Population monitoring for drug-resistant tuberculosis: is genomics the answer?
Authors: Grant A Hill-Cawthorne
Journal: The Lancet Infectious Diseases (2018)

The first approximation akin to a population survey of drug resistance in tuberculosis was done in the UK in the 1950s, just a few years after the introduction of streptomycin.1Fox W Wiener A Mitchison DA Selkon JB Sutherland I The prevalence of drug-resistant tubercle bacilli in untreated patients with pulmonary tuberculosis; a national survey, 1955–56.Tubercle. 1957; 38: 71-84Summary Full Text PDF PubMed Scopus (32) Google Scholar Although the incidence of drug-resistant tuberculosis is reported annually by WHO, these reports can only be based on routinely collected laboratory data in countries where drug susceptibility testing is commonly done. In many of the worst-affected countries, the burden of disease is extrapolated from periodic epidemiological surveys, but these surveys are still dependent on laboratory facilities with a sufficient biosafety level and the expertise to do phenotypic testing.2Zignol M Dean AS Falzon D et al.Twenty years of global surveillance of antituberculosis-drug resistance.N Engl J Med. 2016; 375: 1081-1089Crossref PubMed Scopus (91) Google Scholar In The Lancet Infectious Diseases, Matteo Zignol and colleagues3Zignol M Cabibbe AM Dean AS et al.Genetic sequencing for surveillance of drug resistance in tuberculosis in highly endemic countries: a multi-country population-based surveillance study.Lancet Infect Dis. 2018; (published online March 21.)http://dx.doi.org/10.1016/S1473-3099(18)30073-2Summary Full Text Full Text PDF PubMed Scopus (85) Google Scholar report on the surveillance of the drug resistance of tuberculosis to commonly used first-line and second-line treatments by use of genetic, rather than phenotypic, susceptibility testing. Zignol and colleagues isolated and cultured more than 7000 samples from population surveys in seven countries, after which they used standard phenotypic drug susceptibility testing (DST) and whole-genome or targeted gene sequencing of the regions that are important for conferring drug resistance. However, the number of isolates for which both phenotypic and genotypic DST data were available varied by country and by drug, with relatively fewer results available regarding resistance to the second-line injectable drugs kanamycin, amikacin, and capreomycin. Despite this, pooled sensitivities could be estimated for genetic testing, which varied from 51% for pyrazinamide to 91% for rifampicin. This is not the first time that sequencing has been used for DST in tuberculosis; in fact, genomic work on Mycobacterium tuberculosis resistance has been part of the vanguard of the modernising microbiology agenda. The slow-growing nature of M tuberculosis and the technical difficulty in doing some phenotypic DST means that M tuberculosis has been the focus of a substantial amount of research, albeit in local outbreaks and high-income settings. Proof-of-concept studies for routine genetic DST have been done,4Walker TM Kohl TA Omar SV et al.Whole-genome sequencing for prediction of Mycobacterium tuberculosis drug susceptibility and resistance: a retrospective cohort study.Lancet Infect Dis. 2015; 15: 1193-1202Summary Full Text Full Text PDF PubMed Scopus (387) Google Scholar and software has been developed to minimise the need for dedicated bioinformatics expertise.5Bradley P Gordon NC Walker TM et al.Rapid antibiotic-resistance predictions from genome sequence data for Staphylococcus aureus and Mycobacterium tuberculosis.Nat Comm. 2015; 6: 10063Crossref PubMed Scopus (331) Google Scholar, 6Coll F McNerney R Preston MD et al.Rapid determination of anti-tuberculosis drug resistance from whole-genome sequences.Genome Med. 2015; 7: 51Crossref PubMed Scopus (240) Google Scholar Studies7Pankhurst LJ Del Ojo Elias C Votintseva AA et al.Rapid, comprehensive, and affordable mycobacterial diagnosis with whole-genome sequencing: a prospective study.Lancet Respir Med. 2016; 4: 49-58Summary Full Text Full Text PDF PubMed Scopus (211) Google Scholar, 8Martinez E Bustamante A Menon R et al.Whole-genome sequencing of Mycobacterium tuberculosis for rapid diagnostics: feasibility of a decentralised model.Lancet Respir Med. 2016; 4: e13-e14Summary Full Text Full Text PDF PubMed Scopus (9) Google Scholar on the real-time use of genomics in clinical settings have found whole genome sequencing-based DST to be accurate, faster, and cheaper than phenotypic DST. This finding has led to a routine whole-genome sequencing service being offered by Public Health England from March, 2017.9Walker TM Cruz ALG Peto TE Smith EG Esmail H Crook DW Tuberculosis is changing.Lancet Infect Dis. 2017; 17: 359-361Summary Full Text Full Text PDF PubMed Scopus (36) Google Scholar By showing that population-based surveillance in low-income settings is a reality,3Zignol M Cabibbe AM Dean AS et al.Genetic sequencing for surveillance of drug resistance in tuberculosis in highly endemic countries: a multi-country population-based surveillance study.Lancet Infect Dis. 2018; (published online March 21.)http://dx.doi.org/10.1016/S1473-3099(18)30073-2Summary Full Text Full Text PDF PubMed Scopus (85) Google Scholar Zignol and colleagues have advanced our understanding of how genetic DST can be implemented in real-life scenarios. Zignol and colleagues also highlight two important points. First, the sensitivity of genetic DST was greatly reduced for those drugs for which the whole spectrum of resistance-determining mutations has not been elucidated. The sensitivities of genetic DST for pyrazinamide, ethionamide, and para-aminosalicylic acid are generally lower than for other drugs because of the low number of samples globally for which both genotypic and phenotypic data are available.4Walker TM Kohl TA Omar SV et al.Whole-genome sequencing for prediction of Mycobacterium tuberculosis drug susceptibility and resistance: a retrospective cohort study.Lancet Infect Dis. 2015; 15: 1193-1202Summary Full Text Full Text PDF PubMed Scopus (387) Google Scholar, 6Coll F McNerney R Preston MD et al.Rapid determination of anti-tuberculosis drug resistance from whole-genome sequences.Genome Med. 2015; 7: 51Crossref PubMed Scopus (240) Google Scholar The sensitivity of genetic DST is likely to increase as more diverse isolates are added to the global database; a 2018 large sequencing study10Coll F Phelan J Hill-Cawthorne GA et al.Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis.Nat Genet. 2018; 50: 307-316Crossref PubMed Scopus (186) Google Scholar of more than 7000 M tuberculosis isolates increased the sensitivity of the detection of pyrazinamide-resistance from 52% to 65%, and of detection of para-aminosalicylic acid-resistance from 10% to 65%. Another important aspect of the Zignol study is that a wide range of sensitivity values was seen across sites and it is difficult to determine how much of this result is caused by the low numbers of isolates available from some sites and the problems in reproducibility seen with some phenotypic DST. We cannot be sure that this finding was not caused by a sublineage or genetic diversity effect, and further clarification will only be provided by the addition of sequences from several low-income and middle-income settings. The rapid decrease in the costs of genetic sequencing now allows us to use genomics in several settings, not just well resourced public health systems. In the study by Zignol and colleagues, dependency on a culture step remained,3Zignol M Cabibbe AM Dean AS et al.Genetic sequencing for surveillance of drug resistance in tuberculosis in highly endemic countries: a multi-country population-based surveillance study.Lancet Infect Dis. 2018; (published online March 21.)http://dx.doi.org/10.1016/S1473-3099(18)30073-2Summary Full Text Full Text PDF PubMed Scopus (85) Google Scholar which is a common bottleneck for many health systems. Work is progressing on low-cost extraction methods to enable direct sequencing from patient samples with technologies that can easily be applied in low-income laboratory settings and in the field.11Votintseva AA Bradley P Pankhurst L et al.Same-day diagnostic and surveillance data for tuberculosis via whole-genome sequencing of direct respiratory samples.J Clin Microbiol. 2017; 55: 1285-1298Crossref PubMed Scopus (208) Google Scholar In the next 5–10 years, for the first time, these technologies will make individual patient DST and detailed population surveillance possible in many settings. This step will be an important movement forwards for tuberculosis programmes, enabling provision of active drug regimens in initial treatment of new cases. I declare no competing interests. Genetic sequencing for surveillance of drug resistance in tuberculosis in highly endemic countries: a multi-country population-based surveillance studyGenetic sequencing can be a valuable tool for surveillance of drug resistance, providing new opportunities to monitor drug resistance in tuberculosis in resource-poor countries. Before its widespread adoption for surveillance purposes, there is a need to standardise DNA extraction methods, recording and reporting nomenclature, and data interpretation. Full-Text PDF Open Access