Nutritional interventions for reducing morbidity and mortality in people with HIV

 

Characteristics of included studies [ordered by study ID]

Berneis 2000

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Methods	Generation of allocation sequence: Adequate Allocation concealment: Unclear Blinding: Participants - no; Providers - no; Assessor-unclear Exclusions: Overall - 16.7% (3/18). Insufficient information provided to ascertain which experimental group those lost to follow-up were allocated to. Duration of follow-up: 12 weeks. Frequency of follow-up: Weekly for the first 4 weeks and every 2nd week for 8 weeks.
Participants	Participants recruited from the outpatient clinic at the University Hospital, Basel, Switzerland between 1995-1997. Inclusion criteria:HIV infected, weight loss of 5% or more in the past 6 months OR body mass index of less than 21 kg/m2 OR CD4 T-cell count of less than 500/mm-3. ARV therapy unchanged throughout study. Exclusion criteria:Unstable patients with acute infectious complications. AGE NOT STATED
Interventions	Experimental group: 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] + nutritional counseling by dietician* Control group: Nutritional counseling by dietician* *Nutritional counseling by dietician involved teaching the principles of a balanced nutrition and discussion of individual problems relating to nutrition (e.g. diarrhea, nausea, weight loss) and the aspects of hygiene. 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 to treatment was monitored during visits to the research dietician. Duration of treatment: 12 weeks
Outcomes	·Body composition (BIA) ·Body weight ·Lean mass ·Fat mass ·Lymphocyte counts (CD3, CD4, CD8) ·Serum albumin, ALAT and ASAT ·Plasma TNFa receptors (p55, p75) and interleukin 2 receptors ·Plasma concentration of insulin, glucagons, globulin and NEFAs ·Energy intake ·Resting energy expenditure ·Leucine kinetics ·Quality of life (visual digital analog scale)
Notes	Information requested from the author and response received on 12/04/2006. Stage of HIV (CDC guidelines): Experimental group: A = 2, B = 1, C = 5; Control Group: A = 2, B = 2, C = 3. Baseline CD4 count (cells/mm3): Experimental group: 161± 149.9; Control group: 244 ± 227.5 Baseline viral load: NOT MEASURED Baseline nutritional status (BMI): NOT MEASURED Number on antiretroviral therapy: 8 (2 in the experimental group and 6 in the control group) Ethics approval received from Human Ethics Committee of the Department of Internal Medicine, University Hospital, Basel, Switzerland. Written informed consent received from all participants. Adverse events: Information not provided by the author
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	B - Unclear

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Clark 2000

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Methods	Generation of allocation sequence: Adequate Allocation concealment: Unclear Blinding: Participant-unclear; Provider-unclear; Assessors-YES (unpublished data) Exclusions: Overall - 36.7% (25/68); Experimental group - 35.3% (12/34); control group - 38.2% (13/34). Duration of follow-up: 8 weeks Frequency of follow-up: 0, 1, 2, 4, 8 weeks
Participants	Participants were recruited from the Nassau County Medical Center's HIV outpatient clinic (USA).Trial date and duration unclear. Inclusion criteria:HIV-infected men and women with unintentional weight loss of more than 5% over previous 3 months.Exclusion criteria:Participants were excluded if they had any of the following illnesses: diabetes mellitus; cardiac, liver; and or renal disease. Participants were also excluded if their physicians determined that they would be unable to participate in any of the outlined measurements, if a recent change of antiretroviral therapy had been made, if suffering from acute illnesses and infections and active opportunistic infections. Age: 40.2±6.0 (experimental group) and 40.9±6.6 (control group)
Interventions	Experimental group: Amino acid mixture containing 14g arginine (free base), 14g glutamine and 3g ß-hydroxy-ß-methylbutyrate (HMB, calcium salt) + citric acid (ph 4.5) Control group: Bulk maltodextrin + citric acid (ph 4.5) Experimental and control supplements were isocaloric (200 cal/day). Supplement was supplied in a foil-sealed packet, in two equal doses daily and was mixed with 8 ounces of fruit juice.Compliance monitored by self-reporting, estimating concentration of HMB in blood samples and random urine samples. Duration of treatment: 8 weeks
Outcomes	·Body composition ·Body weight ·Circumference of forearm, upper arm and thigh ·Lean mass ·Fat mass (skinfold thickness & air displacement plethysmography) ·Leg muscle and fat composition (CT scan of thigh) ·Blood chemistry·Liver function tests ·Blood lipids ·Hematological tests ·CD4 cell count ·Viral load
Notes	Information requested from the author and response received on 14/04/2006. Stage of HIV (CDC guidelines): All in stage C and all on ARV therapy. Baseline CD4 count (cells/mm3): Experimental group: 364± 313; Control group: 444 ± 366 Baseline viral load (copies/ml): Experimental group: 3.5 ± 1.2; Control group: 3.4 ± 1.1 Baseline nutritional status (BMI): NOT MEASURED 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. Ethics approval received from Nassau County Medical Center Institutional Review Board. Participants provided written informed consent. Adverse events/effects: No adverse effects noted. Nutrient supplement well tolerated
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	B - Unclear

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de Luis 2003

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Methods	Generation of allocation sequence: Unclear "randomized" Allocation concealment: Unclear Blinding: Participants - no; Providers - no; Assessor-unclear Exclusions: None, although 4 participants (2 from each group) failed to complete treatment. Intention to treat analysis was conducted Duration of follow-up: 12 weeks Frequency of follow-up: baseline and weekly for 3 months
Participants	The country and setting in which the study was conducted are not stated. Trial date and duration unclear. Inclusion criteria: HIV infected males and females, between 20-60 years old, with weight loss > 5% body weight in the past 6 months. Absence of chronic febrile process, diarrhea for 30 days or more with 3 incidences per day and drug consumption that would affect nutritional intake and normal renal and hepatic function. Age: 37.5±11 (experimental group) and 39.9±9 (control group)
Interventions	Experimental group: Oral supplement [standard enteric formula, ENSURE®, 3329kJ (54% CARBOHYDRATE, 32% PROTEIN, 14% FAT, Recommended Daily Allowance (RDA) of vitamins and minerals), three cans/day, 250ml/can] and nutritional education by dietician* Control group: Nutritional education by dietician* *Nutritional education consisted of dietary guidelines on how to achieved normocaloric and normoproteic intake relative to body weight Nutrient intake was assessed by a dietician using 24hour recall and portion models to increase accuracy of recall Duration of treatment: 12 weeks
Outcomes	·%Fat mass (BIA) ·%Fat free mass (BIA) ·Body water ·Body weight (kg) ·Triceps skinfold ·Muscular circumference of upper arm ·Caloric intake ·Protein intake ·Albumin/pre-albumin ·CD4 count·Viral load ·Transferrrin ·Blood biochemistry
Notes	Information requested from the author both in spanish and in english and to date (25/01/2007) no response received. Stage of HIV (CDC guidelines): Experimental group: A&B = 43%(15/35), C = 57%(20/35); Control group: A&B = 46%(16/35), C = 54%(19/35) Baseline CD4 count (cells/mm3): Experimental group: 431± 254; Control group: 621 ± 288 Baseline viral load (copies/ml): Experimental group: 5.8 ± 17.8; Control group: 14 ± 40 Baseline nutritional status (BMI): NOT MEASURED Antiretroviral therapy: All participants had been on ART (TARGA) for at least a year prior to study. Ethics: No details provided by author. All participants gave informed consent to participate in the study. Adverse events: Information not provided by the author
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	B - Unclear

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Karsegard 2004

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Methods	Generation of allocation sequence: Unclear "balanced blocks of 10" Allocation concealment: Adequate Blinding: Participants - yes; Providers - yes; Assessor-Unclear Exclusions: Overall - 37% (17/46); Experimental group - 50%(11/22); Control group - 25% (6/24) Duration of follow-up: 12 weeks Frequency of follow-up: at baseline and every 4 weeks thereafter for 12 weeks
Participants	Trial conducted in Geneva, Switzerland at an outpatients AIDS clinic, between 1995-1997. Inclusion criteria: HIV+ outpatients >18 years, involuntary weight loss > 5-15% of usual weight from beginning of HIV infection, CD4 count>150cells.mm-3, body fat mass > 5% of body weight (BIA), regular food intake and 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 and change in antiretroviral therapy within one month before inclusion.Exclusion criteria during course of study: code disclosure, patient auto-withdrawal, non-authorised concomitant treatment and medical complications requiring hospitalization. Age: 32.4±5.2 (experimental group) and 34.9±5.2 (control group)
Interventions	Experimental group: 10g/day of monohydrated OKG (1.3g of nitrogen) and nutritional counseling by a dietician* Control group: Isonitrogenous (9.1g/day of derived milk proteins) formula with same flavour and nutritional counseling by a dietician* *Nutritional counseling consisted of personalized dietary advice on how to gain weight based on 3-day (2 week days and 1 weekend day) dietary records Adherence was assessed by counting doses not taken in the returned packages at each follow-up visit Duration of treatment: 12 weeks
Outcomes	·Body weight (nutritional status) ·BMI ·Fat free mass ·Fat mass ·Triceps skin fold ·Circumference of arm muscle ·Leukocytes·Lymphocytes ·B2 microglobulin ·CD4 count ·Viral load ·Albumin ·Transthyretin ·Grip strength (dynamometer) ·Endurance test (Queen's college step test) ·Physical activity (pedometer over 48 hours) ·Dietary intake (energy and protein) ·Appetite (visual analogue scale) ·G.I. and food tolerance (visual analogue scale) ·Frequency of adverse events
Notes	Information requested from the author and response received on 23/05/2006. Stage of HIV/AIDS: All participants were stage C. Baseline CD4 count (cells/mm3): Experimental group: 338±172; Control group: 310 ± 136 Baseline viral load (copies/ml): Experimental group: 3.6 ± 1.3; Control group: 3.5± 1.3 Baseline nutritional status (BMI): Experimental group: 20 ± 2.4; Control group: 21± 3 Antiretroviral therapy: 8 control and 5 experimental participants were not on any treatment (33/46 were on some form of treatment). Ethics approval received from the ethics committee of Geneva University Hospital and all participants gave their written informed consent. Adverse events: There was a significantly greater frequency of gastrointestinal events reported in the experimental group compared with the control group (see results for details).
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Yes	A - Adequate

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Keithley 2002a

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Methods	Generation of allocation sequence: Adequate (computer generated randomisation list, balanced for gender and recruitment site) Allocation concealment: Unclear ("randomisation list was maintained by a statistician who was not involved with the study. Group assignment was issued on a sequential basis") Blinding: Participants - no, Providers - no, Assessor- unclear Exclusions: Overall - 27% (24/90); EnsurePlus group - 13% (4/30); Advera group - 32% (10/31); Control group - 34% (10/29) Duration of follow-up: 1 year Frequency of follow-up: every 3 months
Participants	Trial conducted in USA from June 1995 to January 1999. Participants were outpatients attending 3 inner city outpatients HIV/AIDS clinics. Inclusion criteria: Age: 18-65 years, HIV+, CD4 count of 275-550 cells/mm3 within prior two months and at least one month of ARV treatment. Willingness to participate and ability to adequately respond to interview questions in english or spanish. Exclusion criteria: Chronic conditions known to influence nutrient status, were symptomatic or had AIDS-defining conitions, were pregnant or breast-feeding, regular use of oral formulas or had substantial elevation of hepatic aminotransferases. Age: 37±7 (experimental group 1), 37±9 (experimental group 2) and 41±10 (control group)
Interventions	Experimental group (EnsurePlus): Ensure Plus oral formula (1-2 8 ounce cans/day; each can contains 355 calories; of which 14.7% protein, 32% fat, 53.3% carbohydrates, RDA of vitamins and minerals) and nutritional counseling by a dietician* Experimental group (Advera): Advera oral formula (1-2 8 ounce cans/day; each can contains 303 calories; of which 18.7% protein, 15.8% fat, 65.5% carbohydrates; vitamins and minerals) and nutritional counseling by a dietician* Control group: Nutritional counseling by a dietician* *Nutritional counseling consisted 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 was assessed by counting returned pop tops from cans, recorded formula intake in a daily diary and self reported formula use over the past week. Duration of treatment: 1 year
Outcomes	·Height ·Weight (BMI) ·Body composition (BIA) ·Dietary intake (Health Habits and History Questionnaire) ·Serum albumin ·CD4 count and percent ·Feasibility data (completion rate, adherence to protocol and acceptability and tolerance of supplement)
Notes	Information requested from the author and response received on 09/01/2007. Stage of HIV/AIDS: All participants were asymptomatic. Baseline CD4 count (cells/mm3): EnsurePlus group: 448 ± 169 Advera group: 430 ± 110 Control group: 404 ± 124 Baseline viral load (copies/ml): Not measured Baseline nutritional status (BMI): EnsurePlus group: 24 ± 4 Advera group: 25 ± 5 Control group: 26 ± 6 Antiretroviral therapy: All participants were on ART for at least one month prior to enrollment Ethics approval received from the institutional review boards at each site and all participants gave their written informed consent Adverse events: Not specifically measured. Clinical symptoms were assessed at each visit but details not presented in article
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	B - Unclear

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Keithley 2002b

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Methods
Participants
Interventions
Outcomes
Notes
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	D - Not used

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Rabeneck 1998

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Methods	Generation of allocation sequence: Unclear Allocation concealment: Unclear Blinding: Participants - no; Providers - no; Assessor - Unclear Exclusions: Overall - 24% (28/118); at 4 weeks: Experimental group - 17% (10/59); Control group - 15%(9/59); at 6 weeks: Experimental group - 27% (16/59); control group - 20%(12/59). Duration of follow-up: 8 weeks (2 week baseline period; 6 week treatment period) Frequency of follow-up: weekly for 1st 2 weeks and thereafter every 2nd week during treatment period (weeks 2, 4, 6, 8)
Participants	Participants were recruited from the 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, from March 1993 - July 1994. Inclusion criteria:HIV-infected men > 18 years; CD4 count < 500 cells/mm3; < 90% usual weight-for-height/> 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 were to maintain treatment for at least 8 weeks into the study. Exclusion criteria:Dysphagia, severe diarrhea (> 6 watery stools/d for ³ 7 days), CMI/MAC infection, suspected infection (chills, fever), diagnosis of infection or hospitalization during the 2 weeks prior to study entry, ingestion of anabolic agents or appetite stimulants and undergoing chemotherapy. Age: 39.3±8.8 (experimental group) and 41.1±9.7 (control group)
Interventions	Experimental group: Normal diet + daily oral supplement [Lipisorb-specialized medium chain triglyceride formula suitable for HIV infected participants with fat malabsorption (48% carbohydrates, 17% protein, 35% fat, RDA of vitamins and minerals)] + nutritional counseling by dietician* Control Group: Normal diet + nutritional counseling by dietician* *Nutritional counseling consisted of advice on how to achieve 4020kJ/d greater than estimated total energy expenditure Dietary intake was monitored every 2 weeks (3-day dietary food records). During each visit a computer program (Nutritionist IV 1992 N-Squared Computing, Salem Ore) used to evaluate the three days food records. When participant's intake did not achieve the energy target, the study dietician counseled him. Assessed adherence by weekly counseling with dietician. Specific method of assessing adherence to the oral supplement not stated. Duration of treatment: 6 weeks
Outcomes	·Height ·Weight ·Body mass index ·Fat (BIA) ·Fat free mass (BIA) ·Body water mass ·Tricep skinfold thickness ·Subscapular skinfold thickness ·Chest skinfold ·Mid-axilla skinfold ·Abdominal·Supra-illiac ·Thigh skinfold ·Mid arm circumference ·Grip strength (dynomometer) ·Cognitive function (Buschke selective reminding test) ·Quality of life test ·CD4 cell count ·Albumin ·Triglyceride levels
Notes	Information requested from the author but author unable to assist as no longer in possession of study results Stage of HIV (CDC guidelines): NOT STATED Baseline CD4 count (cells/mm3): NO DATA Baseline viral load (copies/ml): NO DATA Baseline nutritional status (BMI): Experimental group: 21± 3; Control group: 21± 3 Antiretroviral therapy: Number of participants on ARVs not stipulated. Participants on ARV were included in the study if the regimen had been unchanged for 8 weeks prior to study entry. 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. Adverse events: One participant from the experimental group discontinued the supplement due to nausea and epigastric burning.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	B - Unclear

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Schwenk 1999

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Methods	Generation of allocation sequence: Unclear "independent person generated the random allocation list and placed allocation to treatment arms in closed numbered envelopes" (unpublished data) Allocation concealment: yes (unpublished data) Blinding: Participants -no; Providers - no; Assessor-unclear Exclusions: Overall - 10%(5/50); Experimental group-8%(2/26); Control group-13%(3/24) Duration of follow-up: 8 weeks Frequency of follow-up: once every 2 weeks (0,2,4,6,8)
Participants	Participants were recruited from an outpatients clinic at the University Hospital of Cologne, Cologne, Germany between March 1996 and December 1997. Inclusion criteria:HIV infected, previous weight loss> 5% total weight loss, currently losing > 3% total weight. Exclusion criteria:Prescription of oral supplementation, nutritional counseling, hormonal or appetite stimulants or enteral or parenteral nutrition within previous 3 months. Unable to swallow normal food or severe lactose intolerance. Participants changing ART within one month of the start of the study were also excluded. Introduction of protease inhibitors, participants losing weight placed on protease inhibitors instead of normal ART. These participants although initially excluded where then included. Age: 39.4±9.2 (experimental group) and 39.5±10.2 (control group)
Interventions	Experimental group: Oral supplement [Clinutren 1.5, HP, fruit and dessert-range of fortified oral supplements providing between 2.5 and 6.3 kJ/ml of energy as well as the RDA of vitamins and minerals in the form of either a 200ml drink (56% CARBOHYDRATE, 15% PROTEIN, 30% FAT), 125g semi liquid dessert (50% CARBOHYDRATE, 30% PROTEIN, 18% FAT), or a maltodextrin-based fruit drink (86% CARBOHYDRATE, 13% PROTEIN, 1% FAT)] + nutritional counseling by dietician* Control group: Nutritional counseling by dietician* *Nutritional counseling to increase food intake by 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. Experimental participants instructed to increase intake using oral supplements provided. Packages were labeled according to energy content and participants recorded the intake of units in a diary. They were not to replace normal food with a supplement. Nutrient intake was assessed by retrospective 24 hour recall Duration of treatment: 8 weeks
Outcomes	Primary outcomes: ·Area under the curve of percent change in body cell mass from baseline. Secondary outcomes: ·Weight change ·Body cell mass ·Food energy intake Other outcomes: ·BMI ·Fat free mass (BIA) ·Fat mass (BIA) ·CD4 cell count ·Viral load ·Number of previous AIDS defining illnesses
Notes	Information requested from the author and response received on 17/07/2006 Stage of HIV (CDC guidelines): CDC C3 = 47 participants, CDC C2 = 3 participants Baseline CD4 count (cells/mm3): Experimental group: 180±198; Control group: 160 ±164 Baseline viral load (copies/ml): Experimental group: 4.1 ± 1.2; Control group: 4.7±1.3 Baseline nutritional status (BMI): Experimental group: 20± 2; Control group: 20± 2 Antiretroviral therapy: All participants on ARV treatment. Ethics obtained by the Medical Research Ethics Committee of the Medical Faculty, University of Cologne. All randomized participants gave their informed consent. Adverse events/effects: Not specifically stated. Treatment interventions well tolerated.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Yes	A - Adequate

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Shabert 1999

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Methods	Generation of allocation sequence:Unclear "balanced block design" Allocation concealment: Unclear Blinding: Participants - yes; Providers - yes; Assessors - yes (unpublished data) Exclusions: Overall - 19% (5/26); Experimental group - 8%(1/13); Control group - 31%(4/13) Duration of follow-up: 12 weeks. Frequency of follow-up: Weekly for 3 weeks before the initiation of the supplement and weekly during the intervention.
Participants	Participants were recruited from private practice physicians in Broward County, Florida, USA, in June 1997. Inclusion criteria: HIV-infected men and non- pregnant women with > 5% involuntary weight loss or > 90% std creatinine/height index (reflecting loss of lean tissue). Not on any other protocol two months prior to receiving supplement. Vitamin B12 or folate supplement must have been initiated two months before start of trial; testosterone supplementation 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, unable to consume the nutrient supplement or unable/unwilling to participate in the periodic evaluation during the protocol, 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. Current use of > 5.0 g/d Glutamine. Liver cirrhosis, renal failure, chronic diarrhea >2 loose stools per day with infection, if non-infectious participants were included. Age: 40 (30-50)(experimental group) and 42 (33-53)(control group)
Interventions	Experimental group: Recommended daily allowance of vitamin and mineral preparation + L-glutamine (GLN) amino acid (400g/day) in 4 equal doses + antioxidant nutrients (ascorbic acid 800mg/d, a-tocopherol 500 IU/d, ß-carotene 27000IU/d, selenium 280ug/d and N-acetyl cysteine 2400mg/d) + weekly nutritional counseling with dietician* Control group: Recommended daily allowance of vitamin and mineral preparation + Glycine (40g/day) in 4 equal doses + weekly nutritional counseling with dietician* *Nutritional counseling occurred with a registered dietician to ensure stable and adequate nutrient intake. Nutrient intake was assessed using the Willett Food Frequency Questionnaire and 3-day (2 week days and 1 weekend day) dietary recall Method of assessing adherence: The supplements were taken daily in four (4) divided doses. Packets were dispensed at 14-d interval. Used packets were returned to monitor compliance. Duration of treatment: 12 weeks
Outcomes	Primary outcomes: ·Body weight ·Body cell mass Secondary outcomes: ·CD4 cell count ·Mood (SF30) ·Dietary intake Other outcomes: ·BMI ·Fat mass ·Body water (intracellular and extracellular body water) ·Side effects
Notes	Information requested from the author and response received 05/04/2006 Stage of HIV (CDC guidelines): All stage C (with AIDS) Baseline CD4 count (cells/mm3): Experimental group: 147±81.5; Control group: 183±87.8 Baseline viral load (copies/ml): NOT MEASURED Baseline nutritional status (BMI): Experimental group: 22±1.5; Control group: 23±1.3 Antiretroviral therapy: Number of participants on ARVs - 10 (83%) in the experimental group and 8 (89%) in the control group. 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. Adverse events: No adverse events were noted in any of the participants
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	B - Unclear

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Characteristics of excluded studies [ordered by study ID]

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Study	Reason for exclusion
Amadi 2005	Included both HIV positive and negative children. Both the experimental and the control group received nutritional supplementation (Neocate vs Complete Feed).
Bakeine 1997	Both groups received nutritional supplementation (Nutrifil vs Corn Soya Blend)
Bell 1999	Both groups received nutritional supplementation (fish oil bars vs safflower oil bars)
Breuikreuitz 2000	Main outcome measures were change in immunological parameters such as natural killer cell and T cell function and viral load.
Charlin 2002	Participants received dietary supplements in both arms of the cross-over study (regular food vs polymeric diet).
Chlebowski 1993	Both groups received nutritional supplements (Ensure vs Advera)
Comi 1996	Both groups received nutritional supplements (hypercaloric, hyperproteic vs normocaloric, normoproteic)
Craig 1997	Both groups received nutritional supplements (Long chain triglycerides vs medium chain triglycerides). Duration of treatment only 15 days
de Luis Roman 2001	Both groups received nutritional supplements (Ensure vs Advera).
Engelson 1998	Duration of treatment was only 10 days Main outcome measure was changes in protein metabolism
Gibert 1999	All three groups received some form of nutritional supplementation (500 kcal daily of caloric supplement with peptides and medium-chain triglycerides + multivitamin and mineral supplement; 500 kcal of a caloric supplement with whole protein and long-chain triglycerides + multivitamin and mineral supplement; multivitamin and mineral supplement only).
Hellerstein 1994	Both groups received nutritional supplementation (whole protein formula vs peptide based formula)
Hellerstein 1996	Not a randomised trial Control group was a convenient sample of men
Hirschel 1996	Both groups received nutritional supplementation (daily oral supplement vs daily oral supplement + arginine and fatty acid)
Hoh 1998	The control group was not randomly assigned. Both experimental groups received nutritional supplements (whole protein formula vs peptide based formula).
Kotler 1998	Inappropriate intervention (total parenteral nutrition). Both groups received nutritional supplementation.
Melchior 1996	Inappropriate intervention (parenteral nutrition)
Melchior 1998	Inappropriate intervention (parenteral nutrition)
Mendez 1998	Both groups received nutritional supplementation (medium chain triglyceride vs long chain triglyceride)
Micke 2001	Both groups received nutritional supplements (Protecamin vs Immunocal). Duration of treatment was only 2 weeks. The control group consisted of HIV negative, health adults
Micke 2002	No control or comparison group
Ndekha 2005	Not a randomized trial
Pichard 1998	Both groups received nutritional supplements (standard nutritional supplement vs standard nutritional supplement enriched with arginine and n-3 polyunsaturated fatty acids)
Schwenk 1996	Both groups received nutritional supplements (polymeric diet vs polymeric diet + fibre)
Suttmann 1996	Participants received nutritional supplements in both arms of the cross-over study (standard nutritional supplement vs standard nutritional supplement enriched with arginine and n-3 fatty acids). The control group was not randomly allocated it was a convenient sample of patients from the Swiss HIV Cohort Study
Wanke 1996	Both groups received nutritional supplementation (medium chain triglycerides vs long chain triglycerides). Duration of treatment was on 12 days
Winkler 2004	Both experimental groups received nutritional supplements ( fruit juice or fruit-vegetable concentrate). The control group consisted on HIV negative individuals.
Wohl 2005	Investigating the safety and efficacy of fish oil supplementation with dietary and exercise counselling for the treatment of a hypertriglyceridemia associated with antiretroviral therapy.

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Comparison 1. Any nutritional supplement vs no nutritional supplement or nutritional placebo

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Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

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 1 Energy intake (kcal/day)

6

254

Mean Difference (IV, Fixed, 95% CI)

366.66 [217.05, 516.26]

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1.1 Balanced supplements to increase energy intake

5

211

Mean Difference (IV, Fixed, 95% CI)

406.59 [250.24, 562.95]

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1.2 Specific supplementation

1

43

Mean Difference (IV, Fixed, 95% CI)

-66.0 [-580.64, 448.64]

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 2 Protein intake (g/day)

3

128

Mean Difference (IV, Fixed, 95% CI)

17.36 [8.37, 26.34]

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2.1 Balanced supplements to increase energy intake

2

85

Mean Difference (IV, Fixed, 95% CI)

23.33 [12.97, 33.70]

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2.2 Specific supplementation

1

43

Mean Difference (IV, Fixed, 95% CI)

-0.70 [-18.71, 17.31]

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 3 Body weight

9

423

Mean Difference (IV, Fixed, 95% CI)

0.24 [-0.57, 1.06]

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3.1 Balanced supplements to increase energy intake

6

313

Mean Difference (IV, Fixed, 95% CI)

-0.20 [-1.12, 0.71]

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3.2 Specific supplement (Amino acid)

3

110

Mean Difference (IV, Fixed, 95% CI)

1.93 [0.15, 3.71]

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 4 Fat mass

6

301

Mean Difference (IV, Fixed, 95% CI)

-0.73 [-1.83, 0.37]

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4.1 Balanced supplements to increase energy intake

4

234

Mean Difference (IV, Fixed, 95% CI)

-1.17 [-2.60, 0.26]

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4.2 amino acid supplements

2

67

Mean Difference (IV, Fixed, 95% CI)

-0.09 [-1.81, 1.63]

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 5 Fat free mass

5

311

Mean Difference (IV, Random, 95% CI)

0.00 [-2.34, 2.35]

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5.1 Balanced supplements to increase energy intake

3

222

Mean Difference (IV, Random, 95% CI)

-0.38 [-2.77, 2.01]

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5.2 amino acid supplements

2

89

Mean Difference (IV, Random, 95% CI)

-0.39 [-8.56, 7.78]

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 6 CD4

7

271

Mean Difference (IV, Fixed, 95% CI)

0.23 [-40.17, 40.64]

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6.1 Balanced supplements to increase energy intake

4

161

Mean Difference (IV, Fixed, 95% CI)

-21.10 [-89.69, 47.49]

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6.2 Specific supplement

3

110

Mean Difference (IV, Fixed, 95% CI)

11.57 [-38.43, 61.57]

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 7 Viral load (log10 copies/ml)

2

88

Mean Difference (IV, Fixed, 95% CI)

-0.45 [-0.87, -0.04]

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Table 1. Search methods

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Query number	PubMed	CENTRAL	EMBASE	AIDSearch
#1	HIV Infections[MeSH] OR HIV[MeSH] OR hiv[tw] OR hiv-1*[tw] OR hiv-2*[tw] OR hiv1[tw] OR hiv2[tw] OR hiv infect*[tw] OR human immunodeficiency virus[tw] OR human immunedeficiency virus[tw] OR human immuno-deficiency virus[tw] OR human immune-deficiency virus[tw] OR ((human immun*) AND (deficiency virus[tw])) OR acquired immunodeficiency syndrome[tw] OR acquired immunedeficiency syndrome[tw] OR acquired immuno-deficiency syndrome[tw] OR acquired immune-deficiency syndrome[tw] OR ((acquired immun*) AND (deficiency syndrome[tw])) OR "sexually transmitted diseases, viral"[MESH:NoExp]	hiv OR hiv-1* OR hiv-2* OR hiv1 OR hiv2 OR (HIV INFECT*) OR (HUMAN IMMUNODEFICIENCY VIRUS) OR (HUMAN IMMUNEDEFICIENCY VIRUS) OR (HUMAN IMMUNE-DEFICIENCY VIRUS) OR (HUMAN IMMUNO-DEFICIENCY VIRUS) OR (HUMAN IMMUN* DEFICIENCY VIRUS) OR (ACQUIRED IMMUNODEFICIENCY SYNDROME) OR (ACQUIRED IMMUNEDEFICIENCY SYNDROME) OR (ACQUIRED IMMUNO-DEFICIENCY SYNDROME) OR (ACQUIRED IMMUNE-DEFICIENCY SYNDROME) OR (ACQUIRED IMMUN* DEFICIENCY SYNDROME) in All Fields, from 1800 to 2004 in all products	('human immunodeficiency virus infection'/exp) OR ('human immunodeficiency virus'/exp) OR (hiv:ti OR hiv:ab) OR ('hiv-1':ti OR 'hiv-1':ab) OR ('hiv-2':ti OR 'hiv-2':ab) OR ('human immunodeficiency virus':ti OR 'human immunodeficiency virus':ab) OR ('human immuno-deficiency virus':ti OR 'human immuno-deficiency virus':ab) OR ('human immunedeficiency virus':ti OR 'human immunedeficiency virus':ab) OR ('human immune-deficiency virus':ti OR 'human immune-deficiency virus':ab) OR ('acquired immune-deficiency syndrome':ti OR 'acquired immune-deficiency syndrome':ab) OR ('acquired immunedeficiency syndrome':ti OR 'acquired immunedeficiency syndrome':ab) OR ('acquired immunodeficiency syndrome':ti OR 'acquired immunodeficiency syndrome':ab) OR ('acquired immuno-deficiency syndrome':ti OR 'acquired immuno-deficiency syndrome':ab)	PT=RANDOMIZED CONTROLLED TRIAL
#2	MACRONUTRIENTS	MeSH descriptor HIV Infections explode all trees in MeSH products	(random*:ti OR random*:ab) OR (factorial*:ti OR factorial*:ab) OR (cross?over*:ti OR cross?over:ab OR crossover*:ti OR crossover*:ab) OR (placebo*:ti OR placebo*:ab) OR (((doubl*:ti AND blind*:ti) OR (doubl*:ab AND blind*:ab))) OR (((singl*:ti AND blind*:ti) OR (singl*:ab AND blind*:ab))) OR (assign*:ti OR assign*:ab) OR (volunteer*:ti OR volunteer*:ab) OR ('crossover procedure'/de) OR ('double-blind procedure'/de) OR ('single-blind procedure'/de) OR ('randomized controlled trial'/de) OR (allocat*:ti OR allocat*:ab)	PT=CONTROLLED CLINICAL TRIAL
#3	DIETARY PROTEIN*	MeSH descriptor HIV explode all trees in MeSH products	macronutrients	RANDOMIZED CONTROLLED TRIALS
#4	DIETARY FAT*	(#1 OR #2 OR #3)	dietary AND 'protein'/de OR dietary AND 'proteins'/de	RANDOM ALLOCATION
#5	DIETARY CARBOHYDRATE*	FATTY ACIDS in All Fields in all products	'dietary fat' OR 'dietary fats'	DOUBLE BLIND METHOD
#6	DIETARY EGG PROTEIN*	LIPIDS in All Fields in all products	'dietary carbohydrate'/de OR 'dietary carbohydrates'/de	SINGLE BLIND METHOD
#7	DIETARY SUPPLEMENTS	DIET THERAPY in All Fields in all products	'dietary egg protein' OR dietary AND egg AND protein	PT=CLINICAL TRIAL
#8	DIETARY SUPPLEMENTATION*	(BALANCED DIET) in All Fields, from 1800 to 2005 in all products	dietary AND supplements	CLINICAL TRIALS OR CLINICAL TRIALS, PHASE I OR CLINICAL TRIALS, PHASE II OR CLINICAL TRIALS, PHASE III OR CLINICAL TRIALS, PHASE IV OR CONTROLLED CLINICAL TRIALS OR MULTICENTER STUDIES
#9	NUTRITION SUPPORT	NUTRITIONAL SUPPLEMENT* in All Fields in all products	('dietary supplementation'/de OR 'dietary supplementation') OR 'dietary supplementations'	(SINGL* OR DOUBL* OR TREBL* OR TRIPL*) NEAR6 (BLIND* OR MASK*)
#10	NUTRITIONAL REQUIREMENT*	ENTERAL FORMULA in All Fields in all products	('nutrition'/de OR 'nutrition') AND support	CLIN* NEAR6 TRIAL*
#11	ENERGY INTAKE	ENTERAL NUTRITION in All Fields in all products	nutritional AND requirement	PLACEBO*
#12	FORTIFIED FOOD	FORMULATED FOOD in All Fields in all products	'energy intake'/de OR 'energy intake'	PLACEBOS
#13	ENRICHED FOOD	ENRICHED FOOD in All Fields in all products	'fortified food' OR 'enriched food' OR 'formulated food' OR ('enteral nutrition'/de OR 'enteral nutrition') OR 'enteral formula' OR ('diet therapy'/de OR 'diet therapy') OR ('lipids'/de OR 'lipids') OR ('fatty acids'/de OR 'fatty acids')	RANDOM*
#14	FORMULATED FOOD	FORTIFIED FOOD in All Fields in all products	'nutritional supplement' OR 'nutritional supplements' OR 'balance diet'	RESEARCH DESIGN
#15	ENTERAL NUTRITION	ENERGY INTAKE in All Fields in all products	#3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14	#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14
#16	ENTERAL FORMULA	NUTRITIONAL REQUIREMENT* in All Fields in all products	#1 AND #2 AND #15	ANIMALS NOT (HUMAN AND ANIMALS)
#17	NUTRITIONAL SUPPLEMENT*	NUTRITION SUPPORT in All Fields in all products		#15 NOT #16
#18	"BALANCED DIET"	DIETARY SUPPLEMENTATION* in All Fields in all products		MACRONUTRIENTS OR DIETARY PROTEIN* OR DIETARY FAT* OR DIETARY CARBOHYDRATE* OR DIETARY EGG PROTEIN* OR DIETARY SUPPLEMENTS OR DIETARY SUPPLEMENTATION* OR NUTRITION SUPPORT OR NUTRITIONAL REQUIREMENT* OR ENERGY INTAKE OR FORTIFIED FOOD OR ENRICHED FOOD OR FORMULATED FOOD OR ENTERAL NUTRITION OR ENTERAL FORMULA OR NUTRITIONAL SUPPLEMENT* OR "BALANCED DIET" OR DIET THERAPY OR LIPIDS OR FATTY ACIDS
#19	DIET THERAPY	DIETARY SUPPLEMENTS in All Fields in all products		#17 AND #18
#20	LIPIDS	DIETARY EGG PROTEIN* in All Fields in all products
#21	FATTY ACIDS	DIETARY CARBOHYDRATE* in All Fields in all products
#22	#2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21	DIETARY FAT* in All Fields in all products
#23	randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized controlled trials [mh] OR random allocation [mh] OR double-blind method [mh] OR single-blind method [mh] OR clinical trial [pt] OR clinical trials [mh] OR ("clinical trial" [tw]) OR ((singl* [tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR blind* [tw])) OR ( placebos [mh] OR placebo* [tw] OR random* [tw] OR research design [mh:noexp] OR comparative study [mh] OR evaluation studies [mh] OR follow-up studies [mh] OR prospective studies [mh] OR control* [tw] OR prospectiv* [tw] OR volunteer* [tw]) NOT (animals [mh] NOT human [mh])	DIETARY PROTEIN* in All Fields in all products
#24	#1 AND #22 AND #23	MACRONUTRIENTS in All Fields in all products
#25		(#5 OR #6 OR #7 OR #8 OR #9 OR #10 OR 16 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24)
#26		((ANIMAL OR ANIMALS) AND (NOT HUMANS)) in All Fields in all products
#27		(#4 AND #25)
#28		(#27 AND NOT #26)

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