jueves, 21 de junio de 2018

Ahead of Print -Therapeutic and Transmission-Blocking 
Efficacy of Dihydroartemisinin/Piperaquine and Chloroquine against Plasmodium vivax Malaria, Cambodia - Volume 24, Number 8—August 2018 - Emerging Infectious Disease journal - CDC

Ahead of Print -Therapeutic and Transmission-Blocking 
Efficacy of Dihydroartemisinin/Piperaquine and Chloroquine against Plasmodium vivax Malaria, Cambodia - Volume 24, Number 8—August 2018 - Emerging Infectious Disease journal - CDC

Centers for Disease Control and Prevention. CDC twenty four seven. Saving Lives, Protecting People

Volume 24, Number 8—August 2018

Dispatch

Therapeutic and Transmission-Blocking 
Efficacy of Dihydroartemisinin/Piperaquine and Chloroquine against Plasmodium vivax Malaria, Cambodia

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Jean Popovici, Amelie Vantaux, Lyse Primault, Reingsey Samreth, Eak Por Piv, Sophalai Bin, Saorin Kim, Dysoley Lek, David Serre, and Didier MenardComments to Author 
Author affiliations: Institut Pasteur, Phnom Penh, Cambodia (J. Popovici, A. Vantaux, L. Primault, R. Samreth, E.P. Piv, S. Bin, S. Kim, D. Menard)National Center for Malaria Control, Phnom Penh (D. Lek)University of Maryland School of Medicine, Baltimore, Maryland, USA (D. Serre)Institut Pasteur, Paris, France (D. Menard)

Abstract

We assessed the efficacy of standard 3-day courses of chloroquine and dihydroartemisinin/piperaquine against Plasmodium vivax malaria. Compared with chloroquine, dihydroartemisinin/piperaquine was faster in clearing asexual P. vivax parasites and blocking human-to-mosquito transmission. This drug combination was also more effective in preventing potential recurrences for >2 months.
Plasmodium vivax is the most widespread human malaria parasite. Almost 2.5 billion persons are at risk for infection in >90 countries (1,2). Since the 1950–1960s, Southeast Asia has been the cradle of emergence and spread of P. falciparum antimalarial drug resistance, a major obstacle for malaria control. Over the past decade, control efforts in Cambodia have led to an impressive decrease in malaria burden, with a slower decrease of P. vivax than for P. falciparum (3).
P. vivax resistance to chloroquine has emerged more recently; the first cases were observed in 2009 in Rattanakiri Province in northeastern Cambodia (17.4% treatment failures after 28 days of follow-up), which led to withdrawal of chloroquine and use of dihydroartemisinin/piperaquine (DHA/PPQ) as first-line therapy for uncomplicated P. vivax malaria in 2012 (4). We assessed the efficacy of standard 3-day courses of chloroquine and DHA/PPQ for treating P. vivax malaria, preventing recurrences, and blocking human-to-mosquito transmission.

The Study

We conducted an open-label, randomized, control trial in June–December 2014 in Rattanakiri Province, Cambodia. Febrile patients or patients with a history of fever in the previous 48 h who sought treatment in health facilities and had positive results by rapid diagnostic test (CareStart Malaria HRP2/pLDH Pf/PAN Combo; Access Bio, Inc., Somerset, NJ, USA) for non–P. falciparum malaria were offered participation in the study. Pregnant or lactating woman, and patients with signs of severe malaria, other known illnesses, or inability to provide informed consent were excluded. Patients with P. vivax monoinfection confirmed by PCR were eligible for the study (5).
At enrollment, after we obtained written informed consent, patients were randomized to receive supervised standard 3-day courses of DHA/PPQ (Duo-Cotecxin; Zhejiang Holley Nanhu Pharmaceutical Co., Ltd, Jiaxing, China) or chloroquine (Nivaquine; Sanofi-Aventis, Paris, France). For each participant, medical histories were obtained and clinical and biological examinations performed. We followed-up with patients according to an extended World Health Organization protocol on days 1, 2, 3, 5, and 7 and then weekly until day 63. At each visit, we performed clinical examinations and obtained an axillary temperature and a capillary blood sample.
Malaria parasites were detected by microscopy (Giemsa-stained blood films) and PCR as described (5). Chloroquine resistance was ruled out for patients if no parasites were detected by microscopy on day 28, or in case of recurrence, if the chloroquine blood concentration on the day of recurrence did not exceed >100 ng/mL (6,7). We measured chloroquine blood concentrations by using liquid chromatography–tandem mass spectrometry for 50-μL samples of whole blood.
During January–March 2016, we conducted an additional study at the same site to evaluate the infectivity of P. vivax from blood of symptomatic patients to Anopheles dirus mosquito vectors; we tested pretreatment and posttreatment blood samples by using membrane feeding assays without serum replacement (8). Any febrile patients seeking antimalarial treatment with similar inclusion/exclusion criteria described previously were enrolled in this study.
After we obtained written informed consent, we fed batches of 50 An. dirus mosquitoes with blood collected from these patients on 3 occasions: 1) before the first dose of DHA/PPQ or chloroquine, 2) on the same day at 9:00 pm (i.e., 2–11 h after treatment), and 3) at 24-h posttreatment for patients treated with chloroquine . We performed statistical analyses by using GraphPad Prism 5 (GraphPad, San Diego, CA, USA) and R software (9). Both studies were approved by the Cambodian National Ethic Committee (038 NECHR, 2/24/2014 and 475 NECHR, 12/28/2015).
For the drug comparison study, we enrolled 50 patients (25 in each study arm); in each arm, 5 patients were lost to follow-up during days 2–35. A total of 40 patients (20 in each study arm) were followed up until day 63. Baseline patient characteristics were similar for both patient groups (Table 1). We did not observe any adverse events or early clinical failures. The proportion of patients still parasitemic on days 1 and 2 (detected by microscopy) was lower in for the DHA/PPQ–treated group than for the chloroquine-treated group (Table 2). Medians of the parasite reduction ratio recorded on days 1 and 2 were higher for the DHA/PPQ–treated patient group (Table 2). All patients, regardless their treatment, were microscopically parasite free at day 3.
Thumbnail of Cumulative proportion of patients with nonrecurrent Plasmodium vivax malaria given a 3-day course of DHA/PPQ and chloroquine detected by PCR within 63 days of follow up, Cambodia. *p<0.01, by log-rank test during Kaplan-Meier survival analysis. DHA/PPQ, dihydroartemisinin/piperaquine.
Figure 1. Cumulative proportion of patients with nonrecurrent Plasmodium vivax malaria given a 3-day course of DHA/PPQ and chloroquine detected by PCR within 63 days of follow up, Cambodia. *p<0.01, by log-rank test...
Within 2 months of follow up, there were fewer patients with a recurrence (detected by PCR) in the DHA/PPQ–treated group than in the chloroquine-treated group (odds ratio 0.17, 95% CI 0.05–0.66; p<0.05, by log-rank test, p<0.01 by Kaplan-Meier survival analysis) (Table 2Figure 1). Median time to recurrence after treatments was also delayed in patients given DHA/PPQ (56 days) compared with those patients given chloroquine (49 days) (Table 2). No recurrence occurred before day 28 in either study arm, which is suggestive of relapse or reinfection, rather than recrudescence of drug-resistant parasites (6,7). In the chloroquine-treated group, 12/20 patients with recurrence had a chloroquine blood concentration <100 ng/mL on the day of recurrence (chloroquine + desethyl chloroquine: median 55.6 ng/mL, interquartile range 40.0–61.7 ng/mL); these results excluded likely chloroquine resistance (6,7).
Thumbnail of Transmission-blocking efficacy of allocated antimalarial drug treatment (chloroquine and DHA/PPQ) on human-to-mosquito transmission of Plasmodium vivax, January–March 2016, Cambodia. Each dot represents the parasite transmissibility reduction ratio (i.e., 100 – [proportion of infected mosquitoes fed with blood samples collected at 9:00 pm after the first dose of treatment × 100/proportion of infected mosquitoes fed with blood samples collected at patient enrollment before the first
Figure 2. Transmission-blocking efficacy of allocated antimalarial drug treatment (chloroquine and DHA/PPQ) on human-to-mosquito transmission of Plasmodium vivax, January–March 2016, Cambodia. Each dot represents the parasite transmissibility reduction ratio (i.e., 100 – [proportion...
For the mosquito-to-human transmission study, we enrolled 19 patients (9 given chloroquine and 10 given DHA/PPQ). Baseline patient characteristics were similar in both patient groups, except for day 0 parasitemia and gametocytemia, which were higher for the DHA/PPQ-treated group (Table 1). The proportion of infectious blood from P. vivax–infected patients and median proportion of infected mosquitoes fed on blood collected before the first dose of DHA/PPQ or chloroquine were similar for both patient groups (Table 1). Despite an initial higher day 0 gametocytemia for the DHA/PPQ-treated group, the proportions of infectious P. vivax blood collected at 9:00 pm after the first dose of DHA/PPQ or chloroquine and the median proportion of infected mosquitoes were lower for the DHA/PPQ-treated group than for the chloroquine-treated group (Table 2). Overall, DHA/PPQ acted faster than chloroquine in decreasing over time the proportion of infectious patients (generalized linear mixed model time for drug interaction, χ12 = 113.1, p < 0.0001) (Figure 2). For the group given chloroquine, 2 (22%) of 9 blood samples were still infectious 24 hours after the first dose (Table 2).
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Conclusions

We confirm that DHA/PPQ acts faster (<48 h) than chloroquine (≈72 h) in eliminating sexual and asexual P. vivax parasites and that DHA/PPQ provides an excellent postexposure prophylaxis against potential recurrences for >2 months (11). This benefit relies on the combination of artemisinin derivatives (DHA), which are fast-acting drugs capable of eliminating any P. vivax blood stages, and a long-lasting partner drug (PPQ), which has a long terminal elimination half-life and is highly effective in preventing P. vivax recurrence for up to 56 days. Although the number of patients enrolled was small, we demonstrated that DHA/PPQ also acts faster (<5 h) than chloroquine in killing P. vivax sexual stages and thus prevents the risk for transmission of parasites to the mosquito vector the night after uptake of the first dose. This rapid clearance of gametocytes is a major benefit of DHA/PPQ in comparison with chloroquine, given that P. vivax gametocytes appear early in the course of disease and must be eliminated as soon as possible to limit risk of transmission (12,13).
In summary, our findings support the recommendation of DHA/PPQ as first-line treatment for P. falciparum and P. vivax uncomplicated malaria in regions to which these species are coendemic. These findings apply to areas in which chloroquine is still effective and no P. falciparum resistance to PPQ has been observed.
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Dr. Popovici is a research scientist the Institut Pasteur, Phnom Penh, Cambodia. His primary research interests are a better understanding P. vivax malaria and providing more adapted control solutions to policy makers.
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Acknowledgments

We thank all patients for participating in this study.
This study was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (grant R01 434 A103328) and the Institut Pasteur (grant PTR 2014–490). A.V. was supported by a Calmette and Yersin fellowship from the Institut Pasteur International Network.
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References

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  2. Gething PWElyazar IRMoyes CLSmith DLBattle KEGuerra CAet al. A long neglected world malaria map: Plasmodium vivax endemicity in 2010. PLoS Negl Trop Dis2012;6:e1814DOIPubMed
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  4. Leang RBarrette ABouth DMMenard DAbdur RDuong Set al. Efficacy of dihydroartemisinin-piperaquine for treatment of uncomplicated Plasmodium falciparum and Plasmodium vivaxin Cambodia, 2008 to 2010. Antimicrob Agents Chemother2013;57:81826DOIPubMed
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  7. World Health Organization. Methods for surveillance of antimalarial drug efficacy, 2009 [cited 2018 Mar 27]. http://apps.who.int/iris/handle/10665/44048
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  11. Sinclair DGogtay NBrand FOlliaro PArtemisinin-based combination therapy for treating uncomplicated Plasmodium vivax malaria. Cochrane Database Syst Rev2011; (7):CD008492.PubMed
  12. Sagara IBeavogui AHZongo ISoulama IBorghini-Fuhrer IFofana Bet al. Safety and efficacy of re-treatments with pyronaridine-artesunate in African patients with malaria: a substudy of the WANECAM randomised trial. Lancet Infect Dis2016;16:18998DOIPubMed
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Figures

Tables

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Suggested citation for this article: Popovici J, Vantaux A, Primault L, Samreth R, Piv EP, Sophalai B, et al. Therapeutic and transmission-blocking efficacy of dihydroartemisinin/piperaquine and chloroquine against Plasmodium vivax malaria, Cambodia. Emerg Infect Dis. 2018 Aug [date cited]. https://doi.org/10.3201/eid2408.170768


DOI: 10.3201/eid2408.170768

Ahead of Print -Piperaquine Resistance in Plasmodium falciparum, West Africa - Volume 24, Number 8—August 2018 - Emerging Infectious Disease journal - CDC

Ahead of Print -Piperaquine Resistance in Plasmodium falciparum, West Africa - Volume 24, Number 8—August 2018 - Emerging Infectious Disease journal - CDC

Centers for Disease Control and Prevention. CDC twenty four seven. Saving Lives, Protecting People

Volume 24, Number 8—August 2018

Research Letter

Piperaquine Resistance in Plasmodium falciparum, West Africa

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Juliana Inoue1, Miguel Silva1, Bakary Fofana, Kassim Sanogo, Andreas Mårtensson, Issaka Sagara, Anders Björkman, Maria Isabel Veiga, Pedro Eduardo Ferreira, Abdoulaye Djimde, and José Pedro GilComments to Author 
Author affiliations: Uppsala University, Uppsala, Sweden (J. Inoue, A. Mårtensson, J.P. Gil)University of Minho, Braga, Portugal (M. Silva, M.I. Veiga, P.E. Ferreira)University of Science, Techniques, and Technologies of Bamako, Bamako, Mali (B. Fofana, K. Sanogo, I. Sagara, A. Djimde)Karolinska Institutet, Stockholm, Sweden (A. Björkman, J.P. Gil)Universidade de Lisboa, Lisbon, Portugal (J.P. Gil)

Abstract

Dihydroartemisinin/piperaquine (DHA/PPQ) is increasingly deployed as antimalaria drug in Africa. We report the detection in Mali of Plasmodium falciparum infections carrying plasmepsin 2 duplications (associated with piperaquine resistance) in 7/65 recurrent infections within 2 months after DHA/PPQ treatment. These findings raise concerns about the long-term efficacy of DHA/PPQ treatment in Africa.
Artemisinin combination therapy has been the cornerstone of malaria control in sub-Saharan Africa for the past 10 years and is typically represented by artemether/lumefantrine and artesunate/amodiaquine. Because of the notorious capacities of Plasmodium falciparum to develop drug resistance, many antimalarial programs have recently included dihydroartemisinin/piperaquine (DHA/PPQ) as a second-line antimalarial drug. This decision is sensible, considering the recent reports of substantially decreased artemether/lumefantrine cure rates in some regions, signaling a potential focus of lumefantrine resistance (1).
DHA/PPQ has shown near-perfect efficacy levels in clinical trials conducted in Africa; the combination also has been proposed as a tool for intermittent preventive approaches (2). Unfortunately, full P. falciparum resistance to DHA/PPQ treatment has been reported recently in Cambodia (3,4). These events were directly associated with increased copy number variations (CNVs) in the plasmepsin system, including the pfpm2 gene (PF3D7_1408000) coding for the food vacuole enzyme plasmepsin II, which is speculated to be a major piperaquine target.
CNV is generally considered as emerging at relatively rapid mutation rates (a rate several orders of magnitude higher compared with that of single-nucleotide polymorphisms [5]) and is able to generate substantial diversity (6). Therefore, preexisting pfpm2 duplications in Cambodia might have been rapidly selected by DHA/PPQ, aided by a less effective protective action of the artemisinin derivative (7). Such a scenario suggests that this mutation may already be present in Africa.
To investigate this possibility, we analyzed a subset of archived P. falciparum DNA samples from clinical infections, derived from a set of large, multicenter comparative artemisinin combination therapy efficacy trials conducted in West Africa by the West African Network for Antimalarial Drugs (8). These trials, performed during October 2011–February 2016 in Mali, Burkina Faso, and Guinea, had a randomized double-blind design with a 2-year follow-up for monitoring repeated treatment. Here we focus on the DHA/PPQ trial conducted at the village of Bougoula-Hameau in Mali, located ≈350 km south of the capital city of Bamako, near the border with Burkina Faso. The weekly control follow-up for each episode at Bougoula-Hameau was 63 days, and the DHA/PPQ arm involved a total of 224 patients who were >6 months of age.
Thumbnail of Timeline distribution of Plasmodium falciparum pfpm2 copy number status during post–DHA/PPQ treatment followup for artemisinin combination therapy efficacy trials conducted by the West African Network for Antimalarial Drugs, Mali, Burkina Faso, and Guinea, October 2011–February 2016. Dark gray bar highlights the period (3 d) of treatment; lighter, longer gray bars represent PPQ average half-life (≈20 d). Circles represent recurrent infections; white circles indicate 1 pfpm2 copy, an
Figure. Timeline distribution of Plasmodium falciparum pfpm2 copy number status during post–DHA/PPQ treatment followup for artemisinin combination therapy efficacy trials conducted by the West African Network for Antimalarial Drugs, Mali, Burkina Faso,...
We conducted a pilot study analyzing the 96 recurrent infections associated with the shortest interepisode periods, assuming that this subgroup, among whom initiation of recurrent infection ranged from 23 to 65 days posttreatment (Figure), would be the most likely to include pfpm2 duplications. The study was reviewed and approved by the Ethics Committee of the Faculty of Medicine, Pharmacy, and Odonto-Stomatology, University of Sciences, Techniques and Technology of Bamako.
We determined copy number by using a SYBR-green based quantitative PCR (ThermoFisher Scientific, Waltham, MA, USA) in a protocol modified from the one previously described by Witkowski et al (4). We used the P. falciparum β-tubulin gene as the internal nonduplicated standard and the 3D7 clone as a parallel 1 copy control. We ran the quantitative PCR thermal cycle at 98°C for 3 min, followed by 45 cycles at 98°C for 15 s, 63°C for 20 s, and 72°C for 20 s on a C1000 Thermal Cycler (Bio-Rad, Marnes-la-Coquette, France) with the CFX96 Real-Time System (Bio-Rad) detection system. We executed all procedures in triplicate.
The analysis was conclusive in 65 of the 96 samples. We confirm the presence of 7 infections carrying 2 copies of pfpm2, representing ≈10% of the successfully analyzed infections. We did not identify any trend of earlier recurrence associated with this group of infections (Figure), a preliminarily observation that needs to be further explored in a larger sample set.
Our results clearly show that piperaquine resistance–associated pfpm2 duplications are probably already frequent in Africa, which is of concern given the long half-life of piperaquine (>20 days). In high-transmission areas, this long period of decreasing drug exposure is likely to progressively select less sensitive, potentially pfpm2 CNV–carrying parasites. Parallel studies conducted in these areas have not detected substantial altered parasite clearance dynamics or K13 mutations associated with artemisinin-derivative therapy (9,10), indicating that these pfpm2 duplications are emerging despite the efficacy of dihydroartemisinin. Further studies are urgently needed to clarify the clinical implications of piperaquine resistance and to monitor occurrence in other areas of high malaria transmission in Africa.
Dr. Inoue is a visiting postdoctoral researcher at the University of Uppsala. Her current research interests include malaria drug resistance with an emphasis on artemisinin combination therapy.
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Acknowledgments

We are grateful to Hamadoun Diakite, Sekou Toure, Amadou H. Togo, Sekou Koumare, and the entire WANECAM team of Bougoula-Hameau. We thank the study patients and their parents and legal guardians, the respective communities involved, and the healthcare authorities of Sikasso.
This work was supported by a Swedish Research Council Grant (no. VR-2014–3134). The WANECAM study is funded by the European and Developing Countries Clinical Trial Partnership and by the Medicines for Malaria Venture (Geneva, Switzerland) and is co-funded by the United Kingdom Medical Research Councils, the Swedish International Development Cooperation Agency, the German Ministry for Education and Research, the University Claude Bernard (Lyon, France), the University of Science, Techniques, and Technologies of Bamako (Bamako, Mali), the Centre National de Recherche et de Formation sur le Paludisme (Burkina Faso), the Institut de Recherche en Sciences de la Santé (Bobo-Dioulasso, Burkina Faso), and the Centre National de Formation et de Recherche en Santé Rurale (Guinea).
J.I. was supported by EuroInkaNet/Erasmus Mundus Program. Fundação para a Ciência e Tecnologia supports M.S. (grant no. SFRH/BD/129769/2017), M.I.V. (grant no. SFRH/BPD/76614/2011), and P.E.F. (grant no. IF/00143/2015).
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References

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Figure

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Suggested citation for this article: Inoue J, Silva M, Fofana B, Sanogo K, Mårtensson A, Sagara I, et al. Plasmodium falciparum plasmepsin 2 duplications, West Africa. Emerg Infect Dis. 2018 Aug [date cited]. https://doi.org/10.3201/eid2408.180370
DOI: 10.3201/eid2408.180370


1These authors shared first authorship on this article.