Antiretroviral Agents and Prevention of Malaria in HIV-Infected Ugandan Children

Abstract

Background Human immunodeficiency virus (HIV) protease inhibitors show activity against Plasmodium falciparum in vitro. We hypothesized that the incidence of malaria in HIV-infected children would be lower among children receiving lopinavir–ritonavir–based antiretroviral therapy (ART) than among those receiving nonnucleoside reverse-transcriptase inhibitor (NNRTI)–based ART. Methods We conducted an open-label trial in which HIV-infected children 2 months to 5 years of age who were eligible for ART or were currently receiving NNRTI-based ART were randomly assigned to either lopinavir–ritonavir–based ART or NNRTI-based ART and were followed for 6 months to 2 years. Cases of uncomplicated malaria were treated with artemether–lumefantrine. The primary end point was the incidence of malaria. Results We enrolled 176 children, of whom 170 received the study regimen: 86 received NNRTI-based ART, and 84 lopinavir–ritonavir–based ART. The incidence of malaria was lower among children receiving the lopinavir–ritonavir–based regimen than among those receiving the NNRTI-based regimen (1.32 vs. 2.25 episodes per person-year; incidence-rate ratio, 0.59; 95% confidence interval [CI], 0.36 to 0.97; P = 0.04), as was the risk of a recurrence of malaria after treatment with artemether–lumefantrine (28.1% vs. 54.2%; hazard ratio, 0.41; 95% CI, 0.22 to 0.76; P = 0.004). The median lumefantrine level on day 7 after treatment for malaria was significantly higher in the lopinavir–ritonavir group than in the NNRTI group. In the lopinavir–ritonavir group, lumefantrine levels exceeding 300 ng per milliliter on day 7 were associated with a reduction of more than 85% in the 63-day risk of recurrent malaria. A greater number of serious adverse events occurred in the lopinavir–ritonavir group than in the NNRTI group (5.6% vs. 2.3%, P = 0.16). Pruritus occurred significantly more frequently in the lopinavir–ritonavir group, and elevated alanine aminotransferase levels significantly more frequently in the NNRTI group. Conclusions Lopinavir–ritonavir–based ART as compared with NNRTI-based ART reduced the incidence of malaria by 41%, with the lower incidence attributable largely to a significant reduction in the recurrence of malaria after treatment with artemether–lumefantrine. Lopinavir–ritonavir–based ART was accompanied by an increase in serious adverse events. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT00978068.)

The Effect of Storage and Extraction Methods on Amplification of Plasmodium falciparum DNA from Dried Blood Spots

“…The details of these studies have been previously published. [6][7][8] These samples were selected randomly for our study after stratifying based on parasite density, which was determined by thick smear.…”

Prevalence of Asymptomatic Parasitemia and Gametocytemia among HIV-Infected Ugandan Children Randomized to Receive Different Antiretroviral Therapies

“…9 In this study the use of PI-based ART was associated with a 41% reduction in the incidence of malaria, largely attributable to ART-antimalarial drug interactions resulting in a significant reduction in the risk of recurrent malaria after treatment with artemether-lumefantrine (AL). In this report, we compare the prevalence of asymptomatic parasitemia and gametocytemia between ART treatment arms in this trial.…”

“…9 Specifically, the ritonavir component of the PI regimen inhibited the metabolism of lumefantrine, leading to prolongation of exposure to lumefantrine, and thus prolonged protection against recurrent malaria after treatment. To explore whether prolonged lumefantrine exposure after treatment also contributed to the lower risk of gametocytemia on the day malaria was diagnosed in the PI-based arm, results were stratified by duration since the last episode of malaria (Figure 1).…”

Malaria Diagnostics in Clinical Trials

“…There is early evidence that antiretroviral therapy (ART) may reduce malaria in HIV-infected persons. 68 Because HIV and malaria endemicity overlap globally, and the overwhelming burden of HIV-malaria co-infection is found in sub-Saharan Africa, 11 RDTs could make an enormous impact. Presumptive treatment of fevers in HIV-positive persons with malaria drugs is extremely common, but laboratory confirmation of malaria infection is not uniformly conducted.…”

“…48 Although evidence supports a higher incidence of clinical malaria and severe malaria in HIV-infected children, recent studies have also reported a reduction in malaria rates in HIV-infected persons receiving trimethoprim-sulfamethoxazole prophylaxis, as well as reports of reduced rates of malaria for those children receiving certain ART regimens. 11,68 Thus, the selected diagnostic modality must be carefully monitored to ensure its continued effectiveness in the setting of this complex and evolving interaction.…”