As noted at this year's 11th Conference on Retroviruses and Opportunistic Infections, Bertz et al¹ sought to increase lopinavir (LPV) levels in patients with protease inhibitor (PI) resistance through two different strategies: increasing the number of capsules to 5, twice daily, or adding an additional 200 mg of ritonavir (RTV, Norvir) twice daily to standard lopinavir/ritonavir (LPV/r, Kaletra) dosing. That report, presented in February 2004, showed that the lopinavir inhibitory quotient (ratio of drug level to IC50 of the virus), the number of active nucleoside reverse transcriptase inhibitors (NRTIs) and baseline HIV RNA were independent predictors of antiviral response. This follow-up study describes the outcome of the Bertz study, with a focus on tolerability and efficacy.

Patients who were triple-class experienced and had virologic failure, defined as >1,000 copies of HIV RNA, were eligible for participation. Patients were randomized to one of the above-mentioned strategies, plus up to 3 NRTIs selected on the basis of resistance testing. Nineteen subjects received the 5 capsules of lopinavir/ritonavir twice daily; 17 received the standard dose of lopinavir/ritonavir plus two 100-mg capsules of ritonavir twice a day.

At the end of 48 weeks, the mean change in HIV RNA from baseline was -1.8 log in the 5-capsule lopinavir/ritonavir group, and 2.1 log in the extra-ritonavir group. On an as-treated basis, 50% and 60%, respectively, achieved an HIV RNA <50 copies/mL, with the results approximately 20% when analyzed by intent-to-treat due to patient dropouts. A high rate of gastrointestinal events characterized the extra-ritonavir group in particular, with diarrhea of moderate severity or worse occurring in 24% of the patients. The extra-ritonavir strategy was also associated with worse lipid elevations, in particular triglycerides.

What is the significance of this study for clinical practice? Individual patients who have PI-resistant virus, and are limited regarding other treatment options, may benefit from higher levels of lopinavir, which can be achieved by increasing the lopinavir/ritonavir dose. This is a safer and better-tolerated approach than increasing the ritonavir dose, which was associated with extra gastrointestinal side effects and hyperlipidemia. One important limitation to this study is that it lacked a control arm with standard-dose lopinavir/ritonavir (3 capsules twice daily), although, based on historical controls, it is unlikely that this group would have achieved the same levels of lopinavir as with the novel dosing strategies tested here.

Footnote

1. Bertz R, Li J, King M, et al. Lopinavir inhibitory quotient predicts virologic response in highly antiretroviral-experienced patients receiving high-dose lopinavir/ritonavir. In: Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, Calif. Abstract 134.