Dataset Information

Molecular Evidence of Drug-Resistant Tuberculosis in the Balimo Region of Papua New Guinea.

ABSTRACT: Papua New Guinea (PNG) has a high burden of tuberculosis (TB), including drug-resistant TB (DR-TB). DR-TB has been identified in patients in Western Province, although there has been limited study outside the provincial capital of Daru. This study focuses on the Balimo region of Western Province, aiming to identify the proportion of DR-TB, and characterise Mycobacterium tuberculosis (MTB) drug resistance-associated gene mutations. Sputum samples were investigated for MTB infection using published molecular methods. DNA from MTB-positive samples was amplified and sequenced, targeting the rpoB and katG genes to identify mutations associated with rifampicin and isoniazid resistance respectively. A total of 240 sputum samples were collected at Balimo District Hospital (BDH). Of these, 86 were classified as positive based on the results of the molecular assays. For samples where rpoB sequencing was successful, 10.0% (5/50, 95% CI 4.4?21.4%) were considered rifampicin-resistant through detection of drug resistance-associated mutations. We have identified high rates of presumptive DR-TB in the Balimo region of Western Province, PNG. These results emphasise the importance of further surveillance, and strengthening of diagnostic and treatment services at BDH and throughout Western Province, to facilitate detection and treatment of DR-TB, and limit transmission in this setting.

SUBMITTER: Diefenbach-Elstob T

PROVIDER: S-EPMC6473227 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Molecular Evidence of Drug-Resistant Tuberculosis in the Balimo Region of Papua New Guinea.

Diefenbach-Elstob Tanya T Guernier Vanina V Burgess Graham G Pelowa Daniel D Dowi Robert R Gula Bisato B Puri Munish M Pomat William W McBryde Emma E Plummer David D Rush Catherine C Warner Jeffrey J

Tropical medicine and infectious disease 20190210 1

Papua New Guinea (PNG) has a high burden of tuberculosis (TB), including drug-resistant TB (DR-TB). DR-TB has been identified in patients in Western Province, although there has been limited study outside the provincial capital of Daru. This study focuses on the Balimo region of Western Province, aiming to identify the proportion of DR-TB, and characterise <i>Mycobacterium tuberculosis</i> (MTB) drug resistance-associated gene mutations. Sputum samples were investigated for MTB infection using p ...[more]

PMID: 30744192

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Project description:BackgroundMolecular mechanisms determining the transmission and prevalence of drug resistant tuberculosis (DR-TB) in Papua New Guinea (PNG) are poorly understood. We used genomic and drug susceptibility data to explore the evolutionary history, temporal acquisition of resistance and transmission dynamics of DR-TB across PNG.MethodsWe performed whole genome sequencing on isolates from Central Public Health Laboratory, PNG, collected 2017-2019. Data analysis was done on a composite dataset that also included 100 genomes previously sequenced from Daru, PNG (2012-2015).ResultsSampled isolates represented 14 of the 22 PNG provinces, the majority (66/94; 70%) came from the National Capital District (NCD). In the composite dataset, 91% of strains were Beijing 2.2.1.1, identified in 13 provinces. Phylogenetic tree of Beijing strains revealed two clades, Daru dominant clade (A) and NCD dominant clade (B). Multi-drug resistance (MDR) was repeatedly and independently acquired, with the first MDR cases in both clades noted to have emerged in the early 1990s, while fluoroquinolone resistance emerged in 2009 (95% highest posterior density 2000-2016). We identified the presence of a frameshift mutation within Rv0678 (p.Asp47fs) which has been suggested to confer resistance to bedaquiline, despite no known exposure to the drug. Overall genomic clustering was significantly associated with rpoC compensatory and inhA promoter mutations (p < 0.001), with high percentage of most genomic clusters (12/14) identified in NCD, reflecting its role as a potential national amplifier.ConclusionsThe acquisition and evolution of drug resistance among the major clades of Beijing strain threaten the success of DR-TB treatment in PNG. With continued transmission of this strain in PNG, genotypic drug resistance surveillance using whole genome sequencing is essential for improved public health response to outbreaks. With occurrence of resistance to newer drugs such as bedaquiline, knowledge of full drug resistance profiles will be important for optimal treatment selection.

Project description:BackgroundPolymorphism in the pfcrt gene underlies Plasmodium falciparum chloroquine resistance (CQR), as sensitive strains consistently carry lysine (K), while CQR strains carry threonine (T) at the codon 76. Previous studies have shown that microsatellite (MS) haplotype variation can be used to study the evolution of CQR polymorphism and to characterize intra- and inter-population dispersal of CQR in Papua New Guinea (PNG).MethodsHere, following identification of new polymorphic MS in introns 2 and 3 within the pfcrt gene (msint2 and msint3, respectively), locus-by-locus and haplotype heterozygosity (H) analyses were performed to determine the distribution of this intronic polymorphism among pfcrt chloroquine-sensitive and CQR alleles.ResultsFor MS flanking the pfcrt CQR allele, H ranged from 0.07 (B5M77, -18 kb) to 0.094 (9B12, +2 kb) suggesting that CQ selection pressure was responsible for strong homogenisation of this gene locus. In a survey of 206 pfcrt-SVMNT allele-containing field samples from malaria-endemic regions of PNG, H for msint2 was 0.201. This observation suggests that pfcrt msint2 exhibits a higher level of diversity than what is expected from the analyses of pfcrt flanking MS. Further analyses showed that one of the three haplotypes present in the early 1980's samples has become the predominant haplotype (frequency = 0.901) in CQR parasite populations collected after 1995 from three PNG sites, when CQR had spread throughout malaria-endemic regions of PNG. Apparent localized diversification of pfcrt haplotypes at each site was also observed among samples collected after 1995, where minor CQR-associated haplotypes were found to be unique to each site.ConclusionIn this study, a higher level of diversity at MS loci within the pfcrt gene was observed when compared with the level of diversity at pfcrt flanking MS. While pfcrt (K76T) and its immediate flanking region indicate homogenisation in PNG CQR parasite populations, pfcrt intronic MS variation provides evidence that the locus is still evolving. Further studies are needed to determine whether these intronic MS introduce the underlying genetic mechanisms that may generate pfcrt allelic diversity.

Dataset Information

Molecular Evidence of Drug-Resistant Tuberculosis in the Balimo Region of Papua New Guinea.

Publications

Molecular Evidence of Drug-Resistant Tuberculosis in the Balimo Region of Papua New Guinea.

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