Intervention Review

You have free access to this content

Micronutrient supplementation in children and adults with HIV infection

  1. James H Irlam1,*,
  2. Marianne ME Visser2,
  3. Nigel N Rollins3,
  4. Nandi Siegfried4

Editorial Group: Cochrane HIV/AIDS Group

Published Online: 8 DEC 2010

Assessed as up-to-date: 25 FEB 2010

DOI: 10.1002/14651858.CD003650.pub3


How to Cite

Irlam JH, Visser MME, Rollins NN, Siegfried N. Micronutrient supplementation in children and adults with HIV infection. Cochrane Database of Systematic Reviews 2010, Issue 12. Art. No.: CD003650. DOI: 10.1002/14651858.CD003650.pub3.

Author Information

  1. 1

    University of Cape Town, Primary Health Care Directorate, Cape Town, Western Cape, South Africa

  2. 2

    Department of Dietetics, University of the Western Cape, Cape Town, South Africa

  3. 3

    World Health Organization, Department of Child and Adolescent Health and Development, Geneva, Switzerland

  4. 4

    University of Cape Town, Department of Public Health and Primary Health Care, Cape Town, South Africa

*James H Irlam, Primary Health Care Directorate, University of Cape Town, E47 OMB, Groote Schuur Hospital, Cape Town, Western Cape, 7925, South Africa. James.Irlam@uct.ac.za.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 8 DEC 2010

SEARCH

 
Characteristics of included studies [ordered by study ID]
Allard 1998

MethodsCountry: Canada

Setting: primary care physicians

Duration of recruitment: Apr 1995 - Aug 1996

Design: Placebo-controlled, parallel group


ParticipantsINCLUSION CRITERIA:

Patients of participating physicians with stable HIV-infection.

EXCLUSION CRITERIA:
Active opportunistic infection, smoking, prior antioxidant therapy, hyperlipidaemia, kidney/liver dysfunction, intractable diarrhoea ( >= 6 liquid stools/d), vomiting, GI bleeding

Participants randomised: 49

- 47 M and 2 F

- mean age = 39 yrs

Participants analysed: 49

Loss to follow-up/ withdrawal: 0

Exclusions post-randomisation: 0


InterventionsINTERVENTION: 800 IU vitamin E, and 1000 mg vitamin C

CONTROL: placebo

DURATION: daily for 3 months.


OutcomesPRIMARY OUTCOMES:
Viral load, oxidative stress (lipid peroxides, malondialdehyde, breath pentane)

SECONDARY OUTCOMES:
Plasma micronutrients (vitamin E, C, A carotenoids, zinc, selenium)

New and recurrent infections (AIDS-defining, HIV-associated and other)


Adverse eventsEpigastric discomfort


NotesNumber of patients on anti-retroviral therapy:
Supplement group: 22/ 23 (85%)
Control group: 18/ 26(78%)
Controlled diet 2 weeks prior to randomisation and throughout study period, and dietary counselling.

Source of funding: Canadian Foundation for AIDS Research


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom number table

Allocation concealment (selection bias)Low riskAllocation code not broken until post-analysis

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and investigators were blinded

Incomplete outcome data (attrition bias)
All outcomes
High riskHigh and unequal proportions of missing outcomes

Selective reporting (reporting bias)Unclear riskInsufficient information; study protocol not available

Other biasUnclear riskDid not declare on conflict of interest

Arpadi 2009

MethodsCountry: US

Setting: 4 hospital-based HIV treatment programmes

Duration of recruitment: 2004-2005

Design: Placebo-controlled, parallel group


ParticipantsINCLUSION CRITERIA:

Perinatally-infected children and adolescents, aged 6-16 years.

EXCLUSION CRITERIA:
severe vitamin D deficiency

Participants randomised: 59

- 26 M and 33 F

- mean age = 10.4 yrs

Participants analysed: 56

Loss to follow-up/ withdrawal: 6

Exclusions post-randomisation: 0


InterventionsINTERVENTION: 100 000 IU vitamin D bimonthly, and 1000 mg calcium (2 chews) per day

CONTROL: double placebo

DURATION: bimonthly/ daily for 12 months.


OutcomesPRIMARY OUTCOMES:

Serum 25 hydroxyvitamin D (25-OHD) concentrations

Serum and urine calcium

SECONDARY OUTCOMES:

HIV disease progression (CD4 count, viral load, ARV failure)


Adverse eventsNone


NotesParticipants were perinatally infected. HIV disease was classified by using Centers for Disease Control and Prevention criteria

Source of funding: National Institutes of Health


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputerised randomisation

Allocation concealment (selection bias)Low riskCentral allocation by study statistician

Blinding (performance bias and detection bias)
All outcomes
Low riskStudy personnel and participants were blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskLow attrition (3 of 59 failed to complete the study)

Selective reporting (reporting bias)Unclear riskInsufficient information; study protocol not available

Other biasUnclear riskDid not declare on conflict of interest

Austin 2006

MethodsCountry: Canada

Setting: 22 outpatient clinics

Duration of recruitment: Aug. 1997 - May 1999

Design: Placebo-controlled, parallel group


ParticipantsINCLUSION CRITERIA:

HIV positive, at risk for HIV disease progression based on ART status, CD4, and viral load; >18 years

EXCLUSION CRITERIA:

Continuing CD4 improvement on ART, severe pre-existing hepatic dysfunction, acute opportunistic infection, missed 2 earlier clinic visits without prior arrangement

Participants randomised:331

- 289 M and 42 F

- median age = 40 yrs (21-65) in treatment, 39 (22-63) in control

Participants analysed: 331

Loss to follow-up/ withdrawal/ death: 67

Discontinued intervention but remained in trial: 48

Exclusions post-randomisation: 0


InterventionsINTERVENTION: Multivitamins (incl. vitamin A and trace elements) + natural mixed carotenoids (equivalent to 120000IU beta-carotene daily)

CONTROL: Multivitamins (incl. vitamin A and trace elements) without carotenoids

DURATION: four capsules daily for mean (s.d.)13 (6) months.


OutcomesPRIMARY OUTCOMES: Mortality (time to death from AIDS-defining illness or any cause); time to new or recurrent AIDS-defining illness.

SECONDARY OUTCOMES: CD4 changes from baseline; viral load changes from baseline


Adverse eventsNone reported


NotesStudy closed early at mean 13 mo. follow-up

Number of patients on anti-retroviral therapy:
Supplement group: 137/ 165 (83%)
Control group: 148/ 166 (89%)

Source of funding: Canadian HIV Trials Network

Declared no conflicts of interest


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCentralised block randomisation

Allocation concealment (selection bias)Low riskCentralised sequential randomisation

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and investigators were blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses to follow up explained and survival analysis used

Selective reporting (reporting bias)Unclear riskInsufficient information; study protocol not available

Other biasHigh riskStudy closed prematurely due to interruption in supply of medication

Baeten 2002

MethodsCountry: Kenya

Setting: hospital outpatient clinic

Duration of recruitment: Sep 1998 - Jun 2000

Design: Placebo-controlled, parallel group


ParticipantsINCLUSION CRITERIA:

HIV-1 seropositive women attending Coast Provincial General Hospital outpatient clinics in Mombasa, Kenya

EXCLUSION CRITERIA:

age <18 or >45; pregnancy, or use of vitamin supplements or oral contraceptive pills

Participants randomised: 400

- 400 F

- median age = 28 yrs

Participants analysed: 354

Loss to follow-up/ withdrawal: 46

Exclusions post-randomisation: 0


InterventionsINTERVENTION: Vitamin A (10 000 IU retinyl palmitate)

CONTROL: placebo

DURATION: daily for 6 weeks


OutcomesPRIMARY OUTCOMES:

Vaginal HIV DNA and RNA

SECONDARY OUTCOMES:

Plasma viral load

CD4 and CD8 counts


Adverse eventsNone reported


NotesNumber of patients on anti-retroviral therapy:
Supplement group: 22/ 23 (85%)
Control group: 18/ 26 (78%)

Source of funding: Research grants from NIH, Univ of Washington, and Fogarty Int. Center; International AIDS Research and Training Program scholarships; Gen-Probe (reagents)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated block randomisation

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and investigators were blinded

Incomplete outcome data (attrition bias)
All outcomes
High riskThose lost to follow up had more advanced HIV disease and vitamin A deficiency

Selective reporting (reporting bias)Unclear riskInsufficient information; study protocol not available

Other biasUnclear riskDid not declare on conflict of interest

Bobat 2005

MethodsCountry: South Africa

Setting: hospital outpatient clinic

Duration of recruitment: Mar - Dec 2003

Design: Placebo-controlled, parallel group


ParticipantsINCLUSION CRITERIA:

Children aged 6-60 months with HIV-1 infection attending hospital clinic in Pietermaritzburg, South Africa

EXCLUSION CRITERIA: Children receiving ARVs

Participants randomised: 96

- 49 F and 46 M

- median age (zinc group): 40.1 months (27.4 to 48.4)

- median age (placebo group): 36.6 months (25 to 49.4)

Participants analysed: 85

Losses to follow-up/ withdrawal: 11

Exclusions post-randomisation: 0


InterventionsINTERVENTION:10 mg zinc sulphate

CONTROL: placebo

DURATION: daily for 6 months


OutcomesPRIMARY OUTCOME:
Viral load

SECONDARY OUTCOMES:

% CD4 cells

Haemoglobin concentrations

Mortality

Morbidity (Watery diarrhoea; Pneumonia; URTI; Ear infection)


Adverse eventsNone


NotesConcentrations of HIV-1 RNA in plasma were measured with a reverse transcriptase-PCR assay (COBAS AmpliPrep/Cobas
Amplicor HIV-1 Monitor version 1.5; Roche Molecular Systems, Branchburg, NJ, USA) at 1 month before randomisation, at the time of randomisation, and at 3, 6, and 9 months after the start of supplementation.

Source of funding: WHO; Johns Hopkins; Global Health Bureau; USAID; commercial (tablets)

Conflicts of interest: none


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputerised randomisation in blocks of size 8

Allocation concealment (selection bias)Unclear riskChildren allocated by investigator at hospital but concealment not explicitly stated

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and investigators were blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskSmall loss to follow up and reasons given

Selective reporting (reporting bias)Unclear riskInsufficient information; study protocol not available

Other biasLow riskDeclared no conflict of interest

Burbano 2002

MethodsCountry: USA

Setting: community-based clinic

Duration of recruitment: 1998 - 2000.

Design: Placebo-controlled, parallel group


ParticipantsINCLUSION CRITERIA:

confirmed HIV, past or present use of illegal drugs, >= 18 years, adequate selenium status (> 85 microgram/l)

EXCLUSION CRITERIA: selenium deficient (< 85 microgram/l)

Participants randomised: 259

- 112 F

- median age = 40 yrs (range 24 to 54)

Participants analysed: 186

Loss to follow-up/ withdrawal: 73 at 12 months

Exclusions post-randomisation: 0


Interventions200 microgram selenium or placebo daily for 12 months.


OutcomesPRIMARY OUTCOMES:

Number of hospital admissions
Type of hospital admissions
Risk of hospitalisation

SECONDARY OUTCOMES:

CD4 count

Hospitalisation cost
Plasma selenium


Adverse eventsNone reported


NotesNumber of patients on anti-retroviral therapy:
Selenium group: 64 (76%)
Control group: 60 (53%)

Number, type and duration of hospital admissions recorded 2 years prior and during study period. Medical records reviewed by team of physicians.

Source of funding: research grant and commercial (materials)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and investigators were blinded

Incomplete outcome data (attrition bias)
All outcomes
High riskExclusions from the analysis (28%) not reported by intervention group

Selective reporting (reporting bias)Unclear riskInsufficient information; study protocol not available

Other biasUnclear riskDid not declare on conflict of interest

Carcamo 2006

MethodsCountry: Peru

Setting: Tertiary hospitals

Duration of recruitment: June 1998-Jan 2000

Design: Placebo-controlled, parallel group


ParticipantsINCLUSION CRITERIA:

HIV-seropositive, persistent diarrhoea (>=7 days) without prior treatment

EXCLUSION CRITERIA: None stated

Participants randomised: 159

- 49 F and 110 M

- median age = 30 yrs (range 19-57) in Zinc group

- median age = 31 yrs (range 19-64) in placebo group

Participants analysed: 159

Loss to follow-up/ withdrawal: 51

Exclusions post-randomisation: 0


InterventionsINTERVENTION: zinc sulphate (100 mg)

CONTROL: placebo

DURATION: daily for 14 days


OutcomesPRIMARY OUTCOMES:

Persistence of diarrhoea

Time until cessation of diarrhoea

SECONDARY OUTCOMES:

Plasma zinc and copper levels


Adverse eventsGastrointestinal symptoms (nausea, vomiting, abdominal pain, fever)


NotesSulfamethoxazole-trimethoprim prescribed for patients with enteric bacterial pathogens (23 in zinc group and 12 in placebo)

Source of funding:Fogarty IARTP grant; Univ. of Washington Center for AIDS Research; Centers for Disease Control and Prevention


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated blocked randomisation

Allocation concealment (selection bias)Low riskAssignment roll inaccessible to treatment allocators

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and investigators were blinded

Incomplete outcome data (attrition bias)
All outcomes
High riskHigh losses to follow up in both groups

Selective reporting (reporting bias)Unclear riskInsufficient information; study protocol not available

Other biasUnclear riskDid not declare on conflict of interest

Coodley 1993

MethodsCountry: USA

Setting: Hospital outpatient clinics

Duration of recruitment: not stated

Design: Randomised cross-over trial; no washout period


ParticipantsINCLUSION CRITERIA:

HIV-seropositive

EXCLUSION CRITERIA:

On other forms of vitamin A supplementation; significant hepatic or renal dysfunction; active opportunistic infection or fever

Participants randomised: 21

- 20 M and 1 F

- median age: not stated

Participants analysed: 17

Loss to follow-up/ withdrawal: 4

Exclusions post-randomisation: 0


InterventionsINTERVENTION: 60mg Beta-carotene

CONTROL: placebo

DURATION: three times daily for 4 weeks


OutcomesPRIMARY OUTCOMES:

CD4 counts

SECONDARY OUTCOMES:

White blood cell count
Lymphocyte count
B-lymphocytes
Serum beta-carotene


Adverse eventsNo toxicity; skin discoloration in treatment group


NotesCD4 count data reported as means and ranges**

16 patients received anti-retroviral therapy.

Source of funding: Hoffman La Roche Inc.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and investigators were blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskLow attrition at 1 month; reasons given

Selective reporting (reporting bias)Unclear riskInsufficient information; study protocol not available

Other biasUnclear riskDid not declare on conflict of interest

Coodley 1996

MethodsCountry: USA

Setting: Hospital outpatient clinic and private practice

Duration of recruitment: not stated

Design: Placebo-controlled, parallel group


ParticipantsINCLUSION CRITERIA:

HIV-seropositive; > 21 years

EXCLUSION CRITERIA:

Other forms of vitamin A supplementation 30 days prior to study; ART 60 days prior to study; significant hepatic or renal dysfunction; CD4 <50 or >600

Participants randomised: 72

- 63 M and 9 F

- median age: not stated

Participants analysed: 68 at 1 month; 50 at 3 months

Loss to follow-up/ withdrawal: 4 at 1 month; 22 at 3 months

Exclusions post-randomisation: 0


InterventionsINTERVENTION: 60mg Beta-carotene + multivitamins

CONTROL: placebo + multivitamins

DURATION: three times daily for 3 months


OutcomesPRIMARY OUTCOMES:

CD4 counts

SECONDARY OUTCOMES:

T-cell counts

White blood cell counts

Natural killer cells

HIV p-24 antigen

Serum beta-carotene

Body weight

Karnofsky scores


Adverse eventsNone reported


NotesNumber of patients on anti-retroviral therapy:
Treatment group: 10 (28%)
Control group: 17 (47%)

Source of funding: research grant and commercial (materials)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and investigators were blinded

Incomplete outcome data (attrition bias)
All outcomes
High riskHigh attrition at 3 months; reasons not given

Selective reporting (reporting bias)Unclear riskInsufficient information; study protocol not available

Other biasUnclear riskDid not declare on conflict of interest

Coutsoudis 1995

MethodsCountry: South Africa

Setting: Tertiary hospital study clinic

Duration of recruitment: April 1991-November 1993

Design: Placebo-controlled, parallel group


ParticipantsINCLUSION CRITERIA:

Infants of HIV-infected women who had attended the antenatal clinic, delivered in hospital, and who lived within 10 miles of the hospital.

EXCLUSION CRITERIA:

Preterm infants

Participants randomised: 118

- 28 HIV-infected (13 in vitamin A group)

- 66 M and 52 F

- mean maternal age = 25 yrs (vitamin A) vs. 24.8 yrs (placebo)

Loss to follow-up:

17% (vitamin A) vs. 25% (placebo) at 6 months

36% (vitamin A) vs. 33% (placebo) at 12 months

58% (vitamin A) vs. 63% (placebo) at 18 months

Exclusions post-randomisation: 0


InterventionsINTERVENTION: Vitamin A

CONTROL: placebo

DURATION: Repeat doses of 50 000 IU retinyl palmitate at 1 and 3 months and 100 000 IU at 6, 9,12 and 15 months


OutcomesPRIMARY OUTCOMES:

Overall morbidity

SECONDARY OUTCOMES:

Acute diarrhoea
Persistent diarrhoea (>=7 days)
Hospitalised for diarrhoea
Thrush
Upper respiratory tract infection
Lower respiratory tract infection (LRTI)
Hospitalised for LRTI
Rash


Adverse eventsVomiting and bulging fontanelle


NotesMonthly morbidity recall.

Multiple episodes of same condition in a single month counted as one episode (per 100 months).

Diagnosis of HIV infection in children based on positive HIV antibody test at 15 months (enzyme-linked immunosorbent assay
[ELISA], Abbott, N Chicago, Ill). Children who had lost maternal antibody by 15 months or sooner were diagnosed as uninfected.

Among the 11 deaths in children younger than 15 months, 9 were
diagnosed as HIV-infected on the basis of the following criteria: at least one HIV-related sign or symptom when last seen and death
from severe infection or persistent diarrhea beyond the first 4 weeks of life

Source of funding: Medical Research Council; University of Natal; Fogarty International Center; National Institute of Mental Health


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom number table

Allocation concealment (selection bias)Unclear riskThe capsules looked identical and were placed in number-coded envelopes from which they were removed
when appropriate.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and investigators were blinded

Incomplete outcome data (attrition bias)
All outcomes
High riskSignificant losses to follow up insufficiently explained

Selective reporting (reporting bias)Unclear riskInsufficient information; study protocol not available

Other biasUnclear riskDid not declare on conflict of interest

Fawzi 1998

MethodsCountry: Tanzania

Setting: Hospital antenatal clinic

Duration of recruitment: Apr 1995 - Jul 1997

Design: Randomised trial with two-by-two factorial design


ParticipantsINCLUSION CRITERIA:

Pregnant women (12-27 weeks gestation) with confirmed HIV infection

EXCLUSION CRITERIA:

Non-resident in Dar es Salaam from recruitment until one year post-delivery

Participants randomised: 1085

- mean age = 24.7 yrs

Participants analysed: 1078

Loss to follow-up/ withdrawal: 54

Exclusions post-randomisation: 7 deaths


InterventionsINTERVENTION: Vitamin A alone (30 mg beta-carotene plus 5000 IU preformed vitamin A) OR vitamin A plus multivitamins (20mg vit B1, 20 mg vit B2, 25 mg vit B6, 100mg niacin, 50 microg vit B12, 500 mg vit C, 30 mg vit E and 0.8 mg folic acid) OR multivitamins without vitamin A

At delivery, women in both vitamin A groups were given an additional 200 000 IU vitamin A, while the other 2 groups received placebo.

CONTROL: placebo

DURATION: Daily for the duration of follow-up i.e. from enrolment until end of study (Aug. 2003).

Median follow-up was 71 months (IQR: 46 to 80) w.r.t. survival


OutcomesPRIMARY OUTCOMES:

Maternal outcomes: Mortality and disease progression from AIDS-related causes; HIV-related complications; viral load; T-cell counts

Birth outcomes: Fetal death; low birth weight (< 2500g); preterm birth (< 37 weeks)

SECONDARY OUTCOMES:

Mortality among all live births and among HIV-infected infants Morbidity among infants (diarrhoea; respiratory tract infections)

Morbidity among mothers (hypertension; depression; social functioning)
Maternal weight gain during pregnancy
Postnatal child growth and development

CD4 counts of infants

Micronutrient status of infants

Haematologic status of children

Psychomotor development index
Mental development index


Adverse eventsNone reported


NotesAll women received 400mg ferrous sulphate and 5 mg folate daily, plus weekly doses of chloroquine antenatally

All infants received 100000 IU vitamin A at 6 months and 200000 IU every 6 months thereafter.

Vitamin A dropped from two of the regimens in Sept. 2000 and replaced with placebo due to safety concerns.

Source of funding: Fogarty International Center; National Institutes of Health; National Institute of Child Health and Human Development


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputerised factorial randomisation in blocks of 20

Allocation concealment (selection bias)Low riskSequentially numbered bottles coded identically

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and investigators were blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskSurvival analysis used to impute missing outcome data

Selective reporting (reporting bias)Low riskRationale and design of study fully reported, and all outcomes were reported on

Other biasLow riskDeclared no conflict of interest

Fawzi 1999

MethodsCountry: Tanzania

Setting: Hospital inpatient and outpatient follow-up

Duration of recruitment: April 1993 - March 1997.

Design: Placebo-controlled, parallel group


ParticipantsINCLUSION CRITERIA:

Admitted to hospital for pneumonia; aged 6 - 60 months; no eye signs or symptoms of vitamin A deficiency

EXCLUSION CRITERIA:

treatment with vitamin A for 4 months prior to study entry; severe malnutrition; measles; pulmonary tuberculosis; diphtheria; whooping cough; xerophthalmia

Participants randomised:687

- 58 HIV-infected of 648 with known status (9%)

- 353 M and 295 F

- mean maternal age = 25.6 yrs (vitamin A group) vs. 26.2 (placebo)

Participants analysed: 648

Loss to follow-up/ withdrawal:76

Exclusions post-randomisation: 0


InterventionsINTERVENTION: vitamin A

CONTROL: placebo

DURATION: single dose on hospital admission, on day 2 and at 4 and 8 months after discharge (100,000 IU dose for infants; 200,000 IU for children)


OutcomesPRIMARY OUTCOMES:

All-cause mortality

Cause-specific mortality (AIDS, diarrhoea, pneumonia, malaria, anaemia and other infections (measles, meningitis, dysentery, fever of unknown origin, malnutrition))

Diarrhoea
Acute respiratory infection

SECONDARY OUTCOMES:

Hospitalisation

Visits to health centre


Adverse eventsRespiratory infections; diarrhoea


NotesSera from children were tested for HIV antibodies by enzyme- linked immunosorbent assay and Western blot tests. For positive children <15 months of age, HIV infection was confirmed by amplified heat-denatured HIV-p24 antigen assays with confirmatory neutralization assays.

Cause of death ascertained by review of hospital records and home verbal autopsy questionnaire by two physicians. Discrepancies resolved by third physician.

Bi-weekly morbidity recall. No data provided on episodes of persistent diarrhoea or hospitalisation of HIV-infected children.

Source of funding: Thrasher Research Fund; International Development Research Center


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation in blocks of 20 insufficiently described

Allocation concealment (selection bias)Low riskVitamin A and placebo were dispensed out of a dropper from identical 25-ml opaque bottles that were labelled with one of four batch numbers. The batch number code was retained by the manufacturer until the end of the study

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and investigators were blinded

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskReasons for losses to follow up (n=76) not given

Selective reporting (reporting bias)Unclear riskInsufficient information; study protocol not available

Other biasUnclear riskDid not declare on conflict of interest

Fawzi 2005

MethodsCountry: Tanzania

Setting: Tertiary hospital antenatal clinic

Duration of recruitment: Sept 2000 - Oct 2002

Design: Randomised placebo-controlled trial


ParticipantsINCLUSION CRITERIA: Pregnant women (12-27 wk.), resident in Dar es Salaam for duration of study

EXCLUSION CRITERIA: None

Participants randomised: 400

- mean maternal age = 27 yrs

Participants analysed: 397

Loss to follow-up/ withdrawal: 3 deaths; 18 left study area after delivery

Exclusions post-randomisation: 3 left study area before delivery


InterventionsINTERVENTION: Zinc (25mg)

CONTROL: placebo

DURATION: daily until 6 weeks after delivery.


OutcomesPRIMARY OUTCOMES:

Maternal haematological indicators at 6 weeks postpartum

Birth outcomes (duration, birthweight, birth length, head circumference, placental weight, preterm births, LBWs, SGAs, fetal loss, early child mortality

Maternal T-cell counts


Adverse eventsZinc had adverse effects on haemoglobin concentrations and other haematological indicators (RBC, PCV)


NotesAll women received weekly ferrous sulphate, folate, chloroquine phosphate, and multivitamin supplements (vitamins B, C, E).

Source of funding: National Institute of Child Health and Human Development


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskA randomisation list was prepared in blocks of 20

Allocation concealment (selection bias)Unclear riskAt enrolment, each eligible woman was assigned to the next numbered bottle of regimen.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and investigators were blinded

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLow loss to follow up, but CD4 data missing without explanation for a high proportion of both groups

Selective reporting (reporting bias)Unclear riskInsufficient information; study protocol not available

Other biasLow riskStudy sponsors had no role in study design and reporting

Hanekom 2000

MethodsCountry: USA

Setting: Hospital HIV clinic

Duration of recruitment: Not stated

Design: Randomised placebo-controlled trial


ParticipantsINCLUSION CRITERIA:

Clinic patients who were eligible for non-primary annual influenza vaccination

EXCLUSION CRITERIA:

Hypersensitivity to eggs, acute febrile illness, recent receipt of intravenous gammaglobulin or vaccination.

Participants randomised: 59 children

- M : F ratio = 0.6 (vitamin A) and 1.3 (placebo)

- median (range) age = 84 (31-209) months in vitamin A group; 77 months (25-142) in placebo group

Participants analysed: 59

Loss to follow-up/ withdrawal: 1

Exclusions post-randomisation: 0


InterventionsINTERVENTION: vitamin A (200 000 IU retinyl palmitate)

CONTROL: placebo

DURATION: daily for 2 days.


OutcomesPRIMARY OUTCOMES:

Viral load changes after vaccination

Antibody levels (H1N1, H3N2) after vaccination

SECONDARY OUTCOMES:

T-cell counts

Vitamin A levels


Adverse eventsNone reported


NotesHIV viral load (branch-chain DNA amplification, Chiton Corp, Emeryville, CA; lower limit of detection 500 copies/mL) measured on study days 0, 14, 28, and 42

All children received inactivated influenza vaccine on study day 14.

All were receiving anti-retroviral therapy. An unknown number who had ARV changes were excluded from viral load analysis.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated by pharmacy

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and investigators were blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskOne exclusion due to incomplete follow up

Selective reporting (reporting bias)Unclear riskInsufficient information; study protocol not available

Other biasUnclear riskDid not declare on funding sources or conflicts of interest

Humphrey 1999

MethodsCountry: USA

Setting: HIV Clinic

Duration of recruitment: Jan - July 1996.

Design: Randomised placebo-controlled safety trial


ParticipantsINCLUSION CRITERIA: 18 to 45 years, CD4 > 200

EXCLUSION CRITERIA: pregnant or breastfeeding

Participants randomised: 40 women

- mean age (SD) in years = 36.2 (5.6) in vitamin A group and 33.2 (5.6) in placebo group

Participants analysed: 39

Loss to follow-up/ withdrawal: 1

Exclusions post-randomisation: 0


InterventionsINTERVENTION: 300 000 IU vitamin A.

CONTROL: placebo

DURATION: Single dose.


OutcomesPRIMARY OUTCOMES:

Viral load

T-cell subsets (%CD4; %CD8 which are CD38+)

SECONDARY OUTCOMES:

Vitamin A status


Adverse eventsSigns or symptoms of toxicity (headache, nausea, vomiting, diarrhoea, fever)


NotesNumber of patients on anti-retroviral therapy:
vitamin A group: 12 (60%)
Control group: 7 (35%)

Source of funding: Paediatric AIDS Foundation grant


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and investigators were blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskOne lost to follow up

Selective reporting (reporting bias)Unclear riskInsufficient information; study protocol not available

Other biasUnclear riskDid not declare on conflict of interest

Hurwitz 2007

MethodsCountry: USA

Setting: University clinic

Duration of recruitment: June 2001 - July 2005

Design: Placebo controlled trial


ParticipantsINCLUSION CRITERIA: aged 18-55 years; no history of major systemic disorders related to HIV; pre-menopausal and non - pregnant

EXCLUSION CRITERIA: on treatment for chronic conditions; selenium deficient

Participants randomised: 310

- mean age = 40.5 yrs

Participants analysed: 262

- 179 M and 86 F

Loss to follow-up/ withdrawal: 88

Exclusions post-randomisation: 48 pre-treatment


InterventionsINTERVENTION:Selenium (200 micrograms)

CONTROL: placebo

DURATION: daily for 9 months


OutcomesPRIMARY OUTCOMES:

Viral load

CD4 count

Serum selenium


Adverse eventsNone


NotesPatients on ARV: 105/141 (74%) in Se group; 87/121 (72%) in placebo group

Preliminary analysis at 9 months of an 18-month trial

Source of funding: National Institutes of Health


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputerised block randomisation

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and investigators were blinded

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskHigh unexplained losses to follow up, balanced between groups. Imputational analyses conducted.

Selective reporting (reporting bias)Unclear riskInsufficient information; study protocol not available

Other biasLow riskDeclared no conflict of interest

Hussey 1996

MethodsCountry: South Africa

Setting: HIV clinic at a children's hospital

Duration of recruitment:1994-1995.

Design: Randomised placebo-controlled trial.

Lost to follow-up at 2 months:
Total sample: 1 (3%)

Intention-to-treat: not performed.


ParticipantsINCLUSION CRITERIA:

Child attendees at HIV clinic

EXCLUSION CRITERIA:

Acute infections, fever

Participants randomised: 75

- mean age = 17 mo.

Participants analysed: 75

Loss to follow-up/ withdrawal: 0

Exclusions post-randomisation: 0.


InterventionsINTERVENTION: 200 000 IU vitamin A

CONTROL: placebo

DURATION: daily for 2 days.


OutcomesPRIMARY OUTCOMES:

T-Cell counts (absolute; CD4; CD56; CD29)

SECONDARY OUTCOMES:

Vitamin A levels


Adverse eventsNone reported


NotesConference abstract only

Children who received vitamin A were more immuno-suppressed

50% of children had vitamin A < 20 microgram/dl.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and investigators

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information

Selective reporting (reporting bias)Unclear riskInsufficient information; study protocol and full report not available

Other biasUnclear riskDid not declare on funding sources or conflicts of interest

Jiamton 2003

MethodsCountry: Thailand

Setting: Outpatient clinic

Duration of recruitment: Mar 2000 - Jan. 2001

Design: Placebo-controlled trial

Duration of recruitment: Mar 2000- Jan 2001.


ParticipantsINCLUSION CRITERIA: older than 18 years; 50<CD4<550;

EXCLUSION CRITERIA:
taking ARV or micronutrients for during month prior to enrollment

Participants randomised: 481

- 189 M and 292 F

- mean age = 32 yrs

Participants analysed: 481

Loss to follow-up/ withdrawal: 79 at 48 weeks

Exclusions post-randomisation: 0


InterventionsINTERVENTION: Micronutrient supplement (3000 micrograms vitamin A, 6mg beta-carotene, 20 micrograms vitamin D, 80 mg vitamin E , 180 micrograms vitamin K, 400 mg vitamin C, 24mg vitamin B1, 15 mg vitamin B2, 40 mg vitamin B6, 30 microg vitamin B12, 0.1 mg folic acid, 40 mg pantothenic acid , 10 mg iron, 200 mg magnesium, 8 mg manganese, 30 mg zinc, 300 micrograms iodine, 3 mg copper, 400 micrograms selenium, 150 micrograms chromium, 60 mg cysteine)

CONTROL: placebo

DURATION: twice daily for 48 weeks.


OutcomesPRIMARY OUTCOMES:

Mortality
Hospital admissions

SECONDARY OUTCOMES:

CD4 counts
Viral load


Adverse eventsA total of 137 minor adverse events reported (dizziness, drowsiness, nausea, rash, urine discolouration)


NotesSource of funding: Nestle Foundation; Vitabiotics


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCentralised randomisation in blocks of 10

Allocation concealment (selection bias)Low riskInterventions packaged in identical coded bottles

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and investigators were blinded

Incomplete outcome data (attrition bias)
All outcomes
High riskThose lost to follow-up were sicker than those who remained in the trial (baseline median CD4 counts among those lost did not differ between groups. Survival analysis used to address missing outcome data.

Selective reporting (reporting bias)Unclear riskInsufficient information; study protocol not available

Other biasLow riskDeclared independence of study investigators declared

Kaiser 2006

MethodsCountry: USA

Setting: Four HIV study centres

Duration of recruitment: Jan. 2002- May 2003

Design: Placebo-controlled trial


ParticipantsINCLUSION CRITERIA:

On stable HAART regimen for >= 3 months; had developed symptoms of mitochondrial toxicity (distal symmetrical polyneuropathy (DSP)) from either stavudine and/or didanosine

EXCLUSION CRITERIA:

Pregnant; on treatment for active opportunistic infection or malignancy; vitamin B12 deficient; already taking more than one micronutrient pill per day

Participants randomised: 40

- 35 M and 5 F

- mean age = 46 yrs

Participants analysed: 40

Loss to follow-up/ withdrawal: 0

Exclusions post-randomisation: 0


InterventionsINTERVENTION:

Micronutrient supplement (33 ingredients)

CONTROL: placebo

DURATION: 2x daily for 12 weeks


OutcomesPRIMARY OUTCOMES:

CD4 counts

Viral load

SECONDARY OUTCOMES:

Metabolic parameters

Neuropathy symptoms (DSP) score

General health status


Adverse eventsNone


NotesSource of funding:Bristol Myers-Squibb


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod of block randomisation method not described

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and investigators were blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo losses to follow up

Selective reporting (reporting bias)Unclear riskInsufficient information; study protocol not available

Other biasLow riskDeclared no conflict of interest

Kelly 1999

MethodsCountry: Zambia

Setting: Home care service of tertiary hospital

Duration of recruitment: not stated

Design: Placebo-controlled trial


ParticipantsINCLUSION CRITERIA:

adults with persistent diarrhoea for more than 1month

EXCLUSION CRITERIA:

< 18 years, pregnancy, administration of antibiotics in the week prior to recruitment, Karnofsky scores > 80 or <50.

Participants randomised: 135

- 79 M and 56 F

- median age = 32.5 yrs (micronutrient); 34 (placebo)

Participants analysed: 106

Loss to follow-up/ withdrawal: 29

Exclusions post-randomisation: 0


InterventionsINTERVENTION: Micronutrient supplement (10 500 IU vitamin A, 300mg vitamin C, 300mg vitamin E, 150 microg Selenium and 200mg Zinc sulphate)
Both treatment groups also received 5mg folic acid and 800mg albendazole twice daily.

CONTROL: placebo

DURATION: daily for 2 weeks


OutcomesPRIMARY OUTCOMES:

Recovery from diarrhoea

- patient weeks with and without diarrhoea during 12 weeks follow up

- remission at 4 weeks

All cause mortality during first 4 weeks

Change in Body Mass Index and MUAC

Change in Karnofsky score

SECONDARY OUTCOMES:

Changes in CD4 and CD8 counts at 4 weeks
Changes in serum vitamin A and E after 4 weeks


Adverse eventsNone


NotesSource of funding: Smithkline Beecham


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod not described

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
High riskMicronutrient and placebo capsules were not identical; unclear whether providers and assessors were blinded

Incomplete outcome data (attrition bias)
All outcomes
High risk25% of patients were lost to follow-up due to death and the tradition of going back to the family home when terminally ill.

Selective reporting (reporting bias)Unclear riskInsufficient information; study protocol not available

Other biasUnclear riskDid not declare on conflicts of interest.

Kupka 2008

MethodsCountry: Tanzania

Setting: antenatal clinics

Duration of recruitment: Sept 2003 - July 2005

Design: Placebo-controlled, parallel group


ParticipantsINCLUSION CRITERIA:

HIV-infected pregnant women (12-27 weeks gestation) seeking care

EXCLUSION CRITERIA:
Non-residents in Dar-es-Salaam or those not intending to stay until at least one year post-delivery

Participants randomised: 915

- mean age = 27.5 yrs

Participants analysed: 913

Loss to follow-up/ withdrawal: 0

Exclusions post-randomisation: 2


InterventionsINTERVENTION: Selenium (200 microgram selenomethionine)

CONTROL: placebo

DURATION: daily until 6 months post-delivery


OutcomesPRIMARY OUTCOMES:

Viral load; CD4 counts; genital shedding of HIV-infected cells; risk of mastitis; birth weight; adverse pregnancy outcomes; maternal and infant mortality

SECONDARY OUTCOMES:

Haemoglobin concentrations; maternal morbidity


Adverse eventsNone


NotesSupported by the National Institute of Child Health and Human Development (NICHD R24 043555-05).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputerised block randomisation

Allocation concealment (selection bias)Low riskStickers used to conceal numeric allocation codes

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and investigators

Incomplete outcome data (attrition bias)
All outcomes
Low riskData on birth outcomes and birth weight missing for a low proportion of participants, and survival analysis used for mortality outcomes

Selective reporting (reporting bias)Unclear riskInsufficient information; study protocol not available

Other biasLow riskDeclared no conflict of interest

Luabeya 2007

MethodsCountry: South Africa

Setting: Five rural primary care clinics

Duration of recruitment: June 2003 - Oct 2004

Design: Controlled trial


ParticipantsINCLUSION CRITERIA:

children 4-6 months old

EXCLUSION CRITERIA:

underweight for age; nutritional oedema; persistent diarrhoea; taking vitamin or micronutrient supplements in past month

Participants randomised: 373

- 32 HIV-infected; 154 born to HIV-infected mothers; 187 born to HIV-uninfected mothers

- 173 M and 162 F

- mean age = 5.5 months

Participants analysed: 335

Loss to follow-up/ withdrawal: 88

Exclusions post-randomisation: 0


InterventionsINTERVENTIONS:

Zinc (10mg) and multiple micronutrients (B vitamins; vitamins C, D, E, K; copper, iron, iodine) vs. zinc and vitamin A (1250 IU)

CONTROL:

Vitamin A

DURATION: daily for median duration of 14.9 months.


OutcomesPRIMARY OUTCOMES:

Percentage of days of diarrhoea per child

SECONDARY OUTCOMES:

Severity of diarrhoea

Percentage of weeks with upper respiratory symptoms

Percentage of children who ever had pneumonia (maternal and field worker reports)


Adverse eventsVomiting reported post-supplementation in 9 children by fieldworkers


NotesHIV testing of children was done between ages of 4 and 6 months using a quantitative HIV RNA assay (Nuclisens HIV-1 QT, Organon Teknika or Nuclisens EasyQ HIV-1, Biomerieux, Boxtel, The Netherlands)

Source of funding: National Institute of Health; Wellcome Trust

Declared no conflicts of interest


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputerised randomisation in blocks of 6

Allocation concealment (selection bias)Low riskPre-packed sequentially numbered study supplements

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and investigators were blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing data addressed used appropriate statistical methods

Selective reporting (reporting bias)Low riskAll outcomes of interest were reported on

Other biasUnclear riskDelay in shipment of supplements prevented 243 children from receiving supplements for 11 weeks

Range 2006

MethodsCountry: Tanzania

Setting: Five district health facilities

Duration of recruitment: August 2001 to July 2002

Design: Placebo-controlled 2x2 factorial trial


ParticipantsINCLUSION CRITERIA:

HIV-positive and HIV-negative persons aged >=15 years with sputum-positive pulmonary tuberculosis (new or relapsed cases)

EXCLUSION CRITERIA:

Patients who defaulted TB chemotherapy or those who remained smear-positive on chemotherapy (failure cases) and those with serious  tuberculosis or other disease unlikely to survive; pregnant and lactating women.

Participants randomised: 530

- 213 HIV-infected

- 325 M and 205 F

- mean age = 35.4 yrs

Participants analysed: 499

Loss to follow-up/ withdrawal: 77 within 244 days post-treatment

Exclusions post-randomisation: 31


InterventionsINTERVENTIONS:

Micronutrient supplement contained vitamin A (1.5mg), vitamin B1 (20 mg), vitamin B2 (20 mg), vitamin B6 (25 mg), vitamin B12 (50mg), folic acid (0·8 mg), niacin (40 mg), vitamin C (200 mg), vitamin E (60 mg), vitamin D3 (5mg), selenium (0·2 mg) and copper (5 mg), and Zn tablets contained 45 mg elementary Zn

CONTROL: placebo (2x2 factorial)

DURATION: daily for 8 months.

All patients received a standard 8 month TB chemotherapy regimen.


OutcomesPRIMARY OUTCOMES:

All-cause mortality at 8 months

SECONDARY OUTCOMES:

Viral load

CD4 counts

Weight gain


Adverse eventsNone reported


NotesSource of funding: Danish International Development Assistance


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputerised randomisation

Allocation concealment (selection bias)Low riskSealed envelopes, codes unbroken until post-analysis

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and investigators were blinded

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskSurvival analysis was done but there were significant imbalances in losses between intervention groups

Selective reporting (reporting bias)Unclear riskInsufficient information; study protocol not available

Other biasLow riskDeclared no conflict of interest

Semba 1998

MethodsCountry: USA

Setting: Community-based clinic

Duration of recruitment: Not stated

Design: Placebo-controlled trial


ParticipantsINCLUSION CRITERIA:

HIV-infected Intravenous Drug Users participating in ALIVE (AIDS Linked to Intravenous Experiences) Cohort (n=630); >= 18 years; not taking vitamin A supplements

EXCLUSION CRITERIA:

CD4 > 500 cells/mm3; pregnancy.

Participants randomised: 120

- 89 M and 31 F

- mean age = 38.2 yrs

- 50% treatment group vs. 43% placebo group on ART

Participants analysed: 120

Loss to follow-up/ withdrawal: 8.3% at 4 weeks

Exclusions post-randomisation: 0


InterventionsINTERVENTION: Single dose of 200 000 IU vitamin A

CONTROL: placebo


OutcomesPRIMARY OUTCOMES:

Viral load
CD4 count

SECONDARY OUTCOMES:
Serum vitamin A


Adverse eventsNone reported


NotesSource of funding: USAID


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom number table in blocks of 10

Allocation concealment (selection bias)Low riskSequentially numbered envelopes used to conceal allocation

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and investigators were blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data were balanced across groups

Selective reporting (reporting bias)Unclear riskInsufficient information; study protocol not available

Other biasUnclear riskDid not declare on conflicts of interest.

Semba 2005

MethodsCountry: Uganda

Setting:Hospital clinic

Duration of recruitment:Jan. 1995 - June 1998

Design: Placebo-controlled trial


ParticipantsINCLUSION CRITERIA:

Children aged 6 months; resident near hospital for duration of trial

EXCLUSION CRITERIA:

Evidence of vitamin A deficiency

Participants randomised: 181 at age 15 months

- 90 M and 91 F

- mean age = 15 months

Participants analysed: 168

Loss to follow-up/ withdrawal: 0

Exclusions post-randomisation: 0


InterventionsINTERVENTION:

200 000 IU vitamin A

CONTROL: placebo

DURATION: every 3 months from 15 to 36 months.


OutcomesPRIMARY OUTCOMES:

Mortality

SECONDARY OUTCOMES:
Morbidity (diarrhoea, cough, fever, ear discharge, hospitalisation)


Adverse eventsNone reported


NotesInfants of HIV-positive women were tested for HIV-1 infection by using a p24 antigen assay (Coulter Diagnostics, Hialeah, FL, USA) until June 1996, after which time infants were tested for HIV-1 by using a qualitative assay for HIV-1 DNA polymerase
chain reaction (PCR; HIV-1 Amplicor, Roche Diagnostics, Indianapolis, IN, USA) or a quantitative assay for HIV-1 RNA PCR (Roche Amplicor Monitor, Roche Diagnostics, Branchburg, NJ, USA). All results were confirmed by serologic testing at ages 15 to 18 mo and by quantitative HIV-1 RNA PCR at age 15 mo (Roche Amplicor Monitor).

All children received daily prophylactic sulfamethoxazole- trimethoprim therapy

Source of funding: National Institutes of Health

Declared no conflicts of interest


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated, random codes

Allocation concealment (selection bias)Low riskSequentially numbered pill cards were used

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants, paediatrician and clinic staff were blinded

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskSurvival analysis used to account for differences in duration of follow up due to early termination of the trial

Selective reporting (reporting bias)Low riskStudy protocol not available but all stated outcomes of interest reported on

Other biasLow riskTrial stopped early due to change in national guideline on vitamin A supplementation

Semba 2007a

MethodsCountry: USA

Setting: Study clinic

Duration of recruitment: Sept. 2002 - Aug. 2005

Design: Controlled trial


ParticipantsINCLUSION CRITERIA:

women >=18 years; history of injection drug use (IDU) within past 10 years; hepatitis C (HCV) antibody-positive; Karnofsky status >80%; serum ferritin <200 ng/ml

EXCLUSION CRITERIA:

Pregnant; history of liver failure, renal disease, interferon therapy for HCV; haemochromatosis; blood disorders

Participants randomised: 458

- mean age = 40 yrs

- 138 (30.1%) HIV-positive

Participants analysed: 115 at 12 months

Loss to follow-up/ withdrawal:151 (33%)

Exclusions post-randomisation: 0


InterventionsINTERVENTION:Micronutrients with iron (18 mg)

CONTROL: Micronutrients only

DURATION: daily for 12 months.


OutcomesPRIMARY OUTCOMES:

Haemoglobin

Iron status

Plasma HCV

Viral load

Liver enzymes


Adverse eventsNot stated


NotesOn HAART: 27/69 (intervention) and 23/69 (control)

Trial stopped early due to slow recruitment.

Source of funding: National Institute on Drug Abuse; National Institute on Nursing Research


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputerised randomisation

Allocation concealment (selection bias)Low riskPre-packed sequentially numbered study supplements

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and investigators were blinded

Incomplete outcome data (attrition bias)
All outcomes
High riskHigh loss to follow up (27.7%) in both groups, and not reported by HIV status

Selective reporting (reporting bias)Unclear riskInsufficient information; study protocol not available

Other biasUnclear riskDid not declare on conflicts of interest.

Semba 2007b

MethodsCountry: Malawi

Setting: Eight community health centres

Duration of recruitment: July 1999 - October 2004

Design: Placebo-controlled


ParticipantsINCLUSION CRITERIA:

HIV-positive and HIV-negative adults with smear-positive pulmonary tuberculosis (new cases)

EXCLUSION CRITERIA:

Prior or current TB chemotherapy, prior vitamin supplements

Participants randomised: 1148

- 829 HIV-positive

- 336 M and 493 F

- mean age = 34 yrs

Participants analysed: 1148

Loss to follow-up: 103 in HIV-positive group (50 and 53 in micronutrient and placebo groups, respectively)

Exclusions post-randomisation: 0


InterventionsINTERVENTION: Micronutrient supplement (vitamin A, C, D, E, B6, B12, Riboflavin, Thiamine, Niacin, folate, zinc, iodine, selenium)

CONTROL: placebo

DURATION: daily for 24 months..

All patients received a standard 8 month TB chemotherapy regimen.


OutcomesPRIMARY OUTCOMES:

All-cause mortality

SECONDARY OUTCOMES:

Serum vitamin A, vitamin E and selenium


Adverse eventsNot reported


NotesSource of funding: National Institutes of Health and the Fogarty International Centre.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskBlocked randomisation

Allocation concealment (selection bias)Low riskpre-packed sequentially numbered study supplements

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and investigators were blinded

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskHigh unexplained loss to follow up but survival analysis was used

Selective reporting (reporting bias)Low riskStudy protocol available; all outcomes of interest were reported on

Other biasUnclear riskDid not declare on conflicts of interest.

Villamor 2008

MethodsCountry: Tanzania

Setting: Five outpatient TB clinics

Duration of recruitment: April 2000 - April 2005

Design: Placebo-controlled


ParticipantsINCLUSION CRITERIA:

age 18-65 years; non-pregnant; no anti-TB treatment for > 4 weeks in previous year; Karnofsky score >=40%; plan to stay in Dar es Salaam for 2 years

EXCLUSION CRITERIA: none

Participants randomised: 887

- 471 HIV-positive

- 273 M and 198 F

- mean age = 34 yrs

Participants analysed: 1148

Loss to follow-up: 67 in HIV-positive group (33 and 34 in micronutrient and placebo groups, respectively)

Exclusions post-randomisation: 0


InterventionsINTERVENTION: Micronutrient supplement (retinol; vitamins B1, B2, B6, B12; niacin; vitamin C; vitamin E; folic acid; selenium)

CONTROL: placebo

DURATION: daily for 24 months..

All patients received DOTS anti-TB chemotherapy.


OutcomesPRIMARY OUTCOMES:

Culture negativity at 1 month after initiation of treatment; mortality during at least 24 months of follow-up; TB recurrences.

SECONDARY OUTCOMES:

Changes from baseline in viral load, CD4 cell counts, and body weight.


Adverse eventsNone reported


NotesSource of funding: National Institute of Allergy and Infectious Diseases; US Department of Agriculture


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskcomputer-generated permuted blocks of 20, stratified by HIV status

Allocation concealment (selection bias)Unclear riskAll clinical and research staff were unaware of the subjects’ treatment assignment, but insufficient information provided

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and investigators were blinded

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskReasons not given for losses to follow-up, although appropriate statistical analyses were used

Selective reporting (reporting bias)Unclear riskInsufficient information; study protocol not available

Other biasLow riskDeclared no conflicts of interest

Wejse 2009

MethodsCountry: Guinea-Bissau

Setting: TB clinics in urban disease surveillance site

Duration of recruitment: Nov 2003 - Dec 2005

Design: Placebo-controlled, parallel group


ParticipantsINCLUSION CRITERIA:

TB patients starting anti-TB treatment, >=15 years.

EXCLUSION CRITERIA:
None

Participants randomised: 367

- 222 M and 143 F

- mean age = 37.5 yrs

- 131 HIV-infected

Participants analysed: 365

Loss to follow-up/ withdrawal: 84

Exclusions post-randomisation: 2


InterventionsINTERVENTION: 100 000 IU cholecalciferol (vitamin D)

CONTROL: placebo

DURATION: at inclusion; 5 and 8 months after inclusion


OutcomesPRIMARY OUTCOMES:
Reduction in a clinical severity score (TB score)

SECONDARY OUTCOMES:
12-month mortality


Adverse eventsMinor events reported; no difference between groups


NotesSource of funding: Aarhus University Hospital; Danish Research Council for Developmental Research


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated sequence

Allocation concealment (selection bias)Low riskIdentical, sequentially numbered containers were used.

Blinding (performance bias and detection bias)
All outcomes
Low riskPatients, staff and researchers

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLoss to follow up unknown in HIV+ subgroup; survival analysis used

Selective reporting (reporting bias)Low riskProtocol available; all outcomes of interest reported on

Other biasLow riskHIV subgroup analyses not pre-specified but proportions were equally distributed; funder and provider had no role in study design

ZVITAMBO 2006

MethodsCountry: Zimbabwe

Setting:Maternity clinics and hospitals

Duration of recruitment:Nov. 1997 - Jan. 2000

Design: Randomised trial with two-by-two factorial design


ParticipantsINCLUSION CRITERIA: Mother-infant pairs; HIV+ mothers; singleton infant with birthweight >=1500 g; resident in Harare after delivery

EXCLUSION CRITERIA: Mother or infant with acute life-threatening condition

Participants randomised: 4495 mothers

- mean age = 25.6 yrs

Participants analysed: 4495 infants of HIV+ mothers at baseline; 2582 infants assessable at 6 weeks for postnatal HIV infection

Loss to follow-up/ withdrawal: 139 infants excluded from 24-month mortality analysis due to loss to follow-up, death from unnatural causes, or missing dates

Exclusions post-randomisation: 0


InterventionsINTERVENTION:Single dose of maternal vitamin A (400 000 IU) and infant vitamin A (50 000 IU) OR maternal dose only OR infant dose only

CONTROL: placebo

DURATION: single dose <=96 hours after delivery


OutcomesPRIMARY OUTCOMES:

Postnatal mother-to-child transmission (MTCT) of HIV

Child HIV-free survival

Infant mortality up to 24 months


Adverse eventsInfant mortality at 24 mo. approx. double in supplemented infants who were HIV negative at 6 weeks


NotesFollow-up period curtailed due to economic conditions in Zimbabwe

Source of funding: Canadian International Development Agency, USAID, Gates Foundation; Rockefeller Foundation; BASF


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputerised factorial randomisation in blocks of 12

Allocation concealment (selection bias)Low riskSealed envelopes and encrypted computer files

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and investigators were blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskSurvival analysis used to include censored data

Selective reporting (reporting bias)Unclear riskInsufficient information; study protocol not available

Other biasLow riskDeclared no conflict of interest

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Austin 2003Trial terminated prematurely due to unstable intervention.

Constans 1996Pilot study; vitamin A group had more advanced disease at baseline

Kennedy 2000Included in Wiysonge 2005 review:
Vitamin A supplementation for reducing the risk of mother-to-child transmission of HIV infection

Kumwenda 2002Included in Wiysonge 2005 review:
Vitamin A supplementation for reducing the risk of mother-to-child transmission of HIV infection

Mehta 2009Observational analysis of perinatal outcomes and mortality vs. maternal vitamin D status in Tanzanian trial (Fawzi et al 1998)

Shor-Posner 2003No outcomes of relevance to this review

 
Characteristics of studies awaiting assessment [ordered by study ID]
Baum 2010

MethodsCountry: USA

Setting:hospital outpatient clinic

Duration of recruitment:March 2002 - December 2005

Design: Placebo-controlled trial

ParticipantsINCLUSION CRITERIA: HIV-infected adults with low plasma zinc levels (<0.75 mg/L) and no history of endocrine or psychiatric disorders

EXCLUSION CRITERIA: premenopausal women who were pregnant or had an intention to become pregnant; plasma zinc levels <=0.35 mg/L at any time during the study

Participants randomised: 231

- 62 F and 169 M

- mean age = 42.7 yrs

Participants analysed:200

Loss to follow-up/ withdrawal:31

Exclusions post-randomisation: 0

InterventionsINTERVENTION:12 mg of elemental zinc for women; 15 mg for men

CONTROL: placebo

DURATION: 18 months

OutcomesPRIMARY OUTCOMES:HIV disease progression, specifically immunological failure (CD4 < 200)

SECONDARY OUTCOMES:HIV viral load, morbidity, and mortality

Notes

CIGNIS 2010

MethodsCountry: Zambia

Setting:Public health sector clinic

Duration of recruitment:October 2005 to July 2009

Design: Placebo-controlled trial

ParticipantsINCLUSION CRITERIA: healthy 6 month old infants

EXCLUSION CRITERIA: no parental consent

Participants randomised:743

- mean age = 6 months

Participants analysed:576

Loss to follow-up/ withdrawal:167

Exclusions post-randomisation: 0

InterventionsINTERVENTION:micronutrient fortified porridge

CONTROL: conventionally fortified porridge

DURATION:12 months

OutcomesPRIMARY OUTCOMES:stunting at age 18 months

SECONDARY OUTCOMES:hospital referral; death

Notes

Mda 2010

MethodsCountry: South Africa

Setting: academic hospital

Duration of recruitment: November 2005 and May 2007

Design: Placebo-controlled trial

ParticipantsINCLUSION CRITERIA: HIV-infected children aged between 4 mo and 2 y; admitted with diarrhoea or pneumonia to the paediatric wards of an academic hospital

EXCLUSION CRITERIA: diarrheal episode longer than 72 h on admission; pneumonia complicated by respiratory failure; children on ART or those who had received vitamin or micronutrient supplementation; children with chronic illness unrelated to HIV

Participants randomised:

-

Participants analysed:

Loss to follow-up/ withdrawal:

Exclusions post-randomisation: 0

Interventions

Outcomes

Notes

Ndeezi 2010

MethodsCountry: Uganda

Setting:Paediatric HIV clinics of the national referral hospital

Duration of recruitment:June 2005-June 2008

Design: Placebo-controlled trial

ParticipantsINCLUSION CRITERIA: children aged 1 - 5 years whose mothers had attended the clinic at least once, and who adhered to a regular study follow-up schedule for one year.

EXCLUSION CRITERIA: Children enrolled in other studies, those residing more than 15 kilometres from the clinic and those whose parents or caretakers were anticipating
moving from the study area

Participants randomised:847

- 56% were less than 36 months

Participants analysed:695

Loss to follow-up/ withdrawal:152

Exclusions post-randomisation: 0

InterventionsINTERVENTION: 2xRDA of 14 micronutrients

CONTROL: RDA of six multivitamins

DURATION:6 months

OutcomesPRIMARY OUTCOMES:Mortality at 12 months

SECONDARY OUTCOMES:Growth (weight-for-height at 12 months); CD4 counts

Notes

 
Comparison 1. Vitamin A in adults

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Maternal mortality1Hazard Ratio (Random, 95% CI)Totals not selected

    1.1 Twelve months
1Hazard Ratio (Random, 95% CI)0.0 [0.0, 0.0]

    1.2 Twenty four months
1Hazard Ratio (Random, 95% CI)0.0 [0.0, 0.0]

 2 Hospitalised at least once by 12 months post partum14495Risk Ratio (M-H, Random, 95% CI)0.96 [0.76, 1.22]

 3 Infant death or HIV infection at 24 months14495Risk Ratio (M-H, Random, 95% CI)1.02 [0.94, 1.10]

 4 Infant HIV infection at 24 months14495Risk Ratio (M-H, Random, 95% CI)0.99 [0.91, 1.09]

 
Comparison 2. Vitamin A in children

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All-cause mortality3262Risk Ratio (M-H, Random, 95% CI)0.55 [0.37, 0.82]

 2 Morbidity rates1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    2.1 All-cause morbidity
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.2 Diarrhoea
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.3 Diarrhoea lasting a week or more
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.4 Lower respiratory tract infection
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 3 Child growth at 12 months1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    3.1 Wasting
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.2 Stunting
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 3. Vitamin D in adults

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical severity score (TBscore) at 8 months171Mean Difference (IV, Random, 95% CI)0.10 [-0.53, 0.73]

 2 All cause mortality at 12 months1131Risk Ratio (M-H, Random, 95% CI)1.15 [0.65, 2.02]

 
Comparison 4. Vitamin D in children

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 CD4 counts at 12 months156Mean Difference (IV, Random, 95% CI)115.0 [-74.26, 304.26]

 2 Viral load at 12 months156Mean Difference (IV, Random, 95% CI)-0.10 [-0.63, 0.43]

 
Comparison 5. Zinc in adults

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Newborn outcomes1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    1.1 Duration of pregnancy
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 Birth weight
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.3 Birth length
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.4 Head circumference
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.5 Placental weight
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Low birth weight and prematurity1Risk Ratio (M-H, Random, 95% CI)Totals not selected

    2.1 Preterm < 37 wks
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    2.2 Low birth weight < 2500 g
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    2.3 Small for gestational age
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 3 Fetal loss and early child mortality1Risk Ratio (M-H, Random, 95% CI)Totals not selected

    3.1 Miscarriage
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.2 Stillbirth
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.3 Fetal death
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.4 Perinatal death
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.5 Neonatal death
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 4 Immune cell counts1Mean Difference (IV, Random, 95% CI)Totals not selected

    4.1 CD4 counts at 6 weeks post partum
1Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    4.2 CD8 counts at 6 weeks postpartum
1Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    4.3 CD3 counts at 6 weeks postpartum
1Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 5 Viral load at 6 weeks postpartum1100Mean Difference (IV, Random, 95% CI)-0.32 [-0.69, 0.05]

 6 Anthropometric outcomes1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    6.1 Overall weight gain during pregancy
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    6.2 Rate of weight gain during pregancy
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    6.3 Total change in MUAC durng pregnancy
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 7 Persistent diarrhoea at 2 weeks1104Risk Ratio (M-H, Random, 95% CI)1.05 [0.76, 1.44]

 
Comparison 6. Zinc in children

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mortality at 9 months196Risk Ratio (M-H, Random, 95% CI)0.31 [0.07, 1.42]

 2 Scheduled and illness visits1Risk Ratio (M-H, Random, 95% CI)Totals not selected

    2.1 Scheduled visits; watery diarrhoea
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    2.2 Scheduled visits; pneumonia
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    2.3 Scheduled visits; URI
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    2.4 Scheduled visits; ear infection
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    2.5 All visits; watery diarrhoea
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    2.6 All visits; URI
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    2.7 All visits; pneumonia
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    2.8 All visits; ear infection
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 3 Viral load at 9 months185Mean Difference (IV, Random, 95% CI)-0.10 [-0.40, 0.20]

 4 CD4 % at 9 months185Mean Difference (IV, Random, 95% CI)1.0 [-2.87, 4.87]

 
Comparison 7. Selenium in adults

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Adverse pregnancy outcomes1Risk Ratio (M-H, Random, 95% CI)Totals not selected

    1.1 Low birth weight < 2500 g
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.2 Very low birth weight < 2000 g
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.3 Preterm birth < 37 weeks
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.4 Preterm birth < 34 weeks
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.5 Low birth weight and preterm birth
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.6 Low birth weight and term birth
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.7 Small for gestational age
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 2 Adverse pregnancy outcomes1Mean Difference (IV, Random, 95% CI)Totals not selected

    2.1 Mean birth weight (g)
1Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 3 Perinatal mortality1Risk Ratio (M-H, Random, 95% CI)Totals not selected

    3.1 Miscarriage before 28 wks.
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.2 Stillbirth between 28 wk and delivery
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.3 Fetal loss
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.4 Perinatal death
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 4 Infant mortality1Risk Ratio (M-H, Random, 95% CI)Totals not selected

    4.1 Neonatal death
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    4.2 Infant death
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    4.3 Neonatal or infant death
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 5 Adult mortality1913Risk Ratio (M-H, Random, 95% CI)1.00 [0.51, 1.98]

 6 Viral load change 0-9 months1130Mean Difference (IV, Random, 95% CI)-0.33 [-0.51, -0.15]

 7 CD4 count change from 0- 9 months1130Mean Difference (IV, Random, 95% CI)65.0 [56.80, 73.20]

 8 Hospitalised for all conditions1Risk Ratio (M-H, Random, 95% CI)Totals not selected

 9 Hospitalised for OIs and HIV-related conditions1Risk Ratio (M-H, Random, 95% CI)Totals not selected

 
Comparison 8. Multiple supplements in non-pregnant adults

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mortality3Risk Ratio (M-H, Random, 95% CI)Subtotals only

 2 Mortality (all cause) by 48 weeks1Hazard ratio (Random, 95% CI)Totals not selected

    2.1 New Subgroup
1Hazard ratio (Random, 95% CI)0.0 [0.0, 0.0]

 3 Mortality by 48 weeks (baseline CD4 < 200)1Hazard ratio (Random, 95% CI)Subtotals only

 4 Mortality by 48 weeks (baseline CD4 >= 200)1Hazard ratio (Random, 95% CI)Totals not selected

 5 Mortality by 48 weeks (baseline CD4 < 100)1Hazard ratio (Random, 95% CI)Totals not selected

 6 Mortality by 48 weeks (baseline CD4 >=100)1Hazard ratio (Random, 95% CI)Totals not selected

 7 New AIDS -defining infections116Risk Ratio (M-H, Random, 95% CI)3.11 [0.44, 22.00]

 8 New HIV-associated infections1Risk Ratio (M-H, Random, 95% CI)Totals not selected

 9 Recurrent HIV-associated infections2Risk Ratio (M-H, Random, 95% CI)Totals not selected

 10 New other infections1Risk Ratio (M-H, Random, 95% CI)Totals not selected

 11 Recurrent other infections1Risk Ratio (M-H, Random, 95% CI)Totals not selected

 12 Viral load at 12 months5401Mean Difference (IV, Fixed, 95% CI)-1.07 [-1.25, -0.90]

 13 CD 4 counts at 12 months4358Mean Difference (IV, Fixed, 95% CI)1.31 [-86.14, 88.76]

 14 CD 8 counts at 12 months2222Mean Difference (IV, Fixed, 95% CI)18.0 [-219.65, 255.65]

 15 CD 3 counts (entire period)1172Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 16 Weight gain at 7 months1192Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 17 Viral load change : Baseline to 2 months196Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 18 CD4 cell count change: Baseline to 2 months2136Mean Difference (IV, Fixed, 95% CI)24.0 [5.75, 42.25]

 19 Change in weight: Baseline to 7 months1192Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 20 Treatment failure after 1 month1322Odds Ratio (M-H, Fixed, 95% CI)0.73 [0.39, 1.37]

 
Comparison 9. Multiple supplements in pregnant and lactating women [maternal outcomes]

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Progression to stage 4 disease / death from AIDS-related causes1Hazard ratio (Random, 95% CI)Totals not selected

 2 Death from AIDS-related causes1Hazard ratio (Random, 95% CI)Totals not selected

 3 Progression to stage 4 disease1Hazard ratio (Random, 95% CI)Totals not selected

 4 Progression to stage 3 disease or higher1Hazard ratio (Random, 95% CI)Totals not selected

 5 HIV-related complications: thrush1Hazard ratio (Random, 95% CI)Totals not selected

 6 HIV-related complications: gingival erythema1Hazard ratio (Random, 95% CI)Totals not selected

 7 HIV-related complications: angular cheilitis1Hazard ratio (Random, 95% CI)Totals not selected

 8 HIV-related complications: oral ulcer1Hazard ratio (Random, 95% CI)Totals not selected

 9 HIV-related complications: reported mouth and throat ulcers1Hazard ratio (Random, 95% CI)Totals not selected

 10 HIV-related complications: painful tongue or mouth1Hazard ratio (Random, 95% CI)Totals not selected

 11 HIV-related complications: difficult or painful swallowing1Hazard ratio (Random, 95% CI)Totals not selected

 12 HIV-related complications: nausea and vomiting1Hazard ratio (Random, 95% CI)Totals not selected

 13 HIV-related complications: diarrhoea1Hazard ratio (Random, 95% CI)Totals not selected

 14 HIV-related complications: dysentery1Hazard ratio (Random, 95% CI)Totals not selected

 15 HIV-related complications: fatigue1Hazard ratio (Random, 95% CI)Totals not selected

 16 HIV-related complications: rash1Hazard ratio (Random, 95% CI)Totals not selected

 17 HIV-related complications: acute upper respiratory tract infection1Hazard ratio (Random, 95% CI)Totals not selected

 18 CD4 difference (baseline up to 3 months)1Mean Difference (IV, Random, 95% CI)Totals not selected

 19 CD4 difference (baseline to over 3 months)1Mean Difference (IV, Random, 95% CI)Totals not selected

 20 CD8 difference (baseline up to 3 months)1Mean Difference (IV, Random, 95% CI)Totals not selected

 21 CD8 difference (baseline to over 3 months)1Mean Difference (IV, Random, 95% CI)Totals not selected

 
Comparison 10. Multiple supplements in pregnant and lactating women [child outcomes]

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Foetal death (miscarriage+stillbirth)1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 2 Total mortality by 24 months including foetal deaths1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 3 Mortality by 24 months among all live births1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 4 Mortality by 24 months among HIV-infected live births1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 5 Mortality by 24 months among HIV-infected infants at 6 weeks of age1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 6 Mean birthweight1Mean Difference (IV, Random, 95% CI)Subtotals only

 7 Birthweight < 2000 g1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 8 Birthweight < 2500 g1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 9 Preterm birth (<37 weeks)1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 10 Severe preterm birth (<34 weeks)1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 11 Small for gestational age1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 12 CD4 count >= 3 months1Mean Difference (IV, Random, 95% CI)Subtotals only