Project

Back to overview

Tuberculosis epidemiology in Papua New Guinea and drug resistance monitoring using molecular markers

Applicant Beck Hans-Peter
Number 123988
Funding scheme Resource not found: 'bd31932a-e257-46d9-9dba-079f6f2c77c6'
Research institution Swiss Tropical and Public Health Institute
Institution of higher education University of Basel - BS
Main discipline Medical Microbiology
Start/End 01.03.2009 - 31.10.2012
Approved amount 410'000.00
Show all

Keywords (6)

Mycobacteria tuberculosis; molecular epidemiology; drug resistance; molecular genotyping; field study; molecular diagnosis

Lay Summary (English)

Lead
Lay summary
Background: In 2005 more than 1.5 million people died from tuberculosis (TB), and 8-9 million people were newly infected with Mycobacterium tuberculosis. TB is a major cause of death among HIV patients. The long therapy and lack of alternative drugs led to the emergence of resistant TB strains and resistance has become a major threat to TB control programs world wide. It is estimated that about 4% of TB patients carry multi-drug resistant Mycobacteria.the World Health Organization considers Papua New Guinea (PNG) as "high burden" TB country. Estimates on multi-drug resistant TB cases increased from 3.6% in 2004 to 5.3% in 2006. However, there is no systematic monitoring in PNG and due to the worsening situation of the health system, the burden of TB is likely to be underestimated. High rates of treatment failure have been reported and a hospital based study showed 17% of primary resistance and 8% of MDR-TB prevalence in 2006. This and a dramatic increase in HIV infections requires urgently accurate assessment of the TB situation in PNG.Approach: In collaboration with the PNG Institute of Medical Research (PNGIMR) we will establish a TB cohort to estimate the burden of TB, to assess drug resistance, and to identify circulating M. tuberculosis strains. The cohort is established according to the National TB control program using a 'Directly Observed Treatment Short Course' (DOTS). Yet, there is no drug susceptibility monitoring and we will introduce minimal susceptibility testing in collaboration with the Australian reference laboratory. In addition, we will locally establish molecular typing methods to characterize mutations associated with resistance to drugs. We will also validate molecular diagnostic assays for sensitivity, feasibility, and cost for rapid 'on site' detection of TB. Several diagnostic methods (e.g. real-time Polymerase Chain Reaction (PCR), antigen detection in urine, etc.) will be compared to sputum smear microscopy and liquid culture. The origin and the dynamics of TB infections in PNG will be determines by standard spoligotyping techniques, Mycobacterial Interspersed Repetitive Unit-Variable Number Repeat (VNTR-MIRU)-typing, and SNP analysis for the characterization of circulating M. tuberculosis strains. Expected outcomes: We will introduce modern diagnostic, genotyping, and drug susceptibility testing techniques to provide essential information to the National TB Control Program for a better understanding of the epidemiology, dynamic, and evolutionary origins of TB in PNG. Furthermore, we will establish research capacity in this area at the PNGIMR by training lab technicians and post-graduate scientists from PNG.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
Mycobacterium tuberculosis lineage 4 comprises globally distributed and geographically restricted sublineages.
Stucki David, Brites D Jeljeli L Coscolla M Liu Q Trauner A Fenner L Rutaihwa L Borrell S Luo T Gao Q Ka, Gagneux Sebastien (2016), Mycobacterium tuberculosis lineage 4 comprises globally distributed and geographically restricted sublineages., in Nature Genetics, 48(12), 1535-1543.
Evolutionary history and global spread of the Mycobacterium tuberculosis Beijing lineage.
Merker Matthias, Blin C Mona S Duforet-Frebourg N Lecher S Willery E Blum MG Rüsch-Gerdes S Mokrousov I Aleks, Wirth Thierry (2015), Evolutionary history and global spread of the Mycobacterium tuberculosis Beijing lineage., in Nature Genetics, 47(3), 242-249.
Diversity of Mycobacterium tuberculosis and drug resistance in different provinces of Papua New Guinea.
Ley Serej, Harino P Vanuga K Kamus R Carter R Coulter C Pandey S Feldmann J Ballif M Siba PM Phuanukoo, Beck Hans-Peter (2014), Diversity of Mycobacterium tuberculosis and drug resistance in different provinces of Papua New Guinea., in BMC Microbiology, (14), 307-319.
Drug resistance-conferring mutations in Mycobacterium tuberculosis from Madang, Papua New Guinea.
Ballif Marie, Harino Paul, Ley Serej, Coscolla Mireia, Niemann Stefan, Carter Robyn, Coulter Christopher, Borrell Sonia, Siba Peter, Phuanukoonnon Suparat, Gagneux Sebastien, Beck Hans-Peter (2012), Drug resistance-conferring mutations in Mycobacterium tuberculosis from Madang, Papua New Guinea., in BMC microbiology, 12, 191-191.
Genetic diversity of Mycobacterium tuberculosis in Madang, Papua New Guinea.
Ballif M, Harino P, Ley S, Carter R, Coulter C, Niemann S, Borrell S, Fenner L, Siba P, Phuanukoonnon S, Gagneux S, Beck H-P (2012), Genetic diversity of Mycobacterium tuberculosis in Madang, Papua New Guinea., in The international journal of tuberculosis and lung disease : the official journal of the Internation, 16(8), 1100-7.

Collaboration

Group / person Country
Types of collaboration
Papua New Guinea Institute of Medical Research PapuaNew Guinea (Oceania)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Associated projects

Number Title Start Funding scheme
131192 Evaluation of new and emerging diagnostics for childhood tuberculosis in high burden countries (TB CHILD) 01.02.2010 Project funding (special)

Abstract

BackgroundAlthough tuberculosis (TB) is a preventable and curable infectious disease, more than 1.5 million people died from it in 2005, and 8-9 million people were newly infected with Mycobacterium tuberculosis in 2005 (WHO TB fact sheet 104, revised March 2007). While the highest mortality per capita is encountered in Africa, the largest number of new TB cases occurs in South-East Asia, with an estimated 34% of new cases globally. TB is a major reason of death among HIV co-infected patients. The emergence of resistance to antimicrobial drugs is also deeply impairing programs to reduce the burden of TB. Both the long duration of therapy (at least 6 months) and the lack of valuable alternative therapies lead to the emergence of resistant strains. Virtually all countries surveyed so far have shown cases of bacterial resistance against the major treatment drugs against TB (Aziz et al., 2006). Estimates showed that more than 4% of all TB infected patients worldwide are multidrug resistant (Zignol et al., 2006). In Papua New Guinea (PNG), the TB situation is identified as “high burden” by WHO. According to estimates, the prevalence of MDR-TB among all TB cases was 3.6% (1.1-13.3) in 2004 (Zignol et al., 2006) and 5.3% (1.7-20.1) in 2006 (Anti-Tuberculosis Drug Resistance in the World, 4th Global Report, WHO/HTM/TB/2008.394). These current estimates of TB prevalence in PNG are based on clinical records of treated patients, as there is no active case finding to allow the determination of the actual TB case number in PNG. Considering the limited access to health centers in many areas due to geographical difficulties, lack of laboratory diagnosis and poor overall monitoring system, the reported TB burden is therefore very likely to be underestimated. Despite the lack of large-scale study on TB drug resistance, clinicians reported a high rate of treatment failure. Indeed, a study conducted in a hospital in Madang Province in 2006 showed 17% of primary resistance among 64 new TB cases, while the prevalence of MDR-TB was of 8% (ref Luke et al., unpublished data). The paucity of accurate data on TB characteristics in PNG hampers the efforts to implement an effective program for the control of TB. Given the dramatically raising numbers of HIV infections, an accurate assessment of the TB situation in PNG is thus of high importance.ApproachThe Papua New Guinea Institute of Medical Research in Goroka currently establishes a TB cohort in order to describe the true burden of disease and to characterize the current situation concerning drug resistance. While the cohort will be established according to clinical standards (enrollment by Ziel.Niellson positive smear) with standard treatment under the ‘direct observed treatment, short course’ (DOTS) program by the Papua New Guinea Institute of Medical Research in collaboration with the National TB Control Program, there is no monitoring of drug susceptibility in treated patients foreseen. Limited drug susceptibility testing by classical culture methods of M. tuberculosis strains is planned to be conducted in collaboration with the Australian reference laboratory, but only on patients failing treatment. Although, due to logistics results are often received up to 12 months later. In this collaborative project, we will establish molecular technologies in Papua New Guinea to characterize mutations related to resistance to given drugs such as rifampicin, isoniazid, pyrazinamide and ethambutol by PCR amplification and sequencing. Currently, our previously developed microarray for the determination of drug resistance associated SNPs in malaria is being further developed for tuberculosis by the Novartis Institute of Tropical Diseases in Singapore and we have an informal agreement of collaboration to use this microarray when it becomes available. Simultaneously, we will apply a similar technique using Bioplex technology, which is already available in PNG.We will also validate molecular diagnostic assays for their sensitivity, feasibility and cost for rapid “on site” detection of TB infected individuals. Several diagnostic methods will be compared to sputum smear microscopy and liquid culture (MODS): real-time PCR, antigen detection using the LAM-ELISA assay, and furthermore, we will test a recently established mass-spectrometry based technology for the identification of M. tuberculosis. Because there is little to nothing known about the origin and the dynamics of infections in Papua New Guinea we also will be using standard spoligotyping and VNTR-MIRU-typing for strain characterization but also an additional technique taking genome wide polymorphisms into account to define the circulating M. tuberculosis isolates. Expected outcomeEstablishment of validated diagnostic, genotyping, and drug susceptibility techniques at the Papua New Guinea Institute of Medical Research.Providing important evidence on drug resistance to the national TB control program.Understanding of the epidemiology and dynamics of TB in Papua New Guinea and knowledge on the evolutionary origin of TB in PNG.Capacity building at the PNG IMR by training of lab technicians and enrollment of qualified PhD student(s) from Papua New Guinea at University of Basel.
-