High dose multivitamin use in advanced HIV has no benefit to CD4 and viral load and may cause liver toxicity
Nathan Geffen, CSSR, University of Cape Town
Whether daily micronutrient supplements improve health has for decades been a hotly debated question. In recent years several large studies have been published and received wide publicity. Results, whether in trials for HIV positive or HIV negative participants, have been inconsistent.
In the 17 October 2012 edition of JAMA, Fawzi and colleagues report results from a randomised double-blind trial that examined high dose vitamin supplements versus standard dose supplements in people with HIV on antiretroviral treatment. This is the first major study published considering high-dose micronutrient supplementation for people on antiretroviral treatment. 
The primary outcome measure was disease progression or death. Over 3,400 patients were randomised, just over 1,700 to each arm, to receive daily oral supplements of vitamin B complex, vitamin C, and vitamin E at either high or standard levels. The standard dose was based on recommended daily allowance (RDA) with high-dose supplements providing 2 to 21 times the RDA for the B vitamins, 2 times the RDA for vitamin E, and 6 times the RDA for vitamin C, see Table 1. Both supplements were matched in appearance and taste.
Over 65% of participants were women. Approximate mean (SD) baseline demographics included age 38 (+ 8.6) years, CD4 count 130 (+ 100) cells/mm3 and BMI 21 (+ 4.1), with no significant differences found between the arms at baseline. Only 20% of patients had a CD4 count > 200 cells/mm3 and 40% had a count <100 cells/mm3 and viral load was 5.2 log (+ 0.7) log copies/mL. All patients were initiated on 3TC plus either nevirapine or efavirenz, with 70% patients using d4T (stavudine) and 30% using AZT.
Recruitment began in November 2006 and was planned to run for two years. An interim analysis in 2007 showed an increase in deaths in the high-dose arm, so the DSMB recommended all patients receive standard-dose supplements between November 2007 and March 2008. However, a further analysis showed that increased risk from high dose supplementation was restricted to patients affected were severely malnourished. This allowed the study to continue, but excluded patients with BMI less than 16 from enrolment.
The study was halted a second time by the DSMB early in March 2009, this time permanently, due to increased levels of alanine transaminase (ALT) in the high-dose arm. Median follow-up at this time was 15 months (IQR 6-19 months).
The absolute risk of HIV progression or death was 72% in the high-dose group vs 72% in the standard-dose group (risk ratio [RR], 1.00; 95% CI, 0.96-1.04). Approximately 1,230 patients experienced HIV progression in each arm with about 450 deaths divided almost evenly between the arms.
High-dose supplementation had no effect on CD4 count, plasma viral load, body mass index, or hemoglobin level concentration, but increased the risk of ALT elevations (1239 events per 1215 person-years vs 879 events per 1236 person-years; RR, 1.44; 95% CI, 1.11-1.87, p = 0.006) vs standard-dose supplementation. However, this was for increases above the upper limit of normal (ULN >40 IU/L). For the more rigorous and clinically relevant cut-off of 5xULN (>200 IU/L) was reported in only 2% of participants with a non significant RR 1.12 (0.50 to 2.50), p = 0.79, NS.
However, the high-dose arm reported a significantly reduced risk of peripheral neuropathy which was extensively reported and still very common in the high dose arm (1213 events per 1503 person years vs 1365 events per 1450 person years). Nevertheless, this difference was significant (RR 0.81 (0.70 to 0.94), p=0.004).
|Vitamin||Standard Dose||High Dose|
|Thiamin||1.2 mg||20 mg|
|Riboflavin||1.2 mg||20 mg|
|Vitamin B6||1.3 mg||25 mg|
|Niacin||15 mg||100 mg|
|Vitamin B12||2.4 μg||50 μg|
|Folic acid||0.4 mg||0.8 mg|
|Vitamin C||80 mg||500 mg|
|Vitamin E||15 mg||30 mg|
This trial is a setback for proponents of high-dose supplementation. At best there was no benefit (or perhaps a reduced rate of neuropathy, though the prevalence of neuropathy in both arms remained alarmingly high) and at worst a potentially negative impact on liver enzymes (though non-significant at a clinically relevant level).
A more compelling study for the benefits of micronutrient supplementation was published in 2004 in the New England Journal of Medicine by Wafaie Fawzi of Harvard Medical School and his colleagues.  In this randomised placebo-controlled trial, 67 of 271 pregnant women who received a supplement containing vitamins B, C and E progressed to WHO stage 4 or died compared to 83 of 267 women who received placebo (24.7% vs. 31.1%; RR:0.71; 95%CI: 0.51-0.98; p=0.04).
The multivitamin arm participants also had significantly higher CD4 and CD8 cell counts and significantly lower viral loads. Interestingly, the study found that adding vitamin A to the regimen reduced its benefit. The quality of this study was high but the targeted population was very specific, i.e. pregnant women in a very poor country. Recommending micronutrient supplementation to people with HIV or even only pregnant women with HIV cannot be generalised on the basis of this study alone.
However, a Cochrane Review published in March 2012 considered 78 clinical trials of antioxidants that included nearly 300,000 patients.  The authors concluded that the “current evidence does not support the use of antioxidant supplements in the general population or in patients with various diseases.” They also wrote, “Beta-carotene and vitamin E seem to increase mortality, and so may higher doses of vitamin A. Antioxidant supplements need to be considered as medicinal products and should undergo sufficient evaluation before marketing.”
Four relevant Cochrane Reviews have been conducted on vitamins and HIV:
- Sinclair and colleagues (November 2011) considered 23 trials with over 6,800 patients that examined nutritional supplements for people with TB. They concluded that there was not enough evidence to judge whether multivitamins reduced mortality in HIV negative people with TB, but found moderate quality evidence that they had little or no effect in people co-infected with HIV. 
- Van den Broek and colleagues considered vitamin A supplementation during pregnancy and examined 31 trials, of which 14 were included in their analysis. They published in March 2011. Overall, vitamin A supplementation did not reduce maternal mortality, perinatal and newborn mortality, stillbirth, preterm birth, low birthweight or newborn anaemia. They did however find good evidence that vitamin A deficiency is common. The evidence also suggested a reduction in maternal infection, but the authors wrote that these data were not of a high quality. 
- Siegfried and colleagues published a review earlier this year that considered four trials in pregnant women and their infants. They concluded that micronutrient supplements improved the health of pregnant women and their infants. They also wrote that no significant adverse effects were reported. However, zinc supplementation did not show any significant benefits. They found that selenium did not benefit mothers HIV progression or their pregnancy but may increase the likelihood of a child surviving and may reduce diarrhoea in mothers. They found insufficient evidence about the effects of supplements on pregnant women living with HIV who were on antiretroviral medicines. 
- The same authors published another review in January 2012 that updated an earlier review they did in 2005 titled, “Micronutrient supplementation for children and adults with HIV infection”. Their findings are quite nuanced. They reviewed 30 trials involving over 22,000 participants. Of these, 20 trials examined single supplements (vitamin A, vitamin D, zinc, selenium) and 10 examined multiple micronutrients. Eight trials were in children. 
Vitamin A had no benefit in adults, but halved all-cause mortality in a meta-analysis of three trials in African children.
Zinc supplements reduced diarrhoea in one trial of South African children, but showed no benefits to adults in a trial of Tanzanian women or Peruvian adults with persistent diarrhoea.
The authors found that selenium reduced diarrhoea in pregnant women in Tanzania, and reduced viral load in two separate small trials in American adults.
Vitamin D showed no benefits when taken alone. They cited the Tanzanian trial described above as evidence for benefit to pregnant women and their children. They also found another Tanzanian trial in which supplements reduced the recurrence of pulmonary TB and increased weight gain in co-infected patients.
- Isanaka S et al. Effect of High-Dose vs Standard-Dose Multivitamin Supplementation at the Initiation of HAART on HIV Disease Progression and Mortality in Tanzania: A Randomized Controlled Trial. JAMA. 2012;308(15):1535-1544. doi:10.1001/jama.2012.13083.
- Fawzi W et al. A Randomized Trial of Multivitamin Supplements and HIV Disease Progression and Mortality. N Engl J Med 2004; 351:23-32July 1, 2004. DOI: 10.1056/NEJMoa040541
- Bjelakovic G et al. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Review March 2012.
- Sinclair D et al. Nutritional supplements for people being treated for active tuberculosis. Cochrane Review November 2011.
- Van den Broek N et al. Vitamin A supplementation during pregnancy for maternal and newborn health outcomes. Cochrane Review March 2011.
- Siegfried N et al. Micronutrient supplementation interventions to reduce harm in pregnant and lactating women living with HIV. Cochrane Review March 2012.
- Irlam JH et al. Micronutrient supplementation for children and adults with HIV infection. Cochrane Review January 2012.