The risk of Plasmodium vivax parasitaemia after P. falciparum malaria: An individual patient data meta-analysis from the WorldWide Antimalarial Resistance Network.

BACKGROUND: There is a high risk of Plasmodium vivax parasitaemia following treatment of falciparum malaria. Our study aimed to quantify this risk and the associated determinants using an individual patient data meta-analysis in order to identify populations in which a policy of universal radical cure, combining artemisinin-based combination therapy (ACT) with a hypnozoitocidal antimalarial drug, would be beneficial. METHODS AND FINDINGS: A systematic review of Medline, Embase, Web of Science, and the Cochrane Database of Systematic Reviews identified efficacy studies of uncomplicated falciparum malaria treated with ACT that were undertaken in regions coendemic for P. vivax between 1 January 1960 and 5 January 2018. Data from eligible studies were pooled using standardised methodology. The risk of P. vivax parasitaemia at days 42 and 63 and associated risk factors were investigated by multivariable Cox regression analyses. Study quality was assessed using a tool developed by the Joanna Briggs Institute. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42018097400). In total, 42 studies enrolling 15,341 patients were included in the analysis, including 30 randomised controlled trials and 12 cohort studies. Overall, 14,146 (92.2%) patients had P. falciparum monoinfection and 1,195 (7.8%) mixed infection with P. falciparum and P. vivax. The median age was 17.0 years (interquartile range [IQR] = 9.0-29.0 years; range = 0-80 years), with 1,584 (10.3%) patients younger than 5 years. 2,711 (17.7%) patients were treated with artemether-lumefantrine (AL, 13 studies), 651 (4.2%) with artesunate-amodiaquine (AA, 6 studies), 7,340 (47.8%) with artesunate-mefloquine (AM, 25 studies), and 4,639 (30.2%) with dihydroartemisinin-piperaquine (DP, 16 studies). 14,537 patients (94.8%) were enrolled from the Asia-Pacific region, 684 (4.5%) from the Americas, and 120 (0.8%) from Africa. At day 42, the cumulative risk of vivax parasitaemia following treatment of P. falciparum was 31.1% (95% CI 28.9-33.4) after AL, 14.1% (95% CI 10.8-18.3) after AA, 7.4% (95% CI 6.7-8.1) after AM, and 4.5% (95% CI 3.9-5.3) after DP. By day 63, the risks had risen to 39.9% (95% CI 36.6-43.3), 42.4% (95% CI 34.7-51.2), 22.8% (95% CI 21.2-24.4), and 12.8% (95% CI 11.4-14.5), respectively. In multivariable analyses, the highest rate of P. vivax parasitaemia over 42 days of follow-up was in patients residing in areas of short relapse periodicity (adjusted hazard ratio [AHR] = 6.2, 95% CI 2.0-19.5; p = 0.002); patients treated with AL (AHR = 6.2, 95% CI 4.6-8.5; p < 0.001), AA (AHR = 2.3, 95% CI 1.4-3.7; p = 0.001), or AM (AHR = 1.4, 95% CI 1.0-1.9; p = 0.028) compared with DP; and patients who did not clear their initial parasitaemia within 2 days (AHR = 1.8, 95% CI 1.4-2.3; p < 0.001). The analysis was limited by heterogeneity between study populations and lack of data from very low transmission settings. Study quality was high. CONCLUSIONS: In this meta-analysis, we found a high risk of P. vivax parasitaemia after treatment of P. falciparum malaria that varied significantly between studies. These P. vivax infections are likely attributable to relapses that could be prevented with radical cure including a hypnozoitocidal agent; however, the benefits of such a novel strategy will vary considerably between geographical areas

Pf7: an open dataset of Plasmodium falciparum genome variation in 20,000 worldwide samples

We describe the MalariaGEN Pf7 data resource, the seventh release of Plasmodium falciparum genome variation data from the MalariaGEN network.  It comprises over 20,000 samples from 82 partner studies in 33 countries, including several malaria endemic regions that were previously underrepresented.  For the first time we include dried blood spot samples that were sequenced after selective whole genome amplification, necessitating new methods to genotype copy number variations.  We identify a large number of newly emerging crt mutations in parts of Southeast Asia, and show examples of heterogeneities in patterns of drug resistance within Africa and within the Indian subcontinent.  We describe the profile of variations in the C-terminal of the csp gene and relate this to the sequence used in the RTS,S and R21 malaria vaccines.  Pf7 provides high-quality data on genotype calls for 6 million SNPs and short indels, analysis of large deletions that cause failure of rapid diagnostic tests, and systematic characterisation of six major drug resistance loci, all of which can be freely downloaded from the MalariaGEN website

New glycosyl-α-aminotetrazole-based catalysts for highly enantioselective aldol reactions

Direct aldol reactions of acetone with aromatic aldehydes have been achieved in high yielding and enantioselective processes using glycosyl-α-aminotetrazoles as a new class of organocatalysts. Computational studies at DFT level have been performed to account for the experimental observations.Peer Reviewe

The prevalence, incidence and prevention of Plasmodium falciparum infections in forest rangers in Bu Gia Map National Park, Binh Phuoc province, Vietnam: a pilot study.

Background Prophylaxis for high-risk populations, such as forest workers, could be one component for malaria elimination in the Greater Mekong Sub-region. A study was conducted to assess the malaria incidence in forest rangers and the feasibility of malaria prophylaxis for rangers sleeping in forest camps. Methods Forest rangers deployed in the Bu Gia Map National Park, Vietnam were invited to participate in the study. Plasmodium infections were cleared using presumptive treatment, irrespective of malaria status, with a 3-day course dihydroartemisinin/piperaquine (DP) and a 14-day course of primaquine. Before returning to the forest, study participants were randomly allocated to a 3-day course of DP or placebo. Fifteen days after returning from their forest deployment the participants were tested for Plasmodium infections using uPCR. Results Prior to treatment, 30 of 150 study participants (20%) were found to be infected with Plasmodium. Seventeen days (median) after enrolment the rangers were randomized to DP or placebo 2 days before returning to forest camps where they stayed between 2 and 20 days (median 9.5 days). One ranger in the DP-prophylaxis arm and one in the placebo arm were found to be infected with Plasmodium falciparum 15 days (median) after returning from the forest. The evaluable P. falciparum isolates had molecular markers indicating resistance to artemisinins (K13-C580Y) and piperaquine (plasmepsin), but none had multiple copies of pfmdr1 associated with mefloquine resistance. Conclusion Anti-malarial prophylaxis in forest rangers is feasible. The findings of the study highlight the threat of multidrug-resistant malaria.</p

Evolution of multidrug resistance in Plasmodium falciparum: A longitudinal study of genetic resistance markers in the Greater Mekong subregion

Increasing resistance in Plasmodium falciparum to artemisinins and their artemisinin combination therapy (ACT) partner drugs jeopardizes effective antimalarial treatment. Resistance is worst in the Greater Mekong subregion. Monitoring genetic markers of resistance can help to guide antimalarial therapy. Markers of resistance to artemisinins (PfKelch mutations), mefloquine (amplification of P. falciparum multidrug resistance-1 [PfMDR1]), and piperaquine (PfPlasmepsin2/3 amplification and specific P. falciparum chloroquine resistance transporter [PfCRT] mutations) were assessed in 6,722 P. falciparum samples from Vietnam, Lao People’s Democratic Republic (PDR), Cambodia, Thailand, and Myanmar between 2007 and 2019. Against a high background prevalence of PfKelch mutations, PfMDR1 and PfPlasmepsin2/3 amplification closely followed regional drug pressures over time. PfPlasmepsin2/3 amplification preceded piperaquine resistance-associated PfCRT mutations in Cambodia and reached a peak prevalence of 23/28 (82%) in 2015. This declined to 57/156 (38%) after first-line treatment was changed from dihydroartemisinin-piperaquine to artesunate-mefloquine (ASMQ) between 2014 and 2017. The frequency of PfMDR1 amplification increased from 0/293 (0%) between 2012 and 2017 to 12/156 (8%) in 2019. Amplification of PfMDR1 and PfPlasmepsin2/3 in the same parasites was extremely rare (4/6,722 [0.06%]) and was dispersed over time. The mechanisms conferring mefloquine and piperaquine resistance may be counterbalancing. This supports the development of ASMQ plus piperaquine as a triple artemisinin combination therapy

Evolution of multidrug resistance in plasmodium falciparum: A longitudinal study of genetic resistance markers in the greater mekong subregion

Increasing resistance in Plasmodium falciparum to artemisinins and their artemisinin combination therapy (ACT) partner drugs jeopardizes effective antimalarial treatment. Resistance is worst in the Greater Mekong subregion. Monitoring genetic markers of resistance can help to guide antimalarial therapy. Markers of resistance to artemisinins (PfKelch mutations), mefloquine (amplification of P. falciparum multidrug resistance-1 [PfMDR1]), and piperaquine (PfPlasmepsin2/3 amplification and specific P. falciparum chloroquine resistance transporter [PfCRT] mutations) were assessed in 6,722 P. falciparum samples from Vietnam, Lao People's Democratic Republic (PDR), Cambodia, Thailand, and Myanmar between 2007 and 2019. Against a high background prevalence of PfKelch mutations, PfMDR1 and PfPlasmepsin2/3 amplification closely followed regional drug pressures over time. PfPlasmepsin2/3 amplification preceded piperaquine resistance- associated PfCRT mutations in Cambodia and reached a peak prevalence of 23/28 (82%) in 2015. This declined to 57/156 (38%) after first-line treatment was changed from dihydroartemisinin-piperaquine to artesunate-mefloquine (ASMQ) between 2014 and 2017. The frequency of PfMDR1 amplification increased from 0/293 (0%) between 2012 and 2017 to 12/156 (8%) in 2019. Amplification of PfMDR1 and PfPlasmepsin2/3 in the same parasites was extremely rare (4/6,722 [0.06%]) and was dispersed over time. The mechanisms conferring mefloquine and piperaquine resistance may be counterbalancing. This supports the development of ASMQ plus piperaquine as a triple artemisinin combination therapy

Artemisinin resistance in the malaria parasite, Plasmodium falciparum, originates from its initial transcriptional response

The emergence and spread of artemisinin-resistant Plasmodium falciparum, first in the Greater Mekong Subregion (GMS), and now in East Africa, is a major threat to global malaria elimination ambitions. To investigate the artemisinin resistance mechanism, transcriptome analysis was conducted of 577 P. falciparum isolates collected in the GMS between 2016–2018. A specific artemisinin resistance-associated transcriptional profile was identified that involves a broad but discrete set of biological functions related to proteotoxic stress, host cytoplasm remodelling, and REDOX metabolism. The artemisinin resistance-associated transcriptional profile evolved from initial transcriptional responses of susceptible parasites to artemisinin. The genetic basis for this adapted response is likely to be complex