Dataset Information

Clinical and molecular surveillance of drug resistant vivax malaria in Myanmar (2009-2016).

ABSTRACT: One of the major challenges for control and elimination of malaria is ongoing spread and emergence of drug resistance. While epidemiology and surveillance of the drug resistance in falciparum malaria is being explored globally, there are few studies on drug resistance vivax malaria.To assess the spread of drug-resistant vivax malaria in Myanmar, a multisite, prospective, longitudinal study with retrospective analysis of previous therapeutic efficacy studies, was conducted. A total of 906 from nine study sites were included in retrospective analysis and 208 from three study sites in prospective study. Uncomplicated vivax mono-infected patients were recruited and monitored with longitudinal follow-up until day 28 after treatment with chloroquine. Amplification and sequence analysis of molecular markers, such as mutations in pvcrt-O, pvmdr1, pvdhps and pvdhfr, were done in day-0 samples in prospective study.Clinical failure cases were found only in Kawthaung, southern Myanmar and western Myanmar sites within 2009-2016. Chloroquine resistance markers, pvcrt-O 'AAG' insertion and pvmdr1 mutation (Y976F) showed higher mutant rate in southern and central Myanmar than western site: 66.7, 72.7 vs 48.3% and 26.7, 17.0 vs 1.7%, respectively. A similar pattern of significantly higher mutant rate of antifolate resistance markers, pvdhps (S382A, K512M, A553G) and pvdhfr (F57L/I, S58R, T61M, S117T/N) were noted.Although clinical failure rate was low, widespread distribution of chloroquine and antifolate resistance molecular makers alert to the emergence and spread of drug resistance vivax malaria in Myanmar. Proper strategy and action plan to eliminate and contain the resistant strain strengthened together with clinical and molecular surveillance on drug resistance vivax is recommended.

SUBMITTER: Nyunt MH

PROVIDER: S-EPMC5353783 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Clinical and molecular surveillance of drug resistant vivax malaria in Myanmar (2009-2016).

Nyunt Myat Htut MH Han Jin-Hee JH Wang Bo B Aye Khin Myo KM Aye Kyin Hla KH Lee Seong-Kyun SK Htut Ye Y Kyaw Myat Phone MP Han Kay Thwe KT Han Eun-Taek ET

Malaria journal 20170316 1

<h4>Background</h4>One of the major challenges for control and elimination of malaria is ongoing spread and emergence of drug resistance. While epidemiology and surveillance of the drug resistance in falciparum malaria is being explored globally, there are few studies on drug resistance vivax malaria.<h4>Methods</h4>To assess the spread of drug-resistant vivax malaria in Myanmar, a multisite, prospective, longitudinal study with retrospective analysis of previous therapeutic efficacy studies, wa ...[more]

PMID: 28298235

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Project description:BackgroundPlasmodium vivax remains the predominant species at the China-Myanmar border, imposing a major challenge to the recent gains in regional malaria elimination. To closely supervise the emerging of drug resistance in this area, we surveyed the variations in genes potentially correlated with drug resistance in P. vivax parasite and the possible drug selection with time.MethodsA total of 235 P. vivax samples were collected from patients suffering uncomplicated malaria at Yingjiang, Tengchong, and Longling counties, and Nabang port in China, Yunnan province, and Laiza sub-township in Myanmar, from 2008 to 2017. Five potential drug resistance genes were amplified utilizing nested-PCR and analyzed, including pvdhfr, pvdhps, pvmdr1, pvcrt-o, and pvk12. The Pearson's Chi-squared test or Fisher's exact test were applied to determine the statistical frequency differences of mutations between categorical data.ResultsThe pvdhfr F57I/L, S58R, T61M and S117T/N presented in 40.6%, 56.7%, 40.1%, and 56.0% of the sequenced P. vivax isolates, and these mutations significantly decreased with years. The haplotype formed by these quadruple mutations predominated in Yingjiang, Tengchong, Longling and Nabang. While a mutation H99S/R (56.6%) dominated in Laiza and increased with time. In pvdhps, the A383G prevailed in 69.2% of the samples, which remained the most prevalent haplotype. However, a significant decrease of its occurrence was also noticed over the time. The S382A/C and A553G existed in 8.4% and 30.8% of the isolates, respectively. In pvmdr1, the mutation Y976F occurred at a low frequency in 5/232 (2.2%), while T958M was fixed and F1076L was approaching fixed (72.4%). The K10 insertion was detected at an occurrence of 33.2% in pvcrt-o, whereas there was no significant difference among the sites or over the time. No mutation was identified in pvk12.ConclusionsMutations related with resistance to antifolate drugs are prevalent in this area, while their frequencies decrease significantly with time, suggestive of increased susceptibility of P. vivax parasite to antifolate drugs. Resistance to chloroquine (CQ) is possibly emerging. However, since the molecular mechanisms underneath CQ resistance is yet to be better understood, close supervision of clinical drug efficiency and continuous function investigation is urgently needed to alarm drug resistance.

Project description:BackgroundIn the Greater Mekong Subregion (GMS), current malaria surveillance strategies rely on a network of village health volunteers (VHVs) reporting the results of rapid diagnostic tests (RDTs), known to miss many asymptomatic infections. Integration of more sensitive diagnostic molecular and serological measures into the VHV network may improve surveillance of residual malaria transmission in hard-to-reach areas in the region and inform targeted interventions and elimination responses. However, data on residual malaria transmission that would be captured by these measures in the VHV-led testing and treatment surveillance network in the GMS is unknown.MethodsA total of 114 VHVs were trained to collect dried blood spots from villagers undergoing routine RDTs as part of VHV-led active and passive case detection from April 2015 to June 2016. Samples were subjected to molecular testing (quantitative polymerase chain reaction [qPCR]) to determine Plasmodium falciparum and P. vivax infection and serological testing (against P. falciparum and P. vivax antigens) to determine exposure to P. falciparum and P. vivax.ResultsOver 15 months, 114 VHVs performed 32,194 RDTs and collected samples for molecular (n = 13,157) and serological (n = 14,128) testing. The prevalence of molecular-detectable P. falciparum and P. vivax infection was 3.2% compared to the 0.16% prevalence of Plasmodium spp. by RDT, highlighting the large burden of infections undetected by standard surveillance. Peaks in anti-P. falciparum, but not P. vivax, merozoite IgG seroprevalence coincided with seasonal P. falciparum transmission peaks, even in those with no molecularly detectable parasites. At the individual level, antibody seropositivity was associated with reduced odds of contemporaneous P. falciparum (OR for PfCSP 0.51 [95%CI 0.35, 0.76], p = 0.001, PfAMA1 0.70 [95%CI 0.52, 0.93], p = 0.01, and PfMSP2 0.81 [95%CI 0.61, 1.08], p = 0.15), but not P. vivax infection (OR PvAMA1 1.02 [95%CI 0.73, 1.43], p = 0.89) indicating a potential role of immunity in protection against molecular-detectable P. falciparum parasitaemia.ConclusionsWe demonstrated that integration and implementation of sample collection for molecular and serological surveillance into networks of VHV servicing hard-to-reach populations in the GMS is feasible, can capture significant levels of ongoing undetected seasonal malaria transmission and has the potential to supplement current routine RDT testing. Improving malaria surveillance by advancing the integration of molecular and serological techniques, through centralised testing approaches or novel point-of-contact tests, will advance progress, and tracking, towards malaria elimination goals in the GMS.

Project description:BACKGROUND:In the Greater Mekong sub-region, Plasmodium vivax has become the predominant species and imposes a major challenge for regional malaria elimination. This study aimed to investigate the variations in genes potentially related to drug resistance in P. vivax populations from the China-Myanmar border area. In addition, this study also wanted to determine whether divergence existed between parasite populations associated with asymptomatic and acute infections. METHODS:A total of 66 P. vivax isolates were obtained from patients with acute malaria who attended clinics at the Laiza area, Kachin State, Myanmar in 2015. In addition, 102 P. vivax isolates associated with asymptomatic infections were identified by screening of volunteers without signs or symptoms from surrounding villages. Slide-positive samples were verified with nested PCR detecting the 18S rRNA gene. Multiclonal infections were further excluded by genotyping at msp-3? and msp-3? genes. Parasite DNA from 60 symptomatic cases and 81 asymptomatic infections was used to amplify and sequence genes potentially associated with drug resistance, including pvmdr1, pvcrt-o, pvdhfr, pvdhps, and pvk12. RESULTS:The pvmdr1 Y976F and F1076L mutations were present in 3/113 (2.7%) and 97/113 (85.5%) P. vivax isolates, respectively. The K10 insertion in pvcrt-o gene was found in 28.2% of the parasites. Four mutations in the two antifolate resistance genes reached relatively high levels of prevalence: pvdhfr S58R (53.4%), S117N/T (50.8%), pvdhps A383G (75.0%), and A553G (36.3%). Haplotypes with wild-type pvmdr1 (976Y/997K/1076F) and quadruple mutations in pvdhfr (13I/57L/58R/61M/99H/117T/173I) were significantly more prevalent in symptomatic than asymptomatic infections, whereas the pvmdr1 mutant haplotype 976Y/997K/1076L was significantly more prevalent in asymptomatic than symptomatic infections. In addition, quadruple mutations at codons 57, 58, 61 and 117 of pvdhfr and double mutations at codons 383 and 553 of pvdhps were found both in asymptomatic and symptomatic infections with similar frequencies. No mutations were found in the pvk12 gene. CONCLUSIONS:Mutations in pvdhfr and pvdhps were prevalent in both symptomatic and asymptomatic P. vivax infections, suggestive of resistance to antifolate drugs. Asymptomatic carriers may act as a silent reservoir sustaining drug-resistant parasite transmission necessitating a rational strategy for malaria elimination in this region.

Project description:BackgroundArtemisinin resistance has been reported in Greater Mekong Sub-region countries, including Myanmar. After discovery of artemisinin resistance marker (K13), molecular surveillance on artemisinin resistance in endemic regions have been conducted. As the migrant population represents a high percentage of malaria cases, molecular surveillance of artemisinin resistance among migrant workers is of great concern.MethodsA cross-sectional survey was conducted in Shwegyin Township, where migrants work in the goldmines. Blood samples were collected from uncomplicated Plasmodium falciparum-infected migrant workers by active and passive cases screening with rapid diagnostic testing (RDT) and microscopy. Amplification and sequence analysis of artemisinin resistance molecular markers, such as k13, pfarps10, pffd, pfmdr2, pfmrp1, pfrad5, and pfcnbp, were carried out and pfmdr1 copy number analysis was conducted by real-time PCR.ResultsAmong the 100 falciparum-infected patients, most were male (90%), of working age (20-40 years) with median parasite density of 11,166 parasites/µL (range 270-110,472 parasites/µL). Artemisinin resistance molecular marker, k13 mutations were detected in (21/100, 21.0%) in which composed of a validated marker, C580Y (9/21, 42.9%) and candidate markers such as P574L (5/21, 23.8%), P667T (5/21, 23.8%) and M476I (2/21, 9.5%). Underlying genetic markers predisposing to become k13 mutants were found as V127M of pfarps10 (41/100, 41.0%), D153Y of pffd (64/100, 64.0%), T484I of pfmdr2 (58/100, 58.0%) and F1390I of pfmrp1 (24/100, 24.0%). The pfmdr1 copy number analysis revealed six copy numbers (1/100, 1.0%), three (2/100, 2.0%), two (8/100, 8.0%) and only one copy number (89/100, 89.0%). Only one sample showed both k13 mutation (P667T) and multiple copy number of pfmdr1.ConclusionsHigh mutant rate of artemisinin resistance markers and relatively high pfmdr1 copy number among isolates collected from migrant goldmine workers alert the importance of containment measures among this target population. Clinical and molecular surveillance of artemisinin resistance among migrants should be scaled up.

Dataset Information

Clinical and molecular surveillance of drug resistant vivax malaria in Myanmar (2009-2016).

Publications

Clinical and molecular surveillance of drug resistant vivax malaria in Myanmar (2009-2016).

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