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

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.

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.