A "treatment interruptions think tank" recently took place, as 80 researchers from around the world gathered in Chicago. Martin Delaney, founder and executive director of Project Inform (San Francisco), remarked that a major consensus emerged among the attendees, which included many conservatives and old hat researchers. What Martin has been saying for years, most now seem to agree upon -- that "life-long treatment with antivirals is not a viable option." While current treatments have been life-saving measures for HIV-positive individuals, it is time for researchers to focus more attention on addressing the drug side effects and toxicities. As an approach to long-term treatment, perhaps treatment interruptions may be part of the solution for patients having to deal with these concerns.
Another issue discussed at this meeting was "reversal of resistance," which may be accomplished through treatment interruption. Wild-type virus, the viral population that is usually present during initial infection with HIV, is stronger and usually dominates over the presence of resistant virus. To invoke the emergence of wild type virus, HIV drug therapy may be placed on hold. As wild type begins to replicate it keeps down resistant strains. This method is now increasingly being investigated.
One example of how reversal of resistance occurs in practice is demonstrated with an anecdotal report. One of my new patients, who came in from another clinic, had viral loads approaching 7 million copies (one of the highest that I've ever seen) despite taking a "kitchen sink" regimen of five antivirals including T-20, a fusion inhibitor, and one of the newest treatment breakthroughs. I stopped all the antiviral medications and placed the client on a six-month strategic treatment interruption (drug holiday). Since restarting treatment with a new drug regimen, the client's viral load has dropped to very low levels and CD4+ T-cells have tripled. This probably occurred because wild type virus recurred and suppressed the resistant HIV strains. This approach to treatment is investigative. Many safety questions regarding this approach remain unanswered, and individuals should not attempt this without physician guidance.
While Martin tells me not to call these interruptions "drug holidays," holiday seems to be the "buzz" in the field. And it is increasingly clear that many clients are interested in alternatives to treatment that involve interruptions or holidays. While there remains much uncertainty, if an individual is faced with the pressures of treatment toxicity or multiple failures due to drug resistance, drug holiday, or strategic treatment interruption should be on the table as a viable option.
While attending the International Workshop on Lipodystrophy in Toronto, September 2000, it was refreshing to observe more progress in this area. Two institutions presented groundbreaking research regarding genetically engineered rat models of lipodystrophy. The Department of Molecular Genetics, University of Texas at Southwestern Medical Center has genetically engineered mice that are deficient in fat, similar in many ways to the HIV patients who demonstrate lipodystrophy. The NIH Diabetes Branch has also genetically developed a mouse model that lacks various types of adipose (fat) tissue. Because these mice have a high tendency to develop insulin resistance and diabetes, the researchers conclude that it is the lack of fat that results in various metabolic abnormalities that occur with lipodystrophy. Many HIV-impacted individuals have lipoatrophy, a condition that refers to a loss of fat from the face, buttocks, and/or extremities. With these fat-redistribution changes, these individuals often have diabetic symptoms as well as elevated cholesterol or triglycerides. Having an animal model to study lipodystrophy should improve our knowledge and lead to further developments in this field.
During the International Workshop on Lipodystrophy, Jim Lenhard's group, from the diabetes branch of research at Glaxo-Wellcome, presented results from a recent study. The researchers examined the effects of antioxidant vitamins on metabolic aberrations that occur after treatment with nucleoside reverse transcriptase inhibitors (NRTI, or nukes). In this study mice were the research subjects. The immune competent (HIV-negative) mice were treated with nukes, Retrovir (AZT) or Zerit (d4T) given at 5mg/kg (lower dose) or Zerit at a much higher dose of 50 mg/kg. This resulted in the mice developing many of the metabolic changes associated with lipodystrophy, seen in HIV-treated patients. The abnormalities included elevated lactic acid and lipid levels, as well as increased liver weight. The Zerit-treated animals (although treated at very high doses), developed greater metabolic abnormalities. Subsequently these same study mice were then treated with ascorbate (vitamin C) and tocopherol (vitamin E), which then reversed many of the objective changes. The reversal of metabolic complications of nucleosides by anti-oxidant vitamins holds many implications for further research.
However, during the presentation, many in the largely scientific audience questioned the possibility of marketing bias in the design of the study, since Zerit is a competitor of Glaxo's product, Retrovir. The mice were indeed treated with higher doses of Zerit than their Retrovir counterparts. The "buzz" included cynicism in regards to the design of the study. However, after discussing the results with Dr. Lenhard, he claimed that the focus of the study was not to place Retrovir against Zerit, but to examine the effects of the vitamins on oxidative stress. Toxicology studies with animals traditionally involve the administration at much higher doses, Lenhard stated, since they metabolize drugs more quickly than humans do. It was crucial to realize the metabolic toxicities of the nucleosides, in order to enable testing the effects of antioxidants against those toxicities.
Finally, a word of caution: while the results show that antioxidant vitamins can potentially be helpful, one should not overstate the conclusions of this study and attempt to take high doses of antioxidants without discussion and supervision by one's physician. Normal doses of vitamin C are okay and high doses are rarely toxic, however high doses of vitamin E can be toxic -- and should not be used as a supplement by people taking Agenerase. While the results of this study are interesting and positive, one should not assume that these effects would be reproducible in HIV-positive humans. Further studies at Glaxo-Wellcome are being planned.
On the local news front in Chicago, continuing a trend of all too frequent big business takeovers, Advocate Healthcare has assumed control of Illinois Masonic Medical Center. Illinois Masonic was the first hospital in the Chicago area to have a dedicated HIV unit and has long been a pillar of in-patient hospital care for the community. It is a place where HIV-positive patients who need hospitalization always depend on for the highest quality care. While many ensuing changes are sure to occur, we hope the quality of care continues.
Daniel S. Berger, M.D. is Medical Director for NorthStar Medical Center, Clinical Assistant Professor of Medicine at the University of Illinois at Chicago and editor of AIDS Infosource (www.aidsinfosource.com). Of recent, he is a medical consultant for Positively Aware.