BackgroundIn Vietnam, the artemisinin-based combination therapy (ACT) of dihydroartemisinin-piperaquine is currently used for first-line treatment of uncomplicated Plasmodium falciparum malaria. However, limited efficacy and tolerability data are available on alternative forms of ACT in Vietnam in case there is a reduction in the susceptibility of dihydroartemisinin-piperaquine. A study was conducted to compare the efficacy and tolerability of two fixed-dose formulations of ACT, artemisinin–piperaquine (Artequick®, ARPQ) and artesunate-amodiaquine (Coarsucam™, ASAQ) for the treatment of P. falciparum malaria in south-central Vietnam.MethodsA randomized, open-label trial was conducted comparing the efficacy of a two-day regimen of ARPQ (~2.8 mg/kg artemisinin plus ~17.1 mg/kg of piperaquine per day) and a three-day regimen of ASAQ (~4.7 mg/kg of artesunate plus ~12.6 mg/kg of amodiaquine per day) for the treatment of children and adults with uncomplicated falciparum malaria. Primary efficacy endpoint was day 42, PCR-corrected, parasitological cure rate. Secondary endpoints were parasite and fever clearance times and tolerability.ResultsOf 128 patients enrolled, 63 were administered ARPQ and 65 ASAQ. Of the patients who completed the 42 days follow-up period or had a recurrence of malaria, 55 were on ARPQ (30 children, 25 adults) and 59 were on ASAQ (31 children, 28 adults). Recrudescent parasitaemia was PCR-confirmed for one patient in each treatment group, with cure rates at day 42 of 98% (95% CI: 88–100) for both forms of ACT. The median parasite clearance time was significantly slower in the ARPQ group compared with the ASAQ group (48 h vs. 36 h, P<0.001) and fever clearance times were shorter in the ASAQ group (12 h vs. 24 h, P = 0.07). The two forms of ACT were well tolerated with no serious adverse events.ConclusionBoth forms of ACT were highly efficacious in the treatment of uncomplicated P. falciparum malaria. Although the two-day course of ARPQ was equally as effective as the three-day course of ASAQ, parasite and fever clearance times were shorter with ASAQ. Further studies are warranted in different regions of Vietnam to determine the nationwide efficacy of ASAQ.Trial registrationAustralian New Zealand Clinical Trials Registry Number, ACTRN12609000816257

Summaryobjective Artesunate-amodiaquine (AAQ) is efficacious for the treatment of uncomplicated Plasmodium falciparum malaria in Africa, but little is known about its efficacy in Southeast Asia. We compared the efficacy of dihydroartemisinin-piperaquine (DHP) and AAQ against falciparum malaria in central Vietnam.methods Open, randomized clinical trial of 116 patients (36 children aged 6-14 years, 80 adults aged 15-60 years) were randomly allocated a 3-day course of either DHP (2.3 mg ⁄ kg dihydroartemisinin plus 18.5 mg ⁄ kg of piperaquine per day) or AAQ (4.4 mg ⁄ kg of artesunate plus 10.6 mg ⁄ kg of amodiaquine per day). The follow-up period was 42 days.results The two drug combinations were well tolerated by all age groups with no obvious drug associated adverse events. Of the patients who completed 42 days of follow-up, 49 were on DHP (15 children, 34 adults) and 49 were on AAQ (14 children, 35 adults). The 42 day cure rates adjusted for reinfection identified by PCR genotyping for the two groups were similar [100% (49 ⁄ 49) and 98% (48 ⁄ 49) for DHP and AAQ, respectively]. With fewer reinfections, DHP appears to possess greater posttreatment prophylactic activity than AAQ.conclusion AAQ, an inexpensive artemisinin-based combination, could be an additional option to DHP for the treatment of multidrug-resistant falciparum malaria in Vietnam.

BackgroundReduced artemisinin susceptibility and artemisinin-based combination therapy (ACT)-resistance against Plasmodium falciparum and chloroquine (CQ)-resistant P. vivax malaria has been reported in Vietnam. Two therapeutic efficacy studies were conducted in Thuan Bac District (Ninh Thuan Province, Vietnam) in 2015 and 2016 to determine the extent of reduced artemisinin susceptibility and ACT resistant falciparum malaria, and CQ-resistant vivax malaria were present.MethodsTwenty-seven patients with falciparum malaria were randomized to receive artesunate alone (AS ~ 4 mg/kg/day) for 4 days followed by dihydroartemisinin (DHA) (2.2 mg/kg)–piperaquine (PPQ) (18 mg/kg) daily for 3 days or artemether (AM) (1.7 mg/kg)–lumefantrine (LUM) (12 mg/kg) twice daily for 3 days. Sixteen subjects with vivax malaria received CQ (total 25 mg/kg over 3 days). The therapeutic efficacy study for treating falciparum malaria was complemented with molecular analysis for artemisinin and piperaquine resistance, and in vitro drug susceptibility testing. Patient’s drug exposure following both falciparum and vivax treatment studies was determined.ResultsTwenty-five of 27 patients treated with the artemisinin regimens completed the 42-day follow-up period. None had parasites present on day 3 after commencing treatment with no incidence of recrudescence (100% curative rate). One patient on AS + DHA–PPQ was lost to follow-up and one patient had Plasmodium falciparum and Plasmodium vivax infection on day 0 by PCR. Of the vivax patients, 15 of 16 completed CQ treatment and two had a recurrence of vivax malaria on day 28, a failure rate of 13.3% (2/15). No mutations in the Pfkelch-13 gene for artemisinin resistance or exo-E415G gene polymorphism and amplification in plasmepsins 2 and 3 for piperaquine resistance were observed. In vitro testing of patient’s falciparum parasites indicated susceptibility (low IC50 nM values) to dihydroartemisinin, lumefantrine, piperaquine and pyronaridine. Patient’s drug exposure to artesunate and lumefantrine was comparable to published data, however, blood CQ concentrations were lower.ConclusionsClinical findings, molecular analysis and in vitro testing revealed that the falciparum parasites at Phuoc Chien Commune were artemisinin susceptible. The clinical failure rate of the 15 vivax patients who completed CQ treatment was 13%. Further studies are required to determine whether CQ-resistant vivax malaria is present at the commune.Electronic supplementary materialThe online version of this article (10.1186/s12936-019-2640-2) contains supplementary material, which is available to authorized users.

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.

Abstract. Safe and effective antimalarial drugs are required for the treatment of pregnant women. We report a 3-day regimen of artesunate (4 mg/kg/day)-azithromycin (25 mg/kg/day) (ASAZ) to be efficacious (polymerase chain reactioncorrected cure rate of 96.7%) and well tolerated in the treatment of Plasmodium falciparum malaria in children (N = 11) and adults (N = 19), in Vietnam in 2010. In comparison, the cure rate for artesunate (4 mg/kg on day 0, 2 mg/kg on days 1-6) was 90.0% in children (N = 7) and adults (N = 23). Because azithromycin is considered safe in pregnancy, our findings provide further evidence that ASAZ should be evaluated for the treatment of pregnant women with malaria.Malaria in pregnancy is a serious health problem.1 Treatment options for malaria in pregnant women, particularly during the first trimester, are limited due to the lack of safety, efficacy, and pharmacokinetic data on antimalarials, including artemisinin-based combination therapies (ACT). The World Health Organization (WHO) recommends the coadministration of quinine and clindamycin (10 mg/kg twice a day) for 7 days during the first trimester.1 The disadvantage of this regimen is that it causes cinchonism, 2 and 7-day regimens are associated with poor compliance in an outpatient setting.3 WHO recommends that if quinine-clindamycin is not available or fails to cure, an ACT or artesunate-clindamycin should be used.1 However, there is a paucity of efficacy and safety data on artesunate-clindamycin, with the only published study in malaria-infected children treated with artesunate (2 mg/kg)-clindamycin (7 mg/kg) twice daily for 3 days producing a cure rate of only 87%. 4A potential alternative to artesunate-clindamycin is artesunate-azithromycin (ASAZ). Both clindamycin and azithromycin are broad-acting antibiotics but with different pharmacokinetic properties in pregnant women. Clindamycin has a short elimination half-life of 2-4 hours, 5 necessitating twice-daily dosing, whereas azithromycin has a longer elimination half-life of 78 hours in pregnant women, 6 that allows for once-daily dosing. Azithromycin also is well tolerated and considered safe in pregnancy, 6 and in combination with artesunate could be a safe and effective ACT for the treatment of pregnant women with malaria. Of note, interest in azithromycin has not just been limited to combining with artesunate, but other investigators have been evaluating the antibiotic with chloroquine, piperaquine, or sulfadoxine-pyrimethamine for intermittent preventive treatment of malaria in pregnancy. 7-9The objective of the present study was to obtain efficacy and tolerability data of ASAZ in children and adults with uncomplicated Plasmodium falciparum malaria in south-central Vietnam. The efficacy of artesunate alone was also assessed to obtain an insight into the susceptibility of artesunate without a partner drug. As this was the first efficacy trial of ASAZ in Vietnam, it was conducted as a pilot study, and was not powered to detect a statistically significant difference in cure ...