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H/A: Micronutrient Supplementation (2009)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:

The purpose of this study was to determine if supplementation with oral natural mixed carotenoids and micronutrients can improve the health or survival of AIDS patients on conventional management including antiretroviral therapy (ART).

Inclusion Criteria:
  • HIV seropositive
  • At least 18 years old
  • At risk for the progression of HIV immune disease
    • CD4 T-lymphocyte counts below 50 cells per microliter and expected stability of ART
    • CD4 T-lymphocyte count nadir below 50 cells per microliter and stabilized under 150 cells per microliter with protease inhibitor-based combination ART for at least three months
    • Or CD4 T-lymphocyte count stabilized below 200 cells per microliter and plasma viremia greater than 20,000 copies per ml) (RT-PCR) or 10,000 copies per ml (bDNA) and on stable protease inhibitor-based combination ART for at least three months.
Exclusion Criteria:
  • Shown continuing CD4 T-lymphocyte count improvement on combination protease inhibitor-based anti-HIV therapy
  • Severe pre-existing hepatic dysfunction
  • Missed two earlier clinic appointments without prior arrangement or had acute opportunistic infection.
Description of Study Protocol:

Recruitment

Subjects were recruited from 22 centers of the Canadian HIV Trials Network between August 1997 and May 1999.

Design

  • Randomized, double-blind, placebo controlled multi-center clinical trial
  • Eligible participants were randomized into two groups: Carotenoids treament and control
  • Allocation to study group was stratified by center, using permuted blocks of four from randomization lists prepared before the study, by personnel at the data center of the CTN
  • Daily, participants in both groups orally received specially-formulated multi-vitamins including vitamin A and trace elements. 

Blinding Used

  • The study was double-blinded as both the trial participants and the clinicians were blinded to the study group allocation
  • The carotenoids and multi-vitamins were co-formulated into one caplet. Both the carotenoids and the placebo caplets were identical in appearance. Total number of caplets were identical in both groups.

Intervention

  • Daily, all participants orally received specially-formulated multivitamins including vitamin A and trace elements
  • Participants in the treatment group received the equivalent of 120,000 IU (72mg) of beta carotene daily.

Statistical Analysis

  • The Wilcoxon rank-sum test was used to compare the effect of carotenoids treatment at follow-up on CD4 T-lymphocyte count, serum carotene concentration and plasma viral load
  • Time to development of new or recurrent AIDS-defining illness or death, time to death and adverse events defined as non-AIDS hospitalization were compared between treatment and control groups using the log-rank test
  • Analyses adjusted for clinically important prognostic risk factors were carried out using the Cox proportional hazards model.
Data Collection Summary:

Timing of Measurements

  • Baseline or screening visits consisted of:
    • Complete medical history including previously diagnosed medical conditions, opportunistic infections and medications
    • A complete physical examination
    • CD4 and CD8 T-lymphocyte counts and plasma HIV-1 viral load
    • Biochemical evaluation including serum beta carotene.
  • Quarterly visits were done with an assessment by a physician of clinical examination and laboratory tests similar to those at baseline.

Dependent Variables

  • Serum carotene levels
  • CD4 T-cell count change from baseline
  • Plasma viral load change from baseline
  • Clinical outcomes (death or at least one new or recurrent AIDS-defining event).

Independent Variables

Mixed carotenoid treatment (120,000 IU beta carotene daily).

Control Variables

HIV+ status.

Description of Actual Data Sample:
  • Initial N: 331 (165 treatment, 166 control). Treatment group was 89.4% male, control group was 89.6% male.
  • Attrition (final N): 264 (134 treatment, 130 control). 36 patients died by 18 months.
  • Age: Treatment group was 40 years (mean), control group was 39 (mean)
  • Ethnicity: Treatment group was 86.3% white, control group was 84.7% white.

Anthropometrics

Serum carotene levels: Percentage of group with levels under 1.0 micromol per L (population-based reference values are 1.0micromol to 5.5 micromol per L) 16.8% treatment, 14.9% control. None of the baseline information was statistically signficantly different between groups.

Location

Community-based, tertiary care centers, part of the Canadian HIV Trials network.

Summary of Results:

Intention-to-Treat Analyses of Clinical Outcomes by Carotenoids Treatment

Outcome Treatment Control HR P-Value Adjusted HR
(95% CI)		 P-Value
Death or AIDS
25
(15.2 %)
36
(21.7%)
1.42
(0.85, 2.36)
0.18
1.81
(0.95, 3.42)
0.07
Death
13
(7.8 %)
23
(13.9%)
1.76
(0.89, 3.47)
0.11
3.15
(1.10, 8.98)
0.03

Other Findings

  • Serum carotene concentration below 1.0micromol per L was present in 16% of participants at baseline
  • Despite variation in carotene content of the treatment medication, serum carotene concentrations increased significantly to twice the baseline levels to 18 months' follow-up in participants who received carotenoids treatment, compared with controls (P<0.0001)
  • Serum carotene concentration showed a statistically signficant increase from baseline with carotenoids treatment at three months (P<0.0001), six (P<0.0001), nine (P<0.0001), 12 (P<0.0007) and 18 (P<0.001) months
  • Serial median change from baseline in CD4 T-lymphocyte count showed a statistically-signficant increase with carotenoids treatment at 12 (P=0.04), 15 (P=0.007) and 18 (P=0.008) months
  • Although not statistically significant, mortality was increased in participants who did not receive carotenoids treatment compared with those who did (HR time to death 1.76; 95% confidence interval, 0.89, 3.47; P=0.11)
  • In multivariate analysis, survival was significantly and independently improved in those with higher baseline serum carotene concentrations (P=0.04) or higher baseline CD4 T-lymphocyte counts (P=0.005)
  • Adjusted mortality was also significantly and independently increased in those who did not receive carotenoids treatment compared with those who did (HR time to death 3.15; 95% confidence interval, 1.10, 8.98; P=0.03).
Author Conclusion:
  • Low serum carotene concentration is common in AIDS patients and predicts death
  • Supplementation with micronutrients and natural mixed carotenoids may improve survival by correction of a micronutrient deficiency
  • Further studies are needed to corroborate findings and elucidate mechanisms of action.
Funding Source:
University/Hospital: University of Ottawa, Ottawa Canada;University of Calgary, Calgary, Canada; University of Western Ontario, London, Canada; University of Manitoba, Winnipeg, Canada; St. Paul's Hospital and University of British Columbia, Vancouver, Anada; Queen's University, Kingston,Canada; University of Ottawa, Sp
Reviewer Comments:
  • Study was stopped prematurely due to inability to obtain study medication
  • Attrition rate was 19%
  • Authors did not clearly state reasons for loss of subjects.
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? ???
  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) Yes
  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.) N/A
  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? ???
  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? ???
  6.6. Were extra or unplanned treatments described? ???
  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? ???
  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