Rapid decline in the susceptibility of Plasmodium falciparum to dihydroartemisinin-piperaquine in the south of Vietnam

Abstract

Background: Artemisinin resistant Plasmodium falciparum has emerged in the countries of the Greater Mekong sub-region posing a serious threat to global malaria elimination efforts. The relationship of artemisinin resistance to treatment failure has been unclear.

Methods: In annual studies conducted in three malaria endemic provinces in the south of Vietnam (Binh Phuoc, Ninh Thuan and Gia Lai) between 2011 and 2015, 489 patients with uncomplicated P. falciparum malaria were enrolled in detailed clinical, parasitological and molecular therapeutic response assessments with 42 days follow up. Patients received the national recommended first-line treatment dihydroartemisinin-piperaquine for three days.

Results: Over the 5 years the proportion of patients with detectable parasitaemia on day 3 rose steadily from 38 to 57% (P < 0.001). In Binh Phuoc province, the parasite clearance half-life increased from 3.75 h in 2011 to 6.60 h in 2015 (P < 0.001), while treatment failures rose from 0% in 2012 and 2013, to 7% in 2014 and 26% in 2015 (P < 0.001). Recrudescence was associated with in vitro evidence of artemisinin and piperaquine resistance. In the treatment failures cases of 2015, all 14 parasite isolates carried the C580Y Pfkelch 13 gene, marker of artemisinin resistance and 93% (13/14) of them carried exoE415G mutations, markers of piperaquine resistance.

Conclusions: In the south of Vietnam recent emergence of piperaquine resistant P. falciparum strains has accelerated the reduced response to artemisinin and has led to treatment failure rates of up to 26% to dihydroartemisinin-piperaquine, Vietnam's current first-line ACT. Alternative treatments are urgently needed.

Keywords: Artemisinin resistance; Parasite clearance half-life; Piperaquine resistance.

Fig. 1

The study sites in Vietnam

Fig. 2

Study flow diagram

Fig. 3

Proportion of patients with positive smear on day 3, parasite clearance half-life (PC_1/2) and the treatment failure rate following dihydroartemisin–piperaquine treatment in Binh Phuoc from 2012–2015 in Vietnam

Fig. 4

Ex vivo response to DHA and in vitro response to piperaquine of parasites collected from patients following dihydroartemisin–piperaquine treatment using ring stage assay (RSA) and piperaquine survival assay (PSA), respectively. Black dots represented for parasites from recrudescent cases, white dots represented for parasite from ACPR cases. The Plasmodium falciparum lines of 3D7 and K1 are controls

Fig. 5

Copy variation number of plasmepsin 2 gene in the parasites collected from patients following dihydroartemisin–piperaquine treatment. Green dots represented to parasites form ACPR cases. Red dots represented to parasite form recrudescent cases