| Author |
Kurbatova, Ekaterina V. Cegielski, J. Peter Lienhardt, Christian Akksilp, Rattanawadee Bayona, Jaime Becerra, Mercedes C. Caoili, Janice Contreras, Carmen Dalton, Tracy Danilovits, Manfred Demikhova, Olga V. Ershova, Julia Gammino, Victoria M. Gelmanova, Irina Heilig, Charles M. Jou, Ruwen Kazennyy, Boris Keshavjee, Salmaan Kim, Hee Jin Kliiman, Kai Kvasnovsky, Charlotte Leimane, Vaira Mitnick, Carole D. Quelapio, Imelda Riekstina, Vija Smith, Sarah E. Tupasi, Thelma Van Der Walt, Martie Vasilyeva, Irina A. Via, Laura E. Viiklepp, Piret Volchenkov, Grigory Walker, Allison Taylor Wolfgang, Melanie Yagui, Martin Zignol, Matteo |
| Description |
Author Affiliation: Kurbatova EV ( Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA. Electronic address: ekurbatova@cdc.gov.); Cegielski JP ( Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA.); Lienhardt C ( WHO, Geneva, Switzerland.); Akksilp R ( Office of Disease Prevention and Control, Region 7, Ubon Ratchathani, Thailand.); Bayona J ( Harvard Medical School and Partners In Health, Boston, MA, USA.); Becerra MC ( Harvard Medical School and Partners In Health, Boston, MA, USA.); Caoili J ( Tropical Disease Foundation, Manila, Philippines.); Contreras C ( Socios en Salud Sucursal, Lima, Peru.); Dalton T ( Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA.); Danilovits M ( Tartu University Hospital, Tartu, Estonia.); Demikhova OV ( Central Tuberculosis Research Institute, Russian Academy of Medical Sciences, Moscow, Russia.); Ershova J ( Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA.); Gammino VM ( Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA.); Gelmanova I ( Harvard Medical School and Partners In Health, Boston, MA, USA.); Heilig CM ( Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA.); Jou R ( Reference Laboratory of Mycobacteriology, Taiwan Centers for Disease Control, Taipei, Taiwan.); Kazennyy B ( Orel Oblast Tuberculosis Dispensary, Orel, Russia.); Keshavjee S ( Harvard Medical School and Partners In Health, Boston, MA, USA.); Kim HJ ( Korean Institute of Tuberculosis, Seoul, South Korea.); Kliiman K ( Tartu University Hospital, Tartu, Estonia.); Kvasnovsky C ( Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA.); Leimane V ( Riga East University Hospital, Tuberculosis and Lung Disease Center, Riga, Latvia.); Mitnick CD ( Harvard Medical School and Partners In Health, Boston, MA, USA.); Quelapio I ( Tropical Disease Foundation, Manila, Philippines.); Riekstina V ( Riga East University Hospital, Tuberculosis and Lung Disease Center, Riga, Latvia.); Smith SE ( Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA.); Tupasi T ( Tropical Disease Foundation, Manila, Philippines.); van der Walt M ( Medical Research Council, Pretoria, South Africa.); Vasilyeva IA ( Central Tuberculosis Research Institute, Russian Academy of Medical Sciences, Moscow, Russia.); Via LE ( National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.); Viiklepp P ( National Tuberculosis Registry, National Institute for Health Development, Tallinn, Estonia.); Volchenkov G ( Vladimir Oblast Tuberculosis Dispensary, Vladimir, Russia.); Walker AT ( Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA.); Wolfgang M ( Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA.); Yagui M ( National Institute of Health, Lima, Peru.); Zignol M ( WHO, Geneva, Switzerland.) |
| Abstract |
BACKGROUND: Sputum culture conversion is often used as an early microbiological endpoint in phase 2 clinical trials of tuberculosis treatment on the basis of its assumed predictive value for end-of-treatment outcome, particularly in patients with drug-susceptible tuberculosis. We aimed to assess the validity of sputum culture conversion on solid media at varying timepoints, and the time to conversion, as prognostic markers for end-of-treatment outcome in patients with multidrug-resistant (MDR) tuberculosis. METHODS: We analysed data from two large cohort studies of patients with MDR tuberculosis. We defined sputum culture conversion as two or more consecutive negative cultures from sputum samples obtained at least 30 days apart. To estimate the association of 2 month and 6 month conversion with successful treatment outcome, we calculated odds ratios (ORs) and 95% CIs with random-effects multivariable logistic regression. We calculated predictive values with bivariate random-effects generalised linear mixed modelling. FINDINGS: We assessed data for 1712 patients who had treatment success, treatment failure, or who died. Among patients with treatment success, median time to sputum culture conversion was significantly shorter than in those who had poor outcomes (2 months [IQR 1-3] vs 7 months [3 to ≥24]; log-rank p<0·0001). Furthermore, conversion status at 6 months (adjusted OR 14·07 [95% CI 10·05-19·71]) was significantly associated with treatment success compared with failure or death. Sputum culture conversion status at 2 months was significantly associated with treatment success only in patients who were HIV negative (adjusted OR 4·12 [95% CI 2·25-7·54]) or who had unknown HIV infection (3·59 [1·96-6·58]), but not in those who were HIV positive (0·38 [0·12-1·18]). Thus, the overall association of sputum culture conversion with a successful outcome was substantially greater at 6 months than at 2 months. 2 month conversion had low sensitivity (27·3% [95% confidence limit 16·6-41·4]) and high specificity (89·8% [82·3-94·4]) for prediction of treatment success. Conversely, 6 month sputum culture conversion status had high sensitivity (91·8% [85·9-95·4]), but moderate specificity (57·8% [42·5-71·6]). The maximum combined sensitivity and specificity for sputum culture conversion was reached between month 6 and month 10 of treatment. INTERPRETATION: Time to sputum culture conversion, conversion status at 6 months, and conversion status at 2 months in patients without known HIV infection can be considered as proxy markers of end-of-treatment outcome in patients with MDR tuberculosis, although the overall association with treatment success is substantially stronger for 6 month than for 2 month conversion status. Investigators should consider these results regarding the validity of sputum culture conversion at various timepoints as an early predictor of treatment efficacy when designing phase 2 studies before investing substantial resources in large, long-term, phase 3 trials of new treatments for MDR tuberculosis. FUNDING: US Agency for International Development, US Centers for Disease Control and Prevention, Division of Intramural Research of the US National Institute of Allergy and Infectious Diseases, Korea Centers for Disease Control and Prevention. |
