A Randomized Placebo-Controlled Trial of the Impact of Multiple Micronutrient Supplementation on HIV-1 Genital Shedding Among Thai Subjects

To the Editor: Micronutrient (MN) deficiencies impair immune response and weaken epithelial integrity.1 Various observational studies have suggested that MN deficiency, particularly of vitamin A, is associated with a greater frequency of genital shedding of HIV-infected cells and an increased risk of HIV transmission.2–4 The effects of multiple MN supplementation on HIV genital shedding have not been examined. This is of high public health interest since MN deficiency may be easily modifiable. As part of a large randomized trial to determine the effects of multiple MN supplementation on HIV survival,5 we assessed the impact on HIV genital shedding and plasma viral load. Recruitment took place at Siriraj Hospital, Bangkok. HIV-infected individuals were contacted through community-based patients’ representative organizations and invited to join the trial if they were aged ≥18 years, not taking MNs or antiretrovirals, and had a CD4 count between 50–550 cells/mm3. The trial was double blinded with 481 individuals randomly allocated to receive either the MNs or placebo for 48 weeks. The MNs comprised daily doses of vitamin A 3000 μg, β-carotene 6 mg, vitamin D3 20 μg, vitamin E 80 mg, vitamin K 180 μg, vitamin C 400 mg, vitamin B1 24 mg, vitamin B2 15 mg, vitamin B6 40 mg, vitamin B12 30 μg, folacin 100 μg, panthothenic acid 40 mg, iron 10 mg, magnesium 200 mg, manganese 8 mg, zinc 30 mg, iodine 300 μg, copper 3 mg, selenium 400 μg, chromium 150 μg, and cystine 66 mg. The trial showed that the death rate was significantly lower in the MN group among trial participants whose CD4 counts at baseline were <200 CD4 count/μL: the mortality hazard ratios (95% CI) among those with CD4 count <200, <100, and ≥200 mm3 were, respectively, 0.37 (0.13, 1.06; P = 0.052), 0.26 (0.07, 0.97; P = 0.03), and 1.0 (0.2, 5.0; P = 1.0). There was no impact on hospital admissions or CD4 cell count.5 The first 140 consecutive participants were recruited into the present study following further written informed consent. Approval was received from the ethics committees of The London School of Hygiene and Tropical Medicine, Mahidol University, and the Ministry of Public Health, Bangkok. Sample handling and laboratory methods have been described.5 Male patients provided, in a private room, a sample of semen in a sterile container. From women a swab sample of cervical and vaginal secretions was taken. HIV viral load was tested using the NucliSens assay (Organon Teknika, The Netherlands). Continuous data were compared between groups using t-tests if the data were distributed approximately normally or by the Wilcoxon test. Categorical data were compared by the χ2 test. Seventy-one subjects were randomly allocated to MNs and 69 to placebo. Baseline characteristics were similar between the 2 arms (Table 1). Plasma viral load was correlated with seminal viral load (r = 0.44; P = 0.0003, n = 65) but not with viral load from cervicovaginal secretions (r = 0.18; P = 0.1, n = 71). Three subjects died and 12 were lost to follow-up in the MN group and 4 died and 3 were lost to follow-up in the placebo group, leaving 56 in the MN and 62 in the placebo group for analysis. At 48 weeks, the median CD4 count, mean log viral load in plasma, semen and cervicovaginal secretions did not differ significantly between patients in the MN and placebo groups (P ≥ 0.4 for each comparison) (Table 2). The differences (95% CI) in mean log viral load copies per ml (MN − placebo) were −0.15 (−0.53, 0.23) for plasma; −0.07 (−0.62, 0.48) for seminal shedding; and −0.11 (−0.50, 0.27) for cervicovaginal shedding. The percentage changes from baseline also did not differ between the 2 groups (data not shown).Table 1: Subject Characteristics at RecruitmentTable 2: The Impact of Supplementation on Viral Load at 48 Weeks of Follow-UpOur trial showed no impact of multiple MN supplementation on viral load in seminal or cervicovaginal secretions. We had approximately 80% power to detect 0.62 and 0.31 log10 differences in mean seminal and cervicovaginal viral loads between the 2 arms. It is possible that the effects of MNs are smaller. It is also possible that MNs do not influence the risk of HIV genital shedding or HIV transmission and the findings of previous observational studies suggesting a link2–4 were biased or that the measurement of vitamin levels was unreliable.6,7 Our results are consistent with the recent findings from trials showing no effect of multivitamins on mother-to-child transmission of HIV.8–10 In a trial of 400 women conducted in Kenya, vitamin A supplementation had no impact on HIV cervical and vaginal shedding.6 However, in a trial of 500 women in Tanzania, vitamin A supplementation was associated with an elevated risk of mother-to-child transmission of HIV4 and, more recently, with increased HIV cervicovaginal shedding.11 There are important differences in design between the trials. Unlike in Tanzania, the women in Kenya and in our trial were not pregnant. The daily doses differed. The dose used in Tanzania (vitamin A 5000 IU + 30 mg of β-carotene) was higher than in our trial (vitamin A 3000 IU + 6 mg β-carotene) but lower than that used in Kenya (vitamin A 10,000 IU). We gave vitamin A as part of a package of MNs whereas vitamin A alone was used in Kenya and Tanzania. We supplemented women for 48 weeks compared to 6 weeks in Kenya and a median of 15 weeks in Tanzania. The trial in Tanzania also included women who received multivitamins other than vitamin A; there was no effect on HIV genital shedding in this group. Taken together, the findings from these trials suggest that MN supplementation does not reduce HIV infectivity or prevent HIV transmission. We also showed no effect of MN supplementation on plasma viral load. We had 80% power to detect a difference of 0.43 log10 copies per mL. These findings differ from those reported from a small short-term trial in which supplementation with vitamins E and C led to a 1 log10 reduction in plasma viral load although this was not statistically significant.12 Our larger trial of MN supplementation had shown significantly improved survival among MN recipients whose CD4 count was <200 cell count/mm3.5 The apparent discrepancy might be because the CD4 counts of patients in the current trial were generally high and the effect on plasma viral load may only be apparent among those with CD4 count <200 /mm3, as for survival. It is also possible that the survival benefit was from MNs influencing the immune response to frequent and potentially lethal copathogens, such as Streptococcus pneumoniae and Haemophilus influenzae, rather than through a direct effect on the immune response to HIV. Sukhum Jiamto, MD*† Pongsakdi Chaisilwattana, MD‡ Jacques Pepin, FRCP§ Reungpung Suttent, PhD¶ Bussakorn Mahakkanukrauh, MD† Suzanne Filteau, PhD** Puan Suthipinittharm, MD† Shabbar Jaffar, PhD* *Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, UK †Department of Dermatology and ‡Department of Obstetrics and Gynaecology, Mahidol University, Bangkok, Thailand §Centre for International Health, University of Sherbrooke, Quebec, Canada ¶Department of Microbiology, Mahidol University, Bangkok, Thailand **Centre for International Child Health, Institute of Child Health, London, UK

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