Comparison of four-drug regimens and pairs of sequential three-drug regimens as initial therapy for HIV-1 infection

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.

Figure 1. Study Design and Disposition of Subjects

Panel A shows the factorial design of the trial, with the treatment factors represented in terms of the initial treatment regimens. Panel B shows the numbers of subjects who were randomly assigned to each group, the numbers of virologic and toxicity-related regimen failures, and the numbers of premature discontinuations of study treatment. The primary study end point was defined as the failure of two consecutive regimens for subjects in groups 1, 2, 3, and 4 and the failure of a single regimen for subjects in groups 5 and 6. The premature discontinuation of all study treatment for any reason contributed to the primary study end point but not to the secondary end point of the first regimen failure. Panel C lists the criteria for regimen failure.

Figure 2. Time to the Primary End Point

The Kaplan–Meier curves show the time to the primary study end point — failure of two consecutive three-drug regimens or a single four-drug regimen — in all treatment groups (Panel A) and in individual four-drug groups as compared with individual three-drug groups according to the drugs included in the initial regimen (Panels B, C, D, and E). The hazard ratios given are for the primary end point in the four-drug group as compared with the three-drug group; adjusted 95 percent confidence intervals (CIs) were calculated in order to adjust the significance level to 0.0125 to account for the performance of four comparisons.

Figure 3. Time to the First Regimen Failure

The Kaplan–Meier curves show the time to the first regimen failure in all treatment groups (Panel A) and in individual four-drug groups as compared with individual three-drug groups according to the drugs included in the initial regimen (Panels B, C, D, and E). Because most of the first regimen failures were due to virologic failure, the Kaplan–Meier curves for the time to the first virologic failure were similar to those shown here. The hazard ratios given are for the first regimen failure in the four-drug group as compared with the three-drug group; adjusted 95 percent confidence intervals (CIs) were calculated in order to adjust the significance level to 0.0125 to account for the performance of four comparisons.

Figure 4. Proportions of Subjects Who Had Regimen Failure with Resistance to Nucleoside Analogues (Panel A), Nonnucleoside Reverse-Transcriptase Inhibitors (Panel B), and Protease Inhibitors (Panel C) According to Treatment Group

For subjects in groups 1, 2, 3, and 4, the bars show the cumulative proportions of subjects with drug resistance at the time of the first or second regimen failure; for subjects in groups 5 and 6, the bars show the proportions of subjects with new drug-resistance mutations after the failure of their first regimen. Drug-resistance mutations were identified through the sequencing of the HIV-1 reverse transcriptase and protease of virus isolated from subjects with virologic failure or toxicity-related failure who had plasma HIV-1 RNA levels of at least 1000 copies per milliliter.