Factors associated with culture conversion among adults treated for pulmonary extensively drug-resistant tuberculosis during 2018-2019 in the Russian Federation: an observational cohort study
Treatment outcomes for Multidrug/Rifampicin-Resistant Tuberculosis (MDR/RR-TB) and Extensively Drug-Resistant Tuberculosis (XDR-TB) remain poor across the globe and in the Russian Federation. Treatment of XDR-TB is challenging for programmes and patients often resulting in low success rates and onward transmission of drug-resistant strains. Analysis of factors affecting culture conversion rate among XDR-TB patients may serve as a basis for optimization of treatment regimens. We conducted a retrospective cohort study using health records from 54 patients with pulmonary XDR-TB treated at a tertiary level facility in the Russian Federation. The study population included adult patients with culture-positive pulmonary XDR-TB who started treatment between 1 January 2018-30 June 2019. Culture conversion was defined as two consecutive negative cultures, collected at least 30 days apart. The date of sputum culture conversion was taken from the first of two consecutive negative sputum cultures fulfilling these criteria. We measured time to culture conversion using cumulative incidence functions accounting for competing risks and applied binary cause-specific Cox regressions to assess associated factors. Sputum culture conversion was recorded for 43 (79.6%) patients. Median time to culture conversion adjusted for competing risk of loss to follow up was 4 months [95% confidence interval (CI): 2–5]. The number of patients who had culture converted by treatment months 2, 4, and 6 were 12 (22%), 29 (54%) and 38 (70%) respectively. In unadjusted analysis, positive baseline sputum smear microscopy [hazard ratio (HR): 0.34, 95% CI: 0.18-0.66; p=0.001), hepatitis C (HR: 0.35, 95% CI: 0.14-0.89; p=0.023], and human immunodeficiency virus (HR: 0.30 95%, CI: 0.09-0.97; p=0.045), and receipt of fewer than 4 effective drugs in the treatment regimen (HR: 0.13, 95% CI: 0.03-0.60; p=0.009) were associated with delayed culture conversion. When compared to their combined use, patients receiving regimens with bedaquiline only (HR: 0.12, 95% CI: 0.03-0.49; p=0.003) or linezolid only (HR: 0.21, 95% CI: 0.06-0.69; p=0.010) were less likely to achieve timely culture conversion. Factors delaying sputum culture conversion should be considered in the management of patients with XDR-TB and considered by clinicians for regimen design and treatment strategies. Our study outlines the importance of simultaneous inclusion of bedaquiline and linezolid in treatment regimens for patients with XDR-TB to reduce time to sputum conversion and increase treatment success.
WHO. Global tuberculosis report 2019. Geneva: World Health Organization; 2020. Accessed on: 2020 Jul 7. Available from: http://www.who.int/tb/publications/global_report/en/
WHO. Moscow Declaration to End TB. Geneva: World Health Organization; 2017. Accessed on: 2020 Jul 1. Available from: https://www.who.int/tb/Moscow_Declaration_MinisterialConference_TB/en/
Lange C, Dheda K, Chesov D et al. Management of drug-resistant tuberculosis. Lancet 2019;394:953–66.
Migliori GB, Tiberi S, Zumla A et al. MDR/XDR-TB management of patients and contacts: Challenges facing the new decade. The 2020 clinical update by the Global Tuberculosis Network. Int J Infect Dis 2020;92:S15–25.
WHO. Consolidated Guidelines on Tuberculosis, Module 4: Treatment - Drug-Resistant Tuberculosis Treatment. Geneva: World Health Organization; 2020. Accessed on: 2020 Aug 5. Available from: https://www.who.int/publications/i/item/9789240007048
Pranger AD, van der Werf TS, Kosterink JGW, Alffenaar JWC. The role of fluoroquinolones in the treatment of tuberculosis in 2019. Drugs 2019;79:161–71.
WHO Regional Office for Europe. Tuberculosis action plan for the WHO European Region 2016-2020. Accessed on: 2020 Jul 7. Available from: http://www.euro.who.int/en/who-we-are/governance
WHO. Definitions and reporting framework for tuberculosis. Geneva: World Health Organization; 2020. Accessed on: 2020 Jul 7. Available from: http://www.who.int/tb/publications/definitions/en/
Vasilyeva I, Balasaniantc G, Borisov S, et al. Tuberculosis in adults. Accessed on: 2020 Jul 7. Available from: http://cr.rosminzdrav.ru/#!/recomend/943
WHO. WHO consolidated guidelines on drug-resistant tuberculosis treatment. Geneva: World Health Organization; 2019. Accessed on: 2020 Jul 7. Available from: http://www.who.int/tb/publications/2019/consolidated-guidelines-drug-resistant-TB-treatment/en/
Burmistrovа I, Vаniev EV, Sаmoylovа AG, et al. Amplification of drug resistance against the background of inadequate chemotherapy for pulmonary tuberculosis. Tuberc Lung Dis 2019;97:46–51.
Ahmad N, Ahuja SD, Akkerman OW, et al. Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis. Lancet 2018;392:821–34.
ClinicalTrials.gov. Safety and efficacy of various doses and treatment durations of linezolid plus bedaquiline and pretomanid in participants with pulmonary TB, XDR-TB, pre- XDR-TB or non-responsive/intolerant MDR-TB (ZeNix). Global Alliance for TB Drug Development. ID NCT03086486. Accessed on: 2020 Jul 7. Available from: https://www.clinicaltrials.gov/ct2/show/NCT03086486.
ClinicalTrials.gov. Evaluating newly approved drugs for multidrug-resistant TB. Médecins Sans Frontières, France. ID NCT02754765. Accessed on: 2020 Jul 7. Available from: https://clinicaltrials.gov/ct2/show/NCT02754765
ClinicalTrials.gov. Pragmatic clinical trial for a more effective concise and less toxic MDR-TB treatment regimen(s). Medecins Sans Frontieres, Netherlands. ID NCT02589782. Accessed on: 2020 Jul 7. Available from: https://clinicaltrials.gov/ct2/show/NCT02589782
Pontali E, Raviglione MC, Migliori GB, et al. Regimens to treat multidrug-resistant tuberculosis: Past, present and future perspectives. Eur Res Rev 2019;28:190035.
Bastard M, Sanchez-Padilla E, Hayrapetyan A, et al. What is the best culture conversion prognostic marker for patients treated for multidrug-resistant tuberculosis? Int J Tuberc Lung Dis 2019;23:1060–7.
Lu P, Liu Q, Martinez L, et al. Time to sputum culture conversion and treatment outcome of patients with multidrug-resistant tuberculosis: A prospective cohort study from urban China. Eur Res J 2017;49:1601558.
Kurbatova EV, Cegielski JP, Lienhardt C, et al. Sputum culture conversion as a prognostic marker for end-of-treatment outcome in patients with multidrug-resistant tuberculosis: A secondary analysis of data from two observational cohort studies. Lancet Respir Med 2015;3:201–9.
WHO. Technical report on critical concentrations for TB drug susceptibility testing of medicines used in the treatment of drug-resistant TB. Geneva: World Health Organization; 2018.
Rishi S, Sinha P, Malhotra B, Pal N. A comparative study for the detection of mycobacteria by BACTEC MGIT 960, Lowenstein Jensen media and direct AFB smear examination. Indian J Med Microbiol 2007;25:383–6.
Guglielmetti L, Le Dû D, Jachym M, et al. Compassionate use of bedaquiline for the treatment of multidrug-resistant and extensively drug-resistant tuberculosis: Interim analysis of a French cohort. Clin Infect Dis 2015;60:188-94.
Borisov SE, Dheda K, Enwerem M, et al. Effectiveness and safety of bedaquilinecontaining regimens in the treatment of MDR- and XDR-TB: A multicentre study. Eur Respir J 2017;49: 1700387.
Liu Q, Lu P, Martinez L, et al. Factors affecting time to sputum culture conversion and treatment outcome of patients with multidrug-resistant tuberculosis in China. BMC Infect Dis 2018;18:114.
Qazi F, Khan U, Khowaja S, et al. Predictors of delayed culture conversion in patients treated for multidrug-resistant tuberculosis in Pakistan. Int J Tuberc Lung Dis 2011;15:1556–9.
Gao M, Gao J, Xie L et al. Early outcome and safety of bedaquiline-containing regimens for treatment of MDR- and XDR-TB in China: a multicentre study. Clin Microbiol Infect 2020. doi: 10.1016/j.cmi.2020.06.004
Salhotra VS, Sachdeva KS, Kshirsagar N, et al. Effectiveness and safety of bedaquiline under conditional access program for treatment of drug-resistant tuberculosis in India: An interim analysis. Indian J Tuberc 2020;67:29–37.
Lifan Z, Sainan B, Feng S, et al. Linezolid for the treatment of extensively drug-resistant tuberculosis: A systematic review and meta-analysis. Int J Tuberc Lung Dis 2019;23:1293–307.
Sarin R, Singla N, Vohra V et al. Initial experience of bedaquiline implementation under the National TB Programme at NITRD, Delhi, India. Indian J Tuberc 2019;66:209-13.
Pym AS, Diacon AH, Tang SJ, et al. Bedaquiline in the treatment of multidrug- and extensively drugresistant tuberculosis. Eur Respir J 2016;47:564-74.
Olayanju O, Limberis J, Esmail A, et al. Long-term bedaquiline-related treatment outcomes in patients with extensively drug-resistant tuberculosis from South Africa. Eur Respir J 2018;51:1800544.
Conradie F, Diacon AH, Ngubane N, et al. Treatment of highly drug-resistant pulmonary tuberculosis. N Engl J Med 2020;382:893-902.
Matteelli A, Roggi A, Carvalho ACC. Extensively drug-resistant tuberculosis: Epidemiology and management. Clin Epidemiol 2014;6:111-8.
Migliori GB, Sotgiu G, Gandhi NR, et al. Drug resistance beyond extensively drugresistant tuberculosis: Individual patient data meta-analysis. Eur Respir J 2013;42:169-79.
Wang EY, Arrazola RA, Mathema B, et al. The impact of smoking on tuberculosis treatment outcomes: a meta-analysis. Int J Tuberc Lung Dis 2020;24:170–5.
Reimann M, Schaub D, Kalsdorf B, et al. Cigarette smoking and culture conversion in patients with susceptible and M/XDR-TB. Int J Tuberc Lung Dis 2019;23:93–8.
Lin H-H, Ezzati M, Murray M. Tobacco smoke, indoor air pollution and tuberculosis: A systematic review and meta-analysis. PLoS Med 2007;4:e20.
Mohr E, Cox V, Wilkinson L, et al. Programmatic treatment outcomes in HIV-infected and uninfected drug-resistant TB patients in Khayelitsha, South Africa. Trans R Soc Trop Med Hyg 2015;109:425–32.
Shibabaw A, Gelaw B, Wang S-H, Tessema B. Time to sputum smear and culture conversions in multidrug resistant tuberculosis at University of Gondar Hospital, Northwest Ethiopia. PLoS One 2018;13:e0198080.
Lomtadze N, Kupreishvili L, Salakaia A, et al. Hepatitis C virus co-infection increases the risk of anti-tuberculosis drug-induced hepatotoxicity among patients with pulmonary tuberculosis. PLoS One 2013;8:e83892.
El-Serag HB, Anand B, Richardson P, Rabeneck L. Association between hepatitis C infection and other infectious diseases: A case for targeted screening? Am J Gastroenterol 2003;98:167–74.
Behzadifar M, Heydarvand S, Behzadifar M, Bragazzi NL. Prevalence of hepatitis C virus in tuberculosis patients: A systematic review and meta-analysis. Ethiop J Health Sci 2019;29:945–56.
Agha M, El-Mahalawy I, Seleem H, Helwa M. Prevalence of hepatitis C virus in patients with tuberculosis and its impact in the incidence of anti-tuberculosis drugs induced hepatotoxicity. Eur Res J 2015;PA2983.
Kurbatova E, Gammino VM, Bayona J, et al. Predictors of sputum culture conversion among patients treated for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2012;16:1335–43.
Parmar MM, Sachdeva KS, Dewan PK, et al. Unacceptable treatment outcomes and associated factors among India’s initial cohorts of multidrug-resistant tuberculosis (MDR-TB) patients under the revised national TB control programme (2007–2011): Evidence leading to policy enhancement. PLoS One 2018;13:e0193903.
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