Zidovudine, Lamivudine, and Efavirenz Best Initial Therapy for HIV-1 Infection

Laurie Barclay, MD

December 10, 2003

Dec. 10, 2003 — The triple therapy of zidovudine, lamivudine, and efavirenz is the optimal initial treatment regimen for human immunodeficiency virus type 1 (HIV-1) infection, according to the results of two randomized trials published in the Dec. 11 issue of the New England Journal of Medicine.

"The optimal sequencing of antiretroviral regimens for the treatment of infection with HIV-1 is unknown," write Gregory K. Robbins, MD, MPH, from Harvard Medical School in Boston, Massachusetts, and colleagues from the AIDS Clinical Trials Group 384 Team. "The current standard of care is to use two nucleoside reverse-transcriptase inhibitors (nucleoside analogues) plus a third agent from another class."

This multicenter, randomized, partially double-blind trial used a factorial design to compare pairs of sequential three-drug regimens in 620 subjects who had not previously received antiretroviral therapy. The initial treatment protocol involved a regimen of zidovudine and lamivudine, or a regimen of didanosine and stavudine in combination with either nelfinavir or efavirenz. The primary end point was the length of time to the failure of the second three-drug regimen. Median follow-up was 2.3 years.

When initial therapy involved a three-drug regimen containing efavirenz combined with zidovudine and lamivudine (but not efavirenz combined with didanosine and stavudine), this appeared to delay the failure of the second regimen, as compared with starting with a regimen containing nelfinavir. Hazard ratio (HR) for failure of the second regimen was 0.71; 95% confidence interval [CI], 0.48 - 1.06. Other benefits of this initial therapy were to delay the second virologic failure (HR, 0.56; 95% CI, 0.29 - 1.09), failure of the first regimen (HR, 0.39) and the first virologic failure (HR, 0.34).

Compared with starting with didanosine and stavudine, starting with zidovudine and lamivudine combined with efavirenz (but not zidovudine and lamivudine combined with nelfinavir) appeared to delay the failure of the second regimen (HR, 0.68). Other benefits were significant delay of both the first virologic failure (HR, 0.39) and the second HR, 0.47), as well as the failure of the first regimen (HR, 0.35). The initial use of zidovudine, lamivudine, and efavirenz shortened the time to viral suppression.

"Although the mechanisms underlying the favorable interactions among zidovudine, lamivudine, and efavirenz are still being explored, this combination provided greater antiretroviral potency than the other combinations tested and resulted in a lower rate of failure with genotypic resistance to each class of anti-HIV drugs," the authors write. "Perhaps most important, toxic effects occurred less commonly in subjects who initially received zidovudine and lamivudine."

In the second study, also by the AIDS Clinical Trials Group 384 Team, 980 subjects were followed for a median of 2.3 years. This multicenter trial compared initial therapy involving four-drug regimens containing efavirenz and nelfinavir in combination with either didanosine and stavudine or zidovudine and lamivudine with therapy involving two consecutive three-drug regimens, the first of which contained either efavirenz or nelfinavir.

"Four-drug antiretroviral regimens containing drugs from three drug classes have the potential for increased potency but may also be associated with increased toxicity, decreased adherence, and the limitation of subsequent treatment options," write Robert W. Shafer, MD, from Stanford University Medical Center in California, and colleagues. "Three-drug regimens containing drugs from only two classes may be less potent but more tolerable, and patients treated with regimens that exclude some classes of drugs may have a better response to subsequent treatments."

Regimen failures occurred at a similar rate in the group that received the four-drug regimen containing didanosine, stavudine, nelfinavir, and efavirenz and the groups that received the three-drug regimens beginning with didanosine, stavudine, and nelfinavir (HR for regimen failure, 1.24) or didanosine, stavudine, and efavirenz (HR, 1.01). Similarly, there was no significant difference between the group that received the four-drug regimen containing zidovudine, lamivudine, nelfinavir, and efavirenz and the groups that received the three-drug regimens beginning with zidovudine, lamivudine, and nelfinavir (HR, 1.06) or zidovudine, lamivudine, and efavirenz (HR, 1.45).

A four-drug regimen was associated with a longer time to the first regimen failure than the three-drug regimens containing didanosine, stavudine, and nelfinavir (HR, 0.55); didanosine, stavudine, and efavirenz (HR, 0.63); or zidovudine, lamivudine, and nelfinavir (HR, 0.49). However, compared with the three-drug regimen containing zidovudine, lamivudine, and efavirenz, the four-drug regimen was not associated with a longer time to the first regimen failure (HR, 1.21).

"Although four-drug regimens were effective and did not lead to an increased risk of toxic effects or drug resistance, the simpler three-drug regimen consisting of zidovudine, lamivudine, and efavirenz emerged as the optimal choice for the initiation of therapy," the authors write. "This three-drug regimen was effective in achieving and maintaining viral suppression throughout the study and allowed most subjects who began therapy with this regimen to reserve protease-inhibitor therapy for the future."

Both these studies were supported by the National Institute of Allergy and Infectious Diseases; the General Clinical Research Center Units; the National Center for Research Resources; the HIV Clinical Research Programme; and by virology laboratory contracts with Vanderbilt University, the University of Alabama at Birmingham, and Stanford University.

Multiple authors in both studies report potential conflicts of interest based on their financial arrangements with and/or equity in Agouron, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, ViroLogic, Visible Genetics, Tibotec-Virco, Abbott, Roche, Boehringer-Ingleheim, Pfizer, Hoffmann-LaRoche, Amgen, and/or Triangle Pharmaceuticals.

In an accompanying editorial, Paul R. Skolnik, MD, from Boston University Medical Center in Massachusetts, notes that ongoing issues in HIV treatment are when to start therapy, what to start with, when to switch, what constitutes failure of therapy, and reasons for failure. In addition to supporting triple therapy as initial treatment, these studies confirm that the combination of stavudine and didanosine should not be used for initial therapy because of unacceptably high rates of adverse effects.

"Determining what constitutes the best choice for initial therapy is a balancing act, and adherence is another factor that must be considered," he writes. "Some general principles are clear: adherence is usually better with twice-daily regimens than with those that include a midday dose, and certain side effects result in unacceptably low levels of adherence, but much remains to be learned. Perhaps, for individual patients, the exact balance of risks and benefits — namely, the chance for long-term viral suppression, the risk of certain side effects, the possibility of induction of drug resistance, and the ability to adhere to a particular regimen — is best addressed by open discussions between care providers and their patients."

Dr. Skolnik reports having received consulting fees from Schering-Plough and research grant support from Gilead Sciences and Roche Pharmaceuticals.

N Engl J Med. 2003;349:2293-2303, 2304-2315, 2351-2352

Reviewed by Gary D. Vogin, MD

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