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High-Dose Multivitamin Use in Advanced HIV Has No Benefit to CD4 and Viral Load and May Cause Liver Toxicity

By Nathan Geffen, C.S.S.R.

November/December 2012

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.1

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).


Table 1: Supplement Content for Standard and High Dose
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


Comment

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.2 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.3 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:

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.


References

  1. 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.
  2. 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.
  3. Bjelakovic G et al. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Review March 2012.
  4. Sinclair D et al. Nutritional supplements for people being treated for active tuberculosis. Cochrane Review November 2011.
  5. Van den Broek N et al. Vitamin A supplementation during pregnancy for maternal and newborn health outcomes. Cochrane Review March 2011.
  6. Siegfried N et al. Micronutrient supplementation interventions to reduce harm in pregnant and lactating women living with HIV. Cochrane Review March 2012.
  7. Irlam JH et al. Micronutrient supplementation for children and adults with HIV infection. Cochrane Review January 2012.

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