AIDS

Edited by: Steve Bunk and Eugene Russo S.M. Hammer, D.A. Katzenstein, M.D. Hughes, H. Gundacker, R.T. Schooley, R.H. Haubrich, W.K. Henry, M.M. Lederman, J.P. Phair, M. Niu, M.S. Hirsch, T.C. Merigan, "A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter," The New England Journal of Medicine, 335:1081-90, 1996. (Cited in more than 200 papers since publication) Comments by David A. Katzenstein, associate professor of medicine at Stanford University HIV and AIDS clinical drug trials have progressed at a furious pace in the last few years. In the late 1980s and early 1990s, doctors used nucleoside analogs, mostly zidovudine (AZT), to treat patients with AIDS, but they rarely employed the drugs for persons infected with HIV who had yet to acquire AIDS symptoms. A 1989 study by Paul Volberding of the University of California, San Francisco, was the first to suggest that asymptomatic patients with higher CD4 counts might benefit from AZT.1 Initially, however, there was some doubt as to whether the benefits of using such medications early in the progression of the disease outweighed the drugs' toxic effects. This 1992 follow-up study was, and still is, the largest antiretroviral trial to date. One of hundreds of studies done by the AIDS Clinical Trials Group (ACTG), established by the National Institutes of Health (NIH) in the late 1980s to do multicenter trials in HIV and AIDS, this trial compared the effects of four drug therapies on 2,467 HIV-infected patients, 43 percent of whom had not received prior antiretroviral treatment. (Investigators stratified the study to compare patients who had been taking AZT to those who hadn't.) One group of participants received 600 mg of AZT alone, one received 600 mg of AZT plus 400 mg of didanosine (DDI), another received 600 mg of AZT plus 2.25 mg of zalcitabine (DDC), and a fourth group was given 400 mg of DDI alone. According to coauthor David Katzenstein researchers needed to prove that administering these drugs earlier might in fact retard the rate at which people developed AIDS. "It was an early, and by today's standards, perhaps a primitive attempt to offer a safety net to patients on clinical trials--to allow them access to the more potent or different drug combinations if they appear to be immunologically failing," explains Katzenstein. The trial recruited only those infected subjects who were very close to requiring some kind of treatment according to the Centers for Disease Control's (CDC's) definition for AIDS sufferers at the time--that is, persons with a CD4 cell count between 200 and 500. Researchers concluded that the two combination limbs of the study were more effective than the two monotherapy limbs. There were, however, some subtle distinctions between specific therapies; for example, DDI monotherapy was not quite as effective as either combination, yet it was more effective than AZT alone. As a result of the study, investigators and the AIDS community as a whole began to lean toward the AZT-DDI combination due in large part to DDC's severe neurotoxic effects. "One of the reasons [the paper's] cited so frequently," suggests Katzenstein, "is that it really made the linkage between clinical disease progression and antiretroviral drug therapy in an early disease population .... The main message that people took away was that the combination of AZT-DDI was probably the best way to use nucleosides." More recent findings have made a combination therapy of AZT or stavudine (D4T) and a nucleoside called 3TC (lamivudine) the most popular option for patients. "It was the right thing to do at the time given the limited number of drugs we had, and our limitations of knowing how to use them," remarks Katzenstein. He also notes the importance of the study's considerable size. Investigators and pharmaceutical companies undertook such a large study because they recognized that they'd need pretty big numbers to examine the utility of these drug therapies. But ironically, some results stemming from the study, reported in a companion paper in the same issue of The New England Journal of Medicine (itself cited in more than 155 papers), actually lessened the need for such large participant numbers thereafter.2 According to Katzenstein, this paper held the most significant long-term implications of the study. Using a subset of 375 of the clinical trial participants, he and his colleagues demonstrated a strong correlation between a change in virus load, as measured by a then-experimental HIV-RNA PCR technique, and participants' clinical outcomes. Those with high concentrations of HIV RNA in their blood plasma were more likely to experience rapid disease progression. Finding this so-called surrogate marker for evaluating drug therapies has enabled investigators to make conclusions about drug efficacy based on HIV RNA and CD4 cell changes--no large studies needed to demonstrate statistical significance, no extended studies needed to demonstrate the effects of less-than-adequate drugs while patients suffer. ACTG studies have gone on to include protease inhibitors and reverse transcriptase nucleoside inhibitors. Katzenstein notes that widespread success in the six or seven years since this study has created a bit of a problem: Investigators can't possibly test all of the combinations and permutations of the 14 antiretrovirals now available. Plus, they now need very sophisticated ways of analyzing the genotype and phenotype of the patient's virus to understand why some patients' immune responses improve with antiretroviral drug therapy and some don't. "Determining which [drugs] could be given together in the safest and most effective possible fashion continues to be a really critical question," he says. "We have lots of work cut out for us." P.A. Volberding et al., "Zidovudine in asymptomatic human immunodeficiency virus infection: a controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter," The New England Journal of Medicine, 322:941-9, 1990. D.A. Katzenstein et al., "The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter," The New England Journal of Medicine, 335:1091-8, 1996.

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