43 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
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
Chloroquine–Primaquine versus Chloroquine Alone to Treat Vivax Malaria in Afghanistan: An Open Randomized Superiority Trial
No full textBackground
Afghanistan’s national guidelines recommend primaquine for radical treatment of P. vivax malaria but this is rarely implemented because of concerns over potential hemolysis in patients who have G6PD deficiency.
Methods
Between August 2009 and February 2014, we conducted an open-label, randomized controlled trial of chloroquine (CQ) alone versus chloroquine plus primaquine (0.25mg base/kg/day for 14 days)(CQ+PQ) in patients aged > 6 months with microscopy confirmed P. vivax infection. In the CQ+PQ group G6PD deficiency was excluded by fluorescent spot testing. The primary outcome was P. vivax recurrence assessed by survival analysis.
Results
Of 593 patients enrolled, 570 attended at or after 14 days of follow-up. P. vivax recurrences occurred in 37 (13.1%) of 282 patients in the CQ+PQ arm versus 86 (29.9%) of 288 in the CQ arm . Cox Proportional Hazard Ratio 0.37, 95% CI 0.25 – 0.54) (ITT analysis). Protection against recurrence was greater in the first six months of follow-up (HR 0.082; 95% CI 0.029-0.23) than later (HR 0.65, 95% CI 0.41-1.03). Five of seven patients requiring hospital admission were considered possible cases of PQ-related hemolysis, and PQ was stopped in a further six; however in none of these cases did hemoglobin fall by >2g/dl or to below 7 g/dl.
Conclusions
Primaquine 0.25mg/kg/day for 14 days prevents relapse of P. vivax in Afghanistan. Patient visits during the first week may improve adherence. Implementation will require deployment of point of care phenotypic tests for G6PD deficiency.</p
Clinical trials of artesunate plus sulfadoxine-pyrimethamine for Plasmodium falciparum malaria in Afghanistan: maintained efficacy a decade after introduction
No full textBackground
Combination therapy with artesunate plus sulfadoxine-pyrimethamine (SP) was adopted as recommended treatment for Plasmodium falciparum infection in Afghanistan in 2003.
Methods
A series of prospective clinical studies examining the efficacy of artesunate plus sulfadoxine-pyrimethamine (AS + SP) against P. falciparum were undertaken in sentinel sites in Afghanistan from 2007 to 2014, accompanied by relevant molecular studies. The first study was a randomized trial of AS + SP versus dihydroartemisinin-piperaquine, while two subsequent studies were standard therapeutic efficacy studies of AS + SP.
Results
Three hundred and three patients were enrolled across four provinces in the north and east of the country. Curative efficacy was high in all the trials, with an adequate clinical and parasitological response (ACPR) of more than 95 % in all groups and trial stages. Genotyping for drug-resistance alleles at dhfr indicated fixation of the S108 N mutation and a prevalence of the C59R mutation of approximately 95 % across all sites. Other mutations in dhfr and dhps remained rare or absent entirely, although five isolates from the first trial carried the dhps triple mutant SGEGA haplotype. In the last study undertaken in 2012–2014 the K13 artemisinin resistance marker was examined; only two of 60 successfully sequenced samples carried a K13-propeller mutation.
Conclusions
These data confirm maintained efficacy 10 years after introduction of artesunate plus SP as combination treatment of P. falciparum in Afghanistan. The molecular data indicate that despite a substantial fall in incidence, resistance has not developed to artemisinins, or intensified to the ACT partner drug components.
Trial Registration http://www.clinicaltrials.gov/ct NCT00682578, NCT01115439 and NCT0170719
Lineage-informative microhaplotypes for recurrence classification and spatio-temporal surveillance of Plasmodium vivax malaria parasites
No full textChallenges in classifying recurrent Plasmodium vivax infections constrain surveillance of antimalarial efficacy and transmission. Recurrent infections may arise from activation of dormant liver stages (relapse), blood-stage treatment failure (recrudescence) or reinfection. Molecular inference of familial relatedness (identity-by-descent or IBD) can help resolve the probable origin of recurrences. As whole genome sequencing of P. vivax remains challenging, targeted genotyping methods are needed for scalability. We describe a P. vivax marker discovery framework to identify and select panels of microhaplotypes (multi-allelic markers within small, amplifiable segments of the genome) that can accurately capture IBD. We evaluate panels of 50–250 microhaplotypes discovered in a global set of 615 P. vivax genomes. A candidate global 100-microhaplotype panel exhibits high marker diversity in the Asia-Pacific, Latin America and horn of Africa (median HE = 0.70–0.81) and identifies 89% of the polyclonal infections detected with genome-wide datasets. Data simulations reveal lower error in estimating pairwise IBD using microhaplotypes relative to traditional biallelic SNP barcodes. The candidate global panel also exhibits high accuracy in predicting geographic origin and captures local infection outbreak and bottlenecking events. Our framework is open-source enabling customised microhaplotype discovery and selection, with potential for porting to other species or data resources
Supplementary file for Provider and household costs of Plasmodium vivax malaria episodes: a multi-country comparative analysis of primary trial data
No full textThis file contains the supplementary materials for a publication in the WHO Bulletin with the following abstract.Objective: To determine household and health-care provider costs associated with
Plasmodium vivax infection across a range of endemic settings. Methods: We collected cost data alongside three multicentre clinical trials of P.
vivax treatment in Afghanistan, Brazil, Colombia, Ethiopia, Indonesia, Philippines, Peru,
Thailand and Viet Nam conducted between April 2014 to December 2017. We derived
household costs from trial participant surveys administered at enrolment and again
2 weeks later to determine the costs of treatment and transportation, and the number of
days that patients and their household caregivers were unable to undertake their usual
activities. We determined costs of routine care by health-care providers by micro-costing
the resources used to diagnose and treat P. vivax at the study sites.Findings: The mean total household costs ranged from 8.7 United States dollars
(US 254.7 (SD: 148.4) in Colombia.
Across all countries, productivity losses were the largest household cost component,
resulting in mean indirect costs ranging from US 220.8 (SD:
158.40). The range of health-care provider costs for routine care was US 0.9 to 13.5, consistently lower than the costs of the widely-used
fluorescent spot test (US$ 6.3 to 17.4). Conclusion: An episode of P. vivax malaria results in high costs to households.
The costs of diagnosing and treating P. vivax are important inputs for future cost‒effectiveness analyses to ensure optimal allocation of resources for malaria elimination. </div
Provider and household costs of Plasmodium vivax malaria episodes: A multicountry comparative analysis of primary trial data
No full textObjective: To determine household and health-care provider costs associated with Plasmodium vivax infection across a range of endemic settings.
Methods: We collected cost data alongside three multicentre clinical trials of P. vivax treatment in Afghanistan, Brazil, Colombia, Ethiopia, Indonesia, Philippines, Peru, Thailand and Viet Nam conducted between April 2014 to December 2017. We derived household costs from trial participant surveys administered at enrolment and again 2 weeks later to determine the costs of treatment and transportation, and the number of days that patients and their household caregivers were unable to undertake their usual activities. We determined costs of routine care by health-care providers by micro-costing the resources used to diagnose and treat P. vivax at the study sites.
Findings: The mean total household costs ranged from 8.7 United States dollars (US 254.7 (SD: 148.4) in Colombia. Across all countries, productivity losses were the largest household cost component, resulting in mean indirect costs ranging from US 220.8 (SD: 158.40). The range of health-care provider costs for routine care was US 0.9 to 13.5, consistently lower than the costs of the widely-used fluorescent spot test (US$ 6.3 to 17.4).
Conclusion: An episode of P. vivax malaria results in high costs to households. The costs of diagnosing and treating P. vivax are important inputs for future cost-effectiveness analyses to ensure optimal allocation of resources for malaria elimination
The heterogeneity of symptom reporting across study sites: a secondary analysis of a randomised placebo-controlled multicentre antimalarial trial
No full textAbstract Introduction Symptoms reported following the administration of investigational drugs play an important role in decisions for registration and treatment guidelines. However, symptoms are subjective, and interview methods to quantify them are difficult to standardise. We explored differences in symptom reporting across study sites of a multicentre antimalarial trial, with the aim of informing trial design and the interpretation of safety and tolerability data. Methods Data were derived from the IMPROV trial, a randomised, placebo-controlled double blinded trial of high dose primaquine to prevent Plasmodium vivax recurrence conducted in eight study sites in Afghanistan, Ethiopia, Indonesia and Vietnam. At each follow up visit a 13-point symptom questionnaire was completed. The number and percentage of patients with clinically relevant symptoms following the administration of primaquine or placebo, were reported by study site including vomiting, diarrhoea, anorexia, nausea, abdominal pain and dizziness. Multivariable logistic regression was used to estimate the confounder-adjusted site-specific proportion of each symptom. Results A total of 2,336 patients were included. The greatest variation between sites in the proportion of patients reporting symptoms was for anorexia between day 0 and day 13: 97.3% (361/371) of patients in Arba Minch, Ethiopia, reported the symptom compared with 4.7% (5/106) of patients in Krong Pa, Vietnam. Differences attenuated slightly after adjusting for treatment arm, age, sex, day 0 parasite density and fever; with the adjusted proportion for anorexia ranging from 4.8% to 97.0%. Differences between sites were greater for symptoms graded as mild or moderate compared to those rated as severe. Differences in symptom reporting were greater between study sites than between treatment arms within the same study site. Conclusion Despite standardised training, there was large variation in symptom reporting across trial sites. The reporting of severe symptoms was less skewed compared to mild and moderate symptoms, which are likely to be more subjective. Trialists should clearly distinguish between safety and tolerability outcomes. Differences between trial arms were much less variable across sites, suggesting that the relative difference in reported symptoms between intervention and control group is more relevant than absolute numbers and should be reported when possible. Trial registration Clinicaltrials.gov: NCT01814683; March 20th, 2013
Weekly primaquine for radical cure of patients with Plasmodium vivax malaria and glucose-6-phosphate dehydrogenase deficiency
No full textBackground
The World Health Organization recommends that primaquine should be given once weekly for 8-weeks to patients with Plasmodium vivax malaria and glucose-6-phosphate dehydrogenase (G6PD) deficiency, but data on its antirelapse efficacy and safety are limited.
Methods
Within the context of a multicentre, randomised clinical trial of two primaquine regimens in P. vivax malaria, patients with G6PD deficiency were excluded and enrolled into a separate 12-month observational study. They were treated with a weekly dose of 0.75 mg/kg primaquine for 8 weeks (PQ8W) plus dihydroartemisinin piperaquine (Indonesia) or chloroquine (Afghanistan, Ethiopia, Vietnam). G6PD status was diagnosed using the fluorescent spot test and confirmed by genotyping for locally prevalent G6PD variants. The risk of P. vivax recurrence following PQ8W and the consequent haematological recovery were characterized in all patients and in patients with genotypically confirmed G6PD variants, and compared with the patients enrolled in the main randomised control trial.
Results
Between July 2014 and November 2017, 42 male and 8 female patients were enrolled in Afghanistan (6), Ethiopia (5), Indonesia (19), and Vietnam (20). G6PD deficiency was confirmed by genotyping in 31 patients: Viangchan (14), Mediterranean (4), 357A-G (3), Canton (2), Kaiping (2), and one each for A-, Chatham, Gaohe, Ludhiana, Orissa, and Vanua Lava. Two patients had recurrent P. vivax parasitaemia (days 68 and 207). The overall 12-month cumulative risk of recurrent P. vivax malaria was 5.1% (95% CI: 1.3–18.9) and the incidence rate of recurrence was 46.8 per 1000 person-years (95% CI: 11.7–187.1). The risk of P. vivax recurrence was lower in G6PD deficient patients treated with PQ8W compared to G6PD normal patients in all treatment arms of the randomised controlled trial. Two of the 26 confirmed hemizygous males had a significant fall in haemoglobin (>5g/dl) after the first dose but were able to complete their 8 week regimen.
Conclusions
PQ8W was highly effective in preventing P. vivax recurrences. Whilst PQ8W was well tolerated in most patients across a range of different G6PD variants, significant falls in haemoglobin may occur after the first dose and require clinical monitoring.
Trial registration
This trial is registered at ClinicalTrials.gov (NCT01814683)
Microhaplotype deep sequencing assays to capture Plasmodium vivax infection lineages
No full textPlasmodium vivax elimination is challenged by dormant liver stages (hypnozoites) that can reactivate months after initial infection resulting in relapses. Relapsing infections confound antimalarial clinical efficacy trials due to the inability to distinguish between recurrences arising from blood-stage treatment failure (recrudescence), reinfection or relapse. Genetic relatedness of paired parasite isolates, measured by identity-by-descent (IBD), can provide important information on whether individuals have had single or multiple mosquito inoculations, thus informing on recurrence origin. We developed a high-throughput amplicon sequencing assay comprising 93 multi-SNP (microhaplotype) markers to determine IBD between P. vivax clinical isolates. The assay was evaluated in 745 global infections, including 128 infection pairs from a randomized controlled trial (RCT) (ClinicalTrials.gov NCT01680406). Simulations demonstrate low error in pairwise IBD estimation at the panel (RMSE < 0.12) and IBD-based networks illustrate strong clustering by geography. IBD analysis in the RCT demonstrates a lower frequency of suspected relapses or recrudescence in patients treated with primaquine compared to those without primaquine; the impact is greater when paired with chloroquine than with artemether-lumefantrine. Our results demonstrate the potential to derive new information on P. vivax treatment and transmission using IBD generated by amplicon sequencing data that can be further improved with time-to-event models
