Project description: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.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.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/?L who were not receiving ART at Princess Marina Hospital in Gaborone, Botswana, between December 2004 and July 2009.Daily oral supplements of B vitamins and vitamins C and E, selenium alone, or multivitamins plus selenium, compared with placebo.Reaching a CD4 cell count less than 200/?L until May 2008; after this date, reaching a CD4 cell count of 250/?L or less, consistent with the standard of care in Botswana for initiation of ART at the time of the study.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/?L 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/?L, 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.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.

Project description:IntroductionThe MAINTAIN study is an on-going RCT comparing high-dose micronutrient and anti-oxidant supplementation versus recommended daily allowance (RDA) vitamins in slowing HIV immune deficiency progression in ART-naïve people with HIV infection.ObjectiveWe planned analysis of the first 127 participants to determine the baseline prevalence of serum micronutrient deficiencies and correlates, as well as tolerance and adherence to study interventions.MethodsParticipants receive eight capsules twice daily of 1) high-dose or 2) RDA supplements for two years and are followed-up quarterly for measures of immune deficiency progression, safety and tolerability. Regression analysis was used to identify correlates of micronutrient levels at baseline. Adherence was measured by residual pill count, self-report using the General Treatment Scale (GTS) and short-term recall HIV Adherence Treatment Scale (HATS).ResultsPrior micronutrient supplementation (within 30 days) was 27% at screening and 10% of study population, and was not correlated with baseline micronutrient levels. Low levels were frequent for carotene (24%<1 nmol/L), vitamin D (24%<40 nmol/L) and serum folate (20%<15 nmol/L). The proportion with B12 deficiency (<133 pmol/L) was 2.4%. Lower baseline levels of B12 correlated lower baseline CD4 count (r?=?0.21, p?=?0.02) with a 21 pmol/L reduction in B12 per 100 cells/µL CD4. Vitamin D levels were higher in men (p<0.001). After a median follow-up of 1.63 years, there were 19 (15%) early withdrawals from the study treatment. Mean treatment adherence using pill count was 88%. Subjective adherence by the GTS was 81% and was moderately but significantly correlated with pill count (r?=?0.29, p<0.001). Adherence based on short-term recall (HATS) was >80% in 75% of participants.ConclusionMicronutrient levels in asymptomatic HIV+ persons are in keeping with population norms, but micronutrient deficiencies are frequent. Adherence levels are high, and will permit a valid evaluation of treatment effects.Trial registrationClinicalTrials.gov NCT00798772.

Project description:The effect of pre and periconceptional multiple micronutrient supplementation on methylation of CpG loci within CpG islands associated with 14,000 genes across the human genome has been investigated in the offspring of a cohort of Gambian women participating in a controlled double blinded trial. Methylation levels in placebo and micronutrient supplemented cohorts were compared in genomic DNA from cord blood (35 placebo and 21 micronutrient supplemented) and in circulating blood samples (14 placebo and 9 micronutrient supplemented) drawn from the same cohort at 9 months old. A small number of differentially methylated CpG loci were identified in cord blood (14 in males and 21 in females) and a larger number in the 9 month infant comparison (108 in males and 106 in females). Seven differentially methylated loci in males and 8 in females persisted from cord to infant. These findings indicate that micronutrient supplementation pre-conception or early in embryonic development is potentially associated with programming of gene activity at birth, which is maintained into early infanthood. Strikingly, the loci affected by micronutrient supplementation differed between males and females, with no shared changes in cord blood and only 5 shared changes at 9 months. Additionally, a large number of CpG loci showed variation in methylation level when comparing 9-month samples to cord blood samples. These postnatal changes were more consistent between sexes, with 85% of female alterations being found as a subset of male changes in the placebo cohort and 62% of the female changes shared with males in the supplemented cohort. Taken together, the results suggest that there is a core developmental program shared between the sexes that is unaffected by nutrient supplementation, but that there are also sex-specific developmental changes which are altered under conditions of micronutrient supplementation and deficiency. Bisulphite converted DNA from 59 cord (36 placebo and 23 treated) and 25 infant peripheral blood (15 placebo and 10 treated) samples were hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2. (For further analysis, five were excluded during quality control leaving 56 cord (35 placebo and 21 treated) and 23 infant peripheral blood (14 placebo and 9 treated) samples. Full data set of 84 samples were submitted to GEO)

Project description:BackgroundEnvironmental enteropathy (EE) is an asymptomatic abnormality of small bowel structure and function, which may underlie vaccine inefficacy in the developing world. HIV infection co-exists in many of these populations. There is currently no effective treatment. We conducted a secondary analysis of a randomised controlled trial of high dose multiple micronutrient (MM) supplementation on small bowel architecture in EE in participants with or without HIV infection.MethodsIn a double-blind parallel-group trial of the effect of MM on innate immune responses to oral vaccines, consenting Zambian adults were randomised to receive 6 weeks of 24 micronutrients as a daily capsule or placebo. HIV status was established after randomisation. Proximal jejunal biopsies were obtained after the supplementation period. Villous height, crypt depth, villous width, villous perimeter per 100 μm muscularis mucosa (a measure of epithelial surface area), and villous cross sectional area per 100 μm muscularis mucosa (a measure of villous compartment volume) were measured in orientated biopsy sections using semi-automated image analysis. Analysis was by intention to treat.Results18 patients received MM and 20 placebo. 6/18 MM and 9/20 placebo patients had HIV. In HIV negative patients given MM compared to placebo, mean villous height was 24.0% greater (293.3 v. 236.6 μm; 95% CI of difference 17.7-95.9 μm; P = 0.006), mean villous area was 27.6% greater (27623 v. 21650 μm2/100 μm; 95% CI of difference 818-11130 μm2/100 μm; P = 0.03), and median villous perimeter was 29.7% greater (355.0 v. 273.7 μm/100 μm; 95% CI of difference 16.3-146.2 μm/100 μm; P = 0.003). There was no significant effect on crypt depth or villous width. No effect was observed in HIV positive patients. There were no adverse events attributable to MM.ConclusionsMM improved small bowel villous height and absorptive area, but not crypt depth, in adults with EE without HIV. Nutritional intervention may therefore selectively influence villous compartment remodelling. In this small study, there was a clear difference in response depending on HIV status, suggesting that EE with superimposed HIV enteropathy may be a distinct pathophysiological condition.

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Micronutrient supplementation in adults with HIV infection.

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