Effect of micronutrient supplementation on disease progression in asymptomatic, antiretroviral-naive, HIV-infected adults in Botswana: a randomized clinical trial

Abstract

Importance: Micronutrient deficiencies occur early in human immunodeficiency virus (HIV) infection, and supplementation with micronutrients may be beneficial; however, its effectiveness has not been investigated early in HIV disease among adults who are antiretroviral therapy (ART) naive.

Objective: To investigate whether long-term micronutrient supplementation is effective and safe in delaying disease progression when implemented early in adults infected with HIV subtype C who are ART-naive.

Design, setting, and participants: Randomized clinical trial of supplementation with either daily multivitamins (B vitamins and vitamins C and E), selenium alone, or multivitamins with selenium vs placebo in a factorial design for 24 months. The study was conducted in 878 patients infected with HIV subtype C with a CD4 cell count greater than 350/μL who were not receiving ART at Princess Marina Hospital in Gaborone, Botswana, between December 2004 and July 2009.

Interventions: Daily oral supplements of B vitamins and vitamins C and E, selenium alone, or multivitamins plus selenium, compared with placebo.

Main outcomes and measures: Reaching a CD4 cell count less than 200/μL until May 2008; after this date, reaching a CD4 cell count of 250/μL or less, consistent with the standard of care in Botswana for initiation of ART at the time of the study.

Results: There were 878 participants enrolled and randomized into the study. All participants were ART-naive throughout the study. In intent-to-treat analysis, participants receiving the combined supplement of multivitamins plus selenium had a significantly lower risk vs placebo of reaching CD4 cell count 250/μL or less (adjusted hazard ratio [HR], 0.46; 95% CI, 0.25-0.85; P = .01; absolute event rate [AER], 4.79/100 person-years; censoring rate, 0.92; 17 events; placebo AER, 9.22/100 person-years; censoring rate, 0.85; 32 events). Multivitamins plus selenium in a single supplement, vs placebo, also reduced the risk of secondary events of combined outcomes for disease progression (CD4 cell count ≤250/μL, AIDS-defining conditions, or AIDS-related death, whichever occurred earlier [adjusted HR, 0.56; 95% CI, 0.33-0.95; P = .03; AER, 6.48/100 person-years; censoring rate, 0.90; 23 events]). There was no effect of supplementation on HIV viral load. Multivitamins alone and selenium supplementation alone were not statistically different from placebo for any end point. Reported adverse events were adjudicated as unlikely to be related to the intervention, and there were no notable differences in incidence of HIV-related and health-related events among study groups.

Conclusions and relevance: In ART-naive HIV-infected adults, 24-month supplementation with a single supplement containing multivitamins and selenium was safe and significantly reduced the risk of immune decline and morbidity. Micronutrient supplementation may be effective when started in the early stages of HIV disease.

Figure 1. Randomization Flowchart

Flowchart depicts the study participant screening, randomization, disposition, and loss to follow-up by group. Of the 878 participants enrolled and randomized, 872 were included in the primary analysis; data for 6 patients (0.06%) were missing. Total loss to follow-up was 17.5% (153/872), which included those who missed more than 3 monthly visits and were formally declared lost to follow-up; we were unable to contact them, and they did not return for a study visit. This loss to follow-up also included those who moved from the catchment area and those who chose to discontinue participation. Additionally, 7.5% (66/872) had left the study because of pregnancy, for a total loss to follow-up of 25% (219/872) for the 5-year study. χ² analysis showed that there were no significant differences among the groups in loss to follow-up, (df=3, value 0.74, P=.86). BMI indicates body mass index; HIV, human immunodeficiency virus.

Figure 2. Kaplan-Meier Estimates for Reaching the Primary End Point of CD4 Cell Count of 250/μL or Less by Supplementation Group

The numbers at risk refer to the number of participants at risk entering each 6-month interval by supplementation group.