The effects of malnutrition and commonly used African herbal remedies on the effectiveness and safety of antiretroviral therapy are still unknown, according to a leading WHO adviser on nutrition and HIV, speaking last week at a World Health Organization consultation on nutrition and HIV held in Durban, South Africa.
Very little research has been conducted to fully understand how nutritional status could have an impact on antiretroviral therapy (ART) but “the absence of evidence is not the same as evidence of absence,” said Daniel Raiten, Ph.D. of U.S. National Institutes of Health, and a member of WHO’s Technical Advisory Group on Nutrition and HIV/AIDS. “We need to gain some evidence; we need to answer these questions and come up with something definitive — that what we’re doing is best for everybody.”
Dr. Raiten described a myriad of potential interactions between nutrition and antiretroviral drugs.
“The challenge,” said Dr. Raiten, “is how to apply sound principles of clinical care and nutrition science to the safe and efficacious implementation of antiretrovirals (ARVs) and the long-term care for people living with HIV and AIDS.”
Considerations for using ART in the context of food insecurity and malnutition
Food insecurity, malnutrition and HIV co-exist — and are on the rise — in resource-limited countries. But as antiretroviral therapy is being introduced to manage HIV in Africa, more attention needs to be paid to whether a person’s nutritional status could impact on the success of treatment.
Research suggests that there is a bi-directional relationship between nutrition and pharmacology. For example, malnutrition can impact pharmacokinetics (PK) (how drugs are absorbed, metabolised and distributed in the body). In turn, certain drugs can affect how the body processes food and nutrients. But how does this relationship play out when using ART — especially in severely malnourished patients?
Sometimes even a deficiency of one specific nutrient can affect pharmacology. Nutrient insufficiencies are endemic in Africa. What impact might they have on the efficacy, adherence to, and safety of ART?
Similarly, diet and nutrition play a role in the disease itself (HIV/AIDS and its opportunistic infections). How might the complex interaction of nutrition and HIV/AIDS complicate the effective use of antiviral medications?
Also, in Africa, the use of herbal treatments and other complementary therapies is widespread. Do these interact with ART? What impact might indigenous foods and food practices have on the efficacy and/or safety of ART?
Finally, what specific impact might the use of ART have on the nutritional status of HIV infected adults and children in Africa? Will nutrition (or the lack of it) affect the development of longer-term antiretroviral related complications such as lipodystrophy and bone problems.
The available evidence: nutrition and PK
Most of the food drug-interaction studies that have been conducted focused on the bioavailability of the drugs when taken with food or on an empty stomach. In some cases, they have investigated whether the fat content of a meal affects the absorption of drugs. And indeed, those are the primary considerations in the resource-rich countries where most patients have access to an abundance of nutritious food.
But food-drug interactions can become much more complicated in the severely malnourished. Unfortunately, little no or no data exist on the PK of ART in the chronically malnourished — but changes in their ability to absorb and metabolise other medications has been clearly demonstrated, according to Dr Raiten.
Furthermore, many essential nutrients (vitamins and minerals), such as vitamins A, C, B6, riboflavin, niacin, iron and zinc are necessary for metabolism. It's well established that deficiencies in essential nutrients can alter PK — but so far, there hasn’t been a single study investigating the effect of specific nutrient deficiencies on the PK of ARVs.
Confounding matters, these effects may be paradoxical (a minor nutrient deficiency may induce metabolism, while a greater deficiency may inhibit drug metabolism).
Dr. Raiten told the audience that it is not good enough “to focus on a very select, small number of micro-nutrients. We have 29 or 30 essential nutrients that we should be talking about.”
Non-nutrient components of food, such as caffeine, can also have an effect on drug metabolism. This includes dietary supplements, such as herbal and botanical substances widely used in Africa.
“The active ingredients of traditional medicine, whether its herbal or other types of dietary or botanical substances are processed through the same system as ARVs,” said Raiten. “The botanical supplement may stimulate the metabolism of the ARV drug, which may lower or increase its concentration. It presents problems, not just in terms of efficacy of the drugs or the herbals but also of safety.”
Several such interactions have been demonstrated between complementary therapies and ARVs. For example, garlic supplements may decrease plasma levels of saquinavir and St. John’s Wort can decrease concentrations of some protease inhibitors. Studies suggest that the African potato (Hypoxis) and Sutherlandia (cancer bush), two commonly used botanicals in sub-Saharan Africa, also have the potential to interact with ARVs.
ART’s impact on metabolism
Dr. Raiten also reviewed the growing body of evidence in resource rich countries that ART, in turn affects metabolism of adults and children.
These effects include severe disruptions in lipid or fat storage that result in changes to body composition. These changes are indicative of increased cardiovascular risk in HIV-infected people, insulin resistance and impaired glucose tolerance.
Bone metabolism problems including osteopenia and osteoporosis are also common. There is evidence that bone metabolism problems may be the result of ARV-mediated changes in vitamin D metabolism. But how will this play out in Africa where there are deficiencies of bone-related nutrients such as calcium and vitamin D?
“If these drugs have an impact on those nutrients in a population that’s already at risk for deficiency of those nutrients, we need to be aware of that as we move forward so that we can be pro-active in treating adults and children,” said Raiten.
Lactic acidaemia is another complication of ART, usually associated with nucleoside analogues (NRTIs) such as AZT. However, there is evidence that deficiencies of thiamin, riboflavin and carnitine have a role in the development (and, possibly, the treatment) of lactic acidaemia, said Dr Raiten.
There are indications that some of these metabolic changes may vary with gender, environments, lifestyle and with different diets. Also genetic differences may play a significant role in the development of metabolic consequences. If so, a wide number of outcomes might be expected in Africa where there is diversity of genetic variation.
In conclusion
While some in attendance accused Dr. Raiten and other speakers of fear-mongering, it should be remembered that the metabolic consequences of ARVs were not recognised in the developed world until a couple of years after ART was in widespread use. These problems were associated with subsequent poor adherence and led many patients to quit treatment altogether.
While the metabolic consequences of ART should not slow the rollout of treatment in Africa, Raiten said: “its something we need to be aware of, we need to be proactive about. We need to assess, at the beginning and throughout the clinical course of care and treatment for people, so that we can help them make the right decisions and stay on course for a healthy lifestyle.”