Determinants of dihydro- #artemisinin-piperaquine #treatment #failure in #Plasmodium falciparum #malaria in #Cambodia, #Thailand, and #Vietnam: a prospective clinical, pharmacological, and genetic study (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

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

Rob W van der Pluijm, MD, Prof Mallika Imwong, PhD, Nguyen Hoang Chau, MD, Nhu Thi Hoa, MD, Nguyen Thanh Thuy-Nhien, PhD, Ngo Viet Thanh, MD, et al.

Open Access / Published: July 22, 2019 / DOI: https://doi.org/10.1016/S1473-3099(19)30391-3

 

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-3amplifications 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 plasmepsin2/3amplification 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 crtmutations) 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.

Keywords: Malaria; Plasmodium falciparum; Artemisin; Drugs resistance; Thailand; Cambodia; Laos; Vietnam.

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#Evolution and #expansion of #MDR #malaria in southeast #Asia: a #genomic #epidemiology study (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Evolution and expansion of multidrug-resistant malaria in southeast Asia: a genomic epidemiology study

William L Hamilton, PhD †, Roberto Amato, PhD †, Rob W van der Pluijm, MD, Christopher G Jacob, PhD, Huynh Hong Quang, PhD, Nguyen Thanh Thuy-Nhien, PhD, et al.

Open Access / Published: July 22, 2019 / DOI: https://doi.org/10.1016/S1473-3099(19)30392-5

 

Summary

Background

A multidrug-resistant co-lineage of Plasmodium falciparum malaria, named KEL1/PLA1, spread across Cambodia in 2008–13, causing high rates of treatment failure with the frontline combination therapy dihydroartemisinin-piperaquine. Here, we report on the evolution and spread of KEL1/PLA1 in subsequent years.

Methods

For this genomic epidemiology study, we analysed whole genome sequencing data from P falciparum clinical samples collected from patients with malaria between 2007 and 2018 from Cambodia, Laos, northeastern Thailand, and Vietnam, through the MalariaGEN P falciparum Community Project. Previously unpublished samples were provided by two large-scale multisite projects: the Tracking Artemisinin Resistance Collaboration II (TRAC2) and the Genetic Reconnaissance in the Greater Mekong Subregion (GenRe-Mekong) project. By investigating genome-wide relatedness between parasites, we inferred patterns of shared ancestry in the KEL1/PLA1 population.

Findings

We analysed 1673 whole genome sequences that passed quality filters, and determined KEL1/PLA1 status in 1615. Before 2009, KEL1/PLA1 was only found in western Cambodia; by 2016–17 its prevalence had risen to higher than 50% in all of the surveyed countries except for Laos. In northeastern Thailand and Vietnam, KEL1/PLA1 exceeded 80% of the most recent P falciparum parasites. KEL1/PLA1 parasites maintained high genetic relatedness and low diversity, reflecting a recent common origin. Several subgroups of highly related parasites have recently emerged within this co-lineage, with diverse geographical distributions. The three largest of these subgroups (n=84, n=79, and n=47) mostly emerged since 2016 and were all present in Cambodia, Laos, and Vietnam. These expanding subgroups carried new mutations in the crt gene, which arose on a specific genetic background comprising multiple genomic regions. Four newly emerging crt mutations were rare in the early period and became more prevalent by 2016–17 (Thr93Ser, rising to 19·8%; His97Tyr to 11·2%; Phe145Ile to 5·5%; and Ile218Phe to 11·1%).

Interpretation

After emerging and circulating for several years within Cambodia, the P falciparum KEL1/PLA1 co-lineage diversified into multiple subgroups and acquired new genetic features, including novel crt mutations. These subgroups have rapidly spread into neighbouring countries, suggesting enhanced fitness. These findings highlight the urgent need for elimination of this increasingly drug-resistant parasite co-lineage, and the importance of genetic surveillance in accelerating malaria elimination efforts.

Funding

Wellcome Trust, Bill & Melinda Gates Foundation, UK Medical Research Council, and UK Department for International Development.

Keywords: Malaria; Plasmodium falciparum; Drugs resistance; Artemisin; Cambodia; Laos; Thailand; Vietnam.

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#Molecular characterization of #carbapenem-resistant #Escherichia coli and #Acinetobacter baumannii in the #Lao People’s Democratic Republic (J Antimicrob Chemother., summary)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Molecular characterization of carbapenem-resistant Escherichia coli and Acinetobacter baumannii in the Lao People’s Democratic Republic

Tomas-Paul Cusack, Vilayouth Phimolsarnnousith, Khuanta Duangmala, Phonelavanh Phoumin, Jane Turton, Katie L Hopkins, Neil Woodford, Nandini Shetty, Nicole Stoesser, Hang T T Phan, David A B Dance

Journal of Antimicrobial Chemotherapy, dkz234, https://doi.org/10.1093/jac/dkz234

Published: 05 June 2019

___

Sir,

Global dissemination of carbapenemases among Gram-negative bacteria is a growing public health concern. Therapeutic options for these organisms are often limited, with alternative agents such as tigecycline and colistin having potentially less favourable efficacy and toxicity profiles.1,2 Furthermore, these agents are expensive and not readily available in resource-constrained settings. In the Lao People’s Democratic Republic (Laos), carbapenems are not yet on the national list of essential drugs, although in Vientiane the high prevalence of ESBL-producing Enterobacterales3,4 has driven more widespread use of carbapenems imported by individual pharmacies from neighbouring countries. However, while carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Acinetobacter baumannii(CRAB) have been described in neighbouring Thailand and Vietnam,5 little is known about carbapenem resistance in Laos, where few laboratories perform antimicrobial susceptibility testing (AST) and surveillance networks are not well established.

(…)

___

Funding

The Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU) is core funded by Wellcome (grant number 106698/Z/14/Z). The funding body had no role in: the design of the study; collection, analysis and interpretation of data; and writing of the manuscript. Study-related work at the other sites was supported by internal funding.

Transparency declarations

None to declare.

Keywords: Antibiotics; Drugs Resistance; Carbapenem; Acinetobacter baumannii; E. Coli; Laos.

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#Zika virus in #Vietnam, #Laos, and #Cambodia: are there #health #risks for #travelers? (Eur J Clin Microbiol Infect Dis., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Eur J Clin Microbiol Infect Dis. 2019 May 2. doi: 10.1007/s10096-019-03563-6. [Epub ahead of print]

Zika virus in Vietnam, Laos, and Cambodia: are there health risks for travelers?

Dinh TC1, Bac ND2, Minh LB3, Ngoc VTN4, Pham VH5, Vo HL6, Tien NLB7, Van Thanh V7, Tao Y8, Show PL9, Chu DT10,11.

Author information: 1 Institute for Research and Development, Duy Tan University, 03 QuangTrung, Danang, Vietnam. 2 Vietnam Military Medical University, Hanoi, Vietnam. 3 NTT Hi-tech Institute, Nguyen Tat Thanh University, 300A Nguyen Tat Thanh St., Ward 13, District 4, Ho Chi Minh City, Vietnam. 4 School of Odonto Stomatology, Hanoi Medical University, Hanoi, Vietnam. 5 AI Lab, Faculty of Information Technology, Ton Duc Thang University, Ho Chi Minh City, Vietnam. phamvanhuy@tdtu.edu.vn. 6 Institute for Preventive Medicine & Public Health, Hanoi Medical University, Hanoi, Vietnam. 7 Institute of Orthopaedics and Trauma Surgery, Viet Duc Hospital, Hanoi, Vietnam. 8 College of Food Science and Technology, Nanjing Agricultural University, Nanjing 8, 210095, China. 9 Department of Chemical and Environmental Engineering, Faculty of Engineering, University of Nottingham Malaysia Campus, JalanBroga, 43500, Semenyih, Selangor Darul Ehsan, Malaysia. 10 School of Odonto Stomatology, Hanoi Medical University, Hanoi, Vietnam. chudinhtoi.hnue@gmail.com. 11 Faculty of Biology, Hanoi National University of Education, Hanoi, Vietnam. chudinhtoi.hnue@gmail.com.

 

Abstract

Vietnam, Laos, and Cambodia have reported first cases of Zika virus (ZIKV) infection since 2010 (Cambodia) and 2016 (Vietnam and Laos). One case of ZIKV-related microcephaly was recognized among a hundred infected cases in these areas, raising a great concern about the health risk related to this virus infection. At least 5 cases of ZIKV infection among travelers to Vietnam, Laos, and Cambodia were recorded. It is noticeable that ZIKV in these areas can cause birth defects. This work aims to discuss the current epidemics of ZIKV in Vietnam, Laos, and Cambodia and update the infection risk of ZIKV for travelers to these areas.

KEYWORDS: Cambodia; Laos; Travelers; Vietnam; Zika virus infection; Zika virus–infected travelers

PMID: 31044332 DOI: 10.1007/s10096-019-03563-6

Keywords: Zika Virus; Vietnam; Laos; Cambodia.

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A random #survey of the #prevalence of #falsified and substandard #antibiotics in the #Lao PDR (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

A random survey of the prevalence of falsified and substandard antibiotics in the Lao PDR

Patricia Tabernero, Isabel Swamidoss, Mayfong Mayxay, Maniphone Khanthavong, Chindaphone Phonlavong, Chanthala Vilayhong, Sengchanh Yeuchaixiong, Chanvilay Sichanh, Sivong Sengaloundeth, Michael D Green, Paul N Newton

Journal of Antimicrobial Chemotherapy, dkz164, https://doi.org/10.1093/jac/dkz164

Published: 02 May 2019

 

Abstract

Objectives

In 2012, a stratified random survey, using mystery shoppers, was conducted to investigate the availability and quality of antibiotics sold to patients in the private sector in five southern provinces of the Lao People’s Democratic Republic (Laos).

Methods

A total of 147 outlets were sampled in 10 districts. The active pharmaceutical ingredient (API) content measurements for 909 samples, including nine APIs (amoxicillin, ampicillin, ceftriaxone, ciprofloxacin, doxycycline, ofloxacin, sulfamethoxazole, tetracycline and trimethoprim), were determined using HPLC.

Results

All the analysed samples contained the stated API and we found no evidence for falsification. All except one sample had all the units tested with %API values between 75% and 125% of the content stated on the label. However, we identified the presence of substandard antibiotics: 19.6% (201/1025) of samples had their units outside the 90%–110% content of the label claim and 60.2% (617/1025) of the samples had units outside of the International Pharmacopoeia uniformity of content limit range. Amoxicillin had a high number of samples [67.1% (151)] with units above the limit range, followed by ciprofloxacin [58.8% (10)] and ofloxacin [57.4% (39)]. Ceftriaxone, trimethoprim and sulfamethoxazole had the highest number of samples with low API content: 57.1% (4), 51.6% (64) and 34.7% (43), respectively. Significant differences in %API were found between stated countries of manufacture and stated manufacturers.

Conclusions

With the global threat of antimicrobial resistance to patient outcomes, greater understanding of the role of poor-quality antibiotics is needed. Substandard antibiotics will have reduced therapeutic efficacy, impacting public health and control of bacterial infections.

Issue Section: ORIGINAL RESEARCH

Keywords: Antibiotics; Drugs Resistance; Laos.

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Low #Zika Virus #Seroprevalence in Vientiane, #Laos, 2003-2015 (Am J Trop Med Hyg., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Am J Trop Med Hyg. 2019 Jan 28. doi: 10.4269/ajtmh.18-0439. [Epub ahead of print]

Low Zika Virus Seroprevalence in Vientiane, Laos, 2003-2015.

Pastorino B1, Sengvilaipaseuth O2, Chanthongthip A2, Vongsouvath M2, Souksakhone C3, Mayxay M4,5,2, Thirion L1, Newton PN4,2, de Lamballerie X1, Dubot-Pérès A2,1,4.

Author information: 1 Unité des Virus Émergents (UVE: Aix-Marseille Univ-IRD 190-Inserm 1207-IHU Méditerranée Infection), Marseille, France. 2 Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), Microbiology Laboratory, Mahosot Hospital, Vientiane, Lao PDR. 3 National Blood Transfusion Centre, Lao Red Cross, Vientiane, Lao PDR. 4 Nuffield Department of Clinical Medicine, Centre for Tropical Medicine and Global Health, Churchill Hospital, University of Oxford, Oxford, United Kingdom. 5 Institute of Research and Education Development, University of Health Sciences, Vientiane, Lao PDR.

 

Abstract

Zika virus (ZIKV) has been presumed to be endemic in Southeast Asia (SEA), with a low rate of human infections. Although the first ZIKV evidence was obtained in the 1950s through serosurveys, the first laboratory-confirmed case was only detected in 2010 in Cambodia. The epidemiology of ZIKV in SEA remains uncertain because of the scarcity of available data. From 2016, subsequent to the large outbreaks in the Pacific and Latin America, several Asian countries started reporting increasing numbers of confirmed ZIKV patients, but no global epidemiological assessment is available to date. Here, with the aim of providing information on ZIKV circulation and population immunity, we conducted a seroprevalence study among blood donors in Vientiane, Laos. Sera from 359 asymptomatic consenting adult donors in 2003-2004 and 687 in 2015 were screened for anti-ZIKV IgG using NS1 ELISA assay (Euroimmun, Germany). Positive and equivocal samples were confirmed for anti-ZIKV-neutralizing antibodies by virus neutralization tests. Our findings suggest that ZIKV has been circulating in Vientiane over at least the last decade. Zika virus seroprevalence observed in the studied blood donors was low, 4.5% in 2003-2004 with an increase in 2015 to 9.9% (P = 0.002), possibly reflecting the increase of ZIKV incident cases reported over this period. We did not observe any significant difference in seroprevalence according to gender. With a low herd immunity in the Vientiane population, ZIKV represents a risk for future large-scale outbreaks. Implementation of a nationwide ZIKV surveillance network and epidemiological studies throughout the country is needed.

PMID: 30693859 DOI: 10.4269/ajtmh.18-0439

Keywords: Zika Virus; Seroprevalence; Laos.

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#Antiviral Drug– #Resistant #Influenza B Viruses Carrying H134N Substitution in #Neuraminidase, #Laos, February 2016 (@CDC_EIDjournal, abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 23, Number 4—April 2017 / Dispatch

Antiviral Drug–Resistant Influenza B Viruses Carrying H134N Substitution in Neuraminidase, Laos, February 2016

Tatiana Baranovich, Phengta Vongphrachanh, Pakapak Ketmayoon, Thongchanh Sisouk, Khampheng Chomlasack, Viengphone Khanthamaly, Ha Thuy Nguyen, Vasiliy P. Mishin, Henju Marjuki, John R. Barnes, Rebecca J. Garten, James Stevens, David E. Wentworth, and Larisa V. Gubareva

Author affiliations: Carter Consulting, Inc., Atlanta, Georgia, USA (T. Baranovich); World Health Organization Collaborating Center for Surveillance, Epidemiology and Control of Influenza, Atlanta (T. Baranovich, V. Khanthamaly, H.T. Nguyen, V.P. Mishin, H. Marjuki, J.R. Barnes, R.J. Garten, J. Stevens, D.E. Wentworth, L.V. Gubareva); Centers for Disease Control and Prevention, Atlanta (T. Baranovich, V. Khanthamaly, H.T. Nguyen, V.P. Mishin, H. Marjuki, J.R. Barnes, R.J. Garten, J. Stevens, D.E. Wentworth, L.V. Gubareva); National Center for Laboratory and Epidemiology, Vientiane, Laos (P. Vongphrachanh, P. Ketmayoon, T. Sisouk, K. Chomlasack); World Health Organization Emerging Disease Surveillance and Response Unit, Vientiane, Laos (P. Ketmayoon); Battelle Memorial Institute, Atlanta (H.T. Nguyen)

 

Abstract

In February 2016, three influenza B/Victoria/2/87 lineage viruses exhibiting 4- to 158-fold reduced inhibition by neuraminidase inhibitors were detected in Laos. These viruses had an H134N substitution in the neuraminidase and replicated efficiently in vitro and in ferrets. Current antiviral drugs may be ineffective in controlling infections caused by viruses harboring this mutation.

Keywords: Seasonal Influenza; Influenza B, Antivirals; Drugs Resistance; Laos; Oseltamivir.

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