Dihydroartemisinin-Piperaquine in the Context of Antiretroviral Therapy (DPART)

DPART Study: Dihydroartemisinin-Piperaquine in the Context of Antiretroviral Therapy

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.

Study Overview

• Status: Completed
• Conditions: HIV Infection; Drug-Drug Interaction
• Intervention / Treatment: Drug: Dihydroartemisinin-piperaquine

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.

• Study Type: Interventional
• Enrollment (Actual): 194
• Phase: Phase 4

Contacts and Locations

Study Locations

• Uganda
  • Kampala, Uganda
    • Baylor-Uganda Center of Excellence on Mulago Hospital Complex and Masafu General Hospital
  • Busia
    • Masafu, Busia, Uganda
      • Masafu General Hospital (MGH) at Busia District, Eastern Uganda

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 months to 13 years (Child)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

All participants:

• Agreement to come to clinic for all follow-up PK and safety evaluations
• Provision of informed consent.

HIV-infected participants:

• Residency within 30km of Mulago Hospital.
• Confirmed HIV infection (confirmed positive rapid HIV test or HIV RNA as per
• Ugandan guidelines).
• On stable EFV-, LPV/r- or DTG-based ART for at least 10 days prior to enrollment.
• Age 3 - 10 years if on EFV-based ART or LPV/r-based ART.
• Age 11 - 17 years if on DTG-based ART.

HIV-uninfected participants:

• Residency within 30km of Masafu General Hospital
• Confirmed HIV negative test (confirmed positive rapid HIV test or HIV RNA as
• per Ugandan guidelines)
• Age 3 - 17 years.

Exclusion Criteria:

• History of significant comorbidities such as malignancy, active tuberculosis or
• other active WHO stage 4 disease
• Receipt of any medications known to affect CYP450 metabolism (except ART)
• within 14 days of study enrolment (see 4.2.1)
• Hemoglobin < 7.0 g/dL
• Current malaria infection or recent treatment with antimalarials within 28 days of
• enrolment.
• Asymptomatic parasitemia detected by microscopy or rapid diagnostic test (RDT)
• History of side effects with DP
• Prior history of cardiac disease (personal or family), baseline corrected QT intervals (QTc) >450msec, or
• receipt of any cardiotoxic drugs or those known to prolong QT intervals History of
• significant comorbidities such as malignancy, active tuberculosis or other WHO
• stage 4 disease
• Weight < 6kg
• HIV-infected females on DTG-based ART and age 13-17 years who are pregnant
• or of childbearing potential and do not agree to consistent and reliable
• contraception.

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

• Carbamazepine
• Clarithromycin
• Erythromycin (oral)
• Ketoconazole
• Phenobarbital
• Phenytoin
• Rifabutin
• Rifampicin
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HIV-infected children on EFV-based ART (E3); 30 HIV-infected children age 3 - 10 years on EFV-based ART for at least 10 days will take standard 3 consecutive once-daily oral doses of DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used.	Drug: Dihydroartemisinin-piperaquine; It is expected that efavirenz (EFV), lopinavir/ritonavir (LPV/r), and/or dolutegravir (DTG) will alter DP exposure.; Other Names: Eurartesim; DP; Duocotexin; DHA-PQ
Experimental: HIV-infected children on DTG-based ART (D3); 30 HIV-infected children age 11 - 17 years on DTG-based ART for at least 10 days will take standard 3 consecutive once-daily oral doses of DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used.	Drug: Dihydroartemisinin-piperaquine; It is expected that efavirenz (EFV), lopinavir/ritonavir (LPV/r), and/or dolutegravir (DTG) will alter DP exposure.; Other Names: Eurartesim; DP; Duocotexin; DHA-PQ
Experimental: HIV-infected children on LPV/r-based ART (L3); 30 HIV-infected children age 3 - 10 years on LPV/r-based ART for at least 10 days will take standard 3 consecutive once-daily oral doses of DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used.	Drug: Dihydroartemisinin-piperaquine; It is expected that efavirenz (EFV), lopinavir/ritonavir (LPV/r), and/or dolutegravir (DTG) will alter DP exposure.; Other Names: Eurartesim; DP; Duocotexin; DHA-PQ
Active Comparator: HIV-uninfected children (C1); 20 HIV-uninfected children age 3-10 years not on ART will take standard 3 consecutive once-daily oral doses of DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used. PK samples are collected after the 1st dose. Control group for L1.	Drug: Dihydroartemisinin-piperaquine; It is expected that efavirenz (EFV), lopinavir/ritonavir (LPV/r), and/or dolutegravir (DTG) will alter DP exposure.; Other Names: Eurartesim; DP; Duocotexin; DHA-PQ
Active Comparator: HIV-uninfected children (C3a); 30 HIV-uninfected children age 3-10 years not on ART will take standard 3 consecutive once-daily oral doses of DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used. PK samples are collected after the 3rd dose. Control group for E3 and L3.	Drug: Dihydroartemisinin-piperaquine; It is expected that efavirenz (EFV), lopinavir/ritonavir (LPV/r), and/or dolutegravir (DTG) will alter DP exposure.; Other Names: Eurartesim; DP; Duocotexin; DHA-PQ
Active Comparator: HIV-uninfected children (C3b); 30 HIV-uninfected children age 11-17 years not on ART will take standard 3 consecutive once-daily oral doses of DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used. Control group for D3.	Drug: Dihydroartemisinin-piperaquine; It is expected that efavirenz (EFV), lopinavir/ritonavir (LPV/r), and/or dolutegravir (DTG) will alter DP exposure.; Other Names: Eurartesim; DP; Duocotexin; DHA-PQ
Experimental: HIV-infected children on LPV/r-based ART (L1); 20 HIV-infected children age 3 - 10 years on LPV/r-based ART for at least 10 days will take one oral dose DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used	Drug: Dihydroartemisinin-piperaquine; It is expected that efavirenz (EFV), lopinavir/ritonavir (LPV/r), and/or dolutegravir (DTG) will alter DP exposure.; Other Names: Eurartesim; DP; Duocotexin; DHA-PQ

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC0-42day in 3-dose Study	AUC 0-day42 (from time 0 to 42 days) for piperaquine	42 days
QTcF in 3-dose Study	Safety of 3-dose DP regimens determined via-assessment of mean change in QT intervals from baseline; Here we reported mild adverse event defined as QTc F change>30ms but <60ms from baseline.	42 days
AUC0-day28 in 3-dose Study	Area under concentration -time curve from pre-3rd dose to day 28	day 2-28
Cmax for Piperaquine in 3-dose Study	maximal piperaquine concentration post the 3rd dose (day 2-42)	day 2-28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The effects of DP on EFV pharmacokinetics as measured by mid-level of EFV	Pre-ART sample to quantify mid-level of EFV, sampled collected via venipuncture on Day 0, 2, & 3 to allow for comparisons of EFV level.	4 days
The association of anthropomorphic indicators of malnutrition measured as weight-for age (WFA) z-score and PK exposure of DP in HIV-infected and HIV-uninfected children	Children will be characterized as a) "stunted" but not underweight [i.e. weight for age (WFA) z-score>-2); b) underweight, but not stunted (WFA z-score ≤-2); or c) of normal nutritional status (WFA z-scores >-1).	42 days
Assess auto-induction of DHA from single dose to 3-doses	DHA AUC after 1st dose will be compared to AUC after 3rd dose.	4 days
CYP2B6 pharmacogenetics and its impact on EFV PK.	To assess prevalence of CYP2B6 pharmacogenetic variants and their impact on EFV PK	4 days
The association of anthropomorphic indicators of malnutrition measured as height-for-age (HFA) z-score and PK exposure of DP in HIV-infected and HIV-uninfected children	Children will be characterized as a) "stunted" but not underweight [i.e. height for age (HFA) z-score ≤-2); b) underweight, but not stunted (HFA z-score>-2); or c) of normal nutritional status (HFA z-scores >-1).	42 days
The effects of DP on DTG pharmacokinetics as measured by trough-level (Cmin) of DTG	Pre-ART sample to quantify trough of DTG, sampled collected via venipuncture on Day 0, 2, & 3 to allow for comparisons of DTG level.	4 days
The effects of DP on LPV/r pharmacokinetics as measured by trough-level (Cmin) of LPV/r	Pre-ART sample to quantify trough of LPV/r, sampled collected via venipuncture on Day 0, 2, & 3 to allow for comparisons of LPV/r level.	4 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax for Piperaquine in Single-dose Study	Cmax for piperaquine: Maximal concentration in single-dose study to evaluate Safety	<24hr
AUC0-24h for Piperaquine in Single-dose Study	AUC 0-24h (from time 0 to 24h) for piperaquine in single-dose study to evaluate safety.	1 day
QTcF in Single-dose Safety Study	Cardiotoxicity associated with PQ is QT interval prolongation. Electrocardiogram (ECG) will be performed to provide data on QT intervals in msec. Reported if QTcF>30ms	28 days
The Association of Malnutrition and PK Exposure of DP in HIV-infected and HIV-uninfected Children	Z-score is the anthropomorphic indicator of malnutrition measured as weight-for age (WFA). Children will be characterized as a) "stunted" but not underweight [i.e. weight for age (WFA) z-score>-2); b) underweight, but not stunted (WFA z-score ≤-2); or c) of normal nutritional status (WFA z-scores >-1).	42 days
Assess Auto-induction of DHA From Single Dose to 3-doses	DHA AUC0-8hr post the 1st dose is compared to AUC0-8hr post the 3rd dose	3 days
CYP2B6 Pharmacogenetics and Its Impact on EFV PK	To assess prevalence of CYP2B6 pharmacogenetic variants and their impact on EFV PK	4 days
The Association of Anthropomorphic Indicators of Malnutrition Measured as Height-for-age (HFA) Z-score and PK Exposure of DP in HIV-infected and HIV-uninfected Children	Children will be characterized as a) "stunted" but not underweight [i.e. height for age (HFA) z-score ≤-2); b) underweight, but not stunted (HFA z-score>-2); or c) of normal nutritional status (HFA z-scores >-1).	42 days
The Effects of DP on EFV Pharmacokinetics as Measured by Trough-level (Cmin) of EFV	Compare the trough EFV concentration on day 0 (pre-DP and EFV doses) to day 3 (24hr after DP and EFV doses)	4 days
The Effects of DP on DTG Pharmacokinetics as Measured by Trough-level (Cmin) of DTG	Pre-ART sample to quantify trough of DTG, sampled collected via venipuncture on Day 0, 2, & 3 to allow for comparisons of DTG level.	4 days
The Effects of DP on LPV/r Pharmacokinetics as Measured by Trough-level (Cmin) of LPV/r	Pre-ART sample to quantify trough of LPV/r, sampled collected via venipuncture on Day 0, 2, & 3 to allow for comparisons of LPV/r level.	4 days

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Yale University; Makerere University
• Investigators: Principal Investigator: Francesca Aweeka, University of California, San Francisco; Principal Investigator: Sunil Parikh, Yale University; Principal Investigator: Norah Mwebaza, Makerere University; Study Chair: Adeodata Kekitiinwa, Baylor College of Medicine Children's foundation Uganda

Study record dates

Study Major Dates

• Study Start (Actual): November 23, 2020
• Primary Completion (Actual): April 11, 2022
• Study Completion (Actual): April 11, 2022

Study Registration Dates

• First Submitted: July 17, 2020
• First Submitted That Met QC Criteria: July 22, 2020
• First Posted (Actual): July 27, 2020

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 26, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: HIV; Children; malaria; efavirenz; ritonavir; dolutegravir; lopinavir; Drug drug interaction; dihydroartemisinin; piperaquine
• Additional Relevant MeSH Terms: Blood-Borne Infections; Urogenital Diseases; Genital Diseases; Immune System Diseases; Infections; RNA Virus Infections; Virus Diseases; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; HIV Infections; Anti-Infective Agents; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Piperaquine; Artenimol
• Other Study ID Numbers: 18-26978; 2R01HD068174-06A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No