AIDS editorial calls for more research into micronutrient supplementation

More research needs to be done in order to establish the role of micronutrient supplementation in maximising both the quality and duration of life of HIV-positive individuals, an area which “may not be part of the traditional care or thought process of the HIV care provider”, concludes an editorial review in the June 10^th issue of the journal, AIDS, now available online.

Dr Alice Tang and her colleagues from Tufts University School of Medicine, Boston, undertook a comprehensive review of prior micronutrient studies carried out before and after the introduction of highly active antiretroviral therapy (HAART), in both resource-limited and well-resourced settings.

Their objectives were to summarize data on the impact of micronutrients prior to 1996-8 (the pre-HAART era); to determine whether past research has answered questions relevant to the needs of individuals living with HIV today, and where more research is needed; and to identify new areas of clinical management where micronutrient supplementation may be helpful.

Pre-HAART studies

It appears, say the reviewers, “that a combination of vitamins may afford some benefits to undernourished HIV-infected populations, particularly those with more advanced disease. However, the role of individual micronutrients (vitamin A and beta-carotene) is less clear.”

Early in the HIV epidemic, low levels of various micronutrients that were associated with disease progression or death were identified, including vitamins A, B6, B12, C and E; carotenoids (precursors of vitamin A); selenium; and zinc. However, since then it has been widely recognised by the reviewers that “assessments of micronutrient status are often imperfect”, since both acute and chronic infection alters micronutrient metabolism, and this can affect the interpretation of measurements with regards to levels of micronutrients in the blood.

“Taken collectively,” the reviewers write, “the results of randomized clinical trials of micronutrient supplements have been somewhat mixed.” Little or no benefit was found when vitamin A or beta-carotene supplementation was studied in the US. Although vitamin A supplementation given to expectant mothers in South Africa was found to reduce diarrhoea in their HIV-positive infants, little effect was seen when vitamin A supplements were given to HIV-positive children with diarrhoea in Tanzania.

The Tanzanian studies did find, however, that multivitamin supplementation, but not vitamin A, appeared to confer some benefits to HIV-positive women and their children: increased CD4 cell counts; more weight gain during the final three months of pregnancy; and higher birth weights and improved infant mortality.

And although a study from Thailand found that multivitamin supplements reduced mortality among HIV-positive individuals with more advanced disease, a Zambian study found that multivitamin supplements had no effect on CD4 cell counts, time with diarrhoea, or mortality.

Unexpectedly, however, the Tanzanian studies found a significant increase in the risk of HIV transmission through breastfeeding amongst mothers who were given vitamin A. The reason for this risk still remains unclear. “The implications of this finding should be explored further,” note the reviewers, “particularly in countries with ongoing vitamin A supplementation programs for children.”

Micronutrients and HAART

A handful of studies have examined the role that HAART may play in affecting micronutrient status, but, write the reviewers, “taken together these initial studies do not overwhelmingly show improvements in serum micronutrient levels after HAART use.” More research is needed, they suggest, regarding the possible interaction between protease inhibitors (PIs) and vitamin B12 absorption.

The effect of HAART on oxidative stress (when cells are forced into a highly activated state due to loss of control of their regulatory systems), a process that may be ameliorated by micronutrient supplementation, is unclear, with inconsistent results from the few studies carried out so far. However, write the reviewers, “two clinical trials, [which] were not designed to determine the effects of HAART use on oxidative stress,” have demonstrated that supplementation with vitamins A, C and E “can reduce oxidative stress levels regardless of the cause.”

A placebo-controlled study from Florida found that 200 microgrammes of selenium given daily over two years to over 200 HIV-positive drug users, half of whom were on HAART, and none of whom had baseline blood levels of selenium below 85 microgrammes/l, significantly reduced the risk of hospitalisation and slowed CD4 cell decline.

Studies that have looked at the role of micronutrient supplementation to treat the side-effects of HAART – including glucose metabolism and plasma lipids; lactate and lactic acidosis and bone density and osteoporosis – have so far been inconclusive.

The reviewers point out that since research in the United States, Canada and Europe has established that many individuals with HIV are often taking high doses of vitamin supplements alongside HAART, it would be useful to determine the possible clinical benefits of micronutrient supplementation in resource-wealthy populations.

Calls for further research

“As HIV becomes a more chronic, manageable disease,” the reviewers write, “and treatment becomes available to more of those infected throughout the world, it may be possible to begin to more precisely define the areas in which micronutrients may help to maximise the clinical status of HIV-infected persons. Studies to date reveal that this is a complex topic, fraught with pitfalls.”

Areas in which further research is needed include:

• HAART-treated patients: is there a role for micronutrients in individuals with low-level viral replication? Can micronutrients enhance durablility of viral suppression and/or improve CD4 cell responses in individuals with adequate viral suppression?
• HAART-naive patients: will the beneficial effects of multivitamin supplementation found in Africa hold true in other parts of the world with differing baseline nutritional status and/or viral subtype?
• Oxidative stress: does antiretroviral therapy increase or decrease oxidative stress, and what role, if any, do micronutrients play? Is there a role for micronutrient supplementation in lipodystophy and/or in preventing or reducing the severity of HIV-related cognitive defects?
• Bone loss: is bone loss due to HIV infection or HAART, and can vitamin D supplementation ameliorate bone loss?
• Co-infections: can micronutrients improve symptoms associated with TB, and hepatitis B and/or C co-infection? If so, which micronutrients, and at what dose?

The review concludes with a reminder that the goal of HIV care in 2005 is to use all means possible to improve “the quality and duration of survival” of HIV-positive individuals, even if certain interventions, including micronutrients, might be outside of the “traditional care" or thought process of the HIV care provider.

“Attempts to improve dietary quality and micronutrient status may play an overall role in maximizing health for the HIV-infected individual, particularly in undernourished populations, and may also play a role in the more subtle management of HIV infection in the future.”