, vegetable oil, sugar, whey protein concentrate, and micronutient pre-mix. The food was provided in 300 gram packets and provided 1320 kcal/day energy and 48 g/day protein. At the time of the study, the cost of the food product was approximately $1/kg, or $0.30/300g dose, or $0.23/1,000 kcal. All patients in the study received nutrition counselling according to national protocols and using counselling materials and job aids provided by NASCOP.  The nutrition counseling was usually carried out by a trained nutritionist or dietician and focused on supporting the client in appropriate weight gain and management of diet-related symptoms and food-drug interactions. 

  • Body weight, change in body weight, BMI and % lean body mass

The authors noted that at baseline pre-ART participants had higher weight and BMI compared to the ART participants. Throughout the trial pre-ART participants gained less weight each month than the ART participants.

Amongst participants receiving ART there was no significant difference in mean body weight at any of the time points between the supplement and no supplement group (See Analysis 2.1. However, in the first 3 months of the trial the supplement group appeared to gain weight more rapidly than the no supplement group, as they had a significantly greater change in body weight gain compared to the no supplement group at these time points. After this time point the change in body weight was not significantly different between the groups (See Analysis 2.2). Mean BMI and change in BMI in the supplement group was significantly higher in the first 3 months compared to the no supplement group (See Analysis 2.3). After 3 months there was no significant difference in weight gain, BMI or BMI gain between the supplement and no supplement groups in the participants receiving ART.

Amongst participants not receiving ART, at 3 months (p=0.0027) and 6 months (p=0.001), the supplement group had a significantly greater mean body weight than the no supplement group (See Analysis 2.1). In the first 4 months of the trial and at the 6 month and 9 month time point, the supplement group had a significantly greater body weight gain compared with the no supplement group (See Analysis 2.2). In the first 3 months of the trial and in month 6, 7 and 9, mean BMI in the supplement group was significantly greater than in the no supplement group (See Analysis 2.3). In the first 4 months of the trial and months 6, 7, 8 and 9 the supplement group exhibited a significantly greater gain in BMI than the no supplement group.

There was no significant difference in % lean body mass or changes in % lean body mass between the supplement and no supplement group at any time point for both the ART arm and the pre-ART arm (See Analysis 2.4).

  • Clinical and immunological outcomes

There was no significant difference in mean CD4 cell count between the supplement and no supplement group at any time point for both the ART arm and the pre-ART arm. However, in the pre-ART arm, at 3 months, the mean CD4 cell count in the supplement group increased by 7.4±123.5 and the mean CD4 cell count in the no supplement group decreased by 32.59±103.5 (p=0.01, authors own data).

Supplemented ART participants had significantly higher increase in hemoglobin levels at month 3 compared to the no supplement group (change in hemoglobin: 1.23±2.3 in supplement group vs 0.69±2.4 in the no supplement group, p=0.05). Supplemented pre-ART participants had a significantly higher increase in hemoglobin levels at 3 (0.93±2.7 in the supplement group vs 0.01±2.3 in the no supplement group; p=0.01) and 6 months (0.78±3.1 in the supplement group vs -0.18±0.6 in the no supplement group; p=0.05) compared to the no supplement group.

The authors only present the 3 month values for changes in serum albumin. Based on this data there was no difference in changes in serum albumin at this time point between the supplement and no supplement groups for either arms of the study.

  • Quality of life

The authors report that most of the changes in quality of life occurred during the initial months of the study. The majority of the ART and pre-ART participants experienced improvements in perceived health or their perceived health remained good, in both supplement and no supplement groups. The authors report that pre-ART participants receiving supplementary food on average experienced significantly greater improvement and less of a decline in perceived health than those not receiving food.  These differences did not persist over longer periods of follow-up.  Among ART participants, the difference in changes in perceived health between those receiving food and those not receiving food was smaller and not statistically significant (data presented graphically).

In the report, quality of life was also measured by the number of days per month that subjects reported having had poor physical health during the first three months. The authors report that among pre-ART participants, those receiving food had fewer poor health days than those not receiving food, and the differences were significant during the first and second months, but not subsequently.  Among ART participants, the difference was significant in the second month only (data presented graphically).   

  • Attrition

Attrition, defined as discontinuation of care and treatment at the health facility for any reason, including death, loss-to-follow-up, or relocation was high in all groups. Authors report that the highest rate of attrition occurred during the first month of the study: with an attrition rate of 26% in the ART arm and 24% in the pre-ART arm.  By the third month of follow-up, 37% and 39% of participants in the food and no-food groups of the ART arm and 37% and 48% of the food and no-food groups in the pre-ART arm respectively had been lost from the study. The difference in attrition between the food and no-food groups in the pre-ART arm was significant (p=.039), and the difference between the groups in the ART arm was not significant (data reported by author).

In the ART arm, the mean durations that participants were retained in the study were 6.3 months and 5.9 months for the food and no-food groups respectively. In the pre-ART arm the mean durations that subjects were retained in the study were 5.9 and 5.4 months for the food and no-food groups respectively (author's results). 

The above data is from an unpublished report prepared by the study coordinators (See FANTA-KEMRI study 2011). The report does not include data on all of the measured outcomes, such as adherence to ART, survival, number of severe clinical events (defined as the sum of hospitalizations and deaths) and number of non-severe clinical events (defined as the number of new opportunistic infections and new symptoms for which medication is required).

In a study conducted in India (Sudarsanam 2011) participants with pulmonary tuberculosis, with and without HIV co-infection, and a BMI <19 kg/m² were randomised to receive a cereal-lentil mixture, micronutrient supplement plus standard care versus standard care alone. The supplement consisted of three daily servings of a cereal and lentil mixture (providing 930 kcal and 31.5 g protein) and a once a day multivitamin tablet. Patients were given a months supply of supplement at a time. TB/HIV-coinfected individuals were treated for TB but did not receive ART, as per protocol in India at the time. Despite randomisation the supplemented group had poorer initial nutritional status as measured by most parameters.

There was no significant difference in risk of death at 6 months (22 TB/HIV participants: RR: 2.14, 95% CI: 0.10, 47.38), cure rate at 6 months (22 TB/HIV participants: RR: 1.38, 95% CI: 0.46, 4.14) and treatment failure before 6 months (22 TB/HIV participants: RR: 0.69, 95% CI: 0.12, 4.05) between the two groups. (Data and information retrieved from recently updated Cochrane review: Nutritional supplements for people being treated for active tuberculosis Sinclair 2011).

At the end of the trial there was no significant difference in mean CD4 cell count (See Analysis 5.2: 221±142 cell count.mm-3 in supplemented group vs 249±387 cell count.mm-3 in no supplement group, SMD: -0.10 95% CI: -0.95, 0.75) and median viral load (845819 HIV viral load.ml-1 in supplemented group vs 1435700 HIV viral load.ml-1 in no supplement group) between the two groups in the TB/HIV-coinfected individuals.

Although supplementation resulted in a significant increase in daily caloric (11.15±882.2 in supplement group vs -375.42±893.2 kcal in no supplement group, p=0.05), protein (4.6±29.2g in supplement group vs -9.85±25.9 g in no supplement group, p=0.019) and fat (2.86±18.9 g in supplement group vs -10.78±17.1 g in no supplement group, p=0.009) intakes, compared to the no supplement group, changes in lean body mass and fat mass in both groups were similar at the end of the trial (change in lean body mass: 2.37±4.97 kg in supplement groups vs 2.40±6.3 kg in no supplement group, p=0.479; change in fat mass: 1.72±4.8 kg in supplement groups vs 1.1±5.4 kg in no supplement group, p=0.573). Data for mean weight are only presented graphically. Authors reported no difference in mean weight changes between the two groups throughout the study. These results are for all the participants, both TB and TB/HIV participants. We have requested information for the TB/HIV participants alone but have not yet received it from the author.

Specific macronutrient supplements versus placebo, no supplements or usual diet

Four trials assessed specific supplements compared either with a placebo or traditional meals in adults (Clark 2000; Karsegard 2004; Shabert 1999; Yamani 2010). Two trials were conducted in participants with weight loss or low BMI (Clark 2000; Yamani 2010). Two trials were conducted in participants with normal or assumed normal weight (Karsegard 2004; Shabert 1999).

ARGININE, GLUTAMINE AND B-HYDROXY-B-METHYLBUTYRATE

Clark 2000 compared the effects of an amino acid mixture containing 14g arginine (free base), 14g glutamine, 3g ß-hydroxy-ß-methylbutyrate (HMB, calcium salt) and citric acid (ph 4.5) with maltodextrin control formulation in participants with unintentional weight loss of 5% or more in the past 3 months who were on ART. After 8 weeks the arginine group gained significantly greater body weight than the control group (MD: 2.63 95% CI: 0.72, 4.54). See Analysis 3.1. There was no significant difference in change in fat mass between the two groups (MD: -0.64 g; 95% CI: -2.69, 1.41; p = 0.54). See Analysis 3.2. The increase in fat-free mass was statistically significantly greater in the arginine group compared with controls (MD: 3.25kg; 95% CI: 1.25 to 5.25; p = 0.001). See Analysis 3.3. CD4 count in the arginine group was reported to increase but not statistically significantly so (p = 0.10). Viral load was reported to decrease statistically significantly (p = 0.007) in the arginine group but actual data for the study endpoint is not presented. Energy intake was not reported on in this study.

SPIRULINA

The trial by Yamani 2010 was conducted in ARV naive adults from the Central African Republic. A total of 160 patients were included in the trial. Patients in the spirulina group (N=79) received 10g spirulina per day and participants in the placebo group (N=81) received green clay. Each week all participants received food packages from the World Food Program consisting of 14g maize flour, 500g mixture of maize and soya bean, 2kg garden peas, 500g sugar, 150g iodized salt and 500ml oil.

During the 6 month follow-up, 16 patients died and 16 patients were lost to follow up. There was no significant difference in the distribution of lost cases or deaths between the two groups (Spirulina group: 6 deaths and 6 lost to follow-up vs placebo group: 10 deaths and 10 lost to follow-up (p=0.8).

The authors report a statistically significant gain in weight from baseline in each group after 6 months. There was no significant difference in weight gain between the two groups over this time period. Arm circumference also increased significantly in each group, without significant difference between both the groups.

At 3 months the authors reported a significant decrease in mean Karnofsky score in the placebo group versus the spirulina group (p=0.0045). Thereafter the mean Karnofsky score in the placebo group increased to a value similar to that of the spirulina group.

The authors reported a lower number of pneumonia cases in the spirulina group versus the placebo group at 6 months (p=0.01, number of pneumonia cases in each group not presented. Specific information has been requested from author). 

After 6 months CD4 count increased in both groups. This increase was not significant and there was no difference in CD4 count between the two groups at the end of the trial. Hemoglobin values decreased in both groups between months 0 and 6, with no significant difference between spirulina and placebo groups.

In both groups serum protein concentration increased in the first 3 months and then decreased in the following 3 months. There was a significant increase in serum protein (g/L) in the spirulina group between months 0-3 (p value not shown) and months 0-6 (p=0.0001). At 3 months (p=0.01) and 6 months (p=0.00001) serum protein concentrations were significantly higher in the spirulina group compared to the placebo group. In both groups, serum creatinine levels decreased at month 3 and then increased again at month 6. At 3 months serum creatinine levels were significantly higher in the spirulina group compared to the placebo group (p=0.01).

MONOHYDRATED L-ORNITHINE ALPHA-KETOGLUTARATE

Karsegard 2004 compared glutarate supplementation with an isonitrogenous placebo containing 9g of milk proteins. Nutrition counselling was provided to all participants. No morbidity data were reported. At study endpoint there were no statistically significant differences between the groups in daily energy intake, body weight, fat mass, fat-free mass or in the CD4 cell counts or viral loads. See Analysis 4.1; Analysis 4.2; Analysis 4.3; Analysis 4.4; Analysis 4.5; Analysis 4.6; Analysis 4.7. The authors conducted ANOVA tests with last known reported values used for missing data and found that there were statistically significant increases in body weight (mean body weight at baseline: 61.2, SD 11.9 in placebo and 56.4 SD 11.2 in OKG group vs mean body weight at 12 weeks: 61.8 SD 11.5 in placebo and 56.8 SD 11.6 in OKG group), BMI (mean BMI at baseline: 20.6, SD 3.0 in placebo and 20.0, SD 2.4 in OKG group vs mean BMI at 12 weeks: 20.8, SD 2.9 in placebo and 20.2, SD 2.5 in OKG group), and triceps skinfold thickness (mean triceps skinfold thickness at baseline: 14.0, SD 5.4 in placebo and 13.4, SD 4.9 in OKG group vs mean triceps skinfold thickness at 12 weeks: 15.5, SD 5.6 in placebo and 15.0, SD 6.1 in OKG group) from baseline in both groups. They do not report specific p values but only p < 0.05 for these outcomes.

The authors report that appetite and food tolerance remained stable over time but that frequency of gastrointestinal events was significantly higher in the OKG group (authors' reported p value < 0.05). Of the 22 participants taking OKG, 19 reported at least one GI adverse event compared with 13 out of 24 in the placebo group with participants in the OKG group one and a half times more likely to experience GI adverse events (RR = 1.59, 95% CI: 1.06, 2.39; p = 0.02).

L-GLUTAMINE AND ANTIOXIDANTS

  Shabert 1999 compared a supplement comprising L-glutamine and antioxidants (ascorbic acid, a-tocopherol, ß-carotene, selenium and N-acetyl cysteine) with a placebo supplement comprising 40g glycine. Nutrition counselling and multivitamin supplementation was provided to all participants.

Mean weight at study endpoint was not statistically significantly different between the groups (MD: -1.30kg; 95% CI: -10.18, 7.58; p = 0.77). See Analysis 5.1. Data were not provided to calculate the change in weight over time, but the authors report in the text that the mean change in weight from baseline to week 12 was 2.2kg in the glutamine group and 0.3kg in the placebo group (p =0.04). Similarly mean change in body cell mass (the total mass of all the cellular elements in the body which constitute all the metabolically active tissue of the body; includes muscle tissue, organ tissue, intracellular and extracellular water, and bone tissue) was reported as statistically significantly different between the groups with a greater increase in the glutamine group (mean gain = 1.8kg) than in the placebo (mean gain = 0.4kg). No standard deviations are provided; the authors report a p = 0.007. Mean fat mass was not different between groups at study endpoint (MD: -1.00kg; 95% CI: -32.40, 30.40; p = 0.95). See Analysis 5.2.

Mean CD4 count was not statistically significant between groups (MD: 66.00; 95% CI: -53.39, 185.39; p = 0.28). See Analysis 5.3. The authors conducted an assessment of mood questionnaire at baseline and week 12 using a 30-item profile of the Short Form 36 and report no statistically significant differences between the groups. The authors did not observe any adverse effects in either of the groups.

CHILDREN

Three trials were conducted in children. One trial investigated enhanced nutritional support compared with standard nutritional support in children with prolonged diarrhoea (Rollins 2007), one trial investigated a whey protein concentrate compared to maltodextrin placebo in children with rapidly progressing HIV (Moreno 2005) and one trial investigated the effects of spirulina plus traditional meals versus traditional meals alone in malnourished HIV-infected children (Simpore 2005).

Macronutrient supplementation (fortified with micronutrients) versus no supplement or standard care

ENHANCED NUTRITIONAL SUPPORT VS STANDARD NUTRITIONAL SUPPORT IN CHILDREN WITH PROLONGED DIARRHOEA

The primary outcome of the study by Rollins 2007 was weight change from enrolment until 8 weeks among 169 HIV-infected children. The study reported that children receiving enhanced nutrition support had significantly more weight gain in the first 8 weeks than children receiving standard care (weight gain was expressed as the median change in age- and sex specific weight standard deviation scores (SDS): +1.02 (enhanced nutritional support group) vs +0.01 (standard nutritional support group), p < 0.0001).

Mean weight-for-age standard deviation score (WFA-SDS) at baseline of those who dropped out was not different between groups: (Standard nutritional support group dropouts: –3.24 vs; enhanced nutritional support group dropouts: –3.39; p > 0.05) standard nutritional support group completers: –3.00, vs enhanced nutritional support group completers: –3.19, p > 0.05). Therefore, the observed outcome among the completers appeared to be unaffected by dropout bias.

After 8 weeks, weight gain was similar between groups, with only a slight increase in weight-SDS over time in each group. Median change in weight-SDS from 8 to 14 weeks of follow-up: +0.21 (enhanced nutritional support group) vs. 0.00 (standard nutrition support group: 14 to 26 weeks of follow-up: +0.12 (enhanced nutritional support group) vs. +0.24 (standard nutritional support).

Children receiving enhanced nutritional support exhibited significantly higher median attained WFA-SDS after 8 weeks (-1.99 vs -3.06, p<0.05), 14 weeks (-1.69 vs -2.96, p,0.05) and 26 weeks (-1.32 vs -2.63, p,0.05) compared to the children receiving standard nutritional support. Children in the enhanced nutritional support group who were randomised to continue with the enhanced nutrition support until 6 months showed a further improvement in median attained WFA-SDS (−1.01 SDS) at 6 months compared to those who reverted back to standard home diet who maintained the same median value attained at 3 months (-1.68 SDS).

No significant differences in CD4 cell counts or viral load between groups or over time were reported. However, it should be noted that changes in viral load could only be assessed in a subset of 70 children. The pattern of morbidity throughout the study was also similar between groups based on the cumulative frequency of clinical signs recorded during the follow-up intervals of 0–8, 8–14 and 14–26 weeks.

Dropout rates at the end of the study were high in both groups (Standard nutritional support: 27/83 (33%); Enhanced nutritional support: 38/86 (44%); difference 11%, 95%CI: −3 to +26). Authors reported the primary reason for attrition in the study was death. There was no significant difference between the two groups for death at 8 weeks (Death at 8 weeks: 10/83 (12%) in standard nutritional support group vs 14/86 (16%) in enhanced nutritional support group; OR: 1.42 95% CI: 0.59, 3.40; p=0.43; See Analysis 6.1) or death at 26 weeks (Death at 26 weeks: 18/83 (22%) in standard nutritional support group vs 25/86 (29%) in enhanced nutritional support group; OR: 1.48 95% CI: 0.74, 2.98; p=0.27; See Analysis 6.2).

Specific macronutrient supplements versus placebo, no supplements or usual diet (two trials)

Two trials assessed supplementation with specific macronutrients compared either with a placebo or traditional meals in children. One trial was conducted in Brazilian children with rapidly progressive HIV infection (Moreno 2005). One trial, conducted in Africa investigated the effects of Spirulina in undernourished children (Simpore 2005).

WHEY PROTEIN CONCENTRATE

Moreno 2005 was conducted in Brazil in rapidly progressive HIV vertically infected children (N=18). Participants received whey protein concentrate, maltodextrin or placebo. In the final data analysis the results of the maltodextrin and the placebo groups were combined (will be referred to as the placebo group) and compared with those of the whey protein concentrate group. All children were on some form of ART.

Overall attrition was high at 27.7% (5/18), but similar in both groups (3 lost from whey protein concentrate group vs 2 lost from the placebo group). Authors reported that 22.2% (2/9) of the children in the whey protein concentrate group developed co-infections during the 16 week study compared to 77.7% (7/9) of the children in the placebo group (p=0.0567, author's data).

While a non-significant increase in median CD4 cell count was demonstrated in both groups, no significant difference in median CD4 cell count between the two groups was noted throughout the study. Median CD8 cell count decreased over time in the whey protein concentrate group, with a significant difference noted between the 8 weeks and the 16 week values (p=0.046). Since viral load was only measured in 6 children in the whey protein concentrate group, differences between treatment groups could not be assessed. There was no significant difference between the groups for levels of leukocytes, erythrocytes, hemoglobin and platelets.

SPIRULINA

The trial by Simpore 2005 was conducted in undernourished HIV-negative and HIV-positive children in Burkina Faso. Only the results of 84 HIV-positive children who participated in the trial will be reported in this review. The intervention group received 10g spirulina daily along with traditional meals of millet, vegetables and fruit whereas the comparison group received traditional meals only for 8 weeks.

There was a significant increase in weight-for-height z scores (WHZ) in both groups after 8 weeks. There was no difference in WHZ between the groups at the end of the study. See Analysis 7.1. There was also a significant increase in weight-for-age z-scores in both groups after 8 weeks but no differences between the groups were noted. See Analysis 7.2.

Authors reported that treatment compliance was excellent and none of the children dropped out or were lost to follow up. 

Discussion

Summary of main results

Our review establishes that experimental evidence on the effects of macronutrient supplementation on important clinical outcomes in HIV-infected adults and children is surprisingly limited; despite an exhaustive search, we found only 14 relatively small randomised controlled trials that met the inclusion criteria of our review. Apart from the two trials evaluating Spirulina, one trial in adults and one trial in children, each of the trials evaluated a different macronutrient supplement. Participants included in the trials also varied quite considerably in terms of stage of HIV, HIV treatment status and general nutrient status. Only three trials reported on mortality, two trials in adults and one trial in children. Meta-analysis was only possible on one class of supplements, viz. balanced macronutrient supplements fortified with micronutrients plus nutrition counselling versus nutritional counselling alone or standard care. GRADE assessments were conducted on outcomes for this meta-analysis and included reviewing the data and the potential biases in each trial before grading the level of evidence. None of the trials were graded as providing strong evidence primarily because of small sample sizes (even after meta-analysis) and the high risk of bias due to a lack of blinding, high attrition and unclear reporting of randomisation methods.

In adult participants with weight loss, balanced macronutrient supplements aimed at improving energy intake by 600-960 kcal/day increased intakes of energy and protein compared with no supplement or nutrition counselling alone, but had no effect on other anthropometric or immunologic parameters. This is an important finding as loss of appetite and consequent decreased food intake is common in people with HIV. The increased energy and protein intake in the supplemented group resulted in increased body weight in most cases. However, only in de Luis 2003 was the increase in body weight in the supplemented group significantly greater than that of the group receiving nutrition counselling alone.

As all the supplements included micronutrients supplementation, it is not possible to determine if the observed effects of an increase in energy and protein intake are due to the combination of the macro- and micronutrient components or the macronutrient component alone. Variation in the nutritional composition of active supplements and in control interventions across studies, as well as differences in the disease stage of the participants in various studies (which can significantly affect intake and absorption of food) limits the value of meta-analysis and complicates the interpretation of the findings of this review. All the trials were of a 12 week or less duration making inferences prone to inaccuracies.

It is worth noting that patients with acute opportunistic infections are most prone to weight loss and theoretically this sub-group would be most likely to experience improvements in nutritional status such as weight gain. However, this sub-group was excluded from all of the studies evaluating balanced macronutrient supplements. Nonetheless, if the finding of increased energy and protein intake in our review is valid, this would be important, given that decreased energy intake, increased resting energy expenditure and accelerated protein turnover is common in people with HIV/AIDS.

In contrast to studies in adults with weight loss, balanced macronutrient supplementation did not have any effect on food intake, nutritional status or anthropometry in adults with assumed normal weight (based on results of one small trial, N=66).

A relatively large trial (N=1057) conducted in Kenya evaluated the effect of providing supplementary food to malnourished adults either initiating ART or pre-ART. Overall, malnourished HIV-infected participants not yet receiving ART (pre-ART) gained less weight than those receiving ART, regardless of supplement status (i.e. whether receiving supplementary food or not). Although there was no significant difference in body weight in the first three months of initiating ART between the supplemented and non-supplemented groups in the ART arm of the trial, participants receiving supplementary food showed a significantly greater weight gain and BMI gain (i.e. the change in weight and BMI at each time point in the first 3 months of the trial was significantly greater in the supplemented group compared to the son-supplemented group)than those not receiving supplementary food. This was evidenced by the significantly greater changes in body weight and BMI at these time points in the supplemented group of the ART arm. These effects did not persist after the first 3 months of the trial. The beneficial effects of supplementary food on body weight, body weight gain, BMI and BMI gain was more pronounced and more prolonged in the pre-ART participants than in the ART participants. At almost every time point in the first 9 months of the trial, pre-ART participants receiving supplementary food weighed significantly more and had a significantly higher BMI than the non-supplemented participants. Supplementary feeding did not affect CD4 cell count or serum albumin levels in either ART or pre-ART participants. Supplementary feeding had a significant beneficial effect on haemoglobin levels in both ART and pre-ART participants. In the initial stages of the trial supplementary food had a significant beneficial effect on the quality of life of pre-ART participants in particular.

In India, providing supplementary food to TB/HIV co-infected adult participants not yet receiving ART did not significantly alter risk of death at 6 months, TB cure rate at 6 months or TB treatment failure before 6 months compared to TB/HIV co-infected participants not receiving supplementary food. The provision of supplementary food did not significantly alter CD4 cell counts or viral load compared with values from the non-supplemented participants.

HIV infection is most prevalent in parts of the world where food security is compromised. These populations at high risk of HIV infection lack appropriate nourishment prior to infection by HIV. Poor nutrient status in HIV-infected individuals is an independent predictor of mortality in both untreated and treated individuals with HIV (Marazzi 2008; Koethe 2010; Liu 2011). These two trials evaluating supplementary feeding in low-income countries are important as they provide some evidence of the effectiveness of macronutrient supplementation in these populations who are likely to benefit the most from such interventions.   

Four small trials evaluated four different specific macronutrient interventions so meta-analysis was not possible. In adult participants with unintentional weight loss of 5% or more supplementation with an amino acid mixture containing arginine, glutamine and beta-hydroxy-beta-methylbutyrate (HMB) significantly increased body weight and fat free mass and significantly reduced viral load. Various anthropometric and immunological outcomes were not significantly affected by daily supplementation with 10g of spirulina compared to placebo of green clay in malnourished, antiretroviral naive participants. It was reported that participants receiving spirulina had a significantly higher Karnofsky score and significantly fewer cases of pneumonia compared to the participants receiving placebo.

In adult participants with assumed normal weight, supplementation with monohydrated L-ornithine alpha-ketoglutarate (OKG) did not significantly alter anthropometric or immunological outcomes compared with a placebo as both groups showed similar increases in all of the measured indices throughout the study. Although there was no significant difference in mean body weight between the groups at the end of the study, supplementation with l-glutamine and antioxidants resulted in a significantly greater mean weight gain over 12 weeks compared with placebo.

Three small trials were conducted in children. All of the trials were conducted in low- to middle-income countries, namely South Africa, Brazil and Burkina Faso. In children with prolonged diarrhea enhanced nutritional support (providing an extra 50kcal/kg/day, double the amount of protein and 5% more protein as a percentage of total calories than standard nutritional support) resulted in significantly greater weight gain after 8 weeks compared with the standard nutritional support. Attrition was high in both groups, mainly due to death of participants. It is worth noting that 43 children died during the 6 month trial. None of these children were receiving ART as was standard care in South Africa at the time of the trial.

The only notable result from the small trial evaluating the effects of whey protein concentrate in rapidly progressive HIV vertically-infected children was the significant reduction in the number of co-infections experienced by the children receiving the whey protein concentrate, compared to those receiving placebo. While this is a very important finding it should be interpreted with caution as this was a very small trial of 18 children and attrition was high in both groups (33% in whey protein concentrate group and 22% in the control group). All of the children were on some form of ART. In undernourished HIV-infected children the addition of 10g of spirulina to daily traditional meals did not significantly alter weight-for-height or weight-for-age z scores compared to the children not receiving spirulina. Compliance was excellent and there was no attrition.

Overall completeness and applicability of evidence

Only two of the 14 trials included in this review evaluated the same supplements. Of those trials that evaluated similar classes of supplements, none of the supplements were identical in composition, formulation or quantity. Comparisons and control interventions also differed across every trial. The length of follow-up varied from 6 weeks to 12 months and few trials measured the same suite of outcomes. Due to this high degree of variation, it was not possible to conduct meta-analysis on most of the trials, leading to reduced confidence in the results arising from single trials. Stronger evidence would be gained from replicating trials of each of the supplements evaluated. This would also facilitate meta-analysis.

Earlier trials evaluated the effects of supplements on body weight and other measures of body composition, but few report on outcomes related to morbidity or mortality. While mortality and morbidity were not the primary outcomes measures of the more recent trials, the majority of them do report on these important outcomes.

Seven of the eight trials included in the original version of this review were conducted in high-income countries, in relatively well nourished (in terms of body mass index) adult males and females between the ages of 30 and 50, almost all of whom were on some type of ART. It is promising to note that all of the six new trials added to the review were conducted in low-to middle-income countries (four trial in Africa) and the interventions tested in these trials are relevant and accessible to the populations in these countries. The addition of three studies conducted in children is also noteworthy. There are major differences between HIV-infected individuals in rich and poor countries with regard to income level, availability of adequate nutrition, and access to basic healthcare or life-prolonging antiretroviral treatment. In addition, patient groups vary in terms of their response to the virus, stage of the disease, susceptibility and exposure to opportunistic infections, nutritional status, and individual response to the various treatments received. These observations highlight some challenges in applying the findings of trials conducted in high-income countries to people in resource-constrained countries, where nutritional status is generally poor and access to antiretroviral therapy is limited. In other words, where supplementation may be most needed.

Importantly this review identified only two potentially eligible trials (Kindra 2011; van der Horst 2009) which were conducted in pregnant and lactating women infected with HIV. Under normal conditions, successful pregnancy and lactation requires an increase in energy intake. In HIV-infected women, HIV-associated anaemia can be exacerbated during pregnancy. This review has identified that we do not have evidence from trials in support of macronutrient supplementation (either fortified with micronutrients, such as iron, or not) in this population.

Table 1 provides information on RCTs comparing two or more macronutrient interventions in HIV-positive individuals. While we did not include the results of these trials in our review we have provided this information for the sake of completeness.

Quality of the evidence

GRADE assessments

GRADEPro was used to create Summary of Findings tables for meta-analyses using the outcomes pre-specified by the WHO expert group. In determining the level of evidence for each outcome, both the efficacy results and the assessment of the risk of bias was integrated into a final assessment of the level of evidence and full details of the decision provided in footnotes. All primary and secondary outcomes were rated as critical by the WHO expert group and received a score of ‘9’ indicating the highest level of importance to patients. For other outcomes included in the meta-analysis, levels were determined at discretion of the authors.

Balanced supplementation versus counselling

See Figure 4 for complete assessment and rationale for ratings.

Figure 4.

GRADE Summary of Findings Table for balanced macronutrient supplements versus counselling

For the outcomes of an increase in the mean change in energy and protein intake the level of evidence was rated as low

For body weight, and fat mass measured in percentage of total body weight, the level of evidence was rated as moderate

Evidence for fat-free mass and change in CD4 count from baseline to study endpoint was rated as low

The evidence for an effect on viral load was rated as very low with this result coming from only one trial.

Potential biases in the review process

In the meta-analysis of trials evaluating balanced macronutrient supplements fortified with micronutrients and nutrition counselling versus nutrition counselling we combined data reflecting both mean change from baseline to end-point and final mean at the end-point of the study as described in the Cochrane Review Authors’ Handbook. Caution must be used when interpreting the outcomes of this meta-analysis as certain effects of the interventions may be hidden when combining these two types of data. Furthermore, the lengths of follow up of the trials included in this meta-analysis were also different (two trials had a 6 week follow up, one trial had an 8 week follow up and one trial had a 12 week follow up). This could also introduce bias into the results of the meta-analysis. Finally, the interventions evaluated in the trials were similar, in a very broad sense, but not identical.

Biases in the review process were minimised by performing a comprehensive search of the literature, independently selecting and appraising the studies, and extracting the data in duplicate. Where data was missing, we sought additional information and data directly from authors where this was possible to do so. We also consulted product web sites to gain more detailed product information regarding several of the commercial supplements.

Although an extensive hand-search for grey literature was not conducted, it is unlikely that important trials have been missed given the high profile nature of the topic and the close partnership established with agencies and organizations working in this area. Indeed, due to the involvement of the WHO in this review, the authors were presented with data from the unpublished FANTA-KEMRI trial. However, the review remains at risk of publication bias from less prominent trials. We attempted to reduce this risk by identifying relevant conference abstracts. A 2010 search of the HIV/AIDS-specific conference database, NLM Gateway, yielded two relevant trials, both of which were already included in the review. Given that NLM Gateway is no longer maintained, conducting an additional search of the new HIV/AIDS conference database, www.aegis.com, could potentially yield unpublished studies and is warranted to reduce  the possible impact of publication in this review.

The search of the trials registry, www.clinicaltrials.gov, to identify trial protocols and ongoing trials yielded 28 potentially relevant trials protocols. These will require further assessment and exploration to either 1) link them to trials already included in the review, or 2) if not included, to attempt to obtain the completed trial reports. This task is time-consuming and has to be balanced against feasibility and time constraints.

Authors' conclusions

Implications for practice

  • In keeping with previous WHO recommendations everything possible should be done to promote and support adequate dietary intake and food security, while recognising that this may not be sufficient to correct specific deficiencies in all HIV-infected individuals;

  • There is evidence of a low quality that provision of a balanced macronutrient supplement, fortified with micronutrients, increases the daily energy and protein intake when compared to receipt of nutritional counselling alone; the choice of supplement is likely to be determined by cost and availability.

Implications for research

  • Adequately powered studies are required to determine the efficacy and safety of macronutrient supplements in HIV-infected  adults and children;

  • Choice of supplements for future research should be guided by the evidence-base and focus on determining the optimal composition and dosage of:

    • Balanced macronutrient supplements fortified with micronutrients

    • Fortified food supplementation delivered by food programmes

  • The cost-benefit or cost-effectiveness of all the nutritional interventions requires evaluation;

  • Research participants should be diverse with respect to stage of disease, use of antiretroviral therapy, immune status, and nutritional status.

In summary, there is limited evidence, from randomized trials mainly conducted in high-income countries that targeted supplementation of the diet with balanced macronutrient supplementation increases energy and protein intake in HIV-infected adults on antiretroviral therapy. The effects of nutritional supplementation on mortality, morbidity, body weight, and immunological parameters remain unclear. There is limited evidence for the optimal type and amount of supplement delivered by food programme interventions for people infected with HIV.

Acknowledgements

The authors would like to thank Este Vorster, Ulrich Keller, Douglas Wilmore, Claude Pichard, John Rathmacher, Achim Schwenk, Joyce Keithley, Elizabeth van der Merwe, and Wieland Gevers for methodological input or assistance in the interpretation of data. The initial review was completed with the guidance and support of the HIV/AIDS mentorship programme coordinated by the South African Cochrane Centre and the HIV/AIDS Review Group. Sarah Mahlungulu received a bursary from the Cochrane Health Promotion and Public Health Field to conduct the review. For the 2011 revision the support of the World Health Organization Nutrition for Health and Development Department, Switzerland.

Data and analyses

Download statistical data

Comparison 1. Balanced macronutrient formulas plus nutrition counselling vs nutrition counselling in participants with weight loss
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Energy intake (kcal/day)3131Mean Difference (IV, Fixed, 95% CI)393.57 [224.66, 562.47]
2 Protein intake (g/day)281Mean Difference (IV, Fixed, 95% CI)23.35 [12.68, 34.01]
3 Body weight4233Mean Difference (IV, Fixed, 95% CI)-0.17 [-1.10, 0.75]
4 Fat mass measured in % of TBW4233Mean Difference (IV, Random, 95% CI)-1.14 [-2.58, 0.29]
5 Fat free mass3218Mean Difference (IV, Random, 95% CI)-0.37 [-2.77, 2.03]
6 CD4281Mean Difference (IV, Fixed, 95% CI)-114.48 [-233.20, 4.23]
7 Viral load (log10 copies/ml)166Mean Difference (IV, Fixed, 95% CI)-3.71 [-12.16, 4.74]
Analysis 1.1.

Comparison 1 Balanced macronutrient formulas plus nutrition counselling vs nutrition counselling in participants with weight loss, Outcome 1 Energy intake (kcal/day).

Analysis 1.2.

Comparison 1 Balanced macronutrient formulas plus nutrition counselling vs nutrition counselling in participants with weight loss, Outcome 2 Protein intake (g/day).

Analysis 1.3.

Comparison 1 Balanced macronutrient formulas plus nutrition counselling vs nutrition counselling in participants with weight loss, Outcome 3 Body weight.

Analysis 1.4.

Comparison 1 Balanced macronutrient formulas plus nutrition counselling vs nutrition counselling in participants with weight loss, Outcome 4 Fat mass measured in % of TBW.

Analysis 1.5.

Comparison 1 Balanced macronutrient formulas plus nutrition counselling vs nutrition counselling in participants with weight loss, Outcome 5 Fat free mass.

Analysis 1.6.

Comparison 1 Balanced macronutrient formulas plus nutrition counselling vs nutrition counselling in participants with weight loss, Outcome 6 CD4.

Analysis 1.7.

Comparison 1 Balanced macronutrient formulas plus nutrition counselling vs nutrition counselling in participants with weight loss, Outcome 7 Viral load (log10 copies/ml).

Comparison 2. Supplementary food plus nutrition counselling vs nutrition counselling in malnourished adults on ART and pre-ART
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Body weight1 Mean Difference (IV, Random, 95% CI)Subtotals only
1.1 ART arm: body weight at baseline1617Mean Difference (IV, Random, 95% CI)-0.58 [-1.47, 0.31]
1.2 pre-ART arm: body weight at baseline1429Mean Difference (IV, Random, 95% CI)0.60 [-0.60, 1.80]
1.3 ART arm: body weight at 1 month1366Mean Difference (IV, Random, 95% CI)0.58 [-0.62, 1.78]
1.4 pre-ART arm: body weight at 1 month1261Mean Difference (IV, Random, 95% CI)1.09 [-0.59, 2.77]
1.5 ART arm: body weight at 3 months1322Mean Difference (IV, Random, 95% CI)0.41 [-0.99, 1.81]
1.6 pre-ART arm: body weight at 3 months1211Mean Difference (IV, Random, 95% CI)2.82 [1.02, 4.62]
1.7 ART arm: body weight at 6 months1237Mean Difference (IV, Random, 95% CI)0.17 [-1.50, 1.84]
1.8 pre-ART arm: body weight at 6 months1157Mean Difference (IV, Random, 95% CI)3.67 [1.50, 5.84]
1.9 ART arm: body weight at 12 months1180Mean Difference (IV, Random, 95% CI)-1.0 [-3.19, 1.19]
1.10 pre-ART arm: body weight at 12 months1118Mean Difference (IV, Random, 95% CI)2.25 [-0.41, 4.91]
2 Change in body weight (kg)1 Mean Difference (IV, Random, 95% CI)Subtotals only
2.1 ART arm: change in body weight at 1 month1366Mean Difference (IV, Random, 95% CI)0.90 [0.40, 1.41]
2.2 pre-ART arm: change in body weight at 1 month1261Mean Difference (IV, Random, 95% CI)0.82 [0.28, 1.36]
2.3 ART arm: change in body weight at 3 months1322Mean Difference (IV, Random, 95% CI)1.12 [0.29, 1.95]
2.4 pre-ART arm: change in body weight at 3 months1211Mean Difference (IV, Random, 95% CI)1.22 [0.31, 2.12]
2.5 ART arm: change in body weight at 6 months1237Mean Difference (IV, Random, 95% CI)0.89 [-0.30, 2.08]
2.6 pre-ART arm: change in body weight at 6 months1157Mean Difference (IV, Random, 95% CI)2.06 [0.82, 3.30]
2.7 ART arm: change in body weight at 12 month1180Mean Difference (IV, Random, 95% CI)-0.03 [-1.78, 1.71]
2.8 pre-ART arm: change in body weight at 12 months1118Mean Difference (IV, Random, 95% CI)0.83 [-0.79, 2.45]
3 Body mass index (BMI)1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
3.1 ART arm: BMI at baseline1617Mean Difference (IV, Fixed, 95% CI)0.02 [-0.15, 0.19]
3.2 pre-ART arm: BMI at baseline1429Mean Difference (IV, Fixed, 95% CI)0.17 [-0.07, 0.41]
3.3 ART arm: BMI at 1 month1366Mean Difference (IV, Fixed, 95% CI)0.36 [0.08, 0.64]
3.4 pre-ART arm: BMI at 1 month1261Mean Difference (IV, Fixed, 95% CI)0.39 [0.05, 0.74]
3.5 ART arm: BMI at 3 months1322Mean Difference (IV, Fixed, 95% CI)0.43 [0.07, 0.79]
3.6 pre-ART arm: BMI at 3 months1211Mean Difference (IV, Fixed, 95% CI)0.73 [0.31, 1.15]
3.7 ART arm: BMI at 6 months1237Mean Difference (IV, Fixed, 95% CI)0.42 [-0.07, 0.91]
3.8 pre-ART arm: BMI at 6 months1157Mean Difference (IV, Fixed, 95% CI)0.78 [0.22, 1.34]
3.9 ART arm: BMI at 12 months1180Mean Difference (IV, Fixed, 95% CI)-0.08 [-0.72, 0.56]
3.10 pre-ART arm: BMI at 12 months1118Mean Difference (IV, Fixed, 95% CI)0.45 [-0.25, 1.15]
4 % lean body mass1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
4.1 ART arm: % lean body mass at baseline1569Mean Difference (IV, Fixed, 95% CI)0.13 [-0.96, 1.23]
4.2 pre-ART arm: % lean body mass at baseline1394Mean Difference (IV, Fixed, 95% CI)-0.30 [-1.51, 0.92]
4.3 ART arm: % lean body mass at 1 month1253Mean Difference (IV, Fixed, 95% CI)0.47 [-1.20, 2.13]
4.4 pre-ART arm: % lean body mass at 1 month1185Mean Difference (IV, Fixed, 95% CI)0.41 [-1.40, 2.22]
4.5 ART arm: % lean body mass at 3 months1283Mean Difference (IV, Fixed, 95% CI)-0.53 [-2.13, 1.07]
4.6 pre-ART arm: % lean body mass at 3 months1179Mean Difference (IV, Fixed, 95% CI)1.14 [-0.70, 2.98]
4.7 ART arm: % lean body mass at 6 months1202Mean Difference (IV, Fixed, 95% CI)0.32 [-1.48, 2.12]
4.8 pre-ART arm: % lean body mass at 6 months1129Mean Difference (IV, Fixed, 95% CI)1.65 [-0.79, 4.09]
4.9 ART arm: % lean body mass (kg) at 12 months1169Mean Difference (IV, Fixed, 95% CI)-1.53 [-3.55, 0.49]
4.10 pre-ART arm: % lean body mass (kg) at 12 months1107Mean Difference (IV, Fixed, 95% CI)0.67 [-1.82, 3.16]
Analysis 2.1.

Comparison 2 Supplementary food plus nutrition counselling vs nutrition counselling in malnourished adults on ART and pre-ART, Outcome 1 Body weight.

Analysis 2.2.

Comparison 2 Supplementary food plus nutrition counselling vs nutrition counselling in malnourished adults on ART and pre-ART, Outcome 2 Change in body weight (kg).

Analysis 2.3.

Comparison 2 Supplementary food plus nutrition counselling vs nutrition counselling in malnourished adults on ART and pre-ART, Outcome 3 Body mass index (BMI).

Analysis 2.4.

Comparison 2 Supplementary food plus nutrition counselling vs nutrition counselling in malnourished adults on ART and pre-ART, Outcome 4 % lean body mass.

Comparison 3. Arginine rich supplements versus nutritional placebo or arginine-free supplements
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Mean change in body weight baseline to 8 weeks143Mean Difference (IV, Fixed, 95% CI)2.63 [0.72, 4.54]
2 Change in fat mass measured in kg143Mean Difference (IV, Fixed, 95% CI)-0.64 [-2.69, 1.41]
3 Change in fat free mass143Mean Difference (IV, Random, 95% CI)3.25 [1.25, 5.25]
Analysis 3.1.

Comparison 3 Arginine rich supplements versus nutritional placebo or arginine-free supplements, Outcome 1 Mean change in body weight baseline to 8 weeks.

Analysis 3.2.

Comparison 3 Arginine rich supplements versus nutritional placebo or arginine-free supplements, Outcome 2 Change in fat mass measured in kg.

Analysis 3.3.

Comparison 3 Arginine rich supplements versus nutritional placebo or arginine-free supplements, Outcome 3 Change in fat free mass.

Comparison 4. Ornithine alpha-ketoglutarate (OKG) versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Mean daily energy intake at study endpoint146Mean Difference (IV, Random, 95% CI)-66.0 [-564.63, 432.63]
2 Mean daily protein intake in kcal at study endpoint143Mean Difference (IV, Random, 95% CI)-0.70 [-18.71, 17.31]
3 Mean fat mass in kg at study endpoint146Mean Difference (IV, Random, 95% CI)0.0 [-2.00, 2.00]
4 Mean weight in kg at study endpoint146Mean Difference (IV, Random, 95% CI)-5.0 [-11.68, 1.68]
5 Mean fat-free mass in kg at study endpoint146Mean Difference (IV, Random, 95% CI)-5.10 [-11.11, 0.91]
6 Mean CD4 count in cells/mm3 at study endpoint146Mean Difference (IV, Random, 95% CI)-28.0 [-134.93, 78.93]
7 Mean viral load in log10 at study endpoint146Mean Difference (IV, Random, 95% CI)0.20 [-0.58, 0.98]
8 Proportion with gastrointestinal event (at least one)146Risk Ratio (M-H, Random, 95% CI)1.59 [1.06, 2.39]
Analysis 4.1.

Comparison 4 Ornithine alpha-ketoglutarate (OKG) versus placebo, Outcome 1 Mean daily energy intake at study endpoint.

Analysis 4.2.

Comparison 4 Ornithine alpha-ketoglutarate (OKG) versus placebo, Outcome 2 Mean daily protein intake in kcal at study endpoint.

Analysis 4.3.

Comparison 4 Ornithine alpha-ketoglutarate (OKG) versus placebo, Outcome 3 Mean fat mass in kg at study endpoint.

Analysis 4.4.

Comparison 4 Ornithine alpha-ketoglutarate (OKG) versus placebo, Outcome 4 Mean weight in kg at study endpoint.

Analysis 4.5.

Comparison 4 Ornithine alpha-ketoglutarate (OKG) versus placebo, Outcome 5 Mean fat-free mass in kg at study endpoint.

Analysis 4.6.

Comparison 4 Ornithine alpha-ketoglutarate (OKG) versus placebo, Outcome 6 Mean CD4 count in cells/mm3 at study endpoint.

Analysis 4.7.

Comparison 4 Ornithine alpha-ketoglutarate (OKG) versus placebo, Outcome 7 Mean viral load in log10 at study endpoint.

Analysis 4.8.

Comparison 4 Ornithine alpha-ketoglutarate (OKG) versus placebo, Outcome 8 Proportion with gastrointestinal event (at least one).

Comparison 5. L-glutamine (GLN) versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Mean weight in kg at study endpoint121Mean Difference (IV, Random, 95% CI)-1.30 [-10.18, 7.58]
2 Mean fat mass in kg at study endpoint121Mean Difference (IV, Random, 95% CI)-1.0 [-32.40, 30.40]
3 Mean CD4 count in cells/mm3 at study endpoint121Mean Difference (IV, Random, 95% CI)66.0 [-53.39, 185.39]
Analysis 5.1.

Comparison 5 L-glutamine (GLN) versus placebo, Outcome 1 Mean weight in kg at study endpoint.

Analysis 5.2.

Comparison 5 L-glutamine (GLN) versus placebo, Outcome 2 Mean fat mass in kg at study endpoint.

Analysis 5.3.

Comparison 5 L-glutamine (GLN) versus placebo, Outcome 3 Mean CD4 count in cells/mm3 at study endpoint.

Comparison 6. Enhanced nutritional support vs std nutritional support in children
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Death at 8 weeks1169Odds Ratio (M-H, Random, 95% CI)1.42 [0.59, 3.40]
2 Death at 26 weeks1169Odds Ratio (M-H, Fixed, 95% CI)1.48 [0.74, 2.98]
Analysis 6.1.

Comparison 6 Enhanced nutritional support vs std nutritional support in children, Outcome 1 Death at 8 weeks.

Analysis 6.2.

Comparison 6 Enhanced nutritional support vs std nutritional support in children, Outcome 2 Death at 26 weeks.

Comparison 7. Spirulina versus traditional meals in children
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Weight for height z score (WHZ)184Mean Difference (IV, Fixed, 95% CI)0.35 [-0.21, 0.91]
2 Weight for age z score (WAZ)184Mean Difference (IV, Random, 95% CI)0.0 [-0.44, 0.44]
Analysis 7.1.

Comparison 7 Spirulina versus traditional meals in children, Outcome 1 Weight for height z score (WHZ).

Analysis 7.2.

Comparison 7 Spirulina versus traditional meals in children, Outcome 2 Weight for age z score (WAZ).

Appendices

Appendix 1. World Health Organization clinical staging of HIV/AIDS for adults and adolescents with confirmed HIV infection

Clinical StageSymptoms
Stage 1

Asymptomatic

Persistent generalized lymphadenopathy

Stage 2

Moderate unexplained weight loss

(<10% of presumed or measured body weight)I

Recurrent respiratory tract infections sinusitis, tonsillitis, otitis media and pharyngitis)

Herpes zoster

Angular cheilitis

Recurrent oral ulceration

Papular pruritic eruptions

Seborrhoeic dermatitis

Fungal nail infections

Stage 3

Unexplained severe weight loss (>10% of presumed or measured body weight)

Unexplained chronic diarrhoea for longer than one month

Unexplained persistent fever (above 37.6°C intermittent or constant,

for longer than one month)

Persistent oral candidiasis

Oral hairy leukoplakia

Pulmonary tuberculosis (current)

Severe bacterial infections (such as pneumonia, empyema, pyomyositis,

bone or joint infection, meningitis or bacteraemia)

Acute necrotizing ulcerative stomatitis, gingivitis or periodontitis

Unexplained anaemia (<8 g/dl), neutropaenia (<0.5 × 109 per litre)

or chronic thrombocytopaenia (<50 × 109 per litre)

Stage 4

HIV wasting syndrome

Pneumocystis pneumonia

Recurrent severe bacterial pneumonia

Chronic herpes simplex infection (orolabial, genital or anorectal

of more than one month’s duration or visceral at any site)

Oesophageal candidiasis (or candidiasis of trachea, bronchi or lungs)

Extrapulmonary tuberculosis

Kaposi’s sarcoma

Cytomegalovirus infection (retinitis or infection of other organs)

Central nervous system toxoplasmosis

HIV encephalopathy

Extrapulmonary cryptococcosis including meningitis

Disseminated non-tuberculous mycobacterial infection

Progressive multifocal leukoencephalopathy

Chronic cryptosporidiosis (with diarrhoel)

Chronic isosporiasis

Disseminated mycosis (coccidiomycosis or histoplasmosis)

Recurrent non-typhoidal Salmonella bacteraemia

Lymphoma (cerebral or B-cell non-Hodgkin) or other solid HIV-associated tumours

Invasive cervical carcinoma

Atypical disseminated leishmaniasis

Symptomatic HIV-associated nephropathy or symptomatic HIV-associated cardiomyopathy

Appendix 2. PubMed search strategy

SearchMost Recent QueriesTimeResult
#65Search #61 AND #62 AND #63 Limits: Publication Date from 2010/01/01 to 2011/08/2407:55:15265
#64Search #61 AND #62 AND #6307:54:402645
#63Search (randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]) NOT (animals [mh] NOT humans [mh])07:54:192433092
#62Search HIV Infections[MeSH] OR HIV[MeSH] OR hiv[tw] OR hiv-1*[tw] OR hiv-2*[tw] OR hiv1[tw] OR hiv2[tw] OR hiv infect*[tw] OR human immunodeficiency virus[tw] OR human immunedeficiency virus[tw] OR human immuno-deficiency virus[tw] OR human immune-deficiency virus[tw] OR ((human immun*) AND (deficiency virus[tw])) OR acquired immunodeficiency syndrome[tw] OR acquired immunedeficiency syndrome[tw] OR acquired immuno-deficiency syndrome[tw] OR acquired immune-deficiency syndrome[tw] OR ((acquired immun*) AND (deficiency syndrome[tw])) OR "Sexually Transmitted Diseases, Viral"[MeSH:NoExp]07:54:05276397
#61Search #52 OR #53 OR #54 OR #55 OR #56 OR #57 OR #58 OR #59 OR #6007:53:511458104
#60Search spirulina07:53:09918
#59Search diet supplementation OR dietary supplement OR dietary supplements OR dietary supplementation OR food supplements OR food supplementation OR supplemented food OR supplemented foods OR nutraceutical OR nutraceuticals OR neutraceutical OR neutraceuticals07:52:5759484
#58Search nutritional requirement OR nutritional requirements OR nutrition therapy OR nutrition supplement OR nutrition supplements OR nutritional supplement OR nutritional supplements OR nutritional supplementation OR nutritional support OR nutrient intervention OR nutrient interventions OR nutritional intervention OR nutritional interventions07:52:38213287
#57Search fortified food OR fortified foods OR enriched food OR enriched foods OR formulated food OR formulated foods07:52:2318692
#56Search energy intake OR caloric intake OR calorie intake OR dietary intake07:52:12101959
#55Search dietary fat OR dietary fats OR fatty acids OR oil OR oils07:51:58467123
#54Search dietary protein OR dietary proteins OR amino acids07:51:44837862
#53Search dietary carbohydrate OR dietary carbohydrates07:51:3529026
#52Search macronutrient OR macronutrients07:51:213907

Appendix 3. EMBASE search strategy

No.QueryResultsDate
#14 #10 AND #11 AND #12 AND [humans]/lim AND [embase]/lim AND [2010-2011]/py15226 Aug 2011
#13 #10 AND #11 AND #12109926 Aug 2011
#12 random*:ti OR random*:ab OR factorial*:ti OR factorial*:ab OR cross?over*:ti OR cross?over:ab OR crossover*:ti OR crossover*:ab OR placebo*:ti OR placebo*:ab OR (doubl*:ti AND blind*:ti) OR (doubl*:ab AND blind*:ab) OR (singl*:ti AND blind*:ti) OR (singl*:ab AND blind*:ab) OR assign*:ti OR assign*:ab OR volunteer*:ti OR volunteer*:ab OR 'crossover procedure'/de OR 'crossover procedure' OR 'double-blind procedure'/de OR 'double-blind procedure' OR 'single-blind procedure'/de OR 'single-blind procedure' OR 'randomized controlled trial'/de OR 'randomized controlled trial' OR allocat*:ti OR allocat*:ab112345226 Aug 2011
#11 'human immunodeficiency virus infection'/exp OR 'human immunodeficiency virus infection' OR 'human immunodeficiency virus'/exp OR 'human immunodeficiency virus' OR hiv:ti OR hiv:ab OR 'hiv-1':ti OR 'hiv-1':ab OR 'hiv-2':ti OR 'hiv-2':ab OR 'human immunodeficiency virus':ti OR 'human immunodeficiency virus':ab OR 'human immuno-deficiency virus':ti OR 'human immuno-deficiency virus':ab OR 'human immunedeficiency virus':ti OR 'human immunedeficiency virus':ab OR 'human immune-deficiency virus':ti OR 'human immune-deficiency virus':ab OR 'acquired immune-deficiency syndrome':ti OR 'acquired immune-deficiency syndrome':ab OR 'acquired immunedeficiency syndrome':ti OR 'acquired immunedeficiency syndrome':ab OR 'acquired immunodeficiency syndrome':ti OR 'acquired immunodeficiency syndrome':ab OR 'acquired immuno-deficiency syndrome':ti OR 'acquired immuno-deficiency syndrome':ab35678926 Aug 2011
#10 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #983328626 Aug 2011
#9 'spirulina'/syn130126 Aug 2011
#8 'dietary intake'/syn OR 'nutritional intake'/syn27953026 Aug 2011
#7 'caloric intake'/syn OR 'calorie intake'/syn OR 'calory intake'/syn OR 'dietary energy'/syn OR 'energy intake'/syn3805026 Aug 2011
#6 'fat intake'/syn OR 'alimentary fat'/syn OR 'diet fat'/syn OR 'diet fats'/syn OR 'dietary fat'/syn OR 'dietary fats'/syn OR 'dietary fatty acid'/syn OR 'dietary lipid'/syn OR 'fat consumption'/syn OR 'fatty acid intake'/syn OR 'lipid intake'/syn OR 'nutrition, fat'/syn OR 'fatty acids'/syn OR 'edible oil'/syn OR 'dietary fats, unsaturated'/syn OR 'dietary oil'/syn49627126 Aug 2011
#5 'carbohydrate intake'/syn OR 'alimentary carbohydrate'/syn OR 'carbohydrate, dietary'/syn OR 'diet carbohydrate'/syn OR 'saccharide intake'/syn1179926 Aug 2011
#4 'protein intake'/syn OR 'diet protein'/syn OR 'dietary protein'/syn OR 'dietary proteins'/syn OR 'egg proteins, dietary'/syn OR 'food protein'/syn OR 'protein consumption'/syn OR 'protein feeding'/syn OR 'protein food'/syn OR 'protein nutrition'/syn3310626 Aug 2011
#3 'nutrition therapy'/syn OR 'nutritional support'/syn OR 'nutritional requirement'/syn OR 'nutritional requirements'/syn OR 'nutrition supplement' OR 'nutrition supplements' OR 'nutritional supplement' OR 'nutritional supplements' OR 'nutritional supplementation'/syn OR 'nutrient intervention' OR 'nutrient interventions' OR 'nutritional intervention' OR 'nutritional interventions'21081726 Aug 2011
#2 'diet therapy'/syn OR 'diet supplementation'/syn OR 'diet additive'/syn OR 'diet supplement'/syn OR 'dietary supplement'/syn OR 'dietary supplementation'/syn OR 'dietary supplements'/syn OR 'food supplement'/syn OR 'food supplementation' OR 'food, fortified'/syn OR 'supplementary diet'/syn19344326 Aug 2011
#1 'macronutrient'/syn OR macronutrients529526 Aug 2011

Appendix 4. Cochrane Library search strategy

IDSearchHits
#1macronutrient OR macronutrients541
#2MeSH descriptor Dietary Carbohydrates explode all trees2144
#3dietary carbohydrate*:ti,ab,kw3093
#4(#2 OR #3)3200
#5MeSH descriptor Dietary Proteins explode all trees2061
#6dietary protein:ti,ab,kw OR dietary proteins:ti,ab,kw OR amino acids:ti,ab,kw7873
#7(#5 OR #6)8256
#8MeSH descriptor Dietary Fats explode all trees4473
#9dietary fat:ti,ab,kw OR dietary fats:ti,ab,kw OR fatty acids:ti,ab,kw OR oil:ti,ab,kw OR oils:ti,ab,kw13215
#10(#8 OR #9)13414
#11MeSH descriptor Energy Intake explode all trees2763
#12energy intake:ti,ab,kw OR caloric intake:ti,ab,kw OR calorie intake:ti,ab,kw OR dietary intake:ti,ab,kw9441
#13(#11 OR #12)9569
#14MeSH descriptor Food, Fortified explode all trees976
#15fortified food:ti,ab,kw OR fortified foods:ti,ab,kw OR enriched food:ti,ab,kw OR enriched foods:tiab,kw OR formulated food:ti,ab,kw OR formulated foods:ti,ab,kw1983
#16(#14 OR #15)2010
#17MeSH descriptor Nutritional Requirements explode all trees442
#18nutritional requirement:ti,ab,kw OR nutritional requirements:ti,ab,kw OR nutrition therapy:ti,ab,kw OR nutrition supplement:ti,ab,kw OR nutrition supplements:ti,ab,kw OR nutritional supplement:ti,ab,kw OR nutritional supplements:ti,ab,kw OR nutritional supplementation:ti,ab,kw OR nutritional support:ti,ab,kw OR nutrient intervention:ti,ab,kw OR nutrient interventions:ti,ab,kw OR nutritional intervention:ti,ab,kw OR nutritional interventions:ti,ab,kw12338
#19(#17 OR #18)12338
#20MeSH descriptor Dietary Supplements explode all trees4943
#21diet supplementation:ti,ab,kw OR dietary supplement:ti,ab,kw OR dietary supplements:ti,ab,kw OR dietary supplementation:ti,ab,kw OR food supplements:ti,ab,kw OR food supplementation:ti,ab,kw OR supplemented food:ti,ab,kw OR supplemented foods:ti,ab,kw OR nutraceutical:ti,ab,kw OR nutraceuticals:ti,ab,kw OR neutraceutical:ti,ab,kw OR neutraceuticals:ti,ab,kw8781
#22(#20 OR #21)9482
#23MeSH descriptor Spirulina explode all trees17
#24spirulina:ti,ab,kw28
#25(#23 OR #24)28
#26(#1 OR #4 OR #7 OR #10 OR #13 OR #16 OR #19 OR #22 OR #25)34902
#27MeSH descriptor HIV Infections explode all trees6278
#28MeSH descriptor HIV explode all trees2113
#29hiv or hiv-1* or hiv-2* or hiv1 or hiv2 or hiv infect* or human immunodeficiency virus or human immunedeficiency virus or human immune-deficiency virus or human immuno-deficiency virus or human immun* deficiency virus or acquired immunodeficiency syndrome or acquired immunedeficiency syndrome or acquired immuno-deficiency syndrome or acquired immune-deficiency syndrome or acquired immun* deficiency syndrome10007
#30MeSH descriptor Lymphoma, AIDS-Related, this term only21
#31MeSH descriptor Sexually Transmitted Diseases, Viral, this term only19
#32(#27 OR #28 OR #29 OR #30 OR #31)10081
#33(#26 AND #32)545
#34(#26 AND #32), from 2010 to 201142

What's new

DateEventDescription
27 February 2013AmendedFixed affiliation.

History

Protocol first published: Issue 4, 2003
Review first published: Issue 3, 2007

DateEventDescription
30 January 2013New citation required but conclusions have not changedNew comprehensive searches and updated review.
30 January 2013New search has been performedUpdated
2 June 2012New search has been performedThe review was updated
29 October 2008AmendedConverted to new review format.

Contributions of authors

SM developed the protocol for this review with the help of MVIS and JV. LG assisted SM and MVIS with data extraction and went on to complete the analysis and the write up of the final review. SM, MVIS and JV assisted in editing the final review. SM, LG and NS screened trials for inclusion in the review. LG and NS conducted the data extraction, analysis and write up of the updated review. JV, MVIS and SM assisted with editing the final version of the updated review.

Declarations of interest

We declare that we have no affiliation with or involvement in any organisation or entity with a direct financial interest in the subject matter of review (e.g. employment, consultancy, stock ownership, honoraria, or expert testimony).

Sources of support

Internal sources

  • UNIVERSITY OF NATAL, DURBAN, South Africa.

External sources

  • SOUTH AFRICAN COCHRANE CENTER, South Africa.

  • COCHRANE HEALTH PROMOTION AND PUBLIC HEALTH FIELD, Australia.

  • WHO Nutrition for Health and Development Department, Switzerland.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Berneis 2000

Methods

COUNTRY:

Switzerland

SETTING:

Outpatient clinic at the University Hospital, Basel,

DURATION OF RECRUITMENT:

1995 - 1997

DURATION OF TRIAL:

Took place over two years but no months reported.

FOLLOW-UP:

At baseline and twice weekly in first month, and monthly thereafter, participants were examined by study physician.

All patients were monitored by dietician weekly for the first four weeks and then every two weeks thereafter.

Monthly food records were completed by participants during three consecutive days.

At baseline and after 12 weeks, whole body leucine kinetics and bioelectrical impedance analysis was conducted.

Quality of life questionnaires were completed monthly.

Participants

INCLUSION CRITERIA:

  • HIV-infected

  • Weight loss of 5% or more in the past 6 months OR body mass index of less than 21 kg/m2 OR CD4 T-cell count of less than 500/mm-3

  • May be on antiretroviral therapy

EXCLUSION CRITERIA:

  • No acute infectious complications

Participants randomised: 18

Mean age at baseline is not reported.

Stage of HIV (CDC guidelines): Experimental group: A = 2, B = 1, C = 5; Control Group: A = 2, B = 2, C = 3.

Mean baseline CD4 count: Experimental group: 161± 149.9cells/mm3: Control group: 244 ± 227.5

Baseline viral load was not measured nor was baseline nutritional status. The report states that baseline concentrations of all parameters were not different between the two groups.

Number on antiretroviral therapy: 8 (2 in the experimental group and 6 in the control group).

Interventions

INTERVENTION:

Liquid supplement containing 2510kJ [Meritene Y® (Novartis Nutrition, Berne, Switzerland):

  • 26g whey protein (17%)

  • 88g carbohydrates (59%)

  • 17g fat as corn oil (26%)

  • Electrolytes trace elements and vitamins

The supplement was taken daily for 12 weeks PLUS nutritional counselling by dietician as for CONTROL group.

CONTROL:

Monitoring by a dietician included weekly nutritional counselling for first four weeks and then every two weeks for remainder of study. Counseling by dietician involved teaching the principles of a balanced nutrition and discussion of individual problems relating to nutrition (e.g. diarrhoea, nausea, weight loss) and the aspects of hygiene.

DURATION:

Twelve weeks
COMPLIANCE:

Nutrient intake was assessed once a month using a 3-day dietary recall questionnaire (3 consecutive days, 2 week days and one weekend day).

ADHERENCE:

Adherence to treatment was monitored during visits to the research dietician.

CO-INTERVENTIONS:

Nil

Outcomes

PRIMARY OUTCOME:

Not clearly reported.

  • Mean change in leucine oxidation from baseline to week 12 reported prominenty.

SECONDARY OUTCOMES:

  • Mean change in body composition from baseline to week 12 measured via Body impedance Analysis

  • Mean change in body weight from baseline to week 12

  • Mean change in Lean mass from baseline to week 12

  • Mean change in Fat mass from baseline to week 12

  • Mean change in Lymphocyte counts (CD3, CD4, CD8) from baseline to week 12

  • Mean change in Serum albumin, ALAT and ASAT from baseline to week 12

  • Mean change in Plasma TNFa receptors (p55, p75) and interleukin 2 receptors from baseline to week 12

  • Mean change in Plasma concentration of insulin, glucagons, globulin and NEFAs from baseline to week 12

  • Change in energy intake measured by 24 hour food records from baseline to week 12

  • Change in resting energy expenditure from baseline to week 12

  • Quality of life (visual digital analog scale) from baseline to week 12

ADVERSE EFFECTS:

Not reported

Notes

Information requested from the author and response received on 12/04/2006.

ETHICS:

Ethics approval received from Human Ethics Committee of the Department of Internal Medicine, University Hospital, Basel, Switzerland. Written informed consent received from all participants.

FUNDING:
Swiss Federal Office grant, Novartis Nutrition and the Swiss National Science Foundation

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of generation not reported.
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding of participants and personnel as no placebo given to those in the control group.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding not reported for assessors.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAttrition was 16.7% (3/18) overall. Insufficient information provided to ascertain which group those lost to follow-up were allocated to.
Selective reporting (reporting bias)Unclear riskProtocol not obtained.

Clark 2000

Methods

COUNTRY:

USA

SETTING:

Participants were recruited from the Nassau County Medical Center's HIV outpatient clinic

DURATION OF RECRUITMENT:

No dates reported

DURATION OF TRIAL:

No dates or durations reported.

FOLLOW-UP:

At enrolment, participants completed a questionnaire on demographics, details of HIV infection, past medical history and family history.

At enrolment and on a weekly basis, participants completed a questionnaire on adverse effects, and a psychological profile.

Body weights and anthropometry were recorded weekly.

At baseline, and weeks 2, 4, 6, and 8, blood sampling was performed for blood chemistry, liver function tests, lipid and haematologic parameters.

At baseline and after 8 weeks additional bloods were sampled for CD4 counts and viral load.

Participants

INCLUSION CRITERIA:

  • HIV-infected men and adult women, age cut-off assumed to be > 18

  • Unintentional weight loss of 5% or more in the past 3 months

  • On antiretroviral (ARV) therapy

EXCLUSION CRITERIA:

  • Diabetes mellitus

  • Cardiac disease

  • Renal disease

  • Liver disease

  • Recent change in ARV treatment

  • No acute infectious complications

  • Active opportunistic infections

Participants randomised: 68

Mean age at baseline: 39.5 +/- SEM 1.2 years (intervention group); 40.0 +/- SEM: 1.1 years (control group)

Sex at baseline: Overall 14/68 (20.6%) were women, but data not provided per treatment group.

Mean CD4 count at baseline: 333.2 =/- SEM 52.0 cells/mm3 (intervention group); 405.4 +/- SEM 63.6 cells/mm3 (control group)

All participants in WHO Stage 3 (WHO 2007) and on antiretroviral therapy.

Baseline viral load (copies/ml): Experimental group: 3.7 ± SEM1.2; Control group: 3.3 ± SEM1.1

Four participants on specific anabolic protocol were included and instructed to maintain the anabolic protocol throughout the study period. Not clear which group these participants were allocated to.

No statistical differences between groups were found at baseline.

Interventions

INTERVENTION:

Amino acid mixture of 200cal/day containing:

  • 14g arginine (free base)

  • 14g glutamine

  • 3g ß-hydroxy-ß-methylbutyrate (HMB, calcium salt)

  • Citric acid (ph 4.5)

The supplementation was in powder form and mixed with 8 ounces of fruit juice and taken in two equal doses daily for 8 weeks.

CONTROL:

Mixture of 200cal/day containing:

  • Bulk maltodextrin

  • Citric acid (ph 4.5)

The supplementation was prepared in the same manner as for the intervention: in powder form and mixed with 8 ounces of fruit juice and taken in two equal doses daily for 8 weeks.

COMPLIANCE:

Compliance monitored by self-reporting, estimating concentration of HMB in blood samples from samples taken at 0, 4 and 9 weeks and random urine samples taken at 0, 2, 4, 6, and 8 weeks. Non-compliance was defined as a participant having greater than 50% of samples lacking elevated HMB levels. Three were deemed to be non-compliant and were dropped from the study.

Outcomes

PRIMARY OUTCOMES:

Not clearly stated, assume body weight

  • Mean change in body weight from baseline to 8 weeks

SECONDARY OUTCOMES:

  • Mean change in body composition from baseline to 8 weeks

  • Mean change in Circumference of forearm, upper arm and thigh from baseline to 8 weeks

  • Mean change in Lean mass from baseline to 8 weeks

  • Mean change in Fat mass (skinfold thickness & air displacement plethysmography) from baseline to 8 weeks

  • Mean change in Leg muscle and fat composition (CT scan of thigh) from baseline to 8 weeks

  • Mean change in blood chemistry·

    • Liver function tests

    • Blood lipids

    • Haematological tests

  • Mean change in CD4 cell count from baseline to 8 weeks

  • Mean change in Viral load from baseline to 8 weeks

ADVERSE EFFECTS:

Not explicitly reported but article notes that the mixture was well-tolerated, no data provided.

Notes

ETHICS

Ethics approval received from Nassau County Medical Center Institutional Review Board. Participants provided written informed consent.

FUNDING:

Study supported partly by grant from Metabolic Technologies, Inc, Ames, Iowa.

AUTHOR INFORMATION:

Information requested from the author and response received on 14/04/2006

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated random numbers
Allocation concealment (selection bias)Unclear riskNot clearly reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskPlacebo used and none of the participants nor personnel were aware of the assignments
Blinding of outcome assessment (detection bias)
All outcomes
Low riskPrimary outcome not clearly reported but assuming it was body weight then assessors were blinded as personnel were clearly reported to be unaware of the group assignment. Additional information obtained from authors confirmed this.
Incomplete outcome data (attrition bias)
All outcomes
High riskAttrition was high. Exclusions: Overall - 36.7% (25/68); Experimental group - 35.3% (12/34); control group - 38.2% (13/34).
Selective reporting (reporting bias)Unclear riskProtoco not obtained

de Luis 2003

Methods

COUNTRY:

Not clearly stated but authors are based in Spain.

SETTING:

Appears to be out-patient clinic but not stated.

DURATION OF RECRUITMENT:

Not reported

DURATION OF TRIAL:

Not reported.

FOLLOW-UP:

At baseline and after three months of treatment, a biochemical and anthropometric evaluation was done, as well as a nutritional survey of 24 hours.

At baseline and after three months, blood samples were taken to assess biochemical markers, haematology and CD4 count and viral load.

Participants

INCLUSION CRITERIA:

  • HIV-infected males and females

  • 20-60 years old

  • Weight loss > 5% body weight in the past 6 months

  • On ART for one year prior to study

EXCLUSION CRITERIA:

  • Absence of chronic febrile process

  • Diarrhoea for 30 days or more with 3 incidences per day

  • Drug consumption that would affect nutritional intake and normal renal and hepatic function.

Participants randomised: 70

Mean age at baseline: 37.5 ± 11 years (experimental group) and 39.9±9 years (control group)

Sex at baseline: 71.4% men in experimental group; 82.8% men in control group

Mean weight at baseline: 67.3 +/- 8.2kg (experimental group); 70.9 +/- 11.1kg (control group)

Mean CD4 count at baseline: 431 +/- 254 cells/microL (experimental group); 621 +/- 288 (control group)

At baseline 42.9% of experimental group were CDC Stage A-B; 45.7% of control group were CD Stage A-B

Mean viral load at baseline: 5.839 +/- 17.817 copies/ml (experimental); 13.733 +/- 40.109 copies/ml (control group)

No baseline differences were reported as statistically significant.

Interventions

INTERVENTION:

Oral supplement [standard enteric formula, ENSURE®,] containing 3329kJ comprising:

  • 37.2g/l protein

  • 37.2g/l fat

  • 145g/l carbohydrate

  • Recommended Daily Allowance (RDA) of vitamins and minerals (from product web site)

Three bottles of 250ml each were taken daily for 12 weeks.

In addition to supplement, nutritional education by dietician was given as for the control group.

CONTROL:

Nutritional education by dietician consisting of dietary guidelines on how to achieved normocaloric and normoproteic intake relative to body weight. Duration of education not reported.

DURATION:

Twelve weeks.

COMPLIANCE:
Nutrient intake was assessed by a dietician using 24hour recall and portion models to increase accuracy of recall. Bottle counts were also conducted and these demonstrated adherence of more than 90%.

Outcomes

PRIMARY OUTCOME:

Not clearly stated.

  • Mean change in weight and caloric intake from baseline to 12 weeks reported prominently.

SECONDARY OUTCOME:

  • Mean change in %Fat mass (measured by Bio-equivalence Impedance Analysis (BIA)) from baseline to 12 weeks

  • Mean change in %Fat free mass (BIA) from baseline to 12 weeks

  • Mean change in triceps skinfold ·

  • Mean change in Muscular circumference of upper arm

  • Change in Protein intake

  • Change in lbumin/pre-albumin

  • Mean change in CD4 count from baseline to 12 weeks

  • Mean change in viral load from baseline to 12 weeks

ADVERSE EVENTS:

Not reported.

Notes

ETHICS:

No details provided. All participants gave informed consent to participate in the study.

FUNDING:
Not reported

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of randomisation not reported
Allocation concealment (selection bias)Unclear riskNot reported.
Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants and personnel administering were not blinded. This is clearly stated
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskPrimary outcome of weight gain unlikely to have been blinded but not clearly reported
Incomplete outcome data (attrition bias)
All outcomes
Low riskExclusions: None, although 4 participants (2 from each group) failed to complete treatment. Intention to treat analysis was conducted
Selective reporting (reporting bias)Unclear riskProtocol not obtained.

FANTA-KEMRI study 2011

Methods

COUNTRY:

Kenya

SETTING:

Six health facilities in Kenya where comprehensive care clinics (CCCs) provide care and treatment services to PLHIV

DURATION OF RECRUITMENT:

Aug 2006 commenced

DURATION OF TRIAL:

Aug 2006 - Jun 2008

FOLLOW UP

Nutrition outcomes assessed monthly

Clinical outcomes assessed at baseline, 3, 6, 12 months

Participants

The trial was stratified according to receipt of ART

ART arm inclusion criteria (Clients must meet all criteria below to be included in the study.)

  1. HIV-infected

  2. Initiating ART within 5 weeks of recruitment.  In Kenya at the time of the study, clients who were in WHO stage IV of the disease or who had CD4 counts < 200 cells/μl were eligible for ART.

  3. BMI < 18.5 kg/m2

  4. Resident within the area for at least 6 months and not likely to move out

ART arm exclusion criteria (Clients who meet any of the exclusion criteria were excluded from the study.)

  1. HIV-negative or status not confirmed

  2. BMI ≥ 18.5 kg/m2

  3. Pregnant or lactating women

  4. Women who became pregnant during the period of participation in the study

  5. Already receiving another food supplement

  6. BMI < 14.0 kg/m2

Pre-ART arm inclusion criteria (Clients must meet all criteria below to be included in the study.)

  1. HIV-infected

  2. CD4 count between 200-500 cells/ml

  3. Do not qualify for ART

  4. Beginning cotrimoxazole prophylaxis or have begun cotrimoxazole prophylaxis within the past 4 months

  5. BMI < 18.5 kg/m2  or BMI 18.5-20 kg/m2 with weight loss in the past month

  6. Resident within the area for at least 6 months and not likely to move ou

Pre-ART arm exclusion criteria (Clients who meet any exclusion criteria were excluded from the study.)

  1. HIV-negative or status not confirmed

  2. BMI ≥ 20 kg/m

  3. BMI 18.5-20 kg/m2 with no weight loss in the past month

  4. Pregnant or lactating women

  5. Women who became pregnant during the period of participation in the study

  6. Already receiving another food supplement

  7. BMI < 14.0 kg/m2

Number randomised: 1057

Mean age at baseline: ART food: 36±8.9; ART no food: 36±8.3; Pre-ART food: 34±8.7; Pre-ART no food:33±8.2

Sex at baseline: ART food: 58% females; ART no food: 55% females; Pre-ART food: 60% females; Pre-ART no food:58% females

Mean BMI (kg.m-2)at baseline:ART food: 17±1.1; ART no food: 16.9±1.1; Pre-ART food: 18.5±1.3; Pre-ART no food:18.3±1.2

Mean CD4 (cells/µl) at baseline:ART food:123±113 ; ART no food: 115±131; Pre-ART food: 274±215; Pre-ART no food:290±225

Interventions

INTERVENTION:

300 g/day of fortified blended food (FBF) for 6 months; and nutrition counselling for 12 months.

The food product used in this study was produced by Insta Products Ltd, based at the Export Processing Zone in Athi River, Kenya. The product is Insta Foundation Plus with whey protein concentrate (WPC) added; it is a blend of maize, soya, vegetable oil, sugar, whey protein concentrate, and micronutrient pre-mix providing:

  • 1320 kcal/day energy

  • 48 g/day protein

CONTROL:

Nutritional counselling alone for 12 months

ADHERENCE:

Method of assessing adherence was not described

Outcomes

Nutrition outcomes: 

  • BMI

  • Lean body mass (LBM) measured by bioelectrical impedance analysis (BIA)

  • Mid-upper arm circumference (MUAC)

  • Haemoglobin

  • Serum albumin

Clinical outcomes:

  • CD4 counts and CD8 counts

  • Quality of Life

  • Attrition

  • Adherence to ART regimen (for subjects in the ART arm)

  • Survival

  • Number of severe clinical events (defined as the sum of hospitalizations and deaths)

  • Number of non-severe clinical events (defined as the number of new opportunistic infections and new symptoms for which medication is required)

  • C-reactive protein (CRP)

  • Erythrocyte supplementation rate (ESR)

Notes

ETHICS:

Study approved by institutional review boards in Kenya and in the US, the Kenyan Research Ethics Committee and the Human Subjects Committee at Washington University in St. Louis.  All Government of Kenya guidelines and norms for research were followed, and the research team coordinated with Kenya National AIDS and STI Control Programme (NASCOP) to ensure research activities were consistent with the Government’s HIV/AIDS strategy.

FUNDING:

Primary funding provided by the United States Agency for International Development Mission in Kenya (USAID/Kenya), with additional funding from the USAID Office of HIV/AIDS in the Bureau for Global Health. Financial assistance also received from Food and Nutrition Technical Assistance (FANTA) Project at the Academy for Educational Development (AED)

Trial has been completed and trial report shared by Dr Tony Castleman: final report is awaited

TRIAL REGISTRATION:

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComplete random block design utilized in the allocation of subjects to the two treatment interventions. Clients from each arm were recruited into blocks of 10 clients each (5 on nutrition counselling alone and 5 on nutrition counselling and food supplements). 
Allocation concealment (selection bias)Low riskA random numbered assignment of 10 numbers was generated, and after completing the informed consent process each patient collected a card number in an opaque sealed envelope, which was matched to one of the two treatments. The subject then presented the card at an adjacent room, where subjects were provided nutrition counselling and – for those in the supplementation group – fortified blended food.        
Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants and personnel were not blinded
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding is not reported for outcome assessors
Incomplete outcome data (attrition bias)
All outcomes
High riskAttrition (defined as discontinuation of care and treatment at the health facility for any reason, including death, loss-to-follow-up, or relocation) rate highest during first month of study: 26% ART arm and 24% pre-ART arm.  Third month of follow-up: ART food: 37% and ART no food: 39% Pre-ART food: 37% and Pre-ART no food: 48% attrition. The difference in attrition between the food and no-food groups in the pre-ART arm was significant (p=.039), and the difference between the groups in the ART arm was not significant.  
Selective reporting (reporting bias)Unclear riskProtocol not obtained

Karsegard 2004

Methods

COUNTRY:

Switzerland

SETTING:

Outpatient AIDS clinic at Geneva University Hospital

DURATION OF RECRUITMENT:

Not clearly reported. Recruitment took place between 1995 to 1997

DURATION OF TRIAL:

1995 - 1997.

FOLLOW-UP:

Participants were seen at baseline, and every 4 weeks for 12 weeks.

At baseline, medical history and assessment of thyroid and hepatic function was conducted.

At baseline, week 8 and week 12, immune parameters assessed.

At baseline, weeks 4, 8 and 12, visceral proteins were measured.

At baseline and at each study visit, oral intake, nutritional status, physical activity, muscle strength and gastro-intestinal tolerance.

Weight and height was measured at each visit.

Participants

INCLUSION CRITERIA:

  • HIV+ outpatients >18 years

  • Involuntary weight loss > 5-15% of usual weight from beginning of HIV infection

  • CD4 count>150cells/mm3

  • Body fat mass > 5% of body weight (by Bioequivalent Impedance Analysis)

  • Regular food intake

  • Ability to answer questions routinely asked at the AIDS clinic.

EXCLUSION CRITERIA:

  • Long term conditions other than HIV known to influence nutritional status (small bowel resection, inflammatory bowel disease, insulin dependent diabetes, renal or hepatic failure, known hypo- or hyperthyroidism)

  • Pregnancy or breast-feeding

  • Diseases impeding muscle function test

  • Change in antiretroviral therapy within one month before inclusion.

  • During course of study additional exclusion criteria:

    • Code disclosure

    • Patient auto-withdrawal

    • Non-authorised concomitant treatment

    • Medical complications requiring hospitalisation.

Participants randomised: 46

Mean age at baseline: 32.4±5.2 years (experimental group) and 34.9±5.2 years (control group)

Sex at baseline: 11/22 (50%) women in intervention group; 7/24 (29%) women in control group

Stage of HIV/AIDS: All participants were stage C.

Mean CD4 count at baseline (cells/mm3): Experimental group: 338±172; Control group: 310 ± 136

Mean viral load at baseline (copies/ml): Experimental group: 3.6 ± 1.3; Control group: 3.5± 1.3

Mean nutritional status (BMI) at baseline: Experimental group: 20.0 ± 2.4; Control group: 20.6± 3.0

Antiretroviral therapy: 8 control and 5 experimental participants were not on any treatment (33/46 were on some form of treatment).

Interventions

INTERVENTION:

Monohydrated L-Ornithine alpha-ketoglutarate (OKG) 10g daily comprising

  • 1.3g of nitrogen

CONTROL:
Isonitrogenous formula with same flavour comprising

  • 9.1g derived milk proteins

The intervention and control supplements were delivered in identically-locking and numbered packages

DURATION:

Twelve weeks

CO-INTERVENTIONS:

Nutritional counselling by a dietician. Nutritional counselling consisted of personalized dietary advice on how to gain weight based on 3-day (2 week days and 1 weekend day) dietary records.

ADHERENCE:

Adherence was assessed by counting doses not taken in the returned packages at each follow-up visit

Outcomes

PRIMARY OUTCOMES:

Not clearly reported. Body weight and BMI reported prominently.

  • Mean change in body weight from baseline to 12 weeks

  • Mean change in BMI from baseline to 12 weeks

SECONDARY OUTCOMES:

  • Mean change in body weight from baseline to 4 weeks and 8 weeks

  • Mean change in BMI from baseline to 4 weeks and 8 weeks

  • Mean change in fat free mass from baseline to 4, 8 and 12 weeks

  • Mean change in fat mass from baseline to 4, 8 and 12 weeks

  • Mean change in Triceps skin fold from baseline to 4, 8 and 12 weeks

  • Mean change in Circumference of arm muscle from baseline to 4, 8 and 12 weeks

  • Mean change in B2 microglobulin from baseline to 4, 8 and 12 weeks

  • Mean change in CD4 count from baseline to 4, 8 and 12 weeks

  • Mean change in Viral load 4, 8 and 12 weeks from baseline to 4, 8 and 12 weeks

  • Mean change in grip strength (dynamometer) from baseline to 4, 8 and 12 weeks

  • Mean change in endurance test (Queen's college step test) from baseline to 4, 8 and 12 weeks

  • Mean change in physical activity (pedometer over 48 hours) from baseline to 4, 8 and 12 weeks

  • Mean change in dietary intake (energy and protein) from baseline to 4, 8 and 12 weeks

  • Change in appetite (visual analogue scale) from baseline to 4, 8 and 12 weeks

ADVERSE EVENTS:

Frequency of adverse events reported.

  • Gastro-intestinal and food tolerance (visual analogue scale)

Notes

ETHICS:

Ethics approval received from the ethics committee of Geneva University Hospital and all participants gave their written informed consent.

FUNDING:

Financial support received from Chiesi Laboratories, SA, France and Fondation Nutrition 2000 Plus

AUTHOR CONTACT:

Information requested from the author and response received on 23/05/2006.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskStated in blocks of 10 patients but methods not reported
Allocation concealment (selection bias)Unclear riskNot clearly reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe intervention and control supplements were provided in identical-looking and numbered packages
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskOne investigator performed the clinical tests but not stated if blinded
Incomplete outcome data (attrition bias)
All outcomes
High riskAttrition was high and differentially distributed between groups. Attrition in experimental group was 50% (11/22) and in control group it was 25% (6/24)
Selective reporting (reporting bias)Unclear riskProtocol not obtained

Keithley 2002

Methods

COUNTRY:

USA

SETTING:

Participants were outpatients attending 3 inner-city outpatients HIV/AIDS clinics

DURATION OF RECRUITMENT:

Not stated

DURATION OF TRIAL:

June 1995 - January 1999. Follow-up was one year.

FOLLOW-UP:

At baseline and at each study visit (3, 6, 9 and 12 months), nutrition, immune and feasibility outcomes were measured and socio-demographic data were collected or updated.

Participants received monthly follow-up calls to ascertain problems and promote adherence.

At baseline, height and frame size determined.

At each visit, measurements of nutritional status obtained and dietary intake was measured using computer analysis of the Health Habits and History Questionnaire.

Participants

INCLUSION CRITERIA:

  • HIV-infected Adults 18-65 years

  • CD4 count of 275-550 cells/mm3 within prior two months

  • At least one month of ARV treatment

  • Willingness to participate and ability to adequately respond to interview questions in English or Sspanish

EXCLUSION CRITERIA:

  • Chronic conditions known to influence nutrient status

  • Symptomatic or had AIDS-defining conditions

  • Pregnant or breast-feeding

  • Regular use of oral formulas

  • Substantial elevation of hepatic aminotransferases (>= 2 times upper limit of normal)

Participants randomised: 90

Mean age at baseline: 37± SD 7 years (Ensure), 37 ± SD 9 years (Advera) and 41± SD 10 years (control group)

Sex at baseline: 54% men in Ensure group; 38% men in Advera group; 47% men in control group

Stage of HIV/AIDS at baseline: All participants were asymptomatic.

Mean baseline CD4 count (cells/mm3): Ensure group: 448 ± SD 169; Advera group: 430 ± SD 110; Control group: 404 ± SD 124

Baseline viral load (copies/ml): Not measured

Mean baseline nutritional status (BMI): Ensure group: 24 ± SD 4, Advera group: 25 ± SD 5; Control group: 26 ± SD 6

Interventions

INTERVENTION 1:

Ensure Plus oral formula, 8 ounce can of 355 calories comprising:

  • 13g (14.7%) protein

  • 12.6g (32%) fat

  • 47.3g (53.3%) carbohydrates

  • Immune-enhancing nutrients:

    • 507mg arginine

    • 2756 glutamine

    • 156mg omega-3 fatty acids

    • 834 IU Vitamin A

    • 7.5IU Vitamin E

    • 50mg Vitamin C

Participants instructed to drink one can formula daily if ideal body weight (IBW) at baseline was >= 95% or two cans daily if IBW < 95%. Duration of treatment was one year

Nutritional counselling was given by a dietician as for the CONTROL group.

INTERVENTION 2:

Advera oral formula 8 ounce can of 303 calories comprising:

  • 14.2g (18.7%) protein

  • 5.4g (15.8%) fat

  • 51.2g (65.5%) carbohydrates

  • Immune-enhancing nutrients:

    • 966mg arginine

    • 3039mg glutamine

    • 467mg omega-3 fatty acids

    • 960 IU Vitamin A

    • 9IU Vitamin E

    • 90mg Vitamin C

    • 1590 IU beta-carotene

Participants instructed to drink one can formula daily if ideal body weight (IBW) at baseline was >= 95% or two cans daily if IBW < 95%. Duration of treatment was one year

Nutritional counselling was given by a dietician as for the CONTROL group.

CONTROL

Nutritional counselling by a dietician, consisting of standardised verbal and written instructions related to the nutritional implications of HIV/AIDS and the importance of maintaining body weight and eating nutritious foods.

ADHERENCE

Adherence was measured three-monthly and assessed by counting returned pop tops from cans, recorded formula intake in a daily diary and self reported formula use over the past week.

More than 80% of the participants took at least 75% of the amount of formula recommended based on self-report.

Outcomes

PRIMARY OUTCOMES:

Not clearly reported. Dietary intake reported prominently.

  • Total dietary intake at baseline, 6 months and 12 months

SECONDARY OUTCOME:

  • Mean weight at 6 and 12 months

  • Mean BMI at 6 and 12 months

  • Mean body cell mass at 6 and 12 months

  • Mean body fat at 6 and 12 months

  • Mean albumin at 6 and 12 months

  • Mean CD4 count and percent at 6 and 12 months

  • Feasibility data (completion rate, adherence to protocol and acceptability and tolerance of supplement)

ADVERSE EFFECTS:

Data collected on acceptability and tolerance of supplements. Clinical symptoms were assessed at each visit but details not presented.

Notes

ETHICS

Ethics approval received from the institutional review boards at each site and all participants gave their written informed consent

FUNDING:

Ross Laboratories donated Ensure and Advera. Study supported by National institute of Nursing Research and Rush University College of Nursing Research Fund.

CONTACT WITH AUTHOR:

Information requested from the author and response received on 09/01/2007.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated. Site and sex used as blocking variables
Allocation concealment (selection bias)Low riskGroup assignments were issued on a sequential basis using a list maintained by a statistician not involved with the study (assume central allocation)
Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding of participants or personnel
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported. Some laboratory assessments so blinding may have occurred
Incomplete outcome data (attrition bias)
All outcomes
High riskAttrition was high and differentially distributed. Exclusions: Overall - 27% (24/90); EnsurePlus group - 13% (4/30); Advera group - 32% (10/31); Control group - 34% (10/29)
Selective reporting (reporting bias)Unclear riskProtocol not obtained and no clear primary outcome.

Moreno 2005

Methods

COUNTRY:

Sao Paulo, Brazil

SETTING:

Participants were outpatients followed by the AIDS Children Division

DURATION OF RECRUITMENT:

Not stated

DURATION OF TRIAL:

June 2001-March 2002

FOLLOW-UP:

At baseline, week 8 and week 16 clinical data, peripheral blood counts, TCD4+ and TCD8+ lymphocytes and erythrocyte glutathione levels were collected.

Participants

INCLUSION CRITERIA:

  • HIV-infected children 12-72 months

  • CD4/CD8 ratios <1.5

  • On ARV therapy

EXCLUSION CRITERIA:

  • Diarrhoea

  • Intolerance to milk products

  • HIV associated infection at study entry

Participants randomised: 18

Median age at baseline (min-max values): 4.86 (2.01-6.37) years (Whey Protein Concentrate group, WPC), 3.96 (1.98-5.7) years (Control group)

Sex at baseline: 5 males and 4 females in WPC group; 5 males and 4 females in control group

Stage of HIV/AIDS at baseline:

A1 (mild symptoms, no immune suppression): 0 (WPC group) 1 control group

A2 (mild symptoms, moderate suppression): 2 (WPC group) 0 control group

B1 (moderately symptomatic, no immune suppression): 1 (WPC group) 2control group

B2 (moderately symptomatic, moderate suppression): 4 (WPC group) 3 control group

C1 (severely symptomatic, no suppression): 1 (WPC group) 0 control group

C2 (severely symptomatic, moderate suppression): 1 (WPC group) 1 control group

C3 (severely symptomatic, severe suppression): 0 (WPC group) 2 control group

Median (min-max values) baseline CD4 count (cells/mm3): WPC group: 875 (624-1293); Control group: 914 (238-1328)

Baseline viral load (copies/ml): Measured in 6 children in WPC group but not reported

Baseline nutritional status: Not reported

Interventions

INTERVENTION:

Whey protein concentrate obtained from pasteurised skimmed bovine milk containing:

  • 79% protein

  • 4.9% lactose

  • 9-12 % lipid

  • 1.8% ash

CONTROL 1:

Maltodextrin

CONTROL 2:

No supplement

Supplements were administered once or twice a day as a powder diluted in water or non proteic cold drinks. The starting dose was based on 20% of total daily protein requirement and then increased by 10% each month over 3 months to reach 50% of total daily protein requirement by the end of the study. The amount of maltodextrin administered corresponded to the calories of the whey protein supplement. The data for the two control groups was combined in the analyses

DURATION:

16 weeks

ADHERENCE:

Not reported

Outcomes

Outcomes not distinguished as primary or secondary.

  • T lymphocyte counts (CD4+ and CD8+)

  • Erythrocyte glutathione concentration

  • Occurence of associated co-infections

  • Hematological parameters

  • Viral load

Notes

ETHICS:

State University of Campinas Medical School Hospital Ethics Committee. Type of informed consent received from all participants unclear

TRIAL REGISTRATION:

Not registered

FUNDING:

Study sponsored by FAPESP, Sao Paulo Brazil

Contacted author on 03/04/12 to clarify results (% of participants in the control group suffering co-infection). Authors responded with the appropriate information (77% with 4 being hospitalised).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskReported that subjects were randomly assigned to the three groups but it does not describe how this is done
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskReported as 'double-blind' but not stated clearly for participants and personnel
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskReported as 'double-blind' but not stated clearly for outcome assessors
Incomplete outcome data (attrition bias)
All outcomes
High risk18 participants at baseline; 16 participants at 8 weeks (7 WPC group; 9 control group); 13 participants at 16 weeks (6 WPC group; control group 7). WPC group 33% attrition rate; control group 22% attrition rate.
Selective reporting (reporting bias)Unclear riskProtocol not obtained

Rabeneck 1998

Methods

COUNTRY:

USA

SETTING:

Participants were recruited from three sources: Houston Veterans Administration Medical Center Special Medicine Clinic, an outpatient facility for HIV-infected veterans; the Thomas Street Clinic, an outpatient facility that serves Harris County, Texas; and the private practices of several physicians in Houston, Texas.

DURATION OF RECRUITMENT:

March 1993 to July 1994

DURATION OF TRIAL:

19 months (assuming 6 weeks follow-up post last month of recruitment)

FOLLOW-UP:

Baseline comprised a two week period. During this period, participants were seen at weekly intervals. At the first visit, physical examination and blood samples were obtained. A study dietician conducted a 24 hour recall diet history. At the second visit nutritional status, grip strength, cognitive function, and quality of life were assessed. During the 6 week trial period, the participants were seen two weekly and nutritional status, grip strength, cognitive function, and quality of life were assessed each time. At each visit 3 day dietary records were done. At final visit another blood sample was done.

Participants

INCLUSION CRITERIA:

  • HIV-infected men > 18 years

  • CD4 count < 500 cells/mm3

  • < 90% usual weight-for-height OR > 10% involuntary weight loss during previous 6 months

  • Able to care for themselves indicated by Karnofsky score > 50

  • Life expectancy of at least 12 weeks

  • Participants on ARVs stable for 8 weeks prior to study

EXCLUSION CRITERIA:

  • Dysphagia

  • Severe diarrhoea (> 6 watery stools/d for 7 days)

  • Cytomegalovirus or Mycobacterium avium

  • Suspected infection (chills, fever)

  • Diagnosis of infection or hospitalisation during the 2 weeks prior to study entry

  • Ingestion of anabolic agents or appetite stimulants and undergoing chemotherapy.

Participants randomised: 118

Baseline data only reported for those who completed the trial: 99

Mean age +/- SD at baseline: 39.3 ± 8.8 years (experimental group) and 41.1 ± 9.7 years (control group)

Baseline nutritional status (BMI) Mean +/- SD: Experimental group: 21± 3; Control group: 21± 3

Number of patients with CD4 cells/mm3 <= 100: 38/49 (77.5 %) (intervention group); 37/50 (74.0 %) (control group)

Antiretroviral therapy: Number of participants on ARVs not stipulated

No information on stage of illness.

No statistically significant differences were noted at baseline for age, CD3 count, Karnofsky score, nutritional parameters, or cognitive function.

Interventions

INTERVENTION GROUP:

Lipisorb-specialized medium chain triglyceride formula suitable for HIV infected participants with fat malabsorption, comprising:

  • 17% protein

  • 35% fat

  • 48% carbohydrates

  • RDA of vitamins and minerals

Taken daily for six weeks. Participants also received nutritional counselling as for the controls.

CONTROL GROUP

Nutritional counselling by dietician consisting of advice on how to achieve 4020kJ/d greater than estimated total energy expenditure.

ADHERENCE:

Assessed adherence by weekly counselling with dietician. Specific method of assessing adherence to the oral supplement not stated.

Outcomes

PRIMARY OUTCOME:

Not clearly reported. Energy target reported prominently:

  • Proportion of participants reaching energy target at week 6

SECONDARY OUTCOMES:

  • Mean and median change in weight from baseline to week 6

  • Mean and median change in Body mass index from baseline to week 6

  • Mean and median change in Fat (BIA) from baseline to week 6

  • Mean and median change in Fat free mass (BIA) from baseline to week 6

  • Mean and median change in Body water mass from baseline to week 6

  • Mean and median change in Tricep skinfold thickness from baseline to week 6

  • Mean and median change in Subscapular skinfold thickness from baseline to week 6

  • Mean and median change in Chest skinfold from baseline to week 6

  • Mean and median change in Mid-axilla skinfold from baseline to week 6

  • Mean and median change in Abdominal·Supra-illiac from baseline to week 6

  • Mean and median change in Thigh skinfold from baseline to week 6

  • Mean and median change in Mid arm circumference from baseline to week 6

  • Mean and median change in Grip strength (dynamometer) from baseline to week 6

  • Change in Cognitive function (Buschke selective reminding test) from baseline to week 6

  • Change in Quality of life test from baseline to week 6

  • Change in CD4 cell count from baseline to week 6

  • Change in Albumin from baseline to week 6

  • Change in Triglyceride levels from baseline to week 6

ADVERSE EFFECTS:

One participant from the experimental group discontinued the supplement due to nausea and epigastric burning; another disliked the taste.

Notes

ETHICS:

Ethics was obtained from the institutional review boards of Baylor College of Medicine and Harris County Hospital District. Informed consent was obtained from all participants.

FUNDING:
Mead Johnson Nutritional Group, Evansville, Ind

AUTHOR CONTACT:

Information requested from the author but author unable to assist as no longer in possession of study results

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
High riskNone
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot clearly reported who did the outcome assessment
Incomplete outcome data (attrition bias)
All outcomes
High riskAttrition was high. Overall 24% (28/118). At 6 weeks attrition was 27% (16/59) in the intervention group and 20% (12/59) in the control group
Selective reporting (reporting bias)Unclear riskProtocol not obtained

Rollins 2007

Methods

COUNTRY:

Durban South Africa

SETTING:

HIV-infected children with diarrhoea for longer than 7 days presenting to King Edward VIII hospital treated as inpatients and outpatients. Hospital serves urban and peri-urban townships

DURATION OF RECRUITMENT:

1 May 1998-31 March 2000

DURATION OF TRIAL:

26 weeks

FOLLOW-UP:

All children received standard management for prolonged diarrhoea, namely fluid and electrolytes, low lactose feeds and micronutrient supplements. Other infections and complications were treated as required. Children were either admitted to hospital or treated as outpatients. Outpatients were seen every 3 days until diarrhoea resolved. Hospitalised patients were discharged after diarrhoea resolved. Children were followed up weekly thereafter.

Participants

INCLUSION CRITERIA:

  • HIV-infected children 6-36 months old

  • Diarrhoea lasting longer than 7 days

  • Clinically stable

EXCLUSION CRITERIA:

  • Administration of antibiotic prior to first stool sample

Participants recruited: 233

Participants randomised: 169

Sex at baseline: 29 males and 57 females (enhanced nutrition group); 37 males and 46 females (standard nutrition group)

Median age (P10;P90) at baseline: 13 (7.0;24.0) months (enhanced nutrition group) and 13 (6.4;29.6) months (standard nutrition group)

Median (P10;P90) weight-for-age SDS at baseline: -3.25(-4.94;-1.79) enhanced nutrition group; -3.09(-5;-1.17) standard nutrition group

Median (P10;P90) weight-for-height SDS at baseline: -2.7 (-5.81; -0.19) enhanced nutrition group; -3.08(-5.42; 0.01) standard nutrition group

Median (P10;P90) height-for-age SDS at baseline: -2.66(-4.92; -1.06) enhanced nutrition group; -2.25 (-5.47; -0.59) standard nutrition group

Percentage participants severely malnourished (weight-for-length,-3SDS) at baseline: 41.3% enhanced nutrition group; 50.7% standard nutrition group

Percentage participants underweight (weight-for-length,-2SDS) at baseline: 86% enhanced nutrition group; 71.8% standard nutrition group

Median (P10;P90) CD4+ count (µl): 705 (147;1416) enhanced nutrition group; 834 (158;1629) standard nutrition group

Median (P10;P90) viral load (log10) at baseline: 6.1 (5.3;6.6) enhanced nutrition group; 6.1(5.2;6.5) standard nutrition group

No participants on antiretroviral therapy

No information on stage of illness.

No significant difference in severity of disease, immunity and nutritional status between groups at baseline. Greater percentage of participants in standard nutrition group had macroscopic blood in their stools at baseline compared to the those in the enhanced nutrition group (11.6% vs 6.9%). Greater percentage of participants in the enhanced nutrition group were underweight compared to the standard nutrition group (86% vs 72%).

Interventions

INTERVENTION:

Standard nutritional support consisting of a casein maltodextrin-based milk formula (AL110) until diarrhoea resolved and appetite re-established. Thereafter, amount of milk formula modified to provide at least 150 kcal/kg/day containing ˜4.0–5.5 g protein/kg/day and 15% of calories as protein. Depending on age and weight of child, sometimes required addition of powdered protein supplement to other food. Enhanced nutritional support provided until child reached 3 months of age. Children randomised at 3 months to continued enhanced nutritional support received the same milk and supplements until 6 months of age

At home, caregivers were advised to provide their normal home foods and additionally give the milk formula and protein supplements as directed by the study dietician.

CONTROL:

Standard nutritional support consisted of casein maltodextrin-based milk formula with 67 kcal/100mL offered at least four times per day and a maize porridge/pureed vegetable/oil diet with fermented milk offered at least four times per day. This diet provided at least 100-110 kcal/kg/day containing ˜2.2g protein/kg/day (9.5% of calories as protein) and total lactose content of <3.2g/kg.

Children older than 12 months were offered predominantly soft diet of porridge and vegetable purees with an equivalent protein and energy content. This diet continued until discharge from hospital. The same casein maltodextrin–based formula was supplied to children treated as outpatients until the child had no watery stools and
less than four loose stools per day.

Following discharge no additional food support was offered unless a child required a specialised feed because of persisting carbohydrate intolerance. When household food insecurity was identified, caregivers were referred to the hospital social worker for assistance with welfare grants. During admission, outpatient visits and subsequent study visits a dietary assistant advised caregivers on food preparation, emphasizing a balanced diet and inexpensive but nutritious food choices, hygiene and advice for children with mouth sores or anorexia.

All children received daily vitamin supplements (A, C, D, thiamine, riboflavin, pyridoxine, nicotinamide and B12) providing approximately twice the USDA-recommended daily requirement for 2 weeks. Children also received folate 5 mg daily for 7 days, zinc sulphate 15 mg daily for 14 days and a single oral dose of vitamin A (6–12 months: 100 000 IU; >12 months: 200 000 IU).

DURATION:

26 weeks

ADHERENCE:

The supplemental milk formula was provided in unlabelled tins, and intake was ascertained by examination of empty tins at follow-up.

Outcomes

PRIMARY OUTCOME:

  • Weight change from study enrolment until 8 weeks

SECONDARY OUTCOMES:

  • Attained weight and height at 8, 14 and 26 weeks

  • Changes in weight and height over 8, 14 and 26 weeks

  • Changes in viral load from enrolment to 8 and 26 weeks

  • Changes in CD4 count from enrolment to 8 and 26 weeks

Notes

ETHICS

Study approved by the Research Ethics Committee of the University of KwaZulu-Natal and the Institutional Review Board of the Tufts-New England Medical Centre. Written informed consent obtained from all mothers or legal caregivers of participants.

FUNDING:

Elizabeth Glaser Pediatric Aids Foundation (grant PG-50890). Dr. Rollins supported by grant from the Wellcome Trust (063009/Z/00/2). Dr. van den Broeck supported by grants from the Wellcome Trust (063009/B/00/Z) and an International Collaboration in Infectious Disease Research (ICIDR) grant from the National Institutes of Allergy and Infectious Diseases and the National Institute of Child Health and Development (1 UO1 AI45508-01). Dr Bennish was supported by mid-career grant from National Institutes of Allergy and Infectious Diseases (1 K24AI/HDO1671-01).

TRIAL REGISTRATION:

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskEnrolled children consecutively assigned study number from randomisation list prepared using computer-generated block randomisation method with block size of 6.
Allocation concealment (selection bias)Unclear riskNot fully described
Blinding of participants and personnel (performance bias)
All outcomes
High riskNot blinded
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding is not reported for the outcome assessors
Incomplete outcome data (attrition bias)
All outcomes
High riskAttrition rate high in both groups (Enhanced nutrition group 26 weeks=44%; standard nutrition group 26 weeks=33%), mainly due to death of participants but also due to high loss to follow up rate.
Selective reporting (reporting bias)Unclear riskProtocol not obtained

Schwenk 1999

Methods

COUNTRY:

Germany

SETTING:

Outpatients clinic at the University Hospital of Cologne, Cologne.

DURATION OF RECRUITMENT:

March 1996 to December 1997

DURATION OF TRIAL:

March 1996 - February 1997 (12 months: 8 weeks after recruitment assumed to be end of trial)

FOLLOW-UP:

No clear procedures are reported. It appears that at baseline and then every two weeks thereafter, body composition was assessed using bioelectrical impedance analysis and energy intake was assessed using 24 hour recall.

Weight was measured at baseline and at week 8.

Participants

INCLUSION CRITERIA:

  • HIV infected

  • Previous weight loss > 5% total weight loss

  • Currently losing > 3% total weight

EXCLUSION CRITERIA:

  • Prescription of oral supplementation

  • Nutritional counselling

  • Hormonal or appetite stimulants within previous 3 months

  • Enteral or parenteral nutrition within previous 3 months

  • Unable to swallow normal food

  • Severe lactose intolerance.

  • Participants changing ART within one month of the start of the study were also excluded. However, with the Introduction of protease inhibitors, participants who were losing weight were placed on protease inhibitors instead of other ART. These participants although initially excluded where then included.

Participants randomised: 50

Mean age +/- SD at baseline: 39.4±9.2 (Intervention group) and 39.5±10.2 (control group)

Sex at baseline: 100% men in the intervention group; 88% men in the control group

Stage of HIV (CDC guidelines): CDC C3 = 47 participants, CDC C2 = 3 participants

Mean baseline CD4 count (cells/µl): Intervention group: 180±198; Control group: 160 ±164

Baseline viral load (log10 copies/ml): Intervention group: 4.1 ± 1.2; Control group: 4.7±1.3

Baseline nutritional status (BMI): Intervention group: 19.6 ± 2.3; Control group: 19.9 ± 2.1

Antiretroviral therapy: All participants on ARV treatment

No significant differences between groups noted at baseline.

Interventions

INTERVENTION:

  • Range of fortified oral supplements with energy density from 0.6 to 1.5 kcal/ml.

  • Supplements were provided in 200ml drinks or 125g semi-liquid dessert with a soy protein basis. One supplement was different in that it was a maltodexrin-based fruit drink.

  • Participants were instructed to increase intake by 600kcal per day using oral supplements provided. Packages were labelled according to energy content and participants recorded the intake of units in a diary. They were not to replace normal food with a supplement.

All participants also received counselling as for the control group.

CONTROL

Nutritional counselling by dietician on how to increase food intake by 600kcal per day (2510 kJ/day). Control participants provided with a list of household measures to increase caloric intake, such as adding butter or cream to usual food.

DURATION:

8 weeks

ADHERENCE:

Food intake was assessed by 24 hour recall. Adherence to supplement was assessed by the number of emptied cartons returned by patients when reporting to dieticians (information obtained from the author)

Outcomes

PRIMARY OUTCOME:

  • Area under the curve of percent change in body cell mass from baseline.

SECONDARY OUTCOMES:

  • Weight change

  • Body cell mass

  • Food energy intake

  • BMI

  • Fat free mass (BIA)

  • Fat mass (BIA)

  • CD4 cell count

  • Viral load

  • Number of previous AIDS defining illnesses

ADVERSE EVENTS:

Not specifically stated. Treatment interventions well tolerated. No adverse events were recorded (information obtained from the author)

Notes

ETHICS:

Ethics obtained by the Medical Research Ethics Committee of the Medical Faculty, University of Cologne. All randomised participants gave their informed consent.

FUNDING:
Nestle Clinical Nutrition, Munich, Germany

AUTHOR CONTACT:

Information requested from the author and response received on 17/07/2006

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot clearly reported and not provided clearly by author in response to queries
Allocation concealment (selection bias)Low riskFrom unpublished data received from author: "independent person generated the random allocation list and placed allocation to treatment arms in closed numbered envelopes"
Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding of participants or personnel
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAttrition was moderate overall but differentially distributed between groups. Overall attrition was 10%(5/50); in the intervention group it was 8% (2/26) and 13% in the control group (3/24)
Selective reporting (reporting bias)Unclear riskProtocol not obtained

Shabert 1999

Methods

COUNTRY:

USA

SETTING:

Participants were recruited from private practice physicians in Broward County, Florida

DURATION OF RECRUITMENT:

June 1997 (obtained from author)

DURATION OF TRIAL:

Dates not reported

FOLLOW-UP:

Weekly before randomisation, participants had bioelectrical impedance analysis (BIA) to determine body composition and body weight was determined as a mean from three baseline weight measurements.

At weekly intervals for 12 weeks, BIA and weight was measured.

At baseline and at end of study, all participants completed a 30-item profile of mood assessment form from the SF-36

Participants

INCLUSION CRITERIA:

  • HIV-infected men and non- pregnant women

  • >= 5% involuntary weight loss or < 90% standard creatinine/height index (reflecting loss of lean tissue)

  • Not on any other protocol two months prior to receiving supplement

  • If on Vitamin B12 or folate, supplement must have been initiated at least one month before start of trial

  • If on testosterone, supplementation must have been initiated 4 months before and continued with it at the same dose throughout the trial

  • N- acetyl cysteine use to be discontinued at start of trial

  • Ascorbic acid use continued if being used as vitamin

EXCLUSION CRITERIA:

  • Acute opportunistic infection

  • Current use of > 5.0 g/daily Glutamine

  • Liver cirrhosis

  • Renal failure

  • Chronic diarrhoea (>2 loose stools per day): if proven non-infectious, could be included into the trial

  • During the trial additional exclusion criteria were used

    • Inter-current illness preventing ingestion of supplement for < 5 days

    • Change in anti-retroviral treatment due to medical reasons

    • Acute catastrophic illness or injury during the course of the study

    • Unable to consume the nutrient supplement or unable or unwilling to participate in the periodic evaluation during the protocol

Participants randomised: 26

Mean age at baseline: 40 years (range: 30-50)(intervention group) and 42 (range: 33-53)(control group)

Stage of HIV (CDC guidelines): All stage C (with AIDS)

Baseline mean (range) CD4 count (cells/mm3):Intervention group: 147 (1 - 327); Control group: 183 (13 - 364)

Baseline viral load (copies/ml): Not measured

Baseline mean (range) nutritional status (BMI): Intervention group: 22.2 (19.9 - 25.5); Control group: 22.9 (19.9 - 24.9)

Antiretroviral therapy: Number of participants on ARVs - 10 (83%) in the intervention group and 8 (89%) in the control group.

Interventions

INTERVENTION:

  • L-glutamine (GLN) amino acid (40g/day) taken in four equal doses

  • Antioxidant nutrients:

    • Ascorbic acid 800mg/d

    • alpha-tocopherol 500 IU/d

    • ß-carotene 27000IU/d

    • selenium 280ug/d

    • N-acetyl cysteine 2400mg/daily

CONTROL:
Glycine 40g daily taken in four equal doses.

DURATION:

Twelve weeks.

CO-INTERVENTIONS:

All participants received a recommended daily allowance of vitamin and mineral preparation

All participants had weekly nutritional counselling with dietician to ensure stable and adequate nutrient intake.

ADHERENCE:

The supplements were taken daily in four divided doses. Packets were dispensed at 14-day intervals. Used packets were returned to monitor compliance.

Outcomes

PRIMARY OUTCOME:

  • Change in body weight from baseline to 12 weeks

  • Change in body cell mass from baseline to 12 weeks

SECONDARY OUTCOMES:

  • Change in CD4 cell count from baseline to 12 weeks

  • Nutrient intake was assessed using the Willett Food Frequency Questionnaire and 3-day (2 week days and 1 weekend day) dietary recall from baseline to 12 weeks

  • Change in Mood (SF30) from baseline to 12 weeks

  • Change in Dietary intake from baseline to 12 weeks

  • Change in BMI from baseline to 12 weeks

  • Change in Fat mass from baseline to 12 weeks

  • Change in Body water (intracellular and extracellular body water) from baseline to 12 weeks

ADVERSE EVENTS

No adverse events were noted in any of the participants

Notes

ETHICS:

Ethics was obtained from the Human Ethics Committee of Pompano Beach Community Hospital. Informed consent was obtained from each participant and written approval obtained from each participant's physician.

FUNDING:

AUTHOR CONTACT:

Information requested from the author and response received 05/04/2006

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskNot reported. From author: computer generated randomisation using block design (gender and origin of disease i.e. STD or IV drug use were used in the block design)
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskConfirmed blinding with author
Blinding of outcome assessment (detection bias)
All outcomes
Low riskConfirmed blinding with author
Incomplete outcome data (attrition bias)
All outcomes
High riskOverall attrition was 19% (5/26) and differential between groups: in the intervention group, attrition was 8%(1/13) and in the control group it was 31% (4/13).
Selective reporting (reporting bias)Unclear riskProtocol not obtained

Simpore 2005

Methods

COUNTRY:

Burkina Faso

SETTING:

Outpatient care at Centre for Education and Nutritional Rehabilitation at Centre Médical St Camille of Ouagadougou, Burkina Faso

DURATION OF RECRUITMENT:

Not specified

DURATION OF TRIAL:

2002-2003

FOLLOW-UP:

Weight and height measured weekly in all participants. Haemoglobin levels and number of leukocytes, lymphocytes and neutrophils measured at baseline and 8 weeks in the supplemented group.

Participants

INCLUSION CRITERIA:

Undernourished HIV-infected and uninfected infants and children < 5years old.

EXCLUSION CRITERIA:

  • Dehydrated children in shock needing rapid transfer to hospital for intensive therapy

  • Refusal to participate in the study

Participants randomised:170 (84 HIV-infected participants)

Mean age of HIV-infected participants at baseline: 15.54 ± 5.3 months (spirulina group); 14.96 ± 5.9 months (traditional meals group)

Mean weight at baseline: 5.91± 1.2 kg (spirulina group); 5.98 ± 1.1 kg (traditional meals group)

Mean weight-for-age z-score (WAZ) of HIV-infected participants at baseline: -4.1± 0.8 (spirulina group); -3.88 ± 1.0 (traditional meals group)

Mean weight-for-height z-score (WHZ) of HIV-infected participants at baseline: -2.87± 1.0 (spirulina group); -2.88 ± 0.9 (traditional meals group)

Mean height-for-age z-score (HAZ) of HIV-infected participants at baseline:-2.88 ± 1.3 (spirulina group); -2.64 ± 2.1 (traditional meals group)

No participants on antiretroviral therapy

Stage of illness not described

No significant differences in baseline characteristics were observed.

Interventions

INTERVENTION:

Mothers of children receiving spirulina (SP) were given weekly rations of 70 g of SP in a sachet. Each day 10 g of SP (measured with a graduated container) was added to the traditional meal (millet flour) of the child. This mixture was made at least twice a day (therefore children received 20g SP per day), was given to children in a quantity covering their caloric requirements, and outside the suckling time in children whose mothers continued to breast-feed. The mothers were instructed how to prepare mixes and feed their children at the Centre. After this they continued to administer the mixture at home. SP comprises˜57% protein and ˜6% lipid.

CONTROL:

Traditional meals comprising millet flour, fruit and vegetables.

Vitamin and mineral deficiencies of all children were corrected at end of study

DURATION:

8 weeks

ADHERENCE:

Authors reported that treatment compliance was excellent although not sure how compliance was assessed. Compliance appears to have been self reported as mothers reported that children accepted the mixes and rarely had difficulties in feeding their children.

Outcomes

PRIMARY OUTCOMES:

  • Weight for age z score (WAZ)

  • Weight for height z score (WHZ)

SECONDARY OUTCOMES only measured in the groups receiving SP:

  • Haemoglobin levels

  • Leukocytes

  • Lymphocytes

  • Neutrophils

Notes

ETHICS:

Ethical Committee of Centre Médical St Camille approved study. Written informed consent obtained from all parents of participants.

FUNDING:

Heinz Karger Memorial Foundation

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskEach child admitted to the protocol study was given a progressive number and at the end, each
was selected with a casual number generator program. This procedure was repeated separately for each group.
Allocation concealment (selection bias)Unclear riskNot described
Blinding of participants and personnel (performance bias)
All outcomes
High riskNo placebo was used so patients and probably personnel too were aware of which treatment they were receiving/administering.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding is not reported for the outcome assessors
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo attrition from any of the groups
Selective reporting (reporting bias)Unclear riskProtocol not obtained

Sudarsanam 2011

Methods

COUNTRY:

India

SETTING:

Four clinics in Vellore town in the southern Indian state of Tamil Nadu

DURATION OF RECRUITMENT:

Recruitment Jan to Nov 2005

DURATION OF TRIAL:

Follow-up 1 year

FOLLOW-UP:

Height, weight, skin-fold thickness, mid-arm circumference measurements and BIA measurements recorded at entry, 2, 4, 5 and 6 months and end of trial. Dietary recall recorded at baseline, 2, 4 and 6 month visits

Participants

INCLUSION CRITERIA:

South Indian patients aged >12 years with tuberculosis (TB) with and without human immunodeficiency virus (HIV) coinfection on anti-tuberculous therapy

EXCLUSION CRITERIA:

  • Patients who had relapsed end-stage renal or liver disease

  • CD4 count > 200

  • BMI > 19

  • Resident outside Vellore district

  • Not willing to give written informed consent to participate

Randomisation was stratified according to HIV status

Number randomised: 103

HIV status at baseline: 13/51 (25.5%) in supplement group and 9/52 (17.3%) in no supplement group

Mean age at baseline: 36.8 years in supplement group; 37.8 years in no supplement group - all of the baseline info is for the whole group and not just for HIV people in the groups - have requested the info for the hiv patients specifically

Sex at baseline: 31/51 (60.8%) males in supplement group; 32/52 (62.7%) males in no supplement group

BMI at baseline: 17.2 kg.m-2 in supplement group; 18.2 kg.m-2 in no supplement group

Mean CD4 count.mm3 at baseline: 168 in supplement group; 146 in no supplement group

Median HIV viral load.ml-1 at baseline: 595715.5 in supplement group; 1018998 in no supplement group

All participants received the same antituberculosis standard therapy in accordance with the DOTS strategy

None of the HIV patients received antiretroviral therapy

The supplemented group had a poorer nutritional status at baseline compared to the no supplement group

Interventions

INTERVENTION:

Macronutrient and micronutrient supplementation for 6 months. The macronutrient was a ready-to-serve powder (locally prepared cereal-lentil mixture), given as monthly rations to supply 930 kcal and 31.5 g protein per day in 3 servings. The micronutrient as a once a day multivitamin tablet containing: copper sulphate 0.1 mg, D-pantheol 1 mg, dibasic calcium phosphate 35 mg, folic acid 500 μg, magnesium oxide 0.15 mg, manganese sulphate 0.01 mg, nicotinamide 25mg, potassium iodide 0.025 mg, vitamin A 5,000 IU, vitamin B1 2.5 mg, B12 2.5 μg, B2 2.5 mg, B6 2.5 mg, vitamin C 40 mg, vitamin D3 200 IU, vitamin E 7.5 mg, zinc sulphate 50 mg.

Dietary advice also provided.

CONTROL:

Dietary advice alone for 6 months

ADHERENCE:

Compliance with supplementation was checked by review by dietician and random home visits by field workers who counted remaining sachets and enquired about their use.

Outcomes

PRIMARY OUTCOME:

  • Outcome of TB treatment as classified by the national programme at the end of anti-tuberculosis therapy

SECONDARY OUTCOMES:

  • Body composition

  • Compliance

  • Condition on follow-up 1 year after cessation of TB therapy and supplementation.

Notes

ETHICS:

Institutional Review Board of the Christian Medical College, Vellore

FUNDING:

The Fogarty AIDS International Research and Training Program

Global Infectious disease Disease Research Training grant

TRIAL REGISTRATION:

Retrospectively registered with Clinical Trials Registry of India (CTRI/2010/091/006112)

Contacted authors for baseline and outcome data for TB/HIV participants on 15/04/12.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riska computer generated randomisation code
Allocation concealment (selection bias)Low riskAllocation was concealed, the randomisation codes were in opaque
envelopes opened by the dietician after dietary counselling.
Blinding of participants and personnel (performance bias)
All outcomes
High riskThere were no attempts made to blind any of the study team or
participants'
Blinding of outcome assessment (detection bias)
All outcomes
High riskThere were no attempts made to blind any of the study team
Incomplete outcome data (attrition bias)
All outcomes
Low risk3.9% were lost to follow-up at 6 months and 11.7% at 1 year.
Selective reporting (reporting bias)Unclear riskTrial protocol not retrieved. No evidence of selective reporting

Yamani 2010

Methods

COUNTRY:

Bangui, Central African Republic

SETTING:

Friends of Africa Centre, outpatient facility for comprehensive management of HIV-infected and affected people in Bangui, CAR.

DURATION OF RECRUITMENT:

Not reported

DURATION OF TRIAL:

March to September 2004

FOLLOW-UP:

At baseline: anthropometry, complete physical examination, full blood count, CD4, creatinine and protein in blood. Followed by weekly visits, physical exam every 21 days and biological tests every 3 months. Every 15 days, patients attended an education session of nutrition, hygiene, prevention and care of people infected by HIV. Patients too ill or those that did not follow the schedule received a home visit by one of the health care members.

Participants

INCLUSION CRITERIA:

  • HIV-infected adults presenting at Friends of Africa Centre

  • ARV naive

  • Individuals with Stage 2 or 3 disease, according to WHO classification

EXCLUSION CRITERIA:

  • Individuals with Stage 1 and 4 disease, according to WHO classification

  • Individuals already on ARV

Number randomised:160

Number included in analyses:128

Mean age at baseline: 36.8 years in spirulina group; 36.6 years in control group

Sex ratio (M/F) at baseline: 0.28 in spirulina group; 0.22 in control group

Mean weight at baseline: 53.3 kg in spirulina group; 52.8 kg in control group

CD4 count at baseline: 249.5 cells.mm-3 in spirulina group; 238.6 cells.mm-3 in control group

ARV treatment naive

All participants were WHO stage 2 or 3

Interventions

INTERVENTION:

  • 10g per day of Spirulina taken at participants convenience

CONTROL:

  • 10g per day of green clay (not absorbed in the intestine)

Each week all patients received 14 kg of corn flour, 500 g of CSB (mixture of corn soya), 2 kg of peas, 500 g of sugar, 150 of iodised salt and 500 ml of oil from World Food Program (WFP).

DURATION:

6 months

ADHERENCE:

Method of assessing adherence not described

Outcomes

OUTCOMES:

  • Socio demographic characteristics and disease history (questionnaire)

  • Clinical outcomes

  • Anthropometry

  • CD4 count

  • Creatinine

  • Protein in blood

  • Karnofsky scores

Notes

ETHICS:

Authority of Ministry of Health and Scientific Committee of the Faculty of Sciences de la sante

FUNDING:

Not reported

No standard deviations provided in the report.

Original article published in French and susequently translated into English for data extraction.

Contacted authors for more detailed outcome data (standard deviations for all outcomes) on 02/03/12 and again on 31/03/12 but have not received a response.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskUnclear how randomisation sequence generated.
Allocation concealment (selection bias)Unclear riskAuthors report the following "Codified with a random assignment of patients to a group and assignment to the use of one product (spirulina and placebo) in envelopes where the name of the patients was written".
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskHealth personnel were blinded to the treatment allocation. It is unclear if the participants were blinded to the treatment
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessors is not reported
Incomplete outcome data (attrition bias)
All outcomes
High riskAttrition moderate in Spirulina group (12/79, 15%) and high in placebo group (20/81, 25%)
Selective reporting (reporting bias)Unclear riskProtocol not obtained

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Amadi 2005Included both HIV positive and negative children. Children not randomised according to HIV status.
Both the experimental and the control group received nutritional supplementation (Neocate vs Complete Feed).
Bakeine 1997Both groups received nutritional supplementation (Nutrifil vs Corn Soya Blend). See Table of comparative studies
Baril 2007Omega-3 fatty acid supplementation for reducing HAART-associated triglyceridemia.
Bell 1999No outcomes reported as defined for inclusion in our review. Main outcome measures were production of dienoic eicosanoids and cytokines in HIV patients. Both groups received nutritional supplementation (fish oil bars vs safflower oil bars).
Breuikreuitz 2000No outcomes reported as defined for inclusion in our review: main outcome measures were change in immunological parameters such as natural killer cell and T cell function and viral load.
Carter 2006Omega-3 fatty acid supplementation for reducing HAART-associated triglyceridemia
Charlin 2002Both groups received nutritional supplements. See Table of comparative studies
Chlebowski 1993Both groups received nutritional supplements (Ensure vs Advera). See Table of comparative studies
Comi 1996Both groups received nutritional supplements (hypercaloric, hyperproteic vs normocaloric, normoproteic). See Table of comparative studies
Craig 1997Both groups received nutritional supplements (Long chain triglycerides vs medium chain triglycerides). Duration of treatment only 15 days
De Luis 2010Both groups received nutritional supplements (Ensure vs Prosure). See Table of comparative studies
de Luis Roman 2001Both groups received nutritional supplements (Ensure vs Prosure). See Table of comparative studies
De Truchis 2007Omega-3 fatty acid supplementation for reducing HAART-associated triglyceridemia
Engelson 1998Duration of treatment was only 10 days. Main outcome measure was changes in protein metabolism
Gerber 2008Omega-3 fatty acid supplementation for reducing HAART-associated triglyceridemia
Gibert 1999All groups received nutritional supplements (Peptamen vs NuBasics vs vitamins and minerals). Table of comparative studies
Hellerstein 1994Both groups received nutritional supplementation (whole protein formula vs peptide based formula). See Table of comparative studies
Hellerstein 1996Not a randomised controlled trial. Control group was a convenient sample of men
Hirschel 1996Abstract with results from Pichard 1998
Hoh 1998The control group was not randomly assigned. Both experimental groups received nutritional supplements (whole protein formula vs peptide based formula).
Kotler 1998Intervention involved total parenteral nutrition. Both groups received nutritional supplementation.
Marcel 2011Effect of Spirulina versus soybean on HAART-associated insulin resistance
Melchior 1996Intervention involved total parenteral nutrition.
Melchior 1998Intervention involved total parenteral nutrition.
Mendez 1998Both groups received nutritional supplementation (medium chain triglyceride vs long chain triglyceride). See Table of comparative studies
Micke 2001Both groups received nutritional supplements (Protecamin vs Immunocal). Duration of treatment was only 2 weeks. The control group consisted of HIV negative, health adults
Micke 2002No control or comparison group
Ndekha 2005Children were systematically allocated to treatments therefore not RCT
Ndekha 2009Both groups received nutritional supplements (Ready-to-use fortified spread vs corn-soy blend). See Table of comparative studies.
Pichard 1998Both groups received nutritional supplements (standard formula vs arginine and fatty acid enriched formula). See Table of comparative studies
PrayGod 2011Objective of study to compare multi-micronutrient supplement. See Micronutrient and HIV review
PrayGod 2012Both groups received nutritional supplement (1 biscuit vs 6 biscuits). See Table of comparative studies.
Sandige 2004It is not a true randomised controlled trial as systematic allocation was used to assign children to the two treatments. Not all of the children were HIV-infected and the children were not randomised according to HIV status.
Sattler 2008Both groups received nutritional supplement (supplement + whey protein vs supplement). See Table of comparative studies.
Schon 2011TB/HIV participants. Randomisation not stratified by HIV status (as confirmed by study author) therefore excluded
Schwenk 1996Intervention administered via percutaneous endoscopic gastrostomy (PEG). Both groups received nutritional supplements (polymeric diet vs polymeric diet + fibre)
Suttmann 1996Randomised, cross over trial where participants received either a standard formula or a formula enriched with arginine, RNA and linolenic acid. See Table of comparative studies
Thusgaard 2009Omega-3 fatty acid supplementation for reducing HAART-associated triglyceridemia
Wanke 1996Both groups received nutritional supplementation (medium chain triglycerides vs long chain triglycerides). Duration of treatment was 12 days
Winkler 2004Ingestion of fruit juice or a fruit-vegetable-concentrate rich in polyphenols and antioxidant vitamins. Reported outcomes include lymphocyte proliferation and apoptosis, therefore not eligible for our review.
Winter 2009Study involves feeding concentrated formula to HIV-exposed infants. Article only presents results for HIV-uninfected infants.
Wohl 2005Omega-3 fatty acid supplementation for reducing HAART-associated triglyceridemia
Woods 2009Omega-3 fatty acid supplementation for reducing HAART-associated triglyceridemia

Characteristics of studies awaiting assessment [ordered by study ID]

Kindra 2011

Methods

COUNTRY:

South Africa

TRIAL DURATION:

December 2006 to July 2008, with follow up completed by May 2009

FOLLOW UP:

Study assessments for both mothers and their infants were done at 2 and 6 weeks post-delivery
and monthly thereafter till 6 months of age with a final study visit at 9 months. At each visit, a
clinical examination and anthropometric measurements were done; along with a developmental
assessment on the infants and Karnofsky scoring on the mothers. Body composition and SRQ 20
assessments were done on the mother at 2 weeks and then three monthly till 9 months. Mothers
and the HIV positive infants were assessed for any signs of disease progression; opportunistic
infections; WHO disease staging; and CD4 counts. When indicated they were started on ART as
per national guidelines.

Participants

INCLUSION CRITERIA:

HIV-infected mothers planning to breastfeed for at least 6 months were eligible to enter the study.

EXCLUSION CRITERIA:

Mothers with advanced disease (CD4 < 200 or WHO stage 3 and 4) requiring ART and those not resident in the area were not eligible for recruitment. In addition, mothers of infants requiring specialized management and with gestation less than 36 weeks were not eligible for study enrolment.

Number randomised: 129 (63 in control group, 66 in supplemented group)

InterventionsA food supplement in the form of a peanut/soya milk-based spread enriched with micronutrients.
Outcomes

Body composition (primary outcome reported: Change in lean body mass)

Anthropometry

Haemoglobin

Haematokrit

CD4 count

Notes 

van der Horst 2009

Methods

COUNTRY:

Malawi

Participants

Inclusion Criteria:

Recruitment and primary eligibility criteria:

  • Age > 14 years.

  • Ability to give informed assent or consent.

  • Evidence of HIV infection, as documented by 2 positive ELISA antibody tests; or 1 positive ELISA, and 1 Western Blot; or 2 separate concurrent rapid tests.

  • Currently pregnant (with a single or multiple fetuses).

  • Gestation < 30 weeks at referral from 'Call to Action' Program

  • No serious current complications of pregnancy.

  • Intention to breastfeed.

  • Intention to deliver at the institution at which the study is based.

  • Not previously enrolled in this study for an earlier pregnancy.

  • Other than HIV, no active serious infection, such as tuberculosis or other potentially serious illnesses.

  • No previous use of antiretrovirals including the HIVNET 012 regimen.

  • Mother's CD4 count > 250 cells/uL determined in the antenatal clinic.

  • Mother's ALT < 2.5 x ULN (upper limit of normal) determined in the antenatal clinic

Secondary eligibility criteria and treatment assignment:

  • Mother who delivers outside of the institution at which the study is based must present with her infant to the study site within 36 hours of delivery.

  • Mother accepts nevirapine and zidovudine+lamivudine 7-day regimen for herself and her infant.

  • Infant birth weight > 2000 g.

  • No severe congenital malformations or other condition(s) not compatible with life.

  • Based on clinical assessment, no maternal condition which would preclude the start of the study intervention

Number randomised: 2369 mother-infant pairs

InterventionsIn this factorial design, half of the study mothers are randomized to receive a high-energy, high-protein, micronutrient-fortified food supplement. The supplement provides the daily energy required to support exclusive breastfeeding and 100% of the recommended dietary allowance for all micronutrients except vitamin A, which has been associated with increased postnatal HIV transmission when consumed daily (38). The supplement is supplied for 28 weeks after delivery, or until reported breastfeeding cessation, whichever occurs first.
OutcomesOutcomes are mainly focused on prevention of HIV from mother to child. For the supplement comparison, maternal depletion (weight loss and micronutrient status) are monitored.
NotesPrincipal author contacted to ascertain status of results

Characteristics of ongoing studies [ordered by study ID]

Guha 2011

Trial name or titleA randomised control trial on the effect of nutritional counseling and supplementation on HIV patients initiating Anti Retroviral Therapy
Methods

Randomized, Parallel Group, Active Controlled Trial
Method of generating randomization sequence: Computer generated randomization

Method of allocation concealment: An Open list of random numbers

Blinding and masking:Not Applicable

Participants

Inclusion criteria: HIV positive, Anti Retroviral Therapy (ART) naive

Exclusion criteria: pregnancy, lactation, malignancy, renal disease, diabetes

Interventions

Intervention1:

nutritional counselling: nutritional counselling according to 6 modules for a period of 6 months per subject along with standard ART preparedness counselling for start of ART and first line ART according to National Guidelines
Intervention2:

protein supplementation: oral protein supplementation 16gm per day for six months per subject along with standard ART preparedness counselling and first line ART according to National Guidelines
Intervention3:

protein supplementation and nutritional counselling: A combination of oral protein supplementation (16gm per day)and nutritional counselling according to 6 modules for a period of 6 months per patient.

Intervention4:

protein supplementation, nutritional counselling: 3 arms of the trial has intervention they are as follows
Study Arm 1-oral protein supplementation 16gm per day for six months per
Study Arm 2-nutritional counselling according to 6 modules for a period 6 months
Study Arm 3-A combination of nutritional counselling and oral protein supplementation (16gm per day)for a period of 6 months per patients.

Along with this patient will receive standard ART preparedness counselling and first line ART according to National Guidelines

Control Intervention1:

control arm: standard ART preparedness counselling and first line ART according to National Guidelines. Not receiving protein supplement or nutritional counselling.

Outcomes

improvement in nutritional and immunological statusTimepoint: after 6 months of intervention

dietary profile, clinical status, mortality, quality of lifeTimepoint: after 6 months of intervention

Starting date01-08-2011
Contact informationProf Subhasis Kamal Guha (email: drskguha@gmail.com)
Notes 

Mourmans 2007

Trial name or titleA Randomised, Double-blind, Controlled Study on the Effect of One Year Administration of a Nutritional Concept on Immunological Status in HIV-1 Positive Adults not on Antiretroviral Therapy - BITE (Blinded nutritional study for Immunity and Tolerance Evaluation)
MethodsRandomised: Yes; Masking: Double blind; Control: Placebo; Group: Parallel;
Participants

Inclusion criteria:
1. HIV-1 positive adults who have not received (HA)ART in the past year and are not anticipated to start therapy within the next 6 months;
2. HIV-1 RNA > 5,000 copies/ml in the 3 months prior to screening visit;
3. CD4+ T-cell count ≤ 800 cells/µl in the 3 months prior to screening visit;
4. ≥ 18 years old.

Exclusion criteria:
1. HAART anticipated to be required within the next 6 months;
2. Unintended weight loss of more than 10% in the 3 months prior to screening visit.

InterventionsIntervention group:
A nutritional concept containing specific selected ingredients.
Control group:
Isocaloric nutritional product with an almost identical appearance and flavour as the investigational product though without the specific selected ingredients.
Patients will be supplied with either a nutritional test or a control product for a period of 12 months.
OutcomesChange from baseline in CD4+ T-cell count during 12 months.
Starting date23/01/2007
Contact informationBarbara Mourmans email: barbara.mourmans@danone.com
Notes 

Range 2006

Trial name or titleThe Role of Nutritional Support and Diabetes During Treatment of Pulmonary TB: Two Randomized Nutritional Supplementation Trials in Tanzania
MethodsAllocation: Randomized, Control: Dose Comparison, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
ParticipantsInclusion Criteria:

- Adults with new sputum smear positive or negative pulmonary TB patients

Exclusion Criteria:

- pregnant, terminally ill, other serious diseases (except HIV and diabetes),
non-residents
Interventions

Dietary Supplement: Energy and proteins

Dietary Supplement: Multimicronutrients

Outcomes

Weight gain [Time Frame: 2 and 5 months]

Arm muscle and arm fat areas [Time Frame: 2 and 5 months]

CD4 count [Time Frame: 2 and 5 months]

Grip strength [Time Frame: 2 and 5 months]

HIV load [Time Frame: 2 months]

Mortality [Time Frame: 12 month]

Physical activity [Time Frame: 2 and 5 months]

Serum acute phase reactants [Time Frame: 2 months]

Starting dateApril 2006
Contact informationNyagosya Range, Muhimbili Medical Centre, NIMR
Notes 

Spirulina 2010

Trial name or title" Arthrospira Platensis" as Nutrition Supplementation for Female Adult Patients Infected by HIV in Yaoundé Cameroon
MethodsAllocation: Randomized, Control: Placebo Control, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Supportive Care
ParticipantsInclusion Criteria:

- confirm Infection with HIV

- aged= 18-49 years

- BMI< 23

Exclusion Criteria:

- male

- under HAART

- pregnancy

- severe opportunistic infection requiring intensive medical care

- active smoking

- initiation of antioxidant vitamin therapy

- hyperlipidemia

- diabetes

- kidney/liver dysfunction

- intractable diarrhea (at least six liquid stools daily)
InterventionsDietary Supplement: Arthrospira platensis
Outcomes

CD4 cell account

[Time Frame: 12 weeks]

Starting dateApril 2010
Contact informationNone provided
Notes 

Ancillary