The availability of highly active antiretroviral therapy (HAART) since 1996 has helped to prolong survival for many people with HIV/AIDS (PHAs) in North America and countries of the European Union (EU). Yet HAART is not without limitations. For instance, although at least 15 anti-HIV drugs are licensed in Canada, none of them can cure HIV/AIDS. Moreover, caring for PHAs in the 21st century has become more complex than when HAART first appeared. Some of the reasons for this complexity arise with issues about the timing and composition of therapy, such as:

• When in the course of HIV disease should therapy be started?
• Which combinations of drugs should be used in an initial treatment regimen?
• When should therapy be changed?
• Which drugs should be used in a rescue or salvage regimen?

Medical research teams in different hospitals are trying to resolve some of these issues. One research group in the United States and Italy conducted a study called ACTG 384 to try to answer several similar questions about initial anti-HIV therapy:

• Is better to start with a combination which includes AZT (Retrovir, zidovudine) and 3TC (lamivudine, Epivir) or ddI (Videx, didanosine) and d4T (Zerit, stavudine)?

• Is it better to start with a protease inhibitor, in this case nelfinavir (Viracept) or a non-nuke, in this study efavirenz (Sustiva)?

• Is it better to use one 3-drug combination and then switch to another 3-drug combination when treatment failure occurs or just one 4-drug combination?

Study details

Researchers enrolled 980 subjects who had minimal exposure to anti-HIV drugs (fewer than seven days) for their study. The profile of subjects at the start of the study was as follows:

• 18% female, 82% male
• average age – 36 years
• average CD4+ count – 278 cells
• average viral load – about 80,000 copies

Subjects were randomly assigned to one of the following six study groups or "arms":

If subjects receiving arms 1 through 4 developed treatment failure or toxicity they could switch to another arm of the study, as outlined below:

In the remaining two arms there were no switches:

Readers should note that researchers disguised some of the pills so that subjects could not be certain if they were receiving efavirenz, nelfinavir or efavirenz and nelfinavir. Subjects remained in the study for between two and three years.

Results

• Subjects who started therapy with a combination of AZT, 3TC and efavirenz suppressed their viral load and maintained this suppression longer than subjects who started therapy with ddI, d4T and efavirenz.

• Subjects who started therapy with a combination of AZT, 3TC and efavirenz suppressed their viral load and maintained this suppression longer than subjects who started therapy with AZT, 3TC and nelfinavir. However, this difference between the two arms was not statistically significant.

• Subjects who started therapy with a combination containing AZT and 3TC had fewer toxicities than subjects who started therapy with regimens containing ddI and d4T.

• There appears to be no greater benefit from using a combination of four drugs compared with a 3-drug regimen containing AZT, 3TC and efavirenz.

• In the study, CD4+ cell counts increased significantly and continued to rise over time. CD4+ cell increases were similar across each arm of the study.

Issues to consider

It is important to remember that these are preliminary results. The researchers involved with the study are conducting further analyses to try to find out why they obtained the results seen. While some of the differences between arms containing AZT and 3TC and, ddI and d4T may result from toxicity, this does not fully explain the differences detected between the two combinations. The results of this study suggest that a combination of AZT, 3TC and efavirenz may be worth considering as initial therapy for HIV infection.

Detailed results from ACTG 384 are needed so that doctors and their patients can take them into account when making decisions about starting HIV medications. One important lesson from ACTG 384 is that the potency of a drug clearly depends on the other drugs in a regimen and comparing treatment regimens will likely become more complex in the future.

REFERENCE

Robbins G, Shafer R, Smeaton L, et al. Study of initial antiretroviral strategies for the treatment of HIV infection: a randomized 6-arm trial utilizing a factorial design. XIV International AIDS Conference, July 7-12, 2002, Barcelona. Abstracts LbOr20A and LbOr20B.

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Copyright © 2002 - TreatmentUpdate. Reproduced with permission. Reproduction of this article (other than one copy for personal reference) must be cleared through the Editor, The Canadian AIDS Treatment Information Exchange, 555 Richmond St. West, Suite 505, Box 1104, Toronto, ON, M5V 3B1 • Phone: 416-203-7122 • Toll Free: 1-800-263-1638 • Fax: 416-203-8284  http://www.catie.ca.

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