62 research outputs found
Dihydroartemisinin-piperaquine versus chloroquine to treat vivax malaria in Afghanistan: an open randomized, non-inferiority, trial.
No full textBACKGROUND: Afghanistan's national guidelines recommend chloroquine for the treatment of Plasmodium vivax infection, the parasite responsible for the majority of its malaria burden. Chloroquine resistance in P. vivax is emerging in Asia. Therapeutic responses across Afghanistan have not been evaluated in detail.
METHODS: Between July 2007 and February 2009, an open-label, randomized controlled trial of chloroquine and dihydroartemisinin-piperaquine in patients aged three months and over with slide-confirmed P. vivax mono-infections was conducted. Consistent with current national guidelines, primaquine was not administered. Subjects were followed up daily during the acute phase of illness (days 0-3) and weekly until day 56. The primary endpoint was the overall cumulative parasitological failure rate at day 56 after the start of treatment, with the hypothesis being that dihydroartemisinin-piperaquine was non-inferior compared to chloroquine (Delta = 5% difference in proportion of failures).
RESULTS: Of 2,182 individuals with positive blood films for P. vivax, 536 were enrolled in the trial. The day 28 cure rate was 100% in both treatment groups. Parasite clearance was more rapid with dihydroartemisinin-piperaquine than chloroquine. At day 56, there were more recurrent infections in the chloroquine arm (8.9%, 95% CI 6.0-13.1%) than the dihydroartemisinin-piperaquine arm (2.8%, 95% CI 1.4-5.8%), a difference in cumulative recurrence rate of 6.1% (2-sided 90%CI +2.6 to +9.7%). The log-rank test comparing the survival curves confirmed the superiority of dihydroartemisinin-piperaquine over chloroquine (p = 0.003). Multivariate analysis showed that a lower initial haemoglobin concentration was also independently associated with recurrence. Both regimens were well tolerated and no serious adverse events were reported.
CONCLUSIONS: Chloroquine remains an efficacious treatment for the treatment of vivax malaria in Afghanistan. In a setting where radical therapy cannot be administered, dihydroartemisinin-piperaquine provides additional benefit in terms of post-treatment prophylaxis, reducing the incidence of recurrence from 4-8 weeks after treatment
Polymorphisms in Plasmodium vivax antifolate resistance markers in Afghanistan between 2007 and 2017
No full textBACKGROUND:Plasmodium vivax is the predominant Plasmodium species in Afghanistan. National guidelines recommend the combination of chloroquine and primaquine (CQ-PQ) for radical treatment of P. vivax malaria. Artesunate in combination with the antifolates sulfadoxine-pyrimethamine (SP) has been first-line treatment for uncomplicated falciparum malaria until 2016. Although SP has been the recommended treatment for falciparum and not vivax malaria, exposure of the P. vivax parasite population to SP might still have been quite extensive because of community based management of malaria. The change in the P. vivax antifolate resistance markers between 2007 and 2017 were investigated. METHODS:Dried blood spots were collected (n = 185) from confirmed P. vivax patients in five malaria-endemic areas of Afghanistan bordering Tajikistan, Turkmenistan and Pakistan, including Takhar, Faryab, Laghman, Nangarhar, and Kunar, in 2007, 2010 and 2017. Semi-nested PCR, RFLP and nucleotide sequencing were used to assess the pyrimethamine resistant related mutations in P. vivax dihydrofolate reductase (pvdhfr I13L, P33L, N50I, F57L, S58R, T61I, S93H, S117N, I173L) and the sulfonamide resistance related mutations in P. vivax dihydropteroate synthase (pvdhps A383G, A553G). RESULTS:In the 185 samples genotyped for pvdhfr and pvdhps mutations, 11 distinct haplotypes were observed, which evolved over time. In 2007, wild type pvdhfr and pvdhps were the most frequent haplotype in all study sites (81%, 80/99). However, in 2017, the frequency of the wild-type was reduced to 36%, (21/58; p value ≤ 0.001), with an increase in frequency of the double mutant pvdhfr and pvdhps haplotype S58RS117N (21%, 12/58), and the single pvdhfr mutant haplotype S117N (14%, 8/58). Triple and quadruple mutations were not found. In addition, pvdhfr mutations at position N50I (7%, 13/185) and the novel mutation S93H (6%, 11/185) were observed. Based on in silico protein modelling and molecular docking, the pvdhfr N50I mutation is expected to affect only moderately pyrimethamine binding, whereas the S93H mutation does not. CONCLUSIONS:In the course of ten years, there has been a strong increase in the frequency pyrimethamine resistance related mutations in pvdhfr in the P. vivax population in Afghanistan, although triple and quadruple mutations conferring high grade resistance were not observed. This suggests relatively low drug pressure from SP on the P. vivax parasite population in the study areas. The impact of two newly identified mutations in the pvdhfr gene on pyrimethamine resistance needs further investigation
Lancet Infect Dis
No full textBackgroundPrimaquine radical cure is used to treat dormant liver-stage parasites and prevent relapsing Plasmodium vivax malaria but is limited by concerns of haemolysis. We undertook a systematic review and individual patient data meta-analysis to investigate the haematological safety of different primaquine regimens for P vivax radical cure.MethodsFor this systematic review and individual patient data meta-analysis, we searched MEDLINE, Web of Science, Embase, and Cochrane Central for prospective clinical studies of uncomplicated P vivax from endemic countries published between Jan 1, 2000, and June 8, 2023. We included studies if they had active follow-up of at least 28 days, if they included a treatment group with daily primaquine given over multiple days where primaquine was commenced within 3 days of schizontocidal treatment and was given alone or coadministered with chloroquine or one of four artemisinin-based combination therapies (ie, artemether\u2013lumefantrine, artesunate\u2013mefloquine, artesunate\u2013amodiaquine, or dihydroartemisinin\u2013piperaquine), and if they recorded haemoglobin or haematocrit concentrations on day 0. We excluded studies if they were on prevention, prophylaxis, or patients with severe malaria, or if data were extracted retrospectively from medical records outside of a planned trial. For the meta-analysis, we contacted the investigators of eligible trials to request individual patient data and we then pooled data that were made available by Aug 23, 2021. The main outcome was haemoglobin reduction of more than 25% to a concentration of less than 7 g/dL by day 14. Haemoglobin concentration changes between day 0 and days 2\u20133 and between day 0 and days 5\u20137 were assessed by mixed-effects linear regression for patients with glucose-6-phosphate dehydrogenase (G6PD) activity of (1) 30% or higher and (2) between 30% and less than 70%. The study was registered with PROSPERO, CRD42019154470 and CRD42022303680.FindingsOf 226 identified studies, 18 studies with patient-level data from 5462 patients from 15 countries were included in the analysis. A haemoglobin reduction of more than 25% to a concentration of less than 7 g/dL occurred in one (0\ub71%) of 1208 patients treated without primaquine, none of 893 patients treated with a low daily dose of primaquine (<0\ub7375 mg/kg per day), five (0\ub73%) of 1464 patients treated with an intermediate daily dose (0\ub7375 mg/kg per day to <0\ub775 mg/kg per day), and six (0\ub75%) of 1269 patients treated with a high daily dose ( 650\ub775 mg/kg per day). The covariate-adjusted mean estimated haemoglobin changes at days 2\u20133 were 120\ub76 g/dL (95% CI 120\ub77 to 120\ub75), 120\ub77 g/dL (\u20130\ub78 to 120\ub75), 120\ub76 g/dL (\u20130\ub77 to 120\ub74), and 120\ub75 g/dL (\u20130\ub77 to 120\ub74), respectively. In 51 patients with G6PD activity between 30% and less than 70%, the adjusted mean haemoglobin concentration on days 2\u20133 decreased as G6PD activity decreased; two patients in this group who were treated with a high daily dose of primaquine had a reduction of more than 25% to a concentration of less than 7 g/dL. 17 of 18 included studies had a low or unclear risk of bias.InterpretationTreatment of patients with G6PD activity of 30% or higher with 0\ub725\u20130\ub75 mg/kg per day primaquine regimens and patients with G6PD activity of 70% or higher with 0\ub725\u20131 mg/kg per day regimens were associated with similar risks of haemolysis to those in patients treated without primaquine, supporting the safe use of primaquine radical cure at these doses.FundingAustralian National Health and Medical Research Council, Bill & Melinda Gates Foundation, and Medicines for Malaria Venture.WT_/Wellcome TrustUnited Kingdom/200909/WT_/Wellcome TrustUnited Kingdom/CC999999/ImCDC/Intramural CDC HHSUnited States
Protective effect of Mediterranean-type glucose-6-phosphate dehydrogenase deficiency against Plasmodium vivax malaria
No full textX-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzymopathy. The severe Mediterranean variant (G6PD Med) found across Europe and Asia is thought to confer protection against malaria, but its effect is unclear. We fitted a Bayesian statistical model to observed G6PD Med allele frequencies in 999 Pashtun patients presenting with acute Plasmodium vivax malaria and 1408 population controls. G6PD Med was associated with reductions in symptomatic P. vivax malaria incidence of 76% (95% credible interval [CI], 58–88) in hemizygous males and homozygous females combined and 55% (95% CI, 38–68) in heterozygous females. Unless there is very large population stratification within the Pashtun (confounding these results), the G6PD Med genotype confers a very large and gene-dose proportional protective effect against acute vivax malaria. The proportion of patients with vivax malaria at risk of haemolysis following 8-aminoquinoline radical cure is substantially overestimated by studies measuring G6PD deficiency prevalence in healthy subjects
A Worldwide Map of Plasmodium falciparum K13-Propeller Polymorphisms
No full textThe authors’ full names and academic degrees are as follows: Didier Ménard, Ph.D., Nimol Khim, Ph.D., Johann Beghain, M.Sc.,
Ayola A. Adegnika, M.D., Ph.D., Mohammad Shafiul-Alam, Ph.D., Olukemi Amodu, Ph.D., Ghulam Rahim-Awab, Ph.D., Céline Barnadas,
Ph.D., Antoine Berry, M.D., Ph.D., Yap Boum, Ph.D., Maria D. Bustos, M.D., Ph.D., Jun Cao, Ph.D., Jun-Hu Chen, Ph.D., Louis
Collet, M.D., Liwang Cui, Ph.D., Garib-Das Thakur, M.D., Alioune Dieye, Pharm.D., Ph.D., Djibrine Djallé, M.Sc., Monique A. Dorkenoo,
M.D., Carole E. Eboumbou-Moukoko, Ph.D., Fe-Esperanza-Caridad J. Espino, M.D., Ph.D., Thierry Fandeur, Ph.D., Maria-Fatima
Ferreira-da-Cruz, Ph.D., Abebe A. Fola, M.Sc., Hans-Peter Fuehrer, Ph.D., Abdillahi M. Hassan, B.Sc., Socrates Herrera, M.D., Bouasy
Hongvanthong, M.D., Sandrine Houzé, M.D., Ph.D., Maman L. Ibrahim, M.V.D., Ph.D., Mohammad Jahirul-Karim, M.B., B.S., Lubin
Jiang, Ph.D., Shigeyuki Kano, M.D., Ph.D., Wasif Ali-Khan, M.B., B.S., Maniphone Khanthavong, M.D., Peter G. Kremsner, M.D.,
Marcus Lacerda, M.D., Ph.D., Rithea Leang, M.D., Mindy Leelawong, Ph.D., Mei Li, Ph.D., Khin Lin, M.D., Jean-Baptiste Mazarati,
Ph.D., Sandie Ménard, M.Sc., Isabelle Morlais, Ph.D., Hypolite Muhindo-Mavoko, M.D., Lise Musset, Pharm.D., Ph.D., Kesara
Na-Bangchang, Ph.D., Michael Nambozi, M.P.H., Karamoko Niaré, Pharm.D., Harald Noedl, M.D., Ph.D., Jean-Bosco Ouédraogo,
M.D., Ph.D., Dylan R. Pillai, M.D., Ph.D., Bruno Pradines, Pharm.D., Ph.D., Bui Quang-Phuc, M.D., Michael Ramharter, M.D.,
D.T.M.H., Milijaona Randrianarivelojosia, Ph.D., Jetsumon Sattabongkot, Ph.D., Abdiqani Sheikh-Omar, M.D., Kigbafori D. Silué, Ph.D., Sodiomon B. Sirima, M.D., Ph.D., Colin Sutherland, Ph.D., M.P.H., Din Syafruddin, M.D., Ph.D., Rachida Tahar, Ph.D., Lin-Hua
Tang, M.D., Ph.D., Offianan A. Touré, Ph.D., Patrick Tshibangu-wa-Tshibangu, M.D., Inès Vigan-Womas, Ph.D., Marian Warsame, M.D.,
Ph.D., Lyndes Wini, M.B., B.S., Sedigheh Zakeri, Ph.D., Saorin Kim, B.S., Rotha Eam, B.S., Laura Berne, M.Sc., Chanra Khean, B.S., Sophy
Chy, B.S., Malen Ken, B.S., Kaknika Loch, B.S., Lydie Canier, M.Sc., Valentine Duru, M.Sc., Eric Legrand, Ph.D., Jean-Christophe Barale,
Ph.D., Barbara Stokes, B.Sc., Judith Straimer, Ph.D., Benoit Witkowski, Ph.D., David A. Fidock, Ph.D., Christophe Rogier, M.D., Ph.D.,
Pascal Ringwald, M.D., Frederic Ariey, M.D., Ph.D., and Odile Mercereau-Puijalon, Ph.D.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ. Brasil.BACKGROUND
Recent gains in reducing the global burden of malaria are threatened by the emergence of
Plasmodium falciparum resistance to artemisinins. The discovery that mutations in portions
of a P. falciparum gene encoding kelch (K13)–propeller domains are the major determinant
of resistance has provided opportunities for monitoring such resistance on a global scale.
METHODS
We analyzed the K13-propeller sequence polymorphism in 14,037 samples collected in
59 countries in which malaria is endemic. Most of the samples (84.5%) were obtained
from patients who were treated at sentinel sites used for nationwide surveillance of
antimalarial resistance. We evaluated the emergence and dissemination of mutations
by haplotyping neighboring loci.
RESULTS
We identified 108 nonsynonymous K13 mutations, which showed marked geographic
disparity in their frequency and distribution. In Asia, 36.5% of the K13 mutations were
distributed within two areas — one in Cambodia, Vietnam, and Laos and the other in
western Thailand, Myanmar, and China — with no overlap. In Africa, we observed a
broad array of rare nonsynonymous mutations that were not associated with delayed
parasite clearance. The gene-edited Dd2 transgenic line with the A578S mutation, which
expresses the most frequently observed African allele, was found to be susceptible to
artemisinin in vitro on a ring-stage survival assay.
CONCLUSIONS
No evidence of artemisinin resistance was found outside Southeast Asia and China,
where resistance-associated K13 mutations were confined. The common African A578S
allele was not associated with clinical or in vitro resistance to artemisinin, and many
African mutations appear to be neutral. (Funded by Institut Pasteur Paris and others
Strong protective effect of Mediterranean type glucose-6-phosphate dehydrogenase deficiency against vivax malaria
No full textA population survey of the glucose-6-phosphate dehydrogenase (G6PD) 563C>T (Mediterranean) mutation in Afghanistan
No full textGlucose-6-phosphate dehydrogenase (G6PD) deficiency is a common inherited enzyme defect and an important problem in areas with Plasmodium vivax infection because of the risk of haemolysis following administration of primaquine to treat the liver forms of the parasite. We undertook a genotypic survey of 713 male individuals across nine provinces of Afghanistan in which malaria is found, four in the north and five in the east. RFLP typing at nucleotide position 563 detected 40 individuals with the Mediterranean mutation 563C>T, an overall prevalence of 5.6%. This varied according to self-reported ethnicity, with prevalence in the Pashtun/Pashai group of 33/369 (8.9%) compared to 7/344 individuals in the rest of the population (2.0%; pT in exon 11, and C93T in intron XI) in a subset of 82 individuals wild-type at C563 revealed a mixture of 3 haplotypes in the background population and was consistent with data from the 1000 Genomes Project and published studies. By comparison individuals with G6PD deficiency showed a highly skewed haplotype distribution, with 95% showing the CT haplotype, a finding consistent with relatively recent appearance and positive selection of the Mediterranean variant in Afghanistan. Overall, the data confirm that the Mediterranean variant of G6PD is common in many ethnic groups in Afghanistan, indicating that screening for G6PD deficiency is required in all individuals before radical treatment of P. vivax with primaquine
PLoS Med
No full textBackgroundArtemisinin-based combination therapy (ACT) is recommended for uncomplicated Plasmodium vivax malaria in areas of emerging chloroquine resistance. We undertook a systematic review and individual patient data meta-analysis to compare the efficacies of dihydroartemisinin-piperaquine (DP) and artemether-lumefantrine (AL) with or without primaquine (PQ) on the risk of recurrent P. vivax.Methods and findingsClinical efficacy studies of uncomplicated P. vivax treated with DP or AL and published between January 1, 2000, and January 31, 2018, were identified by conducting a systematic review registered with the International Prospective Register of Systematic Reviews (PROSPERO): CRD42016053310. Investigators of eligible studies were invited to contribute individual patient data that were pooled using standardised methodology. The effect of mg/kg dose of piperaquine/lumefantrine, ACT administered, and PQ on the rate of P. vivax recurrence between days 7 and 42 after starting treatment were investigated by Cox regression analyses according to an a priori analysis plan. Secondary outcomes were the risk of recurrence assessed on days 28 and 63. Nineteen studies enrolling 2,017 patients were included in the analysis. The risk of recurrent P. vivax at day 42 was significantly higher in the 384 patients treated with AL alone (44.0%, 95% confidence interval [CI] 38.7\u201349.8) compared with the 812 patients treated with DP alone (9.3%, 95% CI 7.1\u201312.2): adjusted hazard ratio (AHR) 12.63 (95% CI 6.40\u201324.92), p < 0.001. The rates of recurrence assessed at days 42 and 63 were associated inversely with the dose of piperaquine: AHRs (95% CI) for every 5-mg/kg increase 0.63 (0.48\u20130.84), p = 0.0013 and 0.83 (0.73\u20130.94), p = 0.0033, respectively. The dose of lumefantrine was not significantly associated with the rate of recurrence (1.07 for every 5-mg/kg increase, 95% CI 0.99\u20131.16, p = 0.0869). In a post hoc analysis, in patients with symptomatic recurrence after AL, the mean haemoglobin increased 0.13 g/dL (95% CI 0.01\u20130.26) for every 5 days that recurrence was delayed, p = 0.0407. Coadministration of PQ reduced substantially the rate of recurrence assessed at day 42 after AL (AHR = 0.20, 95% CI 0.10\u20130.41, p < 0.001) and at day 63 after DP (AHR = 0.08, 95% CI 0.01\u20130.70, p = 0.0233). Results were limited by follow-up of patients to 63 days or less and nonrandomised treatment groups.ConclusionsIn this study, we observed the risk of P. vivax recurrence at day 42 to be significantly lower following treatment with DP compared with AL, reflecting the longer period of post-treatment prophylaxis; this risk was reduced substantially by coadministration with PQ. We found that delaying P. vivax recurrence was associated with a small but significant improvement in haemoglobin. These results highlight the benefits of PQ radical cure and also the provision of blood-stage antimalarial agents with prolonged post-treatment prophylaxis.Why was this study done?What did the researchers do and find?What do these findings mean?2019200909/WT_/Wellcome Trust/United Kingdom31584960PMC67777591023
Automated reporting of primaquine dose efficacy, tolerability and safety for Plasmodium vivax malaria using a systematic review and individual patient data meta-analysis
No full textBackground: The antirelapse efficacy of primaquine is related to the total dose administered, whereas the risks of haemolysis and gastrointestinal intolerance are associated with the daily dose administered. National Malaria Control Programmes require local information on efficacy, tolerability and safety to optimize antimalarial treatment policies for Plasmodium vivax malaria control and elimination efforts. Methods: A living systematic review identified efficacy studies of uncomplicated P. vivax malaria including patients treated with daily primaquine regimens, published since January 1, 2000. Available data were pooled and an R Shiny app was developed to integrate statistical analyses performed using R and Stata that assessed the impact of primaquine mg/kg dose on efficacy, hematological safety and gastrointestinal tolerability. Results: As of January 16, 2025, a total of 9,270 individual patient data records from 41 studies have been collated into the standardized repository. Open-access automated reports were generated for user-selected countries or regions to investigate location specific effects of primaquine dose on efficacy, safety and tolerability. The reports include visual and tabular displays of the outcomes. Conclusions: These automated reports leverage a large database to provide accessible data for national and regional policy makers and researchers to assess the clinical consequences of different primaquine regimens in different endemic settings. The reports will inform local and regional policy decisions and research priorities in vivax-endemic areas
Frequency of 1311C>T/IVSXI C93T haplotypes according to allele at 563C>T (Mediterranean).
No full text<p>*Includes 2 individuals with a novel synonymous 1398C>T mutation.</p
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