Pyronaridine-Artesunate (Pyramax) for Treatment of Artemisinin- and Piperaquine-Resistant Plasmodium falciparum in the Central Highlands of Vietnam

Abstract

The rise in Plasmodium falciparum resistance to dihydroartemisinin-piperaquine in Vietnam justifies the need to evaluate alternative artemisinin-based combination therapies. Between July 2018 and October 2019, a single-arm trial of pyronaridine-artesunate (Pyramax, PA) was conducted in Dak Nong province, Vietnam. PA (3-day course) was administered to adults and children infected with P. falciparum . PA was well tolerated by the participants. The proportion of patients with Day 42 PCR-corrected adequate clinical and parasitological response was 95.2% (95% confidence interval [CI], 82.3 to 98.8, n = 40/42) for treating falciparum malaria. The median parasite clearance half-life was 6.7 h (range, 2.6 to 11.9) and the median parasite clearance time was 72 h (range, 12 to 132) with 44.9% (22/49) of patients having positive blood films at 72 h. The two patients that recrudesced had comparable Day 7 blood pyronaridine concentrations (39.5 and 39.0 ng/ml) to the 40 patients who did not recrudesce (median 43.4 ng/ml, 95% CI, 35.1 to 54.9). Ring-stage and piperaquine survival assays revealed that of the 29 P. falciparum isolates collected from the patients before PA treatment, 22 (75.9%) had reduced susceptibility to artemisinins and 17 (58.6%) were resistant to piperaquine. Genotyping confirmed that 92.0% (46/50) of falciparum patients were infected with parasites bearing the Pfkelch13 C580Y mutation associated with artemisinin resistance. Of these, 56.0% (28/50) of the isolates also had multiple copies of the plasmepsin 2/3 genes responsible for piperaquine resistance. Overall, PA was effective in treating P. falciparum in the Central Highlands of Vietnam.

Exploring the feasibility of introducing triple artemisinin-based combination therapies in the malaria treatment policy in Vietnam

“…DHA-PPQ has been replaced by PA in 4 provinces with high rate of resistance from 2020. PA is now commonly used because, contrary to most alternative ACTs, it has high e cacy (1,11) and is now available through external funds. Although treatment guidelines have not yet been revised, many national program leaders consider PA to be the rst-line treatment for malaria.…”

“…This is in line with the World Health Organization (WHO) recommendation stipulating that countries should switch rst-line therapies once treatment failures exceed 10% (5,6). Although PA is an effective treatment for P. falciparum, a relatively high proportion of patients remained aparasitemic on D3 (24.0% − 44.9%) (10,11) calling for continuous monitoring of PA e cacy in Vietnam. This is worrisome because there are very few treatment options remaining if PA fails.…”

Plasmodium falciparum resistance to artemisinin-based combination therapies

“…ASAQ and AS-MQ have been used extensively in the GMS, and high failure rates to both have been reported [ 3 , 55• ]. Artesunate-pyronaridine (AS-PND), the most recently deployed ACT, shows excellent efficacy against DHA-PPQ-resistant infections [ 56 ]. AL is the predominant first-line ACT in Africa, and there is no concrete evidence of lumefantrine (LMF) or pyronaridine (PND) resistance.…”

The Artemiside-Artemisox-Artemisone-M1 Tetrad: Efficacies against Blood Stage P. falciparum Parasites, DMPK Properties, and the Case for Artemiside

“…This intrinsic chemical instability coupled with its implicit involvement in artemisinin resistance [26,27] and its neurotoxicity [28,29] are not reconcilable with its continued use as a frontline antimalarial drug [30]. Even though it now appears that within certain of the current ACTs, the partner drug acts to enhance activity of the artemisinin against artemisinin-tolerant strains, e.g., artemether-lumefantrine [31] or artesunate-pyronaridine [32], the latter in a clinical situation, artemisinin derivatives that do not decompose to DHA are required. [9][10][11][12][13]; the last two are rapidly converted into DHA in vivo [14][15][16][17][18][19][20]; (b) the highly crystalline thiomorpholine derivative artemiside 5, the thiomorpholine S-oxide artemisox 6, the thiomorpholine S,S-dioxide artemisone 7, and the principal metabolites of artemisone: the unsaturated thiomorpholine-S,S-dioxide (1,4-dihydrothiazine-S,S-dioxide) M1 8, and the hydroxylated artemisone derivatives M2 and M3 [24].…”