Extended Duration Artemether-lumefantrine Treatment for Malaria in Children

This is a prospective multi-site study to evaluate the PK/PD of extended duration AL in HIV-infected children on EFV-based ART and HIV-uninfected children not on ART. AL is the first-line treatment for malaria in Uganda. No change in standard of care treatment was made for the purposes of this study except for the extension of AL to 5-day dosing. This study enrolled a) HIV-infected children, and b) HIV-uninfected children. All participants may be enrolled through Tororo District Hospital (TDH) or Masafu General Hospital (MGH) in Busia, or other referral centers the area. we used a design where children were randomized to either 3-day or 5-day AL and then for subsequent episodes of malaria, should they occur. Conservatively, assuming each enrolled child participates for only a single episode of malaria, up to 60 (30 HIV-infected on 3-day and 30 HIV-infected on 5-day) and 100 (50 HIV-uninfected on 3-day and 50 HIV-uninfected on 5-day) subjects were enrolled for each of the intensive study groups. 16 (9 HIV-infected on 3-day and 7 HIV-infected on 5-day) and 120 (60 HIV-uninfected on 3-day and 60 HIV-uninfected on 5-day) subjects were enrolled for each of the population study groups. Enrollment of HIV-infected subjects for population PK study groups was not halted due to the lack of HIV-infected children in the study area. Comparisons of AL PK exposure were made among and between a) HIV-infected children with malaria receiving EFV-based ART and b) HIV-uninfected children who are not on ART. Comparisons were based on an intensive PK design for AL area under the concentration-time curve (AUC) estimations.

Inclusion criteria

1, All participants:

• Residency within 60 km of the study clinics either at TDH or at MGH
• Agreement to come to clinic for all follow-up clinical and PK evaluations
• Provision of informed consent
• Weight ≥6 kg
• Presentation with uncomplicated falciparum malaria as indicated by positive smear for malaria parasites along with clinical evidence of infection (fever or history of fever in the past 24 hours)
• Willingness to undergo intensive PK sampling and/or population PK sampling during episode(s) of malaria.

2 HIV-infected participants:

• Confirmed HIV infection (positive rapid HIV test to be confirmed by Western Blot or HIV RNA after enrollment)
• On stable EFV-based ART for at least 10 days prior to enrollment
• Age 3 years to 18 years

3 HIV-uninfected participants:

• Confirmed HIV negative test (negative rapid HIV test to be confirmed by Western Blot or HIV RNA after enrollment)
• Age 6 months to 18 years

Exclusion criteria

• History of significant comorbidities such as malignancy, active tuberculosis or other World Health Organization (WHO) stage 4 disease
• Current infection with non-P. falciparum species
• Receipt of any medications known to affect CYP450 metabolism (except ART) within 14 days of study enrollment (see 4.2.2)
• Hemoglobin < 7.0 g/dL
• For the population PK study, prior treatment for malaria within 14 days of enrollment
• For the intensive PK study, prior treatment for malaria within 28 days of enrollment
• Signs or evidence of complicated malaria, defined as unarousable coma or any two of the following symptoms: Recent febrile convulsions, altered consciousness, lethargy, unable to drink, unable to stand/sit due to weakness, severe anemia (Hb < 5.0 gm/dL), respiratory distress, jaundice (see Appendix D)
• History of toxicity to AL

The following medications are disallowed within 3 weeks prior to receiving study drug:

• Carbamazepine
• Clarithromycin
• Erythromycin (oral)
• Ketoconazole
• Phenobarbital
• Phenytoin
• Rifabutin
• Rifampin
• Halofantrine
• Any other medication known to significantly affect CYP450 metabolism.
• Grapefruit juice should be avoided during the study due to its potential effects on CYP3A4.