Convenience sampling will be used to enroll a cohort of 600 HIV-uninfected infants between the ages of 4-5 months of age according to the following strata based on the mother's HIV status: 1) 200 HIV-exposed infants born to HIV-infected mothers, and 2) 400 HIV-unexposed infants born to HIV-uninfected mothers. Potential study participants will be identified from the Tororo District Hospital Antenatal Clinic and surrounding clinics providing routine pediatric care. Potential study participants less than 6 months of age and their parents/guardians will be referred to our study clinic for screening. Eligible children will be enrolled when they reach 4-5 months of age and followed until the age of 36 months for all their routine medical care at our designated study clinic. All mother-child pairs will receive 2 long lasting ITNs at enrollment and, as available, a basic care package including a safe water vessel, multivitamins and condoms. HIV-unexposed children will be randomized to one of four chemoprevention arms when they reach 6 months of age. All HIV-exposed children born to HIV-infected mothers will be given TS prophylaxis and mothers will be encouraged to introduce food at 6 months of life and continue breastfeeding until 1 year of life, in accordance with Ugandan Ministry of Health (MOH) guidelines. HIV-exposed children will retested for HIV approximately every 60 days during breastfeeding and 6 weeks following cessation of breastfeeding. HIV-exposed children who remain HIV-uninfected following cessation of breastfeeding will be randomized to one of four chemoprevention arms. HIV-exposed children who test positive for HIV during the course of the study (those who seroconvert during breastfeeding) will be excluded from the study and referred for appropriate care.

During the follow-up period, all patients presenting to the clinic with a new episode of fever will undergo standard evaluation (history, physical examination and Giemsa-stained blood smear) for the diagnosis of malaria. Children diagnosed with uncomplicated malaria will be treated with AL and children diagnosed with complicated malaria will be treated with quinine in accordance with national guidelines. Response to antimalarial therapy will be assessed using standardized guidelines. All AL treatment failures occurring within 14 days of diagnosis will be treated with quinine in accordance with national guidelines. In the event that a patient fails quinine therapy, therapy will be repeated with quinine plus clindamycin. Patients with complicated malaria who have contraindications to giving quinine will be treated with parenteral artesunate. All episodes diagnosed more than 14 days after a previous episode will be considered new episodes for treatment purposes. After two years of age, patients with uncomplicated malaria will have follow up visits on the days Antimalarial drugs are administered only (Day 0, 1, and 2). Routine assessments will be performed in the study clinic approximately every 30 days. Routine assessments will include review of study protocol with parents/guardians of study participants, assessment for any outside medical care, assessment for adherence to assigned chemopreventive therapy, a focused history and physical examination and routine blood smears for the detection of asymptomatic parasitemia. Routine phlebotomy will be performed approximately every 120 days for all study participants for CBC, glucose and ALT measurements.