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The Rationale for Combination Therapy
Combination therapy is now the standard of care for patients with late-stage HIV disease (< 200 CD4 cells/mm3), and the trend is now to prescribe combinations of antiretroviral agents for patients with less advanced disease. Indeed, high-dose triple- and quadruple-
Patients on combination therapy may well ask, "Why so many drugs, all to treat the same problem?" This is a legitimate question, given the added cost, added complexity, and added complications of multi-drug regimens. Even highly motivated, highly compliant patients find the demands of combination therapy hard to meet. Certain drugs must be taken on an empty stomach and with citrus juice -- but only with certain types and brands of citrus juice. Other drugs must be taken on a full stomach, and still others must be taken at a given interval after each meal.
We know that compliance is crucial, especially where the protease inhibitors are concerned: deviations from the recommended regimen can lead to the development of drug-resistant viral strains. Patients are more likely to remain in good compliance if they understand why they are being asked to take so many drugs to treat the same problem. The answer is that the three classes of antiretroviral agents that are currently available act in different ways at different stages in the virus's life-cycle (see diagram below). The objective of combination therapy is to interfere with viral replication in as many ways as possible, to thwart viral proliferation by as many modes as possible. Or, to put it another way: In the war against HIV, the best strategy is to attack the virus on three fronts.
Nucleoside analogs, the first class of drugs approved for use in HIV infection, remain a mainstay of therapy. The nucleoside analogs incorporate themselves directly into the DNA of the virus, halting the development of HIV before it can instruct the CD4 cell to create new copies of itself. The newest class of antiretroviral agents, the so-called non-nucleoside RT inhibitors, also interfere early in the life-cycle of HIV -- in this case by binding directly onto the reverse transcriptase of the virus, thereby preventing the conversion of viral RNA to DNA, a necessary step in reproduction. By contrast, the most powerful of the antiretroviral agents, the protease inhibitors, work at the last stage of the virus's reproductive cycle -- by preventing the immature new HIV copies from adding the protease enzyme that enables them to mature into virus particles capable to infecting and killing CD4 cells.
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Back to the December 1996 HIV Newsline contents page.
This article was provided by San Francisco General Hospital. It is a part of the publication HIV Newsline.