Dihydroartemisinin-Piperaquine in the Context of Antiretroviral Therapy
Condition: Drug-Drug Interaction; HIV Infection
MeSH terms: HIV Infections
Study type: Interventional
Phase: Phase 4

Summary: 
      Open-label prospective intensive pharmacokinetic study of dihydroartemisinin-piperaquine (DP)
      in HIV-infected children on efavirenz (EFV)-, lopinavir/ritonavir (LPV/r)-, or dolutegravir
      (DTG)-based antiretroviral therapy (ART) and HIV-uninfected children not on ART. All children
      will be malaria-uninfected at the time of enrollment.
    

Detailed description: 
      The primary goal of the study is to assess the pharmacokinetics (PK) and safety of DP in the
      setting of co-administration with first-line ART regimens (EFV-, LPV/r- or DTG-based ART) in
      children without malaria. Up to 190 children will be enrolled in one of the 5 groups: 1,
      HIV-infected children age 3 - 10 years on LPV/r-based ART (n=20 for signal dose DP, 30
      standard 3-dose DP). 2, HIV-infected children age 3 - 10 years on EFV-based ART (n=30), 3,
      HIV-infected children age 11 - 17 years on DTG-based ART (n=30), 4, HIV-uninfected children
      age 3-10 years (standard 3-dose DP, n=20 for PK sampling after the 1st dose DP, n=30 for
      sampling after the 3rd dose DP), 5, HIV-uninfected children age 11-17 years (n=30 children
      receiving 3-dose DP).

      HIV-infected participants will be enrolled from the Baylor Uganda Center of Excellence on the
      Mulago Hospital Complex, Kampala, Uganda. HIV-uninfected participants will be enrolled from
      Masafu General Hospital (MGH) complex in Busia, and other clinics in the surrounding area. DP
      weight-based dosing will follow World Health Organization (WHO) Treatment Guidelines for
      uncomplicated malaria (April 2015). All HIV-infected participants must be stabilized (i.e. no
      change in regimen for at least 10 days) on EFV, LPV/r, or DTG + 2 nucleoside reverse
      transcriptase inhibitors (NRTI). HIV-infected children on LPV/r will be enrolled in two
      Phases: Phase I participants (Group L1) will receive a single dose of DP to determine the
      magnitude (PK and safety) of the interaction before 3 doses are evaluated, Phase II
      participants (Group L3) will receive a 3-dose DP regimen (which consists of 3 days of a once
      daily DP dose). Phase I results will inform Phase II dosing, as a lower dose of DP over 3
      days may be warranted. Phase II will not begin until PK and safety results from Phase I are
      evaluated. Participants in L1 and L3 will be encouraged to participate sequentially in Phase
      I and Phase II separated by a minimum 42-day washout period; however different children may
      be enrolled for the 2 phases. Weight-based dose of dihydroartemisinin-piperaquine (DP): 5-
      <8kg, 20+160mg; 8- <11kg, 30+240mg; 11- <17kg, 40+320mg; 17- <25kg, 60+480mg; 25- <36kg,
      80+640mg; 36- <60kg, 120+960mg; 60-<80kg, 160+1280mg; >80kg, 200+1600mg.

      Subjects will undergo an intensive PK study sampling design, which entails multiple venous
      blood collections in a smaller sample of individuals to accurately estimate drug exposure
      over time. These studies will be conducted in both HIV-infected and HIV-uninfected
      participants and will allow the researchers to investigate dihydroartemisinin (DHA) and
      piperaquine (PQ) PK exposure in the context of EFV-, LPV/r- and DTG-based ART in
      HIV-uninfected children. Comparisons will be based on an intensive PK design for DP area
      under the concentration-time curve (AUC) estimations. A sample size of 20
      children/adolescents will be needed in groups L1 and C1. A sample size of 30 will be needed
      for each of the other arms (D3, E3, L3, C3a, and C3b). Sampling will occur up to day 42 in
      the 3-dose groups given the long half-life of PQ and for 14 or 28 days in the single dose
      groups. The generation of an AUC will permit robust comparisons so that results will inform
      treatment guidelines and policy.
    

Intervention name(s): Dihydroartemisinin-piperaquine
Intervention type(s): Drug
Intervention description(s): It is expected that efavirenz (EFV), lopinavir/ritonavir (LPV/r), and/or dolutegravir (DTG) will alter DP exposure.
Other intervention name(s): DP; Duocotexin; Eurartesim; DHA-PQ
Intervention MeSH terms: Piperaquine; Artenimol
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: This is an open-label prospective pharmacokinetic and safety study of DP and 3 different ART regimens (EFV-, LPV/r- and DTG-based ART) in non-malaria-infected 1) HIV-infected children and 2) HIV uninfected children not on ART (controls).
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Drug drug interaction; HIV; malaria; dihydroartemisinin; piperaquine; lopinavir; ritonavir; efavirenz; dolutegravir; Children