Artemisinin resistance (delayed P. falciparum clearance following artemisinin-based combination therapy), is widespread across Southeast Asia but to date has not been reported in Africa1–4. Here we genotyped the P. falciparum K13 (Pfkelch13) propeller domain, mutations in which can mediate artemisinin resistance5,6, in pretreatment samples collected from recent dihydroarteminisin-piperaquine and artemether-lumefantrine efficacy trials in Rwanda7. While cure rates were >95% in both treatment arms, the Pfkelch13 R561H mutation was identified in 19 of 257 (7.4%) patients at Masaka. Phylogenetic analysis revealed the expansion of an indigenous R561H lineage. Gene editing confirmed that this mutation can drive artemisinin resistance in vitro. This study provides evidence for the de novo emergence of Pfkelch13-mediated artemisinin resistance in Rwanda, potentially compromising the continued success of antimalarial chemotherapy in Africa. Identification in Rwanda of mutations in Plasmodium falciparum capable of conferring in vitro resistance to artemisinin, an essential medicine for the treatment of malaria, underscore the crucial need for surveillance in Africa to safeguard efficacy of life-saving therapies.

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Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda.

Summary Background The emergence and spread of resistance in Plasmodium falciparum malaria to artemisinin combination therapies in the Greater Mekong subregion poses a major threat to malaria control and elimination. The current study is part of a multi-country, open-label, randomised clinical trial (TRACII, 2015–18) evaluating the efficacy, safety, and tolerability of triple artemisinin combination therapies. A very high rate of treatment failure after treatment with dihydroartemisinin-piperaquine was observed in Thailand, Cambodia, and Vietnam. The immediate public health importance of our findings prompted us to report the efficacy data on dihydroartemisinin-piperaquine and its determinants ahead of the results of the overall trial, which will be published later this year. Methods Patients aged between 2 and 65 years presenting with uncomplicated P falciparum or mixed species malaria at seven sites in Thailand, Cambodia, and Vietnam were randomly assigned to receive dihydroartemisinin-piperaquine with or without mefloquine, as part of the TRACII trial. The primary outcome was the PCR-corrected efficacy at day 42. Next-generation sequencing was used to assess the prevalence of molecular markers associated with artemisinin resistance ( kelch13 mutations, in particular Cys580Tyr) and piperaquine resistance ( plasmepsin-2 and plasmepsin-3 amplifications and crt mutations). This study is registered with ClinicalTrials.gov , number NCT02453308 . Findings Between Sept 28, 2015, and Jan 18, 2018, 539 patients with acute P falciparum malaria were screened for eligibility, 292 were enrolled, and 140 received dihydroartemisinin-piperaquine. The overall Kaplan-Meier estimate of PCR-corrected efficacy of dihydroartemisinin-piperaquine at day 42 was 50·0% (95% CI 41·1–58·3). PCR-corrected efficacies for individual sites were 12·7% (2·2–33·0) in northeastern Thailand, 38·2% (15·9–60·5) in western Cambodia, 73·4% (57·0–84·3) in Ratanakiri (northeastern Cambodia), and 47·1% (33·5–59·6) in Binh Phuoc (southwestern Vietnam). Treatment failure was associated independently with plasmepsin2/3 amplification status and four mutations in the crt gene (Thr93Ser, His97Tyr, Phe145Ile, and Ile218Phe). Compared with the results of our previous TRACI trial in 2011–13, the prevalence of molecular markers of artemisinin resistance ( kelch13 Cys580Tyr mutations) and piperaquine resistance ( plasmepsin2/3 amplifications and crt mutations) has increased substantially in the Greater Mekong subregion in the past decade. Interpretation Dihydroartemisinin-piperaquine is not treating malaria effectively across the eastern Greater Mekong subregion. A highly drug-resistant P falciparum co-lineage is evolving, acquiring new resistance mechanisms, and spreading. Accelerated elimination of P falciparum malaria in this region is needed urgently, to prevent further spread and avoid a potential global health emergency. Funding UK Department for International Development, Wellcome Trust, Bill & Melinda Gates Foundation, Medical Research Council, and National Institutes of Health.

Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study

New Zealand's early response to the novel coronavirus pandemic included a strict lockdown which eliminated community transmission of COVID-19. However, this success was not without cost, both economic and social. In our study, we examined the psychological wellbeing of New Zealanders during the COVID-19 lockdown when restrictions reduced social contact, limited recreation opportunities, and resulted in job losses and financial insecurity. We conducted an online panel survey of a demographically representative sample of 2010 adult New Zealanders in April 2020. The survey contained three standardised measures-the Kessler Psychological Distress Scale (K10), the GAD-7, and the Well-Being Index (WHO-5)-as well as questions designed specifically to measure family violence, suicidal ideation, and alcohol consumption. It also included items assessing positive aspects of the lockdown. Thirty percent of respondents reported moderate to severe psychological distress (K10), 16% moderate to high levels of anxiety, and 39% low wellbeing; well above baseline measures. Poorer outcomes were seen among young people and those who had lost jobs or had less work, those with poor health status, and who had past diagnoses of mental illness. Suicidal ideation was reported by 6%, with 2% reporting making plans for suicide and 2% reporting suicide attempts. Suicidality was highest in those aged 18-34. Just under 10% of participants had directly experienced some form of family harm over the lockdown period. However, not all consequences of the lockdown were negative, with 62% reporting 'silver linings', which included enjoying working from home, spending more time with family, and a quieter, less polluted environment. New Zealand's lockdown successfully eliminated COVID-19 from the community, but our results show this achievement brought a significant psychological toll. Although much of the debate about lockdown measures has focused on their economic effects, our findings emphasise the need to pay equal attention to their effects on psychological wellbeing.

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Psychological distress, anxiety, family violence, suicidality, and wellbeing in New Zealand during the COVID-19 lockdown: A cross-sectional study.

Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial.

Antimalarial drug resistance, in particular resistance to Plasmodium falciparum, challenges the treatment and control of malaria. In this Review, we summarise evolving patterns of antimalarial drug resistance in Africa. Resistance to aminoquinolines and antifolates is long-standing, yet with greatly decreased use of chloroquine to treat malaria, the prevalence of resistance to chloroquine has decreased. Resistance to antifolates, which are used to prevent malaria in some settings, remains widespread. Resistance to artemisinin-based combination therapies, the standard treatments for malaria in Africa, has emerged in southeast Asia. At present, resistance to artemisinins or key partner drugs included in combination therapies does not appear to be a substantial problem in Africa. However, emergence of resistance to artemisinin-based combination therapies in Africa would probably have devastating consequences, and continued surveillance for the emergence of resistance on this continent is a high priority.

Antimalarial drug resistance in Africa: the calm before the storm?

Background: Plasmodium falciparum infections with slow parasite clearance following artemisinin-based therapies are widespread in the Greater Mekong Subregion. A molecular marker of the slow cleara ...

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Association of mutations in the Plasmodium falciparum Kelch13 gene (Pf3D7_1343700) with parasite clearance rates after artemisinin-based treatments : a WWARN individual patient data meta-analysis

N. V. Hong

Papers

Association of mutations in the Plasmodium falciparum Kelch13 gene (Pf3D7_1343700) with parasite clearance rates after artemisinin-based treatments : a WWARN individual patient data meta-analysis