Efficacy, safety, and adherence with a twice-daily combination lamivudine/zidovudine tablet formulation, plus a protease inhibitor, in HIV infection

A randomized, open-label, multicenter study to establish clinical equivalence (non-inferiority) of a regimen employing a lamivudine 150 mg/zidovudine 300 mg combination tablet, administered twice daily, plus a marketed protease inhibitor, compared with a conventional regimen of 150 mg lamivudine twice daily, 600 mg zidovudine daily, and a protease inhibitor, in antiretroviral-experienced patients infected with HIV-1. Adults who were seropositive for HIV-1 infection with plasma HIV-1 RNA levels < 10000 copies/ml (Roche Amplicor polymerase chain reaction assay, lower limit of quantitation (LLOQ) 400 copies/ml) and CD4+ cell counts > or = 300 x 10(6)/l). All patients had been receiving the conventional lamivudine/zidovudine/protease inhibitor regimen for > or = 10 weeks immediately prior to the study. Patients were randomized to the conventional regimen (n = 113) or combination tablet regimen (n = 110) for 16 weeks. The primary study endpoint was treatment failure, defined as an increase in HIV-1 RNA > or = 0.5 log10 above baseline in patients with viral load > LLOQ at randomization and as HIV-1 RNA increasing to > or = 1250 copies/ml in patients with viral load < LLOQ at randomization. The combination tablet regimen was associated with a 3.5% greater success rate than the conventional regimen (96.4 versus 92.9%), with four and eight patients failing treatment due to increases in HIV-1 RNA levels, respectively. The lower limit of the associated confidence interval for the difference was -2.4%, which was well within the -10% margin predefined as clinically unimportant. This establishes the clinical equivalence (non-inferiority) of the combination tablet regimen to the conventional regimens regarding virologic response. The combination tablet and conventional regimens were similar with respect to percentage of patients maintaining HIV-1 RNA levels < LLOQ at the end of study or improving from baseline to undetectability (94 versus 91%; P= 0.063), overall incidence of drug-related adverse events (21 versus 19%) (P=0.868), and mean area under the curve for CD4+ cell counts [treatment difference, 5.9 cells (95% confidence interval, -15.8 to 27.6 x 10(6) cells/l)]. A self-reported adherence questionnaire indicated that patients in the combination tablet group were less likely to miss doses of nucleoside analogue medication at weeks 8 (P= 0.007) and 16 (P= 0.046). The combination lamivudine/zidovudine tablet/protease inhibitor regimen is clinically equivalent (non-in