Trial supports lopinavir/ritonavir as first-line therapy in HIV infection

A combination of lopinavir and ritonavir is well tolerated and has antiviral activity that is superior to nelfinavir-containing regimens in the initial treatment of HIV infection, a study in the New England Journal of Medicine confirms.

Lopinavir is a newly developed peptidomimetic protease inhibitor that when formulated with low-dose ritonavir, a cytochrome p450 3A4 enzyme inhibitor, has enhanced pharmacokinetic profile. The combination yields mean trough plasma lopinavir concentrations that are at least 75 times as high as that needed to inhibit replication of wild-type HIV by 50%.

The clinical efficacy of the combination had been demonstrated in a previous Phase II study, in which lopinavir/ritonavir plus stavudine and lamivudine was given to antiretroviral-naive HIV-infected patients. On the basis of the trial’s favourable outcome, Sharon Walmsley and colleagues conducted a double-blind trial to compare the safety and efficacy of lopinavir/ritonavir with that of nelfinavir.

In all, 653 HIV-infected patients who had not previously received antiretroviral therapy for more than 14 days were randomly assigned to receive either lopinavir/ritonavir plus nelfinavir placebo, or nelfinavir plus lopinavir/ritonavir placebo. All patients also received open-label stavudine and lamivudine.

At 48 weeks, 75% of patients in the lopinavir/ritonavir group had reached the primary endpoint of HIV RNA <400 copies/ml, compared with 63% in the nelfinavir group. This difference reached statistical significance (P<0.001).

Patients receiving the lopinavir/ritonavir combination also had a longer time to loss of virologic response than those receiving nelfinavir, with a hazard ratio of 2.0 (P<0.001). The proportion of patients with a sustained virological response through the 48-week study period was 84% in the lopinavir/ritonavir group versus 66% in the nelfinavir group.

Significantly, no resistance mutations in HIV protease were reported during the study period in patients with >400 copies HIV RNA/ml taking lopinavir/ritonavir. In the nelfinavir group, such mutations occurred in 33% of patients (P<0.001). Furthermore, the combination regimen was well tolerated, with fewer treatment-related discontinuations than with nelfinavir (3.4% versus 3.7%).

‘The findings from this trial show the benefits of therapy with lopinavir/ritonavir, as demonstrated by its superior antiviral activity in comparison with that of nelfinavir and its continued tolerability and high barrier to resistance,’ Walmsley et al. conclude.

‘These characteristics suggest an important role for lopinavir/ritonavir as an initial protease inhibitor-based treatment for HIV infection.’