Therapeutic efficacy of pyronaridine-artesunate (Pyramax) in treating Plasmodium vivax malaria in the central highlands of Vietnam

Abstract

The emergence and spread of chloroquine-resistant Plasmodium vivax have necessitated the assessment of alternative blood schizonticidal drugs. In Vietnam, chloroquine-resistant P. vivax malaria has been reported. In an open-label, single-arm trial, the safety, tolerability, and efficacy of pyronaridine-artesunate (Pyramax, PA) was evaluated in Dak Nong province, Vietnam. A 3-day course of PA was administered to adults and children (≥20 kg) infected with P. vivax. Patients also received primaquine (0.25 mg/kg daily for 14 days). PA was well tolerated with transient asymptomatic increases in liver transaminases. The per-protocol proportion of patients with day 42 PCR-unadjusted adequate clinical and parasitological response was 96.0% (95% CI, 84.9%-99.0%, n = 48/50). The median parasite clearance time was 12 h (range, 12-36 h), with a median fever clearance time of 24 h (range, 12-60 h). Single nucleotide polymorphisms (SNPs) as potential genetic markers of reduced drug susceptibility were analyzed in three putative drug resistance markers, Pvcrt-o, Pvmdr1, and PvK12. Insertion at position K10 of the Pvcrt-o gene was found in 74.6% (44/59) of isolates. Pvmdr1 SNPs at Y976F and F1076L were present in 61% (36/59) and 78% (46/59), respectively. Amplification of Pvmdr1 gene (two copies) was found in 5.1% (3/59) of parasite samples. Only 5.1% (3/59) of isolates had mutation 552I of the PvK12 gene. Overall, PA rapidly cleared P. vivax blood asexual stages and was highly efficacious in treating vivax malaria, with no evidence of artemisinin resistance found. PA provides an alternative to chloroquine treatment for vivax malaria in Vietnam.

Clinical trials: This study is registered with the Australian New Zealand Clinical Trials Registry as ACTRN12618001429246.

Keywords: Plasmodium vivax; Pyramax; Vietnam; antimalarial drug resistance; molecular markers; pyronaridine-artesunate.

Fig 1

Provincial map of Vietnam with Dak Nong province highlighted in red (A). District map of Dak Nong province (B). Locations of study sites, Dak Drong commune in Cu Jut District, and Thuan An commune in Dak Mil District are indicated by arrows on district maps (C). Map images courtesy of Gerard Kelly, produced using MapInfo Professional v15.0.2 (Pitney Bowes Software Inc. 2015, Stamford, CT) geographic information system mapping software.

Fig 2

Primary efficacy outcome. The Kaplan-Meier probabilities of the PCR-unadjusted ACPR at day 42 after PA treatment of P. vivax malaria across both Dak Drong and Thuan An communes (overall analysis).

Fig 3

(A) Frequency of SNPs identified in Pvcrt-o, Pvmdr1, and PvK12 genes in parasite samples collected before PA treatment. (B) Pvmdr1 gene copy number in parasite samples collected before PA treatment. The median line with the interquartile range is shown.

Fig 4

Artesunate (AS) and dihydroartemisinin (DHA) plasma concentrations at 1 h after the last dose on day 3, as well as blood pyronaridine (PRN) concentrations at day 7 after commencement of PA treatment. Open circles represent plasma concentrations of artesunate and dihydroartemisinin for VPA06, but data were not available for VPA46. Open triangles represent blood PRN concentration in VPA06 and VPA46 participants, who had a recurrence of P. vivax. Median lines with IQR are shown.