Combination, Order of Anti-HIV Drugs Make a Difference in First-Time Recipients
How anti-HIV drugs are combined and the order in which they are given are important factors to consider when designing treatment strategies for patients new to antiretroviral therapy, says a new study funded by the National Institute of Allergy and Infectious Diseases (NIAID), one of the National Institutes of Health. When HIV-infected individuals begin treatment with a combination of the drugs zidovudine, better known as AZT, lamivudine and efavirenz, the drugs retain their effectiveness for a longer period of time than when individuals begin treatment with one of several other three-drug regimens.
The study, which involved researchers and participants from the United States and Italy, was one of the largest and most complex of its kind to help in determining the optimal drug treatment strategy for first-time recipients of antiretroviral drugs. The findings are reported in two papers published in the Dec. 11 issue of The New England Journal of Medicine, and have been incorporated into the U.S. Department of Health and Human Services HIV/AIDS Treatment Guidelines.
"These findings offer new insight into the most effective approach for treating previously untreated HIV-infected individuals," said Anthony S. Fauci, M.D., director of the NIAID. "Through well-conceived, collaborative clinical studies such as this one, researchers are learning how to use the many anti-HIV drugs now on the market to provide the maximum benefit for the longest period of time."
Highly active antiretroviral therapy (HAART) employs combinations of anti-HIV drugs to help suppress the virus in people with HIV/AIDS. The goal of HAART is to combine three or more drugs from one or more different classes of anti-HIV drugs to suppress HIV replication and prevent progression to AIDS and death. Two key classes include those that prevent the virus from copying itself, called reverse transcriptase (RT) inhibitors, and those that prevent the virus from becoming infectious, called protease inhibitors. RT inhibitors can be further broken down into nucleoside RT inhibitors, which halt HIV replication by making faulty DNA building blocks, and non-nucleoside inhibitors, which bind to the enzyme reverse transcriptase to prevent the virus from copying itself. The effectiveness of different drug combinations may diminish over time, however, and physicians often must implement new ones over the course of a person's treatment.
"Until now, it has been unclear which sequences of antiretroviral regimens provide the greatest benefit to patients previously untreated," said Gregory K. Robbins, M.D., clinical researcher at Massachusetts General Hospital and instructor in medicine at Harvard Medical School, and lead author of one of the papers. "Findings from this and similar studies can help reduce some of the guesswork involved, enabling physicians to develop the most effective treatment plan for their HIV-positive patients."
In the first part of the study, Robbins and a team of researchers compared the effectiveness of four three-drug sequencing strategies over roughly a two-year period in 620 HIV-positive individuals who had never before received antiretroviral therapy. Two groups began treatment with didanosine (ddI) and stavudine (d4T), two nucleoside RT inhibitors, with one group also receiving efavirenz (EFV), a non-nucleoside RT inhibitor, and the other receiving nelfinavir (NFV), a protease inhibitor. Two other groups began treatment with zidovudine (ZDV) and lamivudine (3TC), two other nucleoside RT inhibitors, combined, again, with either EFV or NFV.
If the initial regimens failed, patients were given all new HIV medications. For example, the patients failing ddI, d4T and EFV switched to ZDV, 3TC and NFV, while the group that began with ZDV, 3TC and EFV followed up with ddI, d4T and NFV, and so on. The primary measure of a sequence's success was the amount of time before the second regimen failed: the greater the delay, the more successful the sequence. Secondary measures included amount of time before the first regimen failed, as well as ability to suppress viral replication, development of resistance to anti-HIV drugs and drug toxicity.
In the second part of the study, Robert W. Shafer, M.D., assistant professor of medicine at Stanford University Medical Center, and colleagues sought to determine how two four-drug regimens compared in effectiveness with the three-drug sequential regimens. Three-hundred sixty HIV-positive individuals who had never before received antiretroviral treatment were given one of two four-drug treatments: ddI, d4T, EFV and NFV or ZDV, 3TC, EFV and NFV. A key question in this comparison was whether incorporating three anti-HIV drug classes instead of two increases the potency of a drug combination at the expense of increasing the risk of toxicity or drug resistance. Because participants were exposed to three drug classes in the initial regimen, there was no second regimen. Therefore, the primary measure of success was the amount of time before the initial treatment failed (compared with two failures of the sequential three-drug regimens), with secondary measures remaining the same as before.
All six regimens successfully controlled HIV infection. Patients who received ZDV, 3TC and EFV as the first or second regimen delayed failure of the second regimen compared to those who took other three-drug regimens, and patients who started with ZDV, 3TC and EFV delayed first regimen failure compared to the other three-drug treatments. These findings indicate that the combination of ZDV, 3TC and EFV is the best choice for initiating antiretroviral therapy among the drugs studied. In addition, researchers found that after 48 weeks on the initial regimen, approximately 10 percent of individuals taking ZDV, 3TC and EFV experienced failure, as opposed to the other three-drug regimens, in which approximately 30 to 40 percent of individuals experienced failure.
The researchers also found that in regard to the primary measure of success, the four-drug treatments were no more potent than sequential three-drug regimens. In several secondary measures however, such as time to first regimen failure and development of drug resistance, they outperformed all three-drug regimens except one -- ZDV, 3TC and EFV. Finally, although the risk of drug toxicity was no different between four-drug regimens and three-drug sequential treatments, drug toxicity was found to occur more frequently in individuals who began treatment with ddI and d4T than in those who began treatment with ZDV and 3TC. Such individuals experienced more health-related problems such as peripheral neuropathy, a neurological disorder resulting from damage to the peripheral nerves, or inflammation to the pancreas, among other problems. Based in part on the results of this study, leading researchers now recommend that anti-HIV treatment should not begin with regimens that contain both ddI and d4T.
The study was conducted by the Adult AIDS Clinical Trials Group (AACTG), an NIAID-sponsored program that consists of a network of more than 30 clinical research institutions in the United States, with international collaborations. AACTG conducts all phases of clinical trials designed to assess the safety and efficacy of new and improved therapies for HIV/AIDS and its associated illnesses, including those in which combination drugs from different manufacturers are evaluated. AACTG sites are funded through cooperative agreements. This study was conducted in collaboration with the Istituto Superiore di Sanità the Italian National Institute of Health, and enrolled both U.S. and Italian subjects. Pharmaceutical sponsors contributed medications and financial support for the study.
The drugs ZDV and 3TC are manufactured by GlaxoSmithKline; ddI, d4T and EFV are manufactured by Bristol-Myers Squibb Company; and NFV is manufactured by Pfizer.
Gregory K. Robbins et al. Comparison of Sequential Three-Drug Regimens as Initial Therapy for HIV-1 Infection. The New England Journal of Medicine. 349(24): 2293-2303 (2003).
Robert W. Shafer et al. Comparison of Four-Drug Regimens and Pairs of Sequential Three-Drug Regimens as Initial Therapy for HIV-1 Infection. The New England Journal of Medicine. 349(24): 2304-15 (2003).