UC Berkeley

Interactions between HIV infection and malaria in children living in sub-Saharan Africa in the era of widening access to improved interventions

by

Anne Frances Gasasira

Doctor of Philosophy in Epidemiology

University of California, Berkeley

Professor Arthur Reingold, Chair

Over 65% of the world's HIV-infected population lives in sub-Saharan Africa where 350 million people are exposed to infection with malaria. Thus any biological interactions between HIV and malaria would have major public health implications for this region. There is growing evidence that HIV infection leads to negative malaria outcomes and these effects may differ across different populations and epidemiologic settings. In non-pregnant adults and pregnant women, HIV infection increases the risk of asymptomatic parasitemia and clinical malaria. Additionally, in non-pregnant adults, the response to antimalarial therapy may be compromised by HIV infection. There are scanty data describing the effects of HIV infection on the risk of malaria and on malaria outcomes in children, the population at highest risk of clinical malaria and malaria mortality.

Over the last two decades, treatment and control of both HIV infection and malaria in sub-Saharan Africa have undergone major changes. There has been rapid scale-up of programs providing antiretroviral therapy (ART) and trimethoprim-sulfamethoxazole (TS) prophylaxis for HIV care and in parallel, wide scale implementation of malaria control interventions, such as artemisinin-combination therapies (ACTs) for treatment of uncomplicated malaria, indoor residual spraying, and widespread distribution of insecticide treated bednets. It is not clear, how these interventions singly or in combination might affect the interactions between HIV infection and malaria in different risk groups

The goal of this dissertation was to contribute to knowledge on the effects of HIV infection on malaria in children in the era of increasing access to improved HIV and malaria interventions. Data from HIV-infected and HIV-uninfected children enrolled in cohort studies in two settings of differing malaria transmission intensity in Uganda were utilized. The dissertation focused on the risk of malaria in HIV-infected children and antimalarial treatment outcomes in those with uncomplicated malaria. The objectives of studies that comprised this dissertation were 1) to assess the effect of daily TS prophylaxis on the risk of malaria in HIV-infected children, 2) to determine the association between daily TS prophylaxis and infection with antifolate-resistant malaria parasites, 3) to determine the risk factors for malaria in young HIV-infected children living in an area of high malaria transmission, and 4) to determine the efficacies and safety of ACTs for the treatment of uncomplicated malaria in HIV-infected children.

HIV-infected children receiving daily TS had an 80% reduced risk of clinical malaria compared to HIV-uninfected children not receiving TS. However, TS use was associated with infection with parasites with a rare mutation, dhfr 164L, known to mediate high-level antifolate resistance. Among HIV-infected children less than 38 months of age; low CD4 cell percentage, interruption of daily TS prophylaxis, and ART use were independent risk factors for malaria. We hypothesize that non-nucleoside reverse transcriptase inhibitors given as part of ART alter the metabolism of certain ACTs or TS leading to reduced malaria prophylaxis in those receiving these drugs concomitantly. Artemether-lumefantrine (AL), dihydroartemisinin-piperaquine (DP) and artesunate-amodaiquine (AS/AQ) were all 100% efficacious for malaria treatment, however compared to AL, AS/AQ was associated with a higher risk of neutropenia 45% vs. 17% (p=0.001), malaise 27% vs. 5% (p=0.010) and anorexia 24% vs. 5% (p=0.014). Adverse events associated with AS/AQ treatment were highest among those who were concomitantly receiving ART. In the setting of high malaria transmission intensity, DP was superior to AL in preventing recurrent parasitemia (7.1% vs. 34%, p <0.001).

Findings from these studies support the use of daily TS prophylaxis in HIV-infected children living in sub-Saharan Africa. However, there is need for continuous surveillance to monitor the emergence and spread of rare mutations that may be associated with widespread TS use. Artemether-lumefantrine and dihydroartemisinin-piperaquine appear to be safe and efficacious for the treatment of malaria in HIV-infected individuals, even among those concomitantly receiving ART. However the potential interactions between NNRTIs and other drugs given as part of HIV care and ACTs are an urgent concern. Studies in more diverse HIV-infected populations living in different malaria transmission settings are needed to confirm these findings.