Intervention Review

You have free access to this content

Nutritional interventions for reducing morbidity and mortality in people with HIV

  1. Liesl Grobler1,2,*,
  2. Nandi Siegfried3,4,
  3. Marianne E Visser5,
  4. Sarah SN Mahlungulu6,
  5. Jimmy Volmink1,7

Editorial Group: Cochrane HIV/AIDS Group

Published Online: 28 FEB 2013

Assessed as up-to-date: 22 MAY 2012

DOI: 10.1002/14651858.CD004536.pub3


How to Cite

Grobler L, Siegfried N, Visser ME, Mahlungulu SSN, Volmink J. Nutritional interventions for reducing morbidity and mortality in people with HIV. Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD004536. DOI: 10.1002/14651858.CD004536.pub3.

Author Information

  1. 1

    South African Medical Research Council, South African Cochrane Centre, Tygerberg, Western Cape, South Africa

  2. 2

    Stellenbosch University, Centre for Evidence-based Health Care, Cape Town, Western Cape, South Africa

  3. 3

    University of Cape Town, Department of Psychiatry and Mental Health, Faculty of Health Sciences, Cape Town, South Africa

  4. 4

    University of California, San Francisco, Department of Epidemiology and Biostatistics, San Francisco, California, USA

  5. 5

    Stellenbosch University, Division of Human Nutrition, Faculty of Medicine and Health Sciences, Tygerberg, South Africa

  6. 6

    Eastern Cape Department of Health, Lilitha College of Nursing, Lusikisiki, Eastern Cape, South Africa

  7. 7

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

*Liesl Grobler, liesl.nicol@gmail.com.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 28 FEB 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Berneis 2000

MethodsCOUNTRY:

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.


ParticipantsINCLUSION 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).


InterventionsINTERVENTION:

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


OutcomesPRIMARY 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


NotesInformation 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

MethodsCOUNTRY:

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.


ParticipantsINCLUSION 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.


InterventionsINTERVENTION:

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.


OutcomesPRIMARY 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.


NotesETHICS

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

MethodsCOUNTRY:

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.


ParticipantsINCLUSION 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.


InterventionsINTERVENTION:

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%.


OutcomesPRIMARY 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.


NotesETHICS:

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

MethodsCOUNTRY:

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


ParticipantsThe 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


InterventionsINTERVENTION:

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


OutcomesNutrition 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)


NotesETHICS:

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

MethodsCOUNTRY:

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.


ParticipantsINCLUSION 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).


InterventionsINTERVENTION:

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


OutcomesPRIMARY 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)


NotesETHICS:

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

MethodsCOUNTRY:

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.


ParticipantsINCLUSION 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


InterventionsINTERVENTION 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.


OutcomesPRIMARY 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.


NotesETHICS

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

MethodsCOUNTRY:

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.


ParticipantsINCLUSION 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


InterventionsINTERVENTION:

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


OutcomesOutcomes not distinguished as primary or secondary.

  • T lymphocyte counts (CD4+ and CD8+)
  • Erythrocyte glutathione concentration
  • Occurence of associated co-infections
  • Hematological parameters
  • Viral load


NotesETHICS:

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

MethodsCOUNTRY:

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.


ParticipantsINCLUSION 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.


InterventionsINTERVENTION 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.


OutcomesPRIMARY 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.


NotesETHICS:

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

MethodsCOUNTRY:

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.


ParticipantsINCLUSION 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%).


InterventionsINTERVENTION:

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.


OutcomesPRIMARY 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


NotesETHICS

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

MethodsCOUNTRY:

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.


ParticipantsINCLUSION 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.


InterventionsINTERVENTION:

  • 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)


OutcomesPRIMARY 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)


NotesETHICS:

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

MethodsCOUNTRY:

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


ParticipantsINCLUSION 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.


InterventionsINTERVENTION:

  • 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.


OutcomesPRIMARY 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


NotesETHICS:

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

MethodsCOUNTRY:

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.


ParticipantsINCLUSION 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.


InterventionsINTERVENTION:

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.


OutcomesPRIMARY 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


NotesETHICS:

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

MethodsCOUNTRY:

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


ParticipantsINCLUSION 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


InterventionsINTERVENTION:

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.


OutcomesPRIMARY 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.


NotesETHICS:

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

MethodsCOUNTRY:

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.


ParticipantsINCLUSION 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


InterventionsINTERVENTION:

  • 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


OutcomesOUTCOMES:

  • Socio demographic characteristics and disease history (questionnaire)
  • Clinical outcomes
  • Anthropometry
  • CD4 count
  • Creatinine
  • Protein in blood
  • Karnofsky scores


NotesETHICS:

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

MethodsCOUNTRY:

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.

ParticipantsINCLUSION 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.

OutcomesBody composition (primary outcome reported: Change in lean body mass)

Anthropometry

Haemoglobin

Haematokrit

CD4 count

Notes

van der Horst 2009

MethodsCOUNTRY:

Malawi

ParticipantsInclusion 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

MethodsRandomized, 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

ParticipantsInclusion criteria: HIV positive, Anti Retroviral Therapy (ART) naive

Exclusion criteria: pregnancy, lactation, malignancy, renal disease, diabetes

InterventionsIntervention1:

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.

Outcomesimprovement 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;

ParticipantsInclusion 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

InterventionsDietary Supplement: Energy and proteins

Dietary Supplement: Multimicronutrients

OutcomesWeight 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

OutcomesCD4 cell account

[Time Frame: 12 weeks]

Starting dateApril 2010

Contact informationNone provided

Notes

 
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]

 
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 weight1Mean Difference (IV, Random, 95% CI)Subtotals only

    1.1 ART arm: body weight at baseline
1617Mean Difference (IV, Random, 95% CI)-0.58 [-1.47, 0.31]

    1.2 pre-ART arm: body weight at baseline
1429Mean Difference (IV, Random, 95% CI)0.60 [-0.60, 1.80]

    1.3 ART arm: body weight at 1 month
1366Mean Difference (IV, Random, 95% CI)0.58 [-0.62, 1.78]

    1.4 pre-ART arm: body weight at 1 month
1261Mean Difference (IV, Random, 95% CI)1.09 [-0.59, 2.77]

    1.5 ART arm: body weight at 3 months
1322Mean Difference (IV, Random, 95% CI)0.41 [-0.99, 1.81]

    1.6 pre-ART arm: body weight at 3 months
1211Mean Difference (IV, Random, 95% CI)2.82 [1.02, 4.62]

    1.7 ART arm: body weight at 6 months
1237Mean Difference (IV, Random, 95% CI)0.17 [-1.50, 1.84]

    1.8 pre-ART arm: body weight at 6 months
1157Mean Difference (IV, Random, 95% CI)3.67 [1.50, 5.84]

    1.9 ART arm: body weight at 12 months
1180Mean Difference (IV, Random, 95% CI)-1.0 [-3.19, 1.19]

    1.10 pre-ART arm: body weight at 12 months
1118Mean Difference (IV, Random, 95% CI)2.25 [-0.41, 4.91]

 2 Change in body weight (kg)1Mean Difference (IV, Random, 95% CI)Subtotals only

    2.1 ART arm: change in body weight at 1 month
1366Mean Difference (IV, Random, 95% CI)0.90 [0.40, 1.41]

    2.2 pre-ART arm: change in body weight at 1 month
1261Mean Difference (IV, Random, 95% CI)0.82 [0.28, 1.36]

    2.3 ART arm: change in body weight at 3 months
1322Mean Difference (IV, Random, 95% CI)1.12 [0.29, 1.95]

    2.4 pre-ART arm: change in body weight at 3 months
1211Mean Difference (IV, Random, 95% CI)1.22 [0.31, 2.12]

    2.5 ART arm: change in body weight at 6 months
1237Mean Difference (IV, Random, 95% CI)0.89 [-0.30, 2.08]

    2.6 pre-ART arm: change in body weight at 6 months
1157Mean Difference (IV, Random, 95% CI)2.06 [0.82, 3.30]

    2.7 ART arm: change in body weight at 12 month
1180Mean Difference (IV, Random, 95% CI)-0.03 [-1.78, 1.71]

    2.8 pre-ART arm: change in body weight at 12 months
1118Mean Difference (IV, Random, 95% CI)0.83 [-0.79, 2.45]

 3 Body mass index (BMI)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    3.1 ART arm: BMI at baseline
1617Mean Difference (IV, Fixed, 95% CI)0.02 [-0.15, 0.19]

    3.2 pre-ART arm: BMI at baseline
1429Mean Difference (IV, Fixed, 95% CI)0.17 [-0.07, 0.41]

    3.3 ART arm: BMI at 1 month
1366Mean Difference (IV, Fixed, 95% CI)0.36 [0.08, 0.64]

    3.4 pre-ART arm: BMI at 1 month
1261Mean Difference (IV, Fixed, 95% CI)0.39 [0.05, 0.74]

    3.5 ART arm: BMI at 3 months
1322Mean Difference (IV, Fixed, 95% CI)0.43 [0.07, 0.79]

    3.6 pre-ART arm: BMI at 3 months
1211Mean Difference (IV, Fixed, 95% CI)0.73 [0.31, 1.15]

    3.7 ART arm: BMI at 6 months
1237Mean Difference (IV, Fixed, 95% CI)0.42 [-0.07, 0.91]

    3.8 pre-ART arm: BMI at 6 months
1157Mean Difference (IV, Fixed, 95% CI)0.78 [0.22, 1.34]

    3.9 ART arm: BMI at 12 months
1180Mean Difference (IV, Fixed, 95% CI)-0.08 [-0.72, 0.56]

    3.10 pre-ART arm: BMI at 12 months
1118Mean Difference (IV, Fixed, 95% CI)0.45 [-0.25, 1.15]

 4 % lean body mass1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    4.1 ART arm: % lean body mass at baseline
1569Mean Difference (IV, Fixed, 95% CI)0.13 [-0.96, 1.23]

    4.2 pre-ART arm: % lean body mass at baseline
1394Mean Difference (IV, Fixed, 95% CI)-0.30 [-1.51, 0.92]

    4.3 ART arm: % lean body mass at 1 month
1253Mean Difference (IV, Fixed, 95% CI)0.47 [-1.20, 2.13]

    4.4 pre-ART arm: % lean body mass at 1 month
1185Mean Difference (IV, Fixed, 95% CI)0.41 [-1.40, 2.22]

    4.5 ART arm: % lean body mass at 3 months
1283Mean Difference (IV, Fixed, 95% CI)-0.53 [-2.13, 1.07]

    4.6 pre-ART arm: % lean body mass at 3 months
1179Mean Difference (IV, Fixed, 95% CI)1.14 [-0.70, 2.98]

    4.7 ART arm: % lean body mass at 6 months
1202Mean Difference (IV, Fixed, 95% CI)0.32 [-1.48, 2.12]

    4.8 pre-ART arm: % lean body mass at 6 months
1129Mean Difference (IV, Fixed, 95% CI)1.65 [-0.79, 4.09]

    4.9 ART arm: % lean body mass (kg) at 12 months
1169Mean Difference (IV, Fixed, 95% CI)-1.53 [-3.55, 0.49]

    4.10 pre-ART arm: % lean body mass (kg) at 12 months
1107Mean Difference (IV, Fixed, 95% CI)0.67 [-1.82, 3.16]

 
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]

 
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]

 
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]

 
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]

 
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]

 
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

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)
⊕⊕⊝⊝
low1,2

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)
⊕⊕⊝⊝
low3,4

Body weight
Follow-up: 6 - 12 weeks
The mean body weight ranged across control groups from
71.8 to 73.3 kg5
The mean body weight in the intervention groups was
0.17 lower
(1.1 lower to 0.75 higher)
233
(4 studies)
⊕⊕⊕⊝
moderate6,7

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)
⊕⊕⊕⊝
moderate6,7

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 kg9
The mean fat free mass in the intervention groups was
0.37 lower
(2.77 lower to 2.03 higher)
218
(3 studies)
⊕⊕⊝⊝
low1,2

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)
⊕⊕⊝⊝
low3,10

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 low11,12

*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.

 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.
 
Table 1. Characteristics of comparative studies

Study IDBakeine 1997 (Abstract)

MethodsCOUNTRY:

Uganda

SETTING:

Joint Clinical Research Centre, Kampala

FOLLOW UP:

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

ParticipantsINCLUSION 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)

MethodsCOUNTRY:

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

ParticipantsINCLUSION 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).

InterventionGroup 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.

OutcomesMortality: 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 biasRandom 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)

MethodsCOUNTRY:

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).

ParticipantsINCLUSION CRITERIA:

HIV-infected, early stage, relatively asymptomatic patients

EXCLUSION CRITERIA

Number randomised: 80

InterventionINTERVENTION:

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)

MethodsCOUNTRY:

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.

ParticipantsINCLUSION 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 biasRandom sequence generation:

Allocation concealment:

Study IDde Luis 2010

MethodsCOUNTRY

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.

ParticipantsINCLUSION 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

InterventionINTERVENTION

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

MethodCOUNTRY:

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

ParticipantsINCLUSION 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

InterventionINTERVENTION

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

MethodsCOUNTRY:

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

ParticipantsINCLUSION 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.

InterventionINTERVENTION:

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)

MethodsCOUNTRY:

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)

InterventionsWhole 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

MethodsCOUNTRY:

USA

SETTING:

Seven community research sites

FOLLOW UP:

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

ParticipantsINCLUSION 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)

MethodsCOUNTRY:
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

ParticipantsINCLUSION 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.

InterventionINTERVENTION:

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

MethodsCOUNTRY:
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

ParticipantsINCLUSION 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.

InterventionINTERVENTION:

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.

OutcomesPRIMARY 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

MethodsCOUNTRY:

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

ParticipantsINCLUSION 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

InterventionINTERVENTION:

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

MethodsCOUNTRY:
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

ParticipantsINCLUSION 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.

InterventionINTERVENTION:

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

MethodsCOUNTRY:
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.

ParticipantsINCLUSION 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.

InterventionINTERVENTION:

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.