Efficacy of two versus three-day regimens of dihydroartemisinin-piperaquine for uncomplicated malaria in military personnel in northern Cambodia: an open-label randomized trial

Abstract

Introduction: Emerging antimalarial drug resistance in mobile populations remains a significant public health concern. We compared two regimens of dihydroartemisinin-piperaquine in military and civilians on the Thai-Cambodian border to evaluate national treatment policy.

Methods: Efficacy and safety of two and three-day regimens of dihydroartemisinin-piperaquine were compared as a nested open-label evaluation within a malaria cohort study in 222 otherwise healthy volunteers (18% malaria-infected at baseline). The first 80 volunteers with slide-confirmed Plasmodium falciparum or vivax malaria were randomized 1:1 to receive either regimen (total dose 360 mg dihydroartemisinin and 2880 mg piperaquine) and followed weekly for up to 6 months. The primary endpoint was malaria recurrence by day 42. Volunteers with vivax infection received primaquine at study discharge with six months follow-up.

Results: Eighty patients (60 vivax, 15 falciparum, and 5 mixed) were randomized to dihydroartemisinin-piperaquine. Intention-to-treat all-species efficacy at Day 42 was 85% for the two-day regimen (95% CI 69-94) and 90% for the three-day regimen (95% CI 75-97). PCR-adjusted falciparum efficacy was 75% in both groups with nearly half (45%) still parasitemic at Day 3. Plasma piperaquine levels were comparable to prior published reports, but on the day of recrudescence were below measurable in vitro piperaquine IC50 levels in all falciparum treatment failures.

Conclusions: In the brief period since introduction of dihydroartemisinin-piperaquine, there is early evidence suggesting declining efficacy relative to previous reports. Parasite IC50 levels in excess of plasma piperaquine levels seen only in treatment failures raises concern for clinically significant piperaquine resistance in Cambodia. These findings warrant improved monitoring of clinical outcomes and follow-up, given few available alternative drugs.

Trial registration: ClinicalTrials.gov NCT01280162.

Conflict of interest statement

Competing Interests: The authors state that there are no competing interests relating to employment, consultancy, patents, products in development or marketed products arising from participation of Dr. Doug Tang, a statistician and consultant for Fast Track Biologics, Potomac, Maryland, nor does his participation alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Study Schematic Inset and Trial Profile.

*Randomization goal met, 2 withdrew. **Prolonged QTc. ¥PCR-corrected speciation. aNot included are 2nd recurrences (1 Pf, 1 Pv, 1 mixed). bNot included are 2nd recurrences (2 Pf, 5 Pv) and a 3rd recurrence (1 Pv). #Study discharge varied, median 115 days follow-up.

Figure 2. Comparison of plasma piperaquine levels between ACPR and recrudescent patients.

(A) Concentration–time profiles (geometric mean concentrations with 95% CI) for ACPR and recrudescent groups. There were no statistically significant differences beween groups at any timepoint. (B) AUC0-∞ (2 compartment analysis) in ACPR and LTF groups. Black lines represent geomean with 95%CI. Note that AUC could not be calculated in 4 and 2 patients in the ACPR and LTF groups, respectively due to limited timepoints (only 3) in the terminal phase.

Figure 3. Cumulative incidence of recurrence by modified intention-to-treat analysis at Day 42 and study discharge.

(A) No statistical difference between regimens for all-species recurrence at primary endpoint Day 42 (p = 0.63) and at day of discharge (p = 0.84). (B) In persons with an initial falciparum parasitemia (alone or mixed), there was no difference in true falciparum recrudescence at Day 42 (p = 0.73) and at day of study discharge (p = 0.91). (C) In persons with an initial vivax parasitemia (alone or mixed), there was no difference in vivax recurrence at Day 42 (0.94) and at day of study discharge (p = 0.22).

Figure 4. Piperaquine plasma concentration-time profiles in relation to IC50 for cases of P. falciparum recrudescence.

The pink line represents the plasma piperaquine concentration, and the green line represents Day 0 IC50, with time of recurrence noted by arrows. Plasma piperaquine is shown as piperaquine phosphate salt concentration (MW 999·56) to match IC50 calculation method. NI = new infection in case 091. The IC50 for 149RC could not be assessed due to non-recovery of parasites from the clinical sample.

Figure 5. Mean trough QTcF intervals for patients treated daily with DHA-piperaquine (360/2880 mg cumulative) divided over 2 or 3 days (n = 40 in each group).

Error bars indicate +1 standard deviation.

Figure 6. Six-month cumulative incidence of reported vivax recurrence following primaquine administration.

Cumulative incidence (Kaplan-Meier) of reported vivax recurrence in 2-day (n = 37) versus 3-day (n = 29) regimens following primaquine (PQ) administration at study discharge by monthly follow-up in 66 volunteers over 6 months (P = 0.62). Six cohort volunteers who were not randomized to dihydroartemisinin-piperaquine treatment also developed vivax infection and received primaquine, but are not included in analysis above. *G6PD-normal volunteers received daily primaquine30mg for 14 days whereas G6PD-deficient volunteers received a weekly regimen of 45mg for 8 weeks.