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Nutritional interventions for reducing morbidity and mortality in people with HIV

  1. Sarah S. N. Mahlungulu2,
  2. Liesl Grobler1,*,
  3. Marianne ME Visser3,
  4. Jimmy Volmink4

Editorial Group: Cochrane HIV/AIDS Group

Published Online: 21 JAN 2009

Assessed as up-to-date: 21 MAY 2007

DOI: 10.1002/14651858.CD004536.pub2

Database Title

Additional Information

How to Cite

Mahlungulu SSN, Grobler L, Visser MME, Volmink J. Nutritional interventions for reducing morbidity and mortality in people with HIV. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD004536. DOI: 10.1002/14651858.CD004536.pub2.

Author Information

  1. 1

    University of Cape Town, Institute of Infectious Disease and Molecular Medicine (IIDMM), Observatory, Western Province, South Africa

  2. 2

    East London, South Africa

  3. 3

    Welgemoed, Western Cape, South Africa

  4. 4

    University of Stellenbosch, Faculty of Health Sciences, Tygerberg, South Africa

*Liesl Grobler, Institute of Infectious Disease and Molecular Medicine (IIDMM), University of Cape Town, Faculty of Health Sciences, Anzio Road, Observatory, Western Province, 7925, South Africa. liesl.grobler@uct.ac.za.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 21 JAN 2009

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

A lack of nutritious food (often the case in developing countries), loss of appetite, decreased absorption of nutrients due to gastrointestinal complications, and an increased resting energy expenditure (REE) all play an integral role in HIV-associated weight loss and wasting. Poor nutrient status in HIV-infected individuals worsens their immune status, rendering them vulnerable to infections and further deterioration in nutrient status (Scrimshaw 1997; Anabwani 2005). In HIV-infected children, the clinical picture is further complicated by the metabolic demands of growth and development. Dietary therapy is 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 the quality of life, and ultimately reduce mortality associated with the disease (Hsu 2005).

HIV-associated weight loss and wasting are independent contributing factors to poor clinical outcomes in people living with HIV/AIDS (Wheeler 1998). A 10% or greater loss of body weight over a year is common in HIV-infected people, although there is a high degree of variability in the extent of weight loss and wasting. 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).

In uncomplicated starvation, the body slows down its metabolic processes, minimising both resting energy expenditure (REE) and total energy expenditure (TEE), and conserving the body's protein stores at the expense of the fat stores. By contrast, in HIV infection, REE is increased in asymptomatic persons, and even more so in symptomatic persons, (Macallan 1995a; Grinspoon 1998; Batterham 2005), with both fat and protein stores being oxidised to fuel the body's energy requirements. Whole-body protein turnover is up to 25% higher in untreated HIV-infected individuals than in HIV-negative controls (Macallan 1995b). The increased protein turnover is positively correlated with REE (Melchior 1997). Furthermore, even in the face of adequate nutrition, fat stores are replenished more readily than protein stores (Kotler 1999). The resultant loss of body protein could further compromise the immune system of the HIV-infected individual.

In this review, the concept of a "balanced diet" refers to the regular intake of meals that contain all the essential nutrients that cannot be synthesised in adequate quantities by the body. A balanced diet will provide the necessary nutrients and energy required for the maintenance of body cells, tissues, and organs, and for normal growth and development. A balanced diet should generally consist of approximately 50% carbohydrates (e.g. fruit, vegetables, breads, cereals, rice, and pasta), 20% protein (e.g. meat, beans and peas, nuts and seeds) and 30% fat (e.g. oil, butter, cheese) and should provide between 5000-7000 kJ/day. These nutrient and energy requirements will vary depending on age, gender, level of physical activity, pregnancy and lactation needs, and general health status. In order to prevent weight loss and wasting, HIV-infected individuals should ensure that, at the very least, these basic nutrient and energy requirements are met.

Various nutritional interventions, including food-based interventions (high energy, protein, or fat diets), oral supplements with specific nutrients, enteral and total parenteral therapy, appetite stimulants and anabolic hormones (growth hormone), have been tested in HIV-infected individuals. An existing Cochrane review has summarised the effects of micronutrient supplementation in people with HIV/AIDS (Irlam 2005). We decided to synthesise the existing research on the effectiveness of macronutrients for improving outcomes in persons with HIV infection, particularly for those living in developing countries. This evidence should further assist professionals in managing malnutrition associated with the disease.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

The objective of this review was to evaluate the effectiveness of various macronutrient interventions, such as a balanced diet or a high protein, high carbohydrate, or high fat diet, given orally, in reducing morbidity and mortality in adults and children living with HIV infection.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
 

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. Studies involving HIV-infected pregnant women, as well as those assessing the effects of total parenteral or enteral nutritional interventions, and comparative studies examining the effect of two or more nutritional interventions, were excluded from this review. Trials evaluating micronutrient supplements in people with HIV infection were also excluded, as they form part of an existing Cochrane review (Irlam 2005).

 

Types of participants

Adults and children with HIV infection.

 

Types of interventions

Experimental
Various forms of macronutrient therapy administered orally (balanced diets or supplements; high fat, carbohydrate, and protein diets or supplements; diets or supplements containing specific nutritional elements, such as amino acids). The duration of the nutritional intervention had to be four weeks or more.

Control
No nutritional therapy or nutritional placebo.

 

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 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 measurements, such as body weight, body mass index (BMI), energy expenditure, and biochemical markers, such as serum albumin
  • dietary intake and appetite

 

Search methods for identification of studies

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).

Specific search strategies ( Table 1) were used to identify eligible randomised controlled trials or review articles in the following databases:
CENTRAL (up to March 2006)
MEDLINE (1966 to March 2006)
EMBASE (1988 to march 2006)
LILACS (up to March 2006)
AIDSearch (up to March2006)

Conference abstracts from the International AIDS Conference, reference lists of all relevant articles obtained (including those from previously published reviews), and clinical trial registers (www.clinicaltrials.gov and www.controlled-trials.com) were screened for potentially relevant articles or studies in progress.

 

Data collection and analysis

Trial selection
Three authors (SM, MV, and LG) independently applied the selection criteria to the results of the search to identify potentially relevant studies. If there was uncertainty about a study's eligibility, the full article was obtained. Any disagreements regarding study eligibility were resolved through discussion with the co-author (JV). Where disagreements could not be resolved, we sought clarification from the original investigators before reaching a decision. All studies not meeting the inclusion criteria were excluded and the reasons for exclusion were stated in the table "Characteristics of Excluded Studies."

Assessment of the methodological quality
Three authors (SM, MV, and LG) independently assessed the methodological quality of the included trials using the following criteria (Jadad 1996).

Generation of allocation sequence
The generation of allocation sequence was considered adequate if a truly random method had been used (computer-generated random numbers, table of random numbers, drawing of lots or envelopes, tossing a coin, shuffling cards, throwing dice, or other methods of allocation that appear to be unbiased and lead to an unpredictable sequence); or unclear if authors stated that the trial was randomised, but the method was not described). Trials using quasi-random methods where the allocation sequence could potentially be related to prognosis (e.g. based on case record number, date of birth, or date of admission) were not considered in this review.

Allocation concealment
Allocation concealment was considered adequate (a) if participants and the investigators enrolling participants could not foresee assignmenta priori numbered or coded drug containers of identical appearance prepared by an independent pharmacy; central randomisation performed at a site remote from trial location; sequentially numbered, opaque, sealed envelopes; or other descriptions that contained convincing elements of concealment; inadequate (b) if participants and investigators enrolling participants could foresee upcoming assignmentall procedures based on inadequate generation of allocation sequences; an open allocation schedule; unsealed or non-opaque envelopes; or a reported approach that could not be considered adequate; unclear (c) if unclear or the method was not adequately described.

Blinding
It was noted who (participant, care provider, assessor) was blinded in the trial.

Completeness of follow-up
We recorded the adequacy of follow-up as the % of randomised participants included in the analysis according to the following scale: a=>80%; b=<80%, c=unclear.

Data extraction
The full text of all included studies was obtained. SM, MV, and LG independently extracted data using a standardised and pre-piloted data-extraction form. Data relating to study design, participant characteristics, interventions, and outcomes were collected and entered into RevMan 4.2.8. Discrepancies regarding extracted data were resolved by discussion and, if necessary, referred to an additional reviewer (JV).

Data analysis
The data were analysed using RevMan Analyses (Version 1.0.3). Weighted mean difference was calculated for continuous data, with 95% confidence intervals as the measure of precision of the estimates. We planned to calculate relative risks for dichotomous data; however, at this stage none of the included studies have reported on dichotomous outcomes. We assessed homogeneity in the study results using the Chi-square test for heterogeneity with a 10% level of significance as the cut-off. Meta-analysis employed a fixed-effects model where results were homogeneous; otherwise, we used a random-effects model.

We planned to explore clinical heterogeneity based on participants' age, sex, socioeconomic status, ethnicity, and stage of HIV infection where possible. Furthermore, we planned to conduct a sensitivity analysis to determine the influence of adequacy of allocation concealment on the review results. We also planned to assess publication bias based on the degree of symmetry of the funnel plot. Currently, the available data do not permit any of these analyses.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

Search results
Eight trials involving 486 participants met our criteria. Twenty-eight studies initially deemed to be eligible for inclusion were subsequently excluded. Reasons for their exclusion are provided in the table "Characteristics of excluded studies."

Study setting
Four studies were conducted in the USA (Rabeneck 1998; Shabert 1999; Clark 2000; Keithley 2002a), two in Switzerland (Berneis 2000; Karsegard 2004) and one in Germany (Schwenk 1999). 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.

Participants
Male and female participants (mean±SD age: 39 ± 7 years) at different stages of HIV/AIDS were included in the studies. Seventy-three percent of the participants had advanced stage HIV/AIDS (stage C according to Centers for Disease Control and Prevention classification system), with baseline CD4 count below 350 cells/mm3 (mean±SD=299±203) and a viral load of about 3.8±1.2 log10 copies/µl1. Almost all (99%) participants were receiving some form of antiretroviral therapy. The mean body mass index of participants ranged from 19.9 to 26 kg/m2. Upon enrollment into the study, all participants were free of confirmed secondary infections or other signs and symptoms of infection, such as fever, chills, or persistent diarrhoea.

Nutritional interventions and comparison groups
Various types of macronutrient interventions were tested in the studies (for further details, see the table "Characteristics of Included Studies"). In five studies, participants in the experimental group supplemented their normal diet with balanced oral supplements in an attempt to increase energy intake by 600-960 kcal/day (Rabeneck 1998; Schwenk 1999; Berneis 2000; Keithley 2002a; de Luis 2003). All of these macronutrient interventions contained the required daily allowance (RDA) of various vitamins and minerals. 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. Furthermore, control participants in these studies received nutritional counselling alone. There were three comparison groups in Keithley 2002 (Keithley 2002a), two nutritional supplementation arms, and a control arm. In three studies, specific nutritional supplements (amino acid mixture containing arginine, glutamine and ß-hydroxy-ß-methylbutyrate (Clark 2000); monohydrated L-ornithine a-ketoglutarate (Karsegard 2004); L-glutamine and antioxidants (ascorbic acid, a-tocopherol, ß-carotene, selenium and N-acetyl cysteine) (Shabert 1999) were compared with isocaloric (Shabert 1999; Clark 2000) or isonitrogenous nutritional placebos (Karsegard 2004). In Shabert 1999, (Shabert 1999) all participants received the recommended daily allowance of vitamins and minerals. In seven studies, both the experimental and the control group received nutritional counselling in conjunction with either the nutritional intervention or placebo (Rabeneck 1998; Shabert 1999; Schwenk 1999; Berneis 2000; Keithley 2002a; de Luis 2003; Karsegard 2004). Nutritional counselling was not provided to any of the participants in the study by Clark 2000 (Clark 2000). The duration of intervention varied from one year (Keithley 2002a) to 12 weeks (Shabert 1999; Berneis 2000; de Luis 2003; Karsegard 2004) to eight weeks (Schwenk 1999; Clark 2000) to six weeks (Rabeneck 1998).

Outcomes
Body weight was reported in all of the studies. Fat-free mass and fat mass were measured using bioelectrical impedance in seven studies (Rabeneck 1998; Shabert 1999; Schwenk 1999; Berneis 2000; Keithley 2002a; de Luis 2003; Karsegard 2004). In Clark 2000 (Clark 2000) fat-free mass and fat mass were measured using skinfold thickness, air displacement plethysmography and computed tomography scan of the thigh musculature. Six studies reported CD4 counts (Shabert 1999; Berneis 2000; Clark 2000; Keithley 2002a ; de Luis 2003; Karsegard 2004) and three studies reported viral loads (Clark 2000; de Luis 2003; Karsegard 2004) although in de Luis 2003 (de Luis 2003) viral load was reported in copies/ml (1). Five studies reported the total energy intake (kcal/day-1 ) (Schwenk 1999; Berneis 2000; Keithley 2002a; de Luis 2003; Karsegard 2004) and three studies reported the daily protein intake (g day-1) (Berneis 2000; de Luis 2003; Karsegard 2004) of the participants. Five studies reported on the adverse events encountered during the study period (Rabeneck 1998; Shabert 1999; Schwenk 1999; Clark 2000; Karsegard 2004).

 

Risk of bias in included studies

Generation of allocation sequence
The generation of the allocation sequence was adequate in three studies (Berneis 2000; Clark 2000; Keithley 2002a) and unclear in five studies (de Luis 2003; Karsegard 2004; Rabeneck 1998; Schwenk 1999;).

Allocation concealment
Allocation concealment was adequate in 2 studies (Karsegard 2004; Schwenk 1999) and unclear in 6 studies (Rabeneck 1998; Shabert 1999; Shabert 1999; Berneis 2000; Clark 2000; de Luis 2003; Keithley 2002a).

Blinding
In one study, participants, care providers, and outcome assessors were all blinded to the treatment being received (Shabert 1999). In another study, participants and providers were blinded, but it is not clear if the outcome assessors were blinded (Karsegard 2004). In a third study, the outcome assessors were blinded, but it is not clear if the participants or providers were blinded (Clark 2000). In the five remaining studies, participants and providers were not blinded and it is not clear if the assessors were blinded (Rabeneck 1998; Schwenk 1999; Berneis 2000; Keithley 2002a; de Luis 2003).

Completeness of follow-up
All of the studies accounted for participants lost to follow-up (withdrawals, dropouts, and protocol deviations) during the course of each trial. In four studies, follow-up rates were greater than 80% (Shabert 1999; Schwenk 1999; Berneis 2000; de Luis 2003) and in the remaining four studies it was less than 80% (Rabeneck 1998; Clark 2000; Keithley 2002a; Karsegard 2004).

 

Effects of interventions

None of the studies included in this review assessed the effects of macronutrient interventions the on 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.

Any nutritional supplementation (with or without nutritional counselling) versus no nutritional supplementation or nutritional placebo (with or without nutritional counselling)
There were three comparison groups in Keithley 2002 (Keithley 2002a), two nutritional supplementation arms, and a control arm. In order to include both nutritional supplementation arms in the meta-analysis, the participants in the control arm were divided in two (Ramsay 2003). Overall, nutritional supplementation significantly improved energy intake (Analysis 01.01: five trials; n=254; WMD 367 kcal/day-1; 95% CI: 217 to 516), protein intake (Analysis 01.02: three trials; n=128; WMD 17 g.day-1; 95% CI: 8 to 26) and viral load (Analysis 01.08: two trials; n=88; WMD -0.45 log10 copies/ml-1; 95% CI: -0.87 to -0.04) compared with no nutritional supplementation or placebo. There was no evidence of an effect on body weight (Analysis 01.03: eight trials; n=423; WMD 0.24 kg; 95% CI: -0.6 to 1.1), fat mass (Analysis 01.04: six trials; n=305; WMD -0.73 kg; 95% CI: -1.83 to 0.37), fat-free mass (Analysis 01.05: five trials; n=311; WMD 0 kg; 95% CI: -2.3 to 2.4) or CD4 count (Analysis 01.06: 6 trials; n=271; WMD 0.23 cells/mm-3; 95% CI: -40.2 to 40.6). Although three studies reported on HIV viral load, only two of the studies (Clark 2000; Karsegard 2004) could be included in the meta-analysis. Additionally, the results from de Luis (de Luis 2003) could not be included in the meta-analysis, as the viral load values were presented in copies.ml-1 instead of log10 copies.ml-1 (Authors were contacted on numerous occasions for this information, but no response was received).

Balanced nutritional supplementation versus no nutritional supplementation or nutritional placebo
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-1, compared with no nutritional supplements, significantly increased energy (Analysis 01.01: four trials; n=211; WMD 407 kcal.day-1; 95% CI: 250 to 563) and protein intake (Analysis 01.02: two trials; n=85; WMD 23 g.day-1; 95% CI 13 to 34). No differences in body weight (Analysis 01.03: five trials; n=313; WMD -0.2 kg; 95% CI: -1.1 to 0.7), fat mass (Analysis 01.04: four trials; n=234; WMD -1.17 kg; 95% CI: -2.6 to 0.26), fat-free mass (Analysis 01.05: three trials; n=222; WMD -0.38 kg; 95% CI: -2.8 to 2.0) or CD4 count (Analysis 01.06: three trials; n=161; WMD -21.1 cells/mm3; 95% CI: -89.69 to 47.49) was noted between the supplemented and non-supplemented groups. No difference was noted in HIV viral load (copies/ml-1) between the supplemented and non-supplemented groups, post-intervention, in the study reporting on this outcome (de Luis 2003). Nutritional counselling was provided to all of the participants included in these studies.

Specific nutritional supplementation versus no nutritional supplementation or nutritional placebo
Specific nutritional supplements investigated in these trials included an amino acid mixture containing arginine, glutamine and ß-hydroxy-ß-methylbutyrate (Clark 2000); monohydrated L-ornithine a-ketoglutarate (Karsegard 2004); L-glutamine and antioxidants (ascorbic acid, a-tocopherol, ß-carotene, selenium and N-acetyl cysteine) (Shabert 1999). These specific nutritional supplements were compared with isocaloric (Shabert 1999; Clark 2000) or isonitrogenous nutritional placebos (Karsegard 2004). Nutritional counselling was provided to all participants in Karsegard 2004 (Karsegard 2004) and Shabert 1999 (Shabert 1999) but no participants received nutritional counselling in Clark 2000 (Clark 2000).

Supplementation with specific nutritional supplements significantly increased body weight (Analysis 01.03: three trials; n=110; WMD 1.93 kg; 95% CI: 0.15 to 3.71) and decreased HIV-viral load (Analysis 01.08: two trials; n=88; WMD -0.45 log10 copies/ml-1; 95% CI: -0.87 to -0.04). However, supplementation with specific nutrients did not alter energy intake (Analysis 01.01: one trial; n=43; WMD -66 kcal/day-1; 95% CI: -581 to 449), protein intake (Analysis 01.02: one trial; n=43; WMD -0.7 g.day-1; 95% CI: -19 to 17), fat mass (Analysis 01.04: two trials; n=67; WMD -0.1 kg; 95% CI: -1.8 to 1.6), fat-free mass (Analysis 01.05: two trials; n=89; WMD -0.4 kg; 95% CI: -8.6 to 7.8) or CD4 count (Analysis 01.06: three trials; n=110; WMD 11.57 cells/mm3; 95% CI: -38.43 to 61.57).

Although adverse events were reported in five studies (Rabeneck 1998; Shabert 1999; Schwenk 1999; Clark 2000; Karsegard 2004) only two studies noted any adverse events in any of the participants. In Rabeneck 1998 (Rabeneck 1998), one participant discontinued the supplement (Lipisorb, Mead Johnson, Evansville, Indiana, USA) due to nausea and epigastric burning. In Karsegard 2004 (Karsegard 2004) the frequency of gastrointestinal events was closely monitored in both comparison groups. A higher frequency of gastrointestinal events was noted in the group receiving monohydrated L-ornithine a-ketoglutarate compared with the placebo group (RR: 1.59, 95% CI: 1.06 to 2.39).

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

HIV/AIDS has many faces. There are major differences between HIV-positive individuals in developed and developing 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 to secondary infections, nutritional status, and individual response to the various treatments received. These complexities must be taken into account when formulating recommendations and guidelines on nutrient and energy supplementation for HIV-infected individuals.

Our review establishes that experimental evidence on the effects of macronutrient supplementation on important clinical outcomes in HIV-infected individuals is surprisingly limited; despite an exhaustive search, we found only eight small, randomised trials that met our inclusion criteria. Overall, macronutrient interventions, compared with placebo or no nutritional supplementation, increased energy and protein intakes but had no effect on other parameters. When analysed separately, balanced nutritional supplements aimed at improving energy intake by 600-960 kcal/day increased intakes of energy and protein; while supplementation with specific nutritional supplements increased body weight and decreased HIV viral load, leaving other outcomes unchanged.

These findings must be interpreted with caution for several reasons. The studies included in this review are all relatively small (combined sample sizes for the various outcomes range from 128 to 178 participants) and, therefore, the play of chance cannot be ruled out as a possible explanation of the results obtained. There are a number of concerns around key aspects of study quality, which may be, in part, a result of poor reporting. The relatively high degree of loss to follow-up of participants (ranging from 6% to 37%), as well as differences in loss to follow-up of participants between the comparison groups (ranging from 0% to 25%), may also bias the study results.

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. Worth noting is that patients with acute opportunistic infectionsthe category most prone to weight losswho are theoretically most likely to experience improvements in nutritional status (such as weight gain), were not assessed in the studies we evaluated. Nonetheless, if the finding of increased energy and protein intake in our review is valid, this would be important, given that decreased energy intake and accelerated protein turnover is common in people with HIV/AIDS. The statistically significant reduction in HIV viral load in patients receiving specific nutritional supplements is encouraging, although this change can be considered to be within the margin of technical or biological variation, and therefore may not be clinically important (Chernoff 2002).

To date, few nutritional intervention studies have been conducted in malnourished HIV-infected children. In two quasi-randomised studies conducted in Malawi, ready-to-use-food (an energy-dense liquid paste made from peanut butter, milk powder, oil, sugar, vitamins, and minerals) was significantly more effective than traditional food (a blend of maize and soy flour) in relieving malnutrition in HIV-infected and non-infected children (Sandige 2004; Ndekha 2005). In a randomised study conducted in Zambia, HIV-infected and non-infected children receiving an amino-acid-based elemental feed for four weeks gained more weight than children receiving standard nutritional rehabilitation (Amadi 2005).

Finally, the generalisability of our findings to patients in developing countries must be carefully considered. All of the trials were conducted in either North America or Europe and evaluated males and females between 30 and 50 years old who were reasonably well-nourished in terms of their body mass index, and were receiving antiretrovirals. These observations highlight some challenges in applying the trial findings to people in developing countries, where nutritional status is generally poor and access to antiretroviral therapy is limited.

In sum, there is limited evidence from randomised trials conducted in high-income countries that targeted supplementation of the diet with macronutrients increases energy intake and reduces HIV viral load in HIV-infected patients on antiretroviral therapy. However, the effect of nutritional supplementation on mortality, morbidity, body weight, and immunological parameters remains unclear.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

 

Implications for practice

The evidence base on the effects of macronutrients in people living with HIV is limited to only a few small, randomised trials conducted in high-income countries. These studies have measured intermediate endpoints (such as energy intake) but not important clinical outcomes (such as death and morbidity). There are also substantial variations between studies in the nutritional composition of the experimental and control interventions, the use of dietary counselling, disease stage, and treatment status of the participants. These limitations currently preclude any firm conclusions regarding the effects of macronutrient supplementation on morbidity and mortality in HIV-infected individuals

 
Implications for research

There is an urgent need for high-quality, adequately powered randomised controlled trials investigating the effectiveness of clearly specified macronutrient interventions in reducing morbidity and mortality in HIV-infected individuals living in developing countries. Interventions should be well-defined and targeted at specific target populations defined by age (adults and children), CD4 cell count, viral load, treatment status (presence and absence of treatment; type of antiretroviral therapy) and baseline nutritional status (under-nourished, adequately nourished or over-nourished).

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

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. This 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.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
Download statistical data

 
Comparison 1. Any nutritional supplement vs no nutritional supplement or nutritional placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Energy intake (kcal/day)6254Mean Difference (IV, Fixed, 95% CI)366.66 [217.05, 516.26]
    1.1 Balanced supplements to increase energy intake
5211Mean Difference (IV, Fixed, 95% CI)406.59 [250.24, 562.95]
    1.2 Specific supplementation
143Mean Difference (IV, Fixed, 95% CI)-66.0 [-580.64, 448.64]
 2 Protein intake (g/day)3128Mean Difference (IV, Fixed, 95% CI)17.36 [8.37, 26.34]
    2.1 Balanced supplements to increase energy intake
285Mean Difference (IV, Fixed, 95% CI)23.33 [12.97, 33.70]
    2.2 Specific supplementation
143Mean Difference (IV, Fixed, 95% CI)-0.70 [-18.71, 17.31]
 3 Body weight9423Mean Difference (IV, Fixed, 95% CI)0.24 [-0.57, 1.06]
    3.1 Balanced supplements to increase energy intake
6313Mean Difference (IV, Fixed, 95% CI)-0.20 [-1.12, 0.71]
    3.2 Specific supplement (Amino acid)
3110Mean Difference (IV, Fixed, 95% CI)1.93 [0.15, 3.71]
 4 Fat mass6301Mean Difference (IV, Fixed, 95% CI)-0.73 [-1.83, 0.37]
    4.1 Balanced supplements to increase energy intake
4234Mean Difference (IV, Fixed, 95% CI)-1.17 [-2.60, 0.26]
    4.2 amino acid supplements
267Mean Difference (IV, Fixed, 95% CI)-0.09 [-1.81, 1.63]
 5 Fat free mass5311Mean Difference (IV, Random, 95% CI)0.00 [-2.34, 2.35]
    5.1 Balanced supplements to increase energy intake
3222Mean Difference (IV, Random, 95% CI)-0.38 [-2.77, 2.01]
    5.2 amino acid supplements
289Mean Difference (IV, Random, 95% CI)-0.39 [-8.56, 7.78]
 6 CD47271Mean Difference (IV, Fixed, 95% CI)0.23 [-40.17, 40.64]
    6.1 Balanced supplements to increase energy intake
4161Mean Difference (IV, Fixed, 95% CI)-21.10 [-89.69, 47.49]
    6.2 Specific supplement
3110Mean Difference (IV, Fixed, 95% CI)11.57 [-38.43, 61.57]
 7 Viral load (log10 copies/ml)288Mean Difference (IV, Fixed, 95% CI)-0.45 [-0.87, -0.04]

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Last assessed as up-to-date: 21 May 2007.

DateEventDescription
29 October 2008AmendedConverted to new review format.


 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

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

 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

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

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
 

Internal sources

  • UNIVERSITY OF NATAL, DURBAN, South Africa.

 

External sources

  • SOUTH AFRICAN COCHRANE CENTER, South Africa.
  • COCHRANE HEALTH PROMOTION AND PUBLIC HEALTH FIELD, Australia.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. Additional references
Berneis 2000 {published data only}
  • Berneis K, Battegay S, Bassetti S, Nuesch R, Leisibach A, Bilz S, Keller U. Nutritional supplements combined with dietary counselling diminish whole body protein catabolism in HIV-infected patients. European Journal of Clinical Investigation 2000;30(1):87-94.
    Direct Link:
Clark 2000 {published data only}
  • Clark RH, Feleke G, Din M, Yasmin T, Singh G, Khan FA, Rathmacher JA. Nutritional treatment for Acquired Immunodeficiency Virus-associated wasting using B-hydroxy B-methylbutyrate, glutamine and arginine: a randomised, double-blind, placebo-controlled study. Journal of Parenteral and Enteral Nutrition 2000;24:133-139.
de Luis 2003 {published data only}
  • de Luis D, Aller R, Bachiller P, Gonzalez-Sagrado M, de Luis J, Izaola O, Terroba MC, Cuellar L. Isolated dietray counselling program versus supplement and dietary counselling in patients with human immunodeficiency virus infection. Med Clin (Barc) 2003;120(15):565-567.
Karsegard 2004 {published data only}
  • Karsegard VL, Raguso CA, Genton L, Hirschel B, Pichard C. L-Ornithine alpha-Ketoglutarate in HIV infection: Effects on muscle, gastrointestinal and immune functions. Nutrition 2004;20:515-520.
Keithley 2002a {published data only}
  • Keithley JK, Swanson B, Zeller JM, Sha BE, Cohen M, Hershow R, et al. Comparison of standard and immune-enhancing oral formulas in asymptomatic HIV-infected persons: a multicenter randomized controlled clinical trial. Journal of Parenteral and Enteral Nutrition 2002;26(1):6-14.
Keithley 2002b {published data only}

 

Rabeneck 1998 {published data only}
  • Rabeneck L, Palmer A, Knowles JB, Seidehamel RJ, Harris CL, Merkel KL, Risser JMH, Akrabawi SS. A randomised controlled trial evaluating nutrition counselling with or without supplementation in malnourished HIV-infected patients. Journal of American Dietary Association 1998;98:434-438.
Schwenk 1999 {published data only}
  • Schwenk A, Steuck H, Kremer G. Oral supplements as adjunctive treatment to nutritional counselling in malnourished HIV-infected patients: randomised controlled trial. Clinical Nutrition 1999;18(6):371-374.
Shabert 1999 {published data only}
  • Shabert JK, Winslow C, Lacey JM, Wilmore DW. Glutamine-antioxidant supplementation increases body cell mass in AIDS patients with weight loss: a randomised, double-blind controlled trial. Nutrition 1999;15:860-864.

References to studies excluded from this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. Additional references
Amadi 2005 {published data only}
  • Amadi B, Mwiya M, Chomba E, Thomson M, Chintu C, Kelly P, et al. Improved nutritional recovery on an elemental diet in Zambian children with persistent diarrhoea and malnutrition. Journal of Tropical Pediatrics 2005;51(1):5-10.
Bakeine 1997 {published data only}
  • Bakeine J, Mathias PM, Mugyeni PN. The effects of early nutritional supplementation with Nutrifil or Corn Soya Blend on the nutritional and immune status of adults with HIV infection in Uganda. Proceedings of the Nutritional Society. 1997; Vol. 56, issue 3:282A.
Bell 1999 {published data only}
  • Bell SJ, Chavali S, Bistrian BR, Connolly CA, Utsunomiya T, Forse RA. Dietary fish oil and cytokine and eicosanoid production during human immunodeficiency virus infection. Journal of Parenteral and Enteral Nutrition 1996;20(1):43-49.
Breuikreuitz 2000 {published data only}
  • Breitkreutz R, Pittack N, Nebe CT, Schuster D, Brust J, Beichert M, Hack V, Daniel V, Edler L, Droge W. Improvement of immune functions in HIV infection by sulfur supplementation: two randomized trials. Journal of Molecular Medicine 2000;78:55-62.
Charlin 2002 {published data only}
  • Charlin V, Carrasco F, Sepulveda C, Torres M, Kehr J. Nutritional supplementation according to energy and protein requirements in malnourished HIV-infected patients. Archives Latinoamerican Nutrition 2002;52(3):267-273.
Chlebowski 1993 {published data only}
  • Cheblowski RT, Beall G, Grosvenor M, Lillington L, Weintraub N, Ambler C, Richards EW, Abbruzzese BC, McCamish MA, Cope FO. Long-term effects of early nutritional support with new enterotropic peptide-based formula vs standard enteral formula in HIV-infected patients: a randomised prospective trial. Nutrition 1993;9(6):554-556.
Comi 1996 {published data only}
  • Comi D, Zambelli A, Meraviglia P, Cargnel A, Martini F. Effects of two different diets on AIDS patients' nutritional status. International Conference on AIDS. 1996; Vol. 11:293.
Craig 1997 {published data only}
  • Craig GB, Darnell BE, Weinsier RL, Saag MS, Epps L, Mullins L, et al. Decreased fat and nitrogen losses in patients with AIDS receiving medium-chain-triglyceride-enriched formula vs those receiving long-chain-triglyceride-containing formula. Journal of the American Dietary Association 1997;97(6):605-611.
de Luis Roman 2001 {published data only}
  • de Luis Roman DA, Bachiller P, Izaola O, Romero E, Martin J, Arranz M, Eiros Bouza JM. Nutritional treatment for acquired immunodeficiency virus. European Journal of Clinical Nutrition 2001;55:1048-1052.
Engelson 1998 {published data only}
  • Engelson ES, Kotler DP, Schur I, Matthews DE. Effect of a high protein diet on protein metabolism in HIV-infected men and women. International Conference on AIDS. 1998; Vol. 12:553.
Gibert 1999 {published data only}
  • Gibert CL, Wheeler DA, Collins G, Madans M, Muurahainen N, Raghavan SS, et al. Randomized, controlled trial of caloric supplements in HIV infection. Terry Beirn Community Programs for Clinical Research on AIDS. Journal of Acquired Immune Deficiency Syndromes 1999;22(3):253-259.
Hellerstein 1994 {published data only}
  • Hellerstein M. Effects of enteral nutrition supplements on HIV disease. International Conference on AIDS. 1994.
Hellerstein 1996 {published data only}
  • Hellerstein MK, Wu K, McGrath M, Faix D, George D, Shackleton CH, Horn W, Hoh R, Neese RA. Effects of dietary n-3 fatty acid supplementation in men with weight loss associated with the acquired immune deficiency syndrome: Relation to indices of cytokine production.. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 1996;11(3):258-270.
Hirschel 1996 {published data only}
  • Hirschel B. Double-blind randomised trial of arginine and omega-3 fatty acids. Oral supplementation in HIV infection. International Conference on AIDS. 1996.
Hoh 1998 {published data only}
  • Hoh R, Pelfini A, Neese RA, Chan M, Cello JP, Cope FO, Abbruzese BC, Richards EW, Courtney K, Hellerstein MK. De novo lipogenesis predicts short-term body-composition response by bioelectrical impedance analysis to oral nutritional supplements in HIV-associated wasting. The American Journal of Clinical Nutrition 1998;68(1):154-163.
Kotler 1998 {published data only}
  • Kotler DP, Fogleman L, Tierney AR. Comparison of total parenteral nutrition and an oral, semielemental diet on body composition, physical function, and nutrition-related costs in patients with malabsorption due to acquired immunodeficiency syndrome. Journal of Parenteral and Enteral Nutrition 1998;22(3):120-126.
Melchior 1996 {published data only}
  • Melchior JC, Chastang C, Gelas P, Carbonnel F, Zazzo JF, Boulier A, Cosnes J, Bouletreau P, Messing B. Efficacy of 2-month total parenteral nutrition in AIDS patients: a controlled randomized prospective trial. The French Multicenter Total Parenteral Nutrition Cooperative Group Study. AIDS 1996;10(4):379-384.
Melchior 1998 {published data only}
  • Melchior JC, Gelas P, Carbonnel F, Zazzo JF, Henzel D, Cosnes J, et al. Improved survival by home total parenteral nutrition in AIDS patients: follow-up of a controlled randomized prospective trial. AIDS 1998;12(3):336-337.
Mendez 1998 {published data only}
  • Mendez D, Glesby M, Muurahainen N, Kotler DP, Tierney AR. Nutritional supplements containing long- or medium-chain triglycerides: effects upon body weight and composition in HIV-infected subjects with less than 100 CD4+ lymphocytes/mm3. International Conference on AIDS. 1998; Vol. 12, issue 42347:843.
Micke 2001 {published data only}
  • Micke P, Beeh KM, Schlaak JF, Buhl R. Oral supplementation with whey proteins increases plasma glutathione levels of HIV-infected patients. European Journal of Clinical Investigation 2001;31(2):171-178.
    Direct Link:
Micke 2002 {published data only}
Ndekha 2005 {published data only}
  • Ndekha MJ, Manary MJ, Ashorn P, Briend A. Home-based therapy with ready-to-use therapeutic food is of benefit to malnourished, HIV-infected Malawian children. Acta Paediatrica, International Journal of Paediatrics 2005;94(2):222-225.
Pichard 1998 {published data only}
  • Pichard C, Sudre P, Karsegard V, Yerly S, Slosman DO, Delley V, Perrin L, Hirschel B. A randomised double-blind controlled study of 6 months of oral nutritional supplementation with arginine and omega-3 fatty acids in HIV-infected patients. Swiss HIV Cohort Study. AIDS 1998;12(1):53-63.
Schwenk 1996 {published data only}
  • Schwenk A, Becker K, Breidenbach M, Schrappe M, Diehl V, Kremer G, et al. Enteral nutrition in AIDS cachexia: controlled study on the role of fibre. International Conference on AIDS. 1996; Vol. 11:102.
Suttmann 1996 {published data only}
  • Suttmann U, Ockenga J, Schneider H, Selberg O, Schlesinger A, Gallati H, Wolfram G, Deicher H, Muller MJ. Weight gain and increased concentrations of receptor proteins for tumor necrosis factor after patients with symptomatic HIV infection received fortified nutrition support. Journal of American Dietary Assocation 1996;96(6):565-569.
Wanke 1996 {published data only}
  • Wanke CA, Pleskow D, Degirolami PC, Lambl BB, Merkel K, Akrabawi S. A medium chain triglyceride-based diet in patients with HIV and chronic diarrhea reduces diarrhea and malabsorption: a prospective, controlled trial. Nutrition 1996;12:766-771.
Winkler 2004 {published data only}
  • Winkler P, Ellinger S, Boetzer AM, Arendt BM, Berthold HK, Rockstroh JK, et al. Lymphocyte proliferation and apoptosis in HIV-seropositive and healthy subjects during long-term ingestion of fruit juices or a fruit-vegetable-concentrate rich in polyphenols and antioxidant vitamins. European Journal of Clinical Nutrition 2004;58(2):317-325.
Wohl 2005 {published data only}
  • Wohl DA, Tien HC, Busby M, Cunningham C, MacIntosh B, Napravnik S, et al. Randomized study of the safety and efficacy of fish oil (omega-3 fatty acid) supplementation with dietary and exercise counseling for the treatment of antiretroviral therapy-associated hypertriglyceridemia. Clinical Infectious Diseases 2005;41(10):1498-1504.

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. Additional references
Anabwani 2005
Batterham 2005
  • Batterham MJ. Investigating heterogeneity in studies of resting energy expenditure in persons with HIV/AIDS: a meta-analysis. American Journal of Clinical Nutrition 2005;81(3):702-713.
Chernoff 2002
  • Chernoff DN. The significance of HIV viral load assay precision: A review of the package insert specifications of two commercial kits. Journal of the International Association of Physicians in AIDS Care 2002;1(4):134-140.
Grinspoon 1998
  • Grinspoon S, Corcoran C, Miller K, Wang E, Hubbard J, Schoenfeld D, et al. Determinants of increased energy expenditure in HIV-infected women. American Journal of Clinical Nutrition 1998;68(3):720-725.
Hsu 2005
  • Hsu JWC, Pencharz PB, Macallan D, Tomkins A. Macronutrients and HIV/AIDS: a review of current evidence. http://www.who.int/nutrition/topics/Paper%20Number%201%20-%20Macronutrients.pdf 2005.
Irlam 2005
  • Irlam JH, Visser ME, Rollins N, Siegfried N. Micronutrient supplementation in children and adults with HIV infection. Cochrane Database of Systematic Reviews 2005, Issue 4. [Art. No.: CD003650. DOI: ]
Jadad 1996
  • Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary. Controlled Clinical Trials 1996;17(1):1-12.
Kotler 1999
  • Kotler DP, Rosenbaum K, Wang J, Pierson RN. Studies of body composition and fat distribution in HIV-infected and control subjects. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 1999;20(3):228-237.
Macallan 1993
  • Macallan DC, Noble C, Baldwin C, Foskett M, McManus T, Griffin GE. Prospective analysis of patterns of weight change in stage IV human immunodeficiency virus infection. The American Journal of Clinical Nutrition 1993;58(3):417-424.
Macallan 1995a
  • Macallan DC, Noble C, Baldwin C, Jebb SA, Prentice AM, Coward WA, et al. Energy expenditure and wasting in human immunodeficiency virus infection. New England Journal of Medicine 1995;333(2):83-88.
Macallan 1995b
  • Macallan DC, McNurlan MA, Milne E, Calder AG, Garlick PJ, Griffin GE. Whole-body protein turnover from leucine kinetics and the response to nutrition in human immunodeficiency virus infection. American Journal of Clinical Nutrition 1995;61(4):818-826.
Macallan 1998
  • Macallan DC. Sir David Cuthbertson Prize Medal Lecture. Metabolic abnormalities and wasting in human immunodeficiency virus infection. The Proceedings of the Nutrition Society 1998;57(3):373-380.
Melchior 1997
Ramsay 2003
  • Ramsay C. How do you include trials with more than two groups into a single meta-analysis?. http://www.epoc.uottawa.ca/FAQmultiplegroups2003.pdf 2003; Vol. [Accessed 04/01/2007].
Sandige 2004
  • Sandige H, Ndekha MJ, Briend A, Ashorn P, Manary MJ. Home-based treatment of malnourished Malawian children with locally produced or imported ready-to-use food.. Journal of pediatric gastroenterology and nutrition 2004;39(2):141-146.
Scrimshaw 1997
Wheeler 1998
  • Wheeler DA, Gibert CL, Launer CA, Muurahainen N, Elion RA, Abrams DI, et al. Weight loss as a predictor of survival and disease progression in HIV infection. Terry Beirn Community Programs for Clinical Research on AIDS. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 1998;18(1):80-85.
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