Perspective

Increasing Choices for HIV Therapy

Scott M. Hammer, M.D.

N Engl J Med 2002; 346:2022-2023June 27, 2002

Article

The field of antiretroviral therapy has witnessed remarkable progress during the past 15 years. There are now 16 approved therapeutic agents for infection with the human immunodeficiency virus (HIV), a pathogen that once caused nearly uniformly fatal illness. These agents target two essential enzymes of the virus, the reverse transcriptase and the protease (see FigureThe Life Cycle of Human Immunodeficiency Virus Type 1 (HIV-1) and Major Antiviral Targets.). The era of potent antiretroviral therapy, also termed highly active antiretroviral therapy, began in 1996 and has been marked by dramatic declines in morbidity and mortality due to HIV disease in the developed world. These advances have not been without their cost in terms of drug resistance and side effects, particularly metabolic abnormalities such as lipodystrophy. Concern about these negative effects has led to a more conservative approach to the timing of the initiation of therapy and to clinical trials of intermittent therapy in an attempt to decrease the total exposure to drugs over time. Immune-based approaches such as therapeutic vaccination may someday permit viremia to be controlled in the absence of drugs.

Antiretroviral management brings a complex series of choices: when to initiate therapy, what regimen to use, which drugs within each class of drugs to use, when to change therapy, and which alternative drugs to use. In this issue of the Journal, Walmsley and colleagues (see pages 2039–2046) report on an important study that illustrates the increasing number of choices facing clinicians and patients. The study compared the efficacy and safety of the most recently approved protease inhibitor, lopinavir (coformulated with low-dose ritonavir), with the efficacy and safety of nelfinavir in patients who had not previously received antiretroviral therapy and who also received two nucleoside analogues (stavudine and lamivudine). The results demonstrate a consistently superior virologic response over a period of 48 weeks in the lopinavir–ritonavir group, as measured by the proportion of subjects with plasma levels of HIV type 1 (HIV-1) RNA below 400 or 50 copies per milliliter. The durability of the virologic response and the genotypic drug-resistance pattern of the viral strains from the subjects with virologic failure were also more favorable with lopinavir–ritonavir. There was no difference between the two groups in the CD4 cell response.

Currently, the three most commonly prescribed initial antiretroviral regimens are a protease inhibitor (with or without low-dose ritonavir as an enhancer) plus two nucleoside analogues; a nonnucleoside reverse-transcriptase inhibitor plus two nucleoside analogues; and three nucleoside analogues. As the study by Walmsley et al. highlights, differences in antiviral potency within each of these types of regimens are becoming increasingly discernible.

How should we incorporate these findings into clinical practice? Should lopinavir–ritonavir now be considered one of the drugs of choice for initial antiretroviral regimens? The answer is not as straightforward as it may appear, for a number of reasons. There is a trend toward prescribing regimens for initial therapy that do not include protease inhibitors, because of concern about metabolic toxic effects. And Walmsley et al. do report a higher incidence of hyperlipidemia in the lopinavir–ritonavir group. Moreover, lopinavir–ritonavir has excellent activity as the core component of alternative regimens in patients in whom initial treatment has failed. Thus, many clinicians may choose to reserve lopinavir for later use. The effects of other approved protease inhibitors — indinavir, saquinavir, and amprenavir — can all be enhanced with low-dose ritonavir, which creates additional choices for clinicians. In the long-term management of HIV disease, a 48-week study that demonstrates the virologic but not the immunologic superiority of one agent over another represents an important finding, but it may not ultimately translate into the desired clinical outcome many years, and potentially several regimens, later.

The chief take-home message from the article by Walmsley et al. is that improvements are being made in the potency of antiretroviral drugs, and this bodes well for the future of the field. Antiviral potency is the key to the initial success of drug regimens, as well as to the durability of their success, the restoration of immune function, the prevention of the emergence of resistance, and ultimately the prevention of disease progression. The key is to link potency with the other desirable aspects of a therapeutic regimen: low pill burden, excellent tolerability, absence of major drug interactions, absence of long-term toxic effects, and absence of cross-resistance to other agents.

Although the article in this issue of the Journal highlights the progress that has been made by using the existing classes of antiretroviral drugs, it also reminds us that drug development in the HIV field remains dynamic. Newer antiretroviral agents, such as entry inhibitors and integrase inhibitors, hold great promise. Encouraging clinical results have already been reported for the HIV fusion inhibitor enfuvirtide, or T-20 (see Figure). Future progress in antiretroviral therapy will bring more choices for physicians and patients and will make an already complex field both more challenging and more rewarding.

Scott M. Hammer, M.D.
Columbia Presbyterian Medical Center, New York, NY 10032

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