• Incidence of malaria defined as the number of treatments for new episodes of malaria per time at risk [ Time Frame: Time from randomization until 24 months of age ] [ Designated as safety issue: No ]
  

• Incidence of any adverse events defined as severity grade 2 or higher that are possibly, probably, or definitely related to study drugs [ Time Frame: Time from randomization until 24 months of age ] [ Designated as safety issue: Yes ]
  
• Rebound incidence of malaria defined as the number of treatments for new episodes of malaria per time at risk [ Time Frame: 24 months to 36 months of age ] [ Designated as safety issue: No ]
  

Convenience sampling will be used to enroll a cohort of 800 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) 400 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 as part of 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 counseled to exclusively breastfeed until their child is 6 months old and then rapidly wean, 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. All episodes diagnosed more than 14 days after a previous episode will be considered new episodes for treatment purposes. 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 90 days for all study participants for CBC and ALT measurements.