H/A: Micronutrient Supplementation (2009)

Citation:
 
Study Design:
Class:
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Quality Rating:
Research Purpose:

To examine the effects of vitamin supplements on wasting in HIV-infected women from the Tanzania trial. Also to assess the risk factors for wasting, which included sociodemographic characteristics, the incidence of morbidity events and immunologic progression of the women during follow-up.

Inclusion Criteria:

HIV-1–infected women who attended their first prenatal care visit in Dar es Salaam, Tanzania.

Exclusion Criteria:

Women who had only one anthropometric measurement during the follow-up (n=27).

Description of Study Protocol:

Recruitment

Between April 1995 and July 1997, HIV-1–infected women who attended their first prenatal care visit in Dar es Salaam, Tanzania.

Design

Randomized controlled trial. Women were randomly assigned to receive a daily oral dose of one of four regimens. The active treatment and placebo tablets were identical in size and color. The endpoints of the study included first episodes of a mid-upper arm circumference less than 22cm or a body mass index (BMI) less than 18 and the incidence of weight loss episodes during a median 5.3 years of follow-up.  

Blinding used

Blinded regimens were used. Nevertheless, the women who had subsequent pregnancies during the follow-up period were given open-label vitamins B, C and E (i.e., the same formulation given in the multivitamin arm of the study) throughout their pregnancies; these women reverted to their originally assigned blinded regimen after delivery.

Intervention

Regimens

  1. Multivitamins (20mg thiamin, 20mg riboflavin, 25mg vitamin B6, 100mg niacin, 50mcg vitamin B12, 500mg vitamin C, 30mg vitamin E, and 0.8mg folic acid)
  2. Vitamin A (5,000 IU preformed) plus beta-carotene (30mg)
  3. Multivitamins with vitamin A plus beta-carotene
  4. Placebo.

All of the women received folic acid and iron as well as malaria prophylaxis during pregnancy, according to the standard of care. At delivery, the women who received multivitamins alone or with vitamin A plus beta carotene received an additional single 200,000 IU dose of vitamin A, whereas the women who received multivitamins alone or placebo alone received placebo.

Statistical Analysis

Effect of vitamin supplements on wasting:

  • Intent-to-treat principle
  • Cumulative incidence 
  • Cox proportional hazards models 
  • Potential interaction between multivitamins and vitamin A plus beta carotene.

 Sociodemographic characteristics and the risk of wasting:

  • Cox models
  • Proportional rates models for recurrent events.

 Morbidity during follow-up:

  • Cox models
  • Poisson regression
  • Likelihood ratio test.

 

Data Collection Summary:

Timing of Measurements

The trial started in April 1995, recruitment finished in July 1997 and the trial ended in August 2003. Monthly visits were schedule for a median of 5.3 years of follow-up.

Dependent Variable

Risk of wasting.

Independent Variables

  • Vitamin supplement regimens: (1) multivitamins (20mg thiamin, 20mg riboflavin, 25mg vitamin B6, 100mg niacin, 50mcg vitamin B12, 500mg vitamin C, 30mg vitamin E, and 0.8mg folic acid); (2) vitamin A (5,000 IU preformed) plus beta carotene (30mg); (3) multivitamins with vitamin A plus beta-carotene; or (4) Placebo. All of the women received folic acid, iron, and malaria prophylaxis during pregnancy, according to the standard of care. At delivery, the women who received multivitamins alone or with vitamin A plus beta carotene received an additional single 200,000 IU dose of vitamin A, whereas the women who received multivitamins alone or placebo alone received placebo.
  • Socioeconomic status
  • Time-varying morbidity events.

 

Description of Actual Data Sample:

Initial N

1,078 HIV-infected women.

Attrition (final N)

1,051 HIV-infected women.

Age

Mean 24.7±4.8 years at recruitment.

Ethnicity

African.

Other relevant demographics

Mean CD4 counts

  • Placebo (n=257): 420±212 cells per mm3
  • Vitamin A and beta-carotene (n=266): 416±200 cells per mm3
  • Multivitamins (n=266): 428±195 cells per mm3
  • Multivitamins, vitamin A and beta-carotene (n=262): 411±204 cells per mm3.

Anthropometrics

The baseline characteristics did not differ significantly by treatment arm.

Location

Dar es Salaam, Tanzania.

Summary of Results:

Multivitamins alone significantly reduced the risk of a first episode of a mid-upper arm circumference less than 22cm (relative risk: 0.66; 95% CI: 0.47, 0.94; P=0.02).

In multivariate-adjusted Cox models, the woman’s age, education level and height were inversely related to the incidence of wasting.

Episodes of diarrhea, nausea or vomiting, lower respiratory tract infections, oral ulcers, thrush, severe anemia and low CD4 cell counts were each significantly related to an increased risk of wasting.

Table 2. Effect of vitamin supplements on wasting outcomes in HIV-1–infected women from Tanzania1

Outcome Effect of Multivitamin

Effect of Vitamin A+Beta-carotene

Multivitamin No Multivitamin Hazard Ratio (95% CI)2,3 Vitamin A+Beta carotene No Vitamin A+Beta carotene Hazard Ratio (95% CI)2,4

MUAC<22cm            
Total n at risk 502 489 500 491
First 2 years (no. of events)5 96 125 0.71 (0.54, 0.93) 116 105 1.09 (0.83, 1.42)
First four years (no. of events) 121 143 0.79 (0.62, 1.00) 142 122 1.14 (0.89, 1.45)
Whole period (no. of events)6 137 154 0.83 (0.66, 1.04) 159 132 1.18 (0.93, 1.48)
BMI<18            
Total n at risk 523 512 521 514
First two years (no. of events) 91 93 0.90 (0.68, 1.20) 94 90 1.00 (0.75, 1.34)
First four years (no. of events) 122 120 0.97 (0.76, 1.25) 131 111 1.14 (0.89, 1.47)
Whole period (no. of events)6 134 140 0.93 (0.73, 1.17) 144 130 1.08 (0.85, 1.37)
Weight loss>10%            
Total n at risk 528 523 528 523
First two years (no. of events) 283 266 1.05 (0.89, 1.24) 289 260 1.09 (0.92, 1.29)
First four years (no. of events) 316 299 1.06 (0.91, 1.24) 319 296 1.07 (0.92, 1.26)
Whole period (no. of events)6 334 324 1.05 (0.90, 1.22) 337 321 1.03 (0.88, 1.20)

1 MUAC, -arm circumference.

2 From Cox proportional hazards models with time-to-first event of each outcome as the dependent variable and treatment assignment as the predictor.

3 Comparison between the women who received multivitamin, namely multivitamin alone or multivitamin and vitamin A+beta-carotene, and the women who did not receive multivitamin, namely those who received vitamin A+beta-carotene alone or placebo.

4 Comparison between the women who received vitamin A+beta-carotene, namely vitamin A+beta-carotene alone or multivitamin and vitamin A+beta-carotene, and the women who did not receive vitamin A+beta-carotene, namely those who received multivitamin alone or placebo.

5 Events correspond to the first occurrence of each outcome during follow-up. Only the women without an outcome at the first visit were considered to be at risk.

6 The median follow-up time was 63 months (5.3 years).

Table 3. Baseline characteristics of HIV-infected women as predictors of wasting1

Variable First Episode of MUAC<22cm

First Episode of BMI<18

Long and Severe Episodes of Weight Loss2

n at risk Events (No./Person-months) Adjusted Hazard Ratio (95% CI)3 P for Trend4 n at risk Events (No./Person-months) Adjusted Hazard Ratio (95% CI)3 P for Trend4 n at risk Events (No./Person-months) Adjusted Hazard Ratio (95% CI)5 P for Trend4

Age (y)       0.003       0.35       0.06
    <20 121 46/4427 1.80 (1.25, 2.61)   131 39/5,810 1.12 (0.76, 1.64)   131 70/5,966 1.37 (1.07, 1.75)  
    20–24 400 116/15,759 1.05 (0.79, 1.39)   421 105/17,386 0.93 (0.70, 1.24)   424 155/17,995 0.98 (0.81, 1.20)  
    25–29 300 85/13,066 1.00   315 87/13,769 1.00   319 136/15,193 1.00  
    ≥30 170 44/7,687 0.85 (0.59, 1.22)   168 43/7,553 0.83 (0.57, 1.20)   171 79/8,803 0.96 (0.76, 1.22)  
Education level (years of formal training)       0.02       0.05       0.46
    None 80 26/3,151 1.16 (0.77, 1.75)   84 23/3,400 1.15 (0.74, 1.77)   85 32/3,655 0.97 (0.74, 1.28)  
    1–4 49 15/1,639 0.94 (0.55, 1.61)   51 15/2,015 1.10 (0.65, 1.87)   54 23/2,255 1.00 (0.67, 1.49)  
    5–8 764 233/31,275 1.00   794 214/33,814 1.00   801 338/36,510 1.00  
    ≥9 98 17/4873 0.47 (0.29, 0.77)   106 22/5,288 0.60 (0.39, 0.94)   105 47/5,537 0.83 (0.65, 1.06)  
Height (cm)       0.02       0.14       0.05
    >150 860 241/36,126 1.00   895 246/38,369 1.00   905 399/41,853 1.00  
    ≤150 131 50/4,813 1.44 (1.06, 1.96)   140 28/6,148 0.72 (0.50, 1.11)   140 41/6,105 0.73 (0.54, 1.00)  
CD4+ cell count (cells/mm3)       <0.0001       <0.0001       <0.0001
    ≥500 291 64/13,644 1.00   304 56/15,037 1.00   301 106/14,977 1.00  
    200–499 529 165/21,989 1.61 (1.20, 2.15)   554 167/23,506 1.80 (1.33, 2.44)   559 255/26,397 1.41 (1.15, 1.72)  
    <200 118 50/3,667 3.08 (2.10, 4.53)   119 40/3,954 2.67 (1.76, 4.05)   126 62/4,480 2.06 (1.57, 2.70)  

1 MUAC, mid-upper arm circumference.

2 Defined as weight loss 1kg per month during more than four months.

3 Multivariate Cox proportional hazards models with time-to-first event as the outcome and predictors that included treatment assignment (three indicator variables), age (three indicators), level of education (three indicators), short stature (yes or no), and CD4+ cell counts at first visit (two indicators and one for missing).

4 Tests for trend for each variable when introduced into the model as a continuous predictor.

5 Multivariate proportional rates model for recurrent events with time-to-weight loss as the outcome and indicator variables for treatment, age, education, short stature, and baseline CD4+ counts as predictors; 95% CIs were constructed with the robust sandwich covariance matrix estimate.


Table 5. Incidence of morbidity episodes during periods of weight loss1

Event No Weight Loss Short Periods of Moderate Weight Loss Short Periods of Severe Weight Loss Long Periods of Moderate Weight Loss Long Periods of Severe Weight Loss P2

Diarrhea           <0.00001
    Events (no./person-months) 579/25,914 165/4,861 201/3,782 286/10,567 136/2,834  
    Rate ratio (95% CI) 1.00 1.52 (1.28, 1.81) 2.38 (2.02, 2.79) 1.21 (1.05, 1.40) 2.14 (1.78, 2.58)  
    P3 <0.0001 <0.0001 0.03 <0.0001  
Dysentery           <0.00001
    Events (no./person-months) 211/25,914 64/4,861 72/3,782 121/10,567 52/2,834  
    Rate ratio (95% CI) 1.00 1.61 (1.21, 2.13) 2.34 (1.79, 3.06) 1.40 (1.12, 1.75) 2.26 (1.67, 3.06)  
    P 0.003 <0.0001 0.01 <0.0001  
Nausea and vomiting           <0.00001
    Events (no./person-months) 336/25,914 89/4,861 97/3,782 109/10,567 73/2,834  
    Rate ratio (95% CI) 1.00 1.41 (1.12, 1.78) 1.97 (1.57, 2.46) 0.79 (0.64, 0.98) 1.97 (1.53, 2.54)  
    P 0.01 <0.0001 NS <0.0001  
Oral ulcer or thrush           <0.00001
    Events (no./person-months) 364/21,595 111/5,169 52/3,882 183/6,915 73/2,344  
    Rate ratio (95% CI) 1.00 1.27 (1.03, 1.57) 0.79 (0.59, 1.06) 1.57 (1.31, 1.87) 1.83 (1.43, 2.36)  
    P NS NS <0.0001 <0.0001  
Upper respiratory infection           0.22
    Events (no./person-months) 1,585/21,595 402/5,169 315/3,882 559/6,915 176/2,344  
    Rate ratio (95% CI) 1.00 1.06 (0.95, 1.18) 1.11 (0.98, 1.25) 1.10 (1.00, 1.21) 1.02 (0.88, 1.20)  
    P NS NS NS NS  
Lower respiratory infection           <0.00001
    Events (no./person-months) 688/21,595 248/5,169 115/3,882 400/6,915 104/2,344  
    Rate ratio (95% CI) 1.00 1.50 (1.30, 1.74) 0.93 (0.77, 1.14) 1.82 (1.61, 2.05) 1.40 (1.14, 1.72)  
    P <0.0001 NS <0.0001 0.005  

1 Moderate weight loss was defined as average monthly decreases between 0.1kg and 1.0kg; severe episodes represent decreases >1.0kg per month. Short weight-loss episodes were those that lasted ≤four months, whereas long periods lasted more than four months.

2 A likelihood ratio test that compared a Poisson model with weight-loss periods as predictors and an intercept-only model; used to ascertain whether the incidence of morbidity events varied across the periods.

3 Bonferroni-corrected for four pairwise comparison.

Author Conclusion:

In conclusion, in this study, supplementation with vitamin B complex and vitamins C and E reduces the risk of wasting in HIV-infected women. This new finding adds to previously reported benefits of this formulation and provides additional support for the recommendation of long-term daily supplementation in HIV-infected individuals at the doses used in the present trial. Whether supplementation at doses resembling the recommended dietary allowance has the same benefits of multiple recommended dietary allowances on the health and survival outcomes of HIV-infected persons urgently needs to be addressed in randomized trials. Similarly, the potential benefits of providing vitamin B complex and vitamins C and E to HIV-uninfected women who attend prenatal care need to be ascertained. The level of education is a robust predictor of wasting in this population from sub-Saharan Africa. This constitutes yet another argument for investing in increased access to formal education for girls in developing countries. Anemia, low CD4 cell counts and morbidity episodes that are likely to be the result of opportunistic infections are important risk factors for wasting in HIV-infected women who were not receiving antiretroviral treatment.

 

Funding Source:
Government: National Institute of Child Health and Human Development, Fogarty International Center
Reviewer Comments:
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) ???
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? Yes
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? Yes
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? N/A
  6.6. Were extra or unplanned treatments described? N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes