HIV/AIDS: March 15, 2004

John Bartlett, MD


March 15, 2004

In This Article

Antiretroviral Therapy and Resistance

Kempf DJ, King MS, Bernstein B, et al. Incidence of resistance in a double-blind study comparing lopinavir/ritonavir plus stavudine and lamivudine to nelfinavir plus stavudine and lamivudine. J Infect Dis. 2004;189:51-60. M98-863 was a double-blind, randomized, phase 3 study comparing lopinavir/low-dose ritonavir with nelfinavir, each in combination with stavudine plus lamivudine. The results of this trial have been previously published[2] and showed a superior outcome for lopinavir/low-dose ritonavir (LPV/r). The present study concerns resistance testing in this trial. The results indicated significantly greater resistance mutations in the nelfinavir arm to the study drugs ( Table 2 ).

The authors conclude that the "differences suggest substantially different genetic and pharmacological barriers to resistance for these 2 protease inhibitors, and this may have implications for strategies in initiating antiretroviral therapy."

Comment: We have seen these results before at the 10th Conference on Retroviruses and Opportunistic Infections. They again emphasize the importance of starting with a potent regimen, although the lack of protease inhibitor resistance mutations, even with virologic failure with lopinavir, remains enigmatic.

Eron JJ, Feinberg J, Kessler HA, et al. Once-daily versus twice-daily lopinavir/ritonavir in antiretroviral-naive HIV-positive patients: a 48-week randomized clinical trial. J Infect Dis. 2004;189:265-272. This is an industry-supported trial comparing once-daily lopinavir/ritonavir (800/200 mg) vs traditional twice-daily lopinavir/ritonavir (400/100 mg), each in combination with stavudine and lamivudine. Participants were treatment naive, had a mean baseline viral load of 4.6 log10 copies/mL, and had a mean CD4+ cell count of approximately 250 cells/mcL. Of the 38 participants, 12 had a baseline viral load that exceeded 100,000 copies/mL. Plasma samples were collected on day 21 for pharmacokinetic tests over a 24-hour dosing interval for the once-daily group and at 12-hour dosing intervals for the twice-daily regimen. In addition, trough levels were obtained at weeks 8, 16, 24, and 48. The results for pharmacokinetics showed no important differences in the treatment groups for peak levels and area under the curve (AUC) values, but trough levels were significantly lower in the once-daily group. Nevertheless, results for viral suppression and for CD4+ cell response were approximately the same ( Table 3 ), which summarizes the pharmacokinetic results and the clinical outcome data.

The authors conclude that the present study supports "the continued evaluation of once-daily lopinavir/ritonavir."

Comment: The obvious concern here is the relatively low trough level for once-daily therapy compared with twice-daily treatment. The differences were significant, but the virologic response was the same. The median inhibitory quotient (IQ) was 84 in the twice-daily group and 40 in the once-daily group (P <.01). The authors point out that in these results, although statistically significantly different for once- vs twice-daily treatment with LPV/r, even the lower value compares well with results for IQ of many other commonly used protease inhibitors: atazanavir (400 mg once daily), 10; fosamprenavir/ritonavir (1400/200 mg once daily), 2.9; and saquinavir/ritonavir (1600/100 mg once daily), 1.3. Nevertheless, it was clear from the report that the authors were not ready to categorically endorse once-daily lopinavir/ritonavir but preferred the conclusion that it needed to be studied more.