Significant Reduction in Risk of Malaria among HIV+ Children Receiving Lopinavir/ritonavir-based ART Compared to NNRTI-based ART, a Randomized Open-label Trial
Jane Achan*1,2, A Kahuru2, G Ikilezi2, T Ruel3, T Clark3, E Charlebois3, P Rosenthal3, G Dorsey3, D Havlir3, and M Kamya1,2
1Makerere Univ Coll of Hlth Sci, Kampala, Uganda; 2Infectious Diseases Res Collaboration, Kampala, Uganda; and 3Univ of California, San Francisco, US
Background: HIV+ children living in Sub-Saharan Africa continue to suffer high morbidity and mortality from malaria. Additional measures to decrease malaria risk in these populations are therefore warranted. HIV protease inhibitors (PI) have shown some activity against Plasmodium falciparum in vitro. We evaluated the efficacy of lopinavir/ritonavir (LPV/r)-based vs NNRTI-based ART regimens for malaria risk reduction in HIV+ children.
Methods: We conducted a randomized open label trial in Tororo, Uganda. Participants were HIV+ children aged 2 months to 5 years eligible for ART or currently receiving NNRTI- based ART with virological suppression (HIV RNA <400 copies/mL). Participants were randomized to receive either LPV/r-based or NNRTI-based ART and followed or 2 years. Uncomplicated malaria was treated with artemether-lumefantrine. We compared the incidence of malaria between the study arms using Poisson regression.
Results: Between September 2009 and July 2011, we enrolled 176 children and randomly assigned 89 to NNRTI-based and 87 to LPV/r-based ART. Median age was 3 years, and 67% were ART naļve. Malaria incidence was significantly higher in the NNRTI arm than in the LPV/r arm: 2.25 vs 1.32 episodes/person-year, IRR 0.59, 95%CI 0.36 to 0.97, p = 0.037. The cumulative 28-day risk of treatment failure unadjusted by genotyping was significantly higher in the NNRTI arm than the LPV/r arm: 40.8%, 95%CI 33.9 to 48.6 vs 14.0%, 95%CI 8.7 to 22.2; HR 0.31, 95%CI 0.14 to 0.68, p = 0.004). Median serum lumefantrine levels on day 7 of follow-up were significantly higher in the LPV/r arm than the NNRTI arm. In the NNRTI arm, day 7 lumefantrine levels were higher in those on nevirapine than those on efavirenz; 388 ng/mL vs 97 ng/mL, respectively, p <0.000. In the LPV/r arm only, day-7 lumefantrine levels >300 ng/mL were associated with a >85% reduction in the risk of recurrent malaria within 63 days following treatment with a dose-dependent reduction in risk compared to levels <300 ng/mL. Studies in vitro showed modest synergy between LPV and lumefantrine. No QTc interval prolongation was noted.
Conclusions: Use of LPV/r-based ART reduced the incidence of malaria by 41% compared to NNRTI-based ART, largely attributable to a significant reduction in the risk of recurrent malaria following artemether-lumefantrine treatment. LPV/r-based ART could therefore be considered as one of the strategies for malaria prevention in HIV+ children.