Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection.
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+14 authors
Journal: 2003/December - New England Journal of Medicine
ISSN: 1533-4406
Abstract:
BACKGROUND
The optimal sequencing of antiretroviral regimens for the treatment of infection with human immunodeficiency virus type 1 (HIV-1) is unknown. We compared several different antiretroviral treatment strategies.
METHODS
This multicenter, randomized, partially double-blind trial used a factorial design to compare pairs of sequential three-drug regimens, starting with a regimen including zidovudine and lamivudine or a regimen including 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.
RESULTS
A total of 620 subjects who had not previously received antiretroviral therapy were followed for a median of 2.3 years. Starting with a three-drug regimen containing efavirenz combined with zidovudine and lamivudine (but not efavirenz combined with didanosine and stavudine) appeared to delay the failure of the second regimen, as compared with starting with a regimen containing nelfinavir (hazard ratio for failure of the second regimen, 0.71; 95 percent confidence interval, 0.48 to 1.06), as well as to delay the second virologic failure (hazard ratio, 0.56; 95 percent confidence interval, 0.29 to 1.09), and significantly delayed the failure of the first regimen (hazard ratio, 0.39) and the first virologic failure (hazard ratio, 0.34). 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, as compared with starting with didanosine and stavudine (hazard ratio, 0.68), and significantly delayed both the first and the second virologic failures (hazard ratio for the first virologic failure, 0.39; hazard ratio for the second virologic failure, 0.47), as well as the failure of the first regimen (hazard ratio, 0.35). The initial use of zidovudine, lamivudine, and efavirenz resulted in a shorter time to viral suppression.
CONCLUSIONS
The efficacy of antiretroviral drugs depends on how they are combined. The combination of zidovudine, lamivudine, and efavirenz is superior to the other antiretroviral regimens used as initial therapy in this study.
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N Engl J Med 349(24): 2293-2303
PMID: 14668455

Comparison of Four-Drug Regimens and Pairs of Sequential Three-Drug Regimens as Initial Therapy for HIV-1 Infection

+10 authors
Stanford University Medical Center, Stanford, Calif. (R.W.S., T.C.M.); the Harvard School of Public Health (L.M.S., V.D.G.) and Harvard Medical School (G.K.R., M.S.H.) — both in Boston; Social & Scientific Systems, Silver Spring, Md. (S.W.S.); the Vanderbilt University Medical Center, Nashville (R.T.D.); the Birmingham Veterans Affairs Medical Center and the University of Alabama at Birmingham School of Medicine, Birmingham (V.A.J.); the State University of New York, Buffalo (G.D.M.); the University of Texas Medical Branch, Galveston (M.A.N.); the Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. (A.I.M.); Case Western Reserve University, Cleveland (B.M.G.); the University of Cincinnati College of Medicine, Cincinnati (P.K.); the University of California–San Diego, San Diego (R.H.); Bristol-Myers Squibb, Plainsboro, N.J. (M.S.); GlaxoSmithKline, Research Triangle Park, N.C. (S.D.M.); and the Istituto Superiore di Sanita, Rome (S.V.)
Address reprint requests to Dr. Robbins at Massachusetts General Hospital, Infectious Disease Unit, 55 Fruit St., Boston, MA 02114, or at gro.srentrap@snibborg
Other members of the AIDS Clinical Trials Group (ACTG) 384 Team are listed in the Appendix.
Copyright notice

Abstract

BACKGROUND

It is unclear whether therapy for human immunodeficiency virus type 1 (HIV-1) should be initiated with a four-drug or two sequential three-drug regimens.

METHODS

In this multicenter trial we 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.

RESULTS

A total of 980 subjects were followed for a median of 2.3 years. There was no significant difference in the occurrence of regimen failures between 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 (hazard ratio for regimen failure, 1.24) or didanosine, stavudine, and efavirenz (hazard ratio, 1.01). 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 (hazard ratio, 1.06) or zidovudine, lamivudine, and efavirenz (hazard ratio, 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 (hazard ratio for a first regimen failure, 0.55); didanosine, stavudine, and efavirenz (hazard ratio, 0.63); or zidovudine, lamivudine, and nelfinavir (hazard ratio, 0.49), but not the three-drug regimen containing zidovudine, lamivudine, and efavirenz (hazard ratio, 1.21).

CONCLUSIONS

There was no significant difference in the duration of successful HIV-1 treatment between a single four-drug regimen and two consecutive three-drug regimens. Among these treatment strategies, initiating therapy with the three-drug regimen of zidovudine, lamivudine, and efavirenz is the optimal choice.

Abstract

Although many drugs are approved for the treatment of human immunodeficiency virus type 1 (HIV-1) infection, the cause of the acquired immunodeficiency syndrome (AIDS), they belong to just four different classes: nucleoside or nucleotide reverse-transcriptase inhibitors (nucleoside analogues), nonnucleoside reverse-transcriptase inhibitors, protease inhibitors, and fusion inhibitors. Because cross-resistance within a class is common, the failure of the initial regimen used may compromise the success of future regimens. Indeed, the results of cohort studies suggest that a patient’s first treatment regimen has the greatest chance of success.1–3

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.4,5 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. We compared the use of four-drug regimens with the use of sequential pairs of three-drug regimens. Comparisons among the pairs of three-drug regimens are presented by Robbins et al. elsewhere in this issue of the Journal.6

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