Zidovudine and lamivudine: results of phase III studies

Abstract

It has become apparent that the beneficial effects of zidovudine (AZT) and other antivirals will not continue indefinitely. However, synergistic activity of lamivudine (3TC) in combination with AZT, as well as reversal of phenotypic AZT resistance due to the presence of 3TC resistance-inducing mutations, has been documented in vitro. Two trials (NUCB 3001 and NUCB 3002) are therefore investigating the potential of the combination of 3TC with AZT. HIV-1-positive patients with CD4 cell counts of 100-400 cells/mm3 who had not previously received AZT were enrolled into study NUCB 3001 and treated with either AZT (200 mg t.i.d.) or 3TC (300 mg b.i.d.) plus AZT (200 mg t.i.d.) for 24 weeks. Open-label treatment with the combination regimen was offered for an additional 24 weeks. Both treatment groups experienced an initial increase in CD4 cell count. This increase was significantly greater and more sustained in the combination treatment group than in those receiving AZT monotherapy. Participants originally receiving AZT monotherapy, who changed to combination therapy after 24 weeks, experienced a rise in CD4 count. Those who began the study receiving combination therapy maintained their increased CD4 count for the duration of the study. A statistically significant difference in CD4 cell count between the two treatment groups was observed over the entire 48-week treatment period (p </= 0.0001) indicating that initial combination therapy was superior to monotherapy followed by a switch combination therapy after 24 weeks. Both treatment groups experienced a reduction in HIV-RNA levels and cellular viraemia, but these reductions were significantly greater in the combination treatment group than in those receiving AZT monotherapy. In addition, among patients initially randomized to AZT monotherapy, a significant reduction in the viral RNA concentration was observed after switching to combination therapy at week 24. There was an 80% reduction in p24 antigen levels from baseline in the combination treatment group compared with a 34% reduction from the baseline in the AZT monotherapy group, at 24 weeks. HIV-1-positive patients with CD4 cell counts of 100-400 cells/mm3 who had previously received a minimum of 24 weeks AZT treatment were enrolled into study NUCB 3002 and received either AZT monotherapy (200 mg t.i.d. plus placebo); AZT (200 mg t.i.d.) plus 3TC (300 mg b.i.d.) or AZT (200 mg t.i.d.) plus 3TC (150 mg b.i.d.) for 24 weeks. Open-label treatment with 3TC plus optional AZT was offered for a further 24 weeks (open-label phase). The study is still ongoing, but an initial increase in CD4 cell count was observed in the combination groups whereas, in the AZT monotherapy group, no discernible increase in CD4 cell count was observed at any time. The favorable effect of combination treatment with AZT and 3TC on CD4 cell count persisted throughout the open-label phase of the study. The addition of 3TC to the treatment regimens of patients who initially received AZT monotherapy had a favorable effect on CD4 cell count. Combination treatment with 3TC and AZT also resulted in a significantly greater reduction in viral load compared with AZT monotherapy. In conclusion, combination therapy with AZT plus 3TC produces beneficial effects on CD4 cell counts, HIV-1 RNA levels, and p24 antigen levels, which appear to be greater and more sustained than those produced by AZT monotherapy or any combination therapy to date. This combination appears to offer increased efficacy compared with AZT monotherapy without an increased risk of adverse experiences. Future studies to identify those patients most likely to benefit from such treatment and the optimum time for its initiation are therefore warranted.