Using Evidence to Make Nutrition Decisions: A Look at Zinc
Evidence-based medicine provides the framework for decisions around clinical practice and treatment guidelines in HIV disease. There is growing pressure in the field of nutrition to make recommendations, especially with regards to supplementation, using this rigorous method of evaluating the evidence. The strength of a recommendation, ranging from "should always be offered" to "should never be offered," depends on the quality of evidence that is available. The gold standard is the randomized clinical trial, usually a double-blinded, placebo-controlled intervention study, which decreases bias and gives the most objective results. The weakest evidence is considered to be "expert opinion."
In nutrition, there have been only a few randomized clinical trials, which makes it difficult to find proof of benefit or proof of cause and effect. Instead, we often rely on in vitro (test-tube) studies, epidemiological evidence (population studies), animal studies, and anecdotal evidence such as case reports and hearsay. As a result, expert opinion often serves to guide our decisions. Nutrients are hard to study with the usual scientific methods because there are complex interactions between the gut, immune system, viral replication and the nutrients. The body's way of handling a systemic infection is called the acute phase response. When this occurs, the metabolism of micronutrients is altered, making it difficult to accurately assess deficiency.
The studies that do exist usually report mildly deficient blood serum levels of a nutrient, which are sub-clinical, meaning that there are no apparent physical symptoms of deficiency. The level at which a nutrient is reported to be deficient depends on the population norms used at the laboratory. It is still unclear whether norms used for the healthy population are applicable for people with HIV. If someone's serum vitamin or mineral level is low, it could mean that there actually is a nutrient deficiency with more generalized malnutrition, or it could reflect a change in the metabolism of the nutrient. It could also be a temporary response to an infection, a marker of disease progression, the result of an interaction between a drug and a nutrient, or even a laboratory error. These confounding variables have resulted in a lack of consensus in the scientific community and a reluctance to make recommendations for specific micronutrient supplements.
Zinc is a nutrient for which there is no consensus regarding the recommended intake in HIV. It has long been known for its role in immune function, which led to a belief that high doses of zinc would stimulate and maintain a healthy immune system in the context of HIV infection. However, like most micronutrients, the most beneficial amount to take in a disease that attacks the immune system is far from conclusive. Zinc acts as a co-factor in hundreds of metabolic actions in the body. Serum zinc levels are affected by time of day, food, stress, and infections. Whenever there is an infectious process, like opportunistic infections and possibly HIV itself, the liver pulls zinc from circulation to make substances that fight infection, known as acute phase reactants. This protective process causes zinc levels to decrease, making it unclear whether it really is beneficial to replace low levels of zinc in these conditions. A number of studies that investigated the role of zinc in immunity, HIV progression, and the risk of dying have influenced supplementation decisions over the years. Most of these studies took place prior to the use of HAART (Highly Active Antiretroviral Therapy) and have not been reproduced in people on HAART.
In 1993, Alice Tang and colleagues from Johns Hopkins University published an epidemiological study in American Journal of Epidemiology that related micronutrient intake from food and/or supplements to HIV disease progression. They investigated several nutrients, including zinc, which was found to be significantly associated with disease progression. Surprisingly, they found that a total intake of zinc from food and supplements greater than 20 mg per day -- which is approximately twice the recommended daily intake -- incurred a relative hazard of 2.06 for disease progression. This means that someone with a higher zinc intake was twice as likely to progress faster to AIDS than someone with a lower zinc intake. One limitation of the study is the potential error introduced by using a food frequency questionnaire to measure general dietary intake, because self-reporting of food intake can be quite inaccurate. Although there was a significant association between zinc intake and disease progression, this study does not prove that higher intakes of zinc caused the disease to progress; people with lower CD4 counts may have started taking more zinc hoping to slow disease progression. Also, the cut off was at 20 mg per day, and the researchers did not differentiate between that and higher intakes of over 50 mg per day, which are fairly typical.
Marianna Baum and other researchers from the University of Miami School of Medicine also looked at serum zinc levels and HIV disease progression. Her findings were published in AIDS in 1995. She found that serum zinc correlated to dietary intake and that serum zinc tended to decrease over time. In the group she looked at, normalizing serum levels with supplementation improved CD4 cell count slightly. This study contradicts the Tang study in that it found statistically significant benefit in zinc supplementation, although the researchers didn't report what dose they used. Interestingly, the prevalence of low zinc was 25-26% in HIV-positive men compared to 17% in HIV negative controls. In 1998, the same researchers published data on HIV-positive, injection drug using men; 56% of them had deficient zinc levels, which were associated with lower CD4 levels and advanced disease (CD4 counts less than 200). Again, low zinc may be a marker of -- not a cause of -- disease progression.
A study published by R.K. Chandra in JAMA in 1984 showed that high doses of zinc suppressed immunity in healthy men. The study participants took 300 mg daily for six weeks, which resulted in decreased immune function. Although this is an extremely high dose, it does show that more is not always better. These are but a few of the many articles looking at the role of nutrients in HIV infection. These studies show that low serum zinc and low dietary zinc intake are linked and both have been associated with faster progression of HIV disease. They provide preliminary evidence that suggests zinc "needs to be investigated further." However, they don't show cause and effect or determine the best dosing regimens. Moreover, the Tang and Chandra studies raise concerns about the wisdom of taking high doses of zinc.
Recommendations for daily nutrient intake have been developed based on deficiency prevention in the healthy population. The requirements for a disease state like HIV are unknown. We still don't completely understand the actions of vitamins and minerals and the long-term consequences of taking nutrients in high doses as a therapy. The first principle in supplementing should be "do no harm." Certainly staying well nourished with a generous intake of nutrients from food should be the first line of defense, supported with a thoughtful and well-planned supplementation regimen.
Diana Peabody is a registered dietitian, specializing in HIV/AIDS. She works at the Oak Tree Clinic, Children's and Women's Health Centre of British Columbia, in Vancouver, Canada.
This article was provided by AIDS Community Research Initiative of America. It is a part of the publication ACRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.