Genetic sequencing for surveillance of drug resistance in tuberculosis in highly endemic countries: a multi-country population-based surveillance study
Zignol, Matteo; Cabibbe, Andrea Maurizio; Dean, Anna S.; Glaziou, Philippe; Alikhanova, Natavan; Ama, Cecilia; Andres, Sonke; Barbova, Anna; Borbe-Reyes, Angeli; Chin, Daniel P.; Cirillo, Daniela Maria; Colvin, Charlotte; Dadu, Andrei; Dreyer, Andries; Driesen, Michele; Gilpin, Christopher; Hasan, Rumina; Hasan, Zahra; Hoffner, Sven; Hussain, Alamdar; Ismail, Nazir Ahmed; Kamal, S.M. Mostofa; Khanzada, Faisal Masood; Kimerling, Michael; Kohl, Thomas Andreas; Mansjo, Mikael; Miotto, Paolo; Mukadi, Ya Diul; Mvusi, Lindiwe; Niemann, Stefan; Omar, Shaheed Vally; Rigouts, Leen; Schito, Marco; Sela, Ivita; Seyfaddinova, Mehriban; Skenders, Girts; Skrahina, Alena; Tahseen, Sabira; Wells, William A.; Zhurilo, Alexander; Weyer, Karin; Floyd, Katherine; Raviglione, Mario C.
Date:
2018-06
Abstract:
BACKGROUND : In many countries, regular monitoring of the emergence of resistance to anti-tuberculosis drugs is
hampered by the limitations of phenotypic testing for drug susceptibility. We therefore evaluated the use of genetic
sequencing for surveillance of drug resistance in tuberculosis. METHODS : Population-level surveys were done in hospitals and clinics in seven countries (Azerbaijan, Bangladesh,
Belarus, Pakistan, Philippines, South Africa, and Ukraine) to evaluate the use of genetic sequencing to estimate the
resistance of Mycobacterium tuberculosis isolates to rifampicin, isoniazid, ofloxacin, moxifloxacin, pyrazinamide,
kanamycin, amikacin, and capreomycin. For each drug, we assessed the accuracy of genetic sequencing by a
comparison of the adjusted prevalence of resistance, measured by genetic sequencing, with the true prevalence of
resistance, determined by phenotypic testing. FINDINGS : Isolates were taken from 7094 patients with tuberculosis who were enrolled in the study between November,
2009, and May, 2014. In all tuberculosis cases, the overall pooled sensitivity values for predicting resistance by genetic
sequencing were 91% (95% CI 87–94) for rpoB (rifampicin resistance), 86% (74–93) for katG, inhA, and fabG promoter
combined (isoniazid resistance), 54% (39–68) for pncA (pyrazinamide resistance), 85% (77–91) for gyrA and gyrB
combined (ofloxacin resistance), and 88% (81–92) for gyrA and gyrB combined (moxifloxacin resistance). For nearly all
drugs and in most settings, there was a large overlap in the estimated prevalence of drug resistance by genetic
sequencing and the estimated prevalence by phenotypic testing.
INTERPRETATION : Genetic 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.
