Malaria Treatment Efficacy among People Living with HIV: The Role of Host and Parasite Factors Miriam K. Laufer,* Joep J. G. van Oosterhout, Phillip C. Thesing, Fraction K. Dzinjalamala, Teresa Hsi, Lorraine Beraho, Stephen M. Graham, Terrie E. Taylor, and Christopher V. Plowe Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland; Department of Medicine, Blantyre Malaria Project and Malawi–Liverpool–Wellcome Trust Programme of Clinical Tropical Research, University of Malawi College of Medicine, Blantyre, Malawi; Michigan State University College of Osteopathic Medicine, East Lansing, Michigan Abstract. Identification of an effect of HIV-associated immunosuppression on response to antimalarial therapy would help guide management of malaria infection in areas of high HIV prevalence. Therefore, we conducted an observational study of people living with HIV infection in Blantyre, Malawi. Participants who developed malaria were treated with sulfadoxine–pyrimethamine (SP) and followed for 28 days. Molecular markers for SP resistance were measured. One hundred seventy-eight episodes of malaria were assessed. The 28-day cumulative treatment failure rate was 29.1%. In univariate analysis, CD4 cell count was not associated with treatment failure (hazard ratio 0.6, 95% confidence interval 0.3–1.2). Among children, the risk of treatment failure increased with infection with SP-resistant parasites and anemia. Decreased CD4 cell count was not associated with impaired response to antimalarial therapy or diminished ability to clear SP-resistant parasites, suggesting that acquired immunity to malaria is retained in the face of HIV-associated immunosuppression. INTRODUCTION Clear evidence of a clinically important impact of HIV in- fection on malaria infection and disease has been difficult to demonstrate, despite the overlapping distribution of these pathogens in sub-Saharan Africa. Among adults living in ar- eas of high malaria transmission who have acquired semi- immunity to malaria, HIV infection has been shown to in- crease modestly the frequency with which clinical episodes of malaria are diagnosed. 1–3 Severe malaria is rare in adults liv- ing in malaria-endemic areas and HIV infection does not ap- pear to increase its incidence. Another important aspect of the potential interaction be- tween HIV and malaria is the effect of HIV-associated im- munosuppression on response to antimalarial therapy. Case series and retrospective reviews comparing the antimalarial drug efficacy among HIV-infected and HIV-uninfected pa- tients have reported mixed results. 4–7 Two recent clinical studies have been conducted in Africa to assess antimalarial efficacy in an HIV-infected population. In Zambia, treatment with sulfadoxine–pyrimethamine (SP) or artemether– lumefantrine was followed by a small increased risk of re- current parasitemia in HIV-infected individuals with CD4 cell count < 300/L compared with those with CD4 counts  300/L, when participants were followed for 45 days, but not after polymerase chain reaction (PCR) correction to ex- clude new infections. 8 In Kenya, the risk of treatment failure after treatment with SP was 3.4-fold greater for HIV-infected adults with CD4 cell counts < 200/L compared with HIV- uninfected adults, only in the presence of anemia. 9 None of the previous studies considered the intrinsic resistance of the parasites to the study treatment. The ability to clear drug-resistant parasites is a model for acquired immunity to malaria. 10 As children get older and develop immunity, they have an improved ability to resolve parasitemia despite treatment with a drug to which the para- sites are resistant. We hypothesized that if HIV-associated immunosuppression interferes with malaria immunity, then lower CD4 cell counts would be associated with an impaired ability of SP treatment to cure infections with SP-resistant parasites. To identify both host and parasite factors that contribute to antimalarial drug efficacy, we studied HIV-infected adults and children enrolled in a longitudinal study in Blantyre, Malawi. When participants developed symptomatic malaria, they were treated with SP, according the Malawi national policy, and were followed for 28 days to assess the efficacy of the drug. Molecular analyses of infecting parasites were car- ried out to identify the presence of genetic mutations associ- ated with resistance to SP. STUDY PARTICIPANTS AND METHODS Study participants and site. In collaboration with the Na- tional AIDS Control Program and the Ndirande District Health Office, we established a Voluntary HIV Counseling and Testing Center at the Blantyre Malaria Project Research Clinic at the Ndirande Health Center, on the outskirts of Blantyre, the largest city in Malawi. Adults and children 2 years of age and older who were found to be infected with HIV were invited to participate in a cohort study of the inci- dence of HIV-associated illnesses, as described elsewhere. 11 Individuals taking trimethoprim–sulfamethoxazole prophy- laxis (which was not the national policy at the time) were excluded from the study. Participants who volunteered for the cohort study were evaluated on the day of enrollment and every 4 weeks thereafter and were instructed to return to the study clinic for evaluation any time they were ill. Specimen collection. CD4 cell counts were measured at en- rollment and every 4 months during participation in the study. Malaria smears and hemoglobin measurements were ob- tained at enrollment, at every scheduled 4-weekly visit re- gardless of symptoms, and at any sick visits when the partici- pant had fever or any other signs or symptoms of malaria disease. Malaria thick smears were stained with Field stain, and parasites were counted against 200 white blood cells. Parasite density was calculated on the basis of an estimated * Address correspondence to Miriam K. Laufer, Center for Vaccine Development, University of Maryland School of Medicine, Balti- more, MD 21201. E-mail: mlaufer@medicine.umaryland.edu Am. J. Trop. Med. Hyg., 77(4), 2007, pp. 627–632 Copyright © 2007 by The American Society of Tropical Medicine and Hygiene 627