Survival of Civilian and Prisoner Drug-Sensitive, Multi- and Extensive Drug- Resistant Tuberculosis Cohorts Prospectively Followed in Russia

Multi- and Extensive Drug- Resistant Tuberculosis Cohorts Prospectively Followed in Russia. PLoS ONE 6(6): e20531. doi:10.1371/journal.pone.0020531 Survival of Civilian and Prisoner Drug-Sensitive, Multi- and Extensive Drug- Resistant Tuberculosis Cohorts Prospectively Followed in Russia Yanina Balabanova 0 Vladyslav Nikolayevskyy 0 Olga Ignatyeva 0 Irina Kontsevaya 0 Clare M. 0 Rutterford 0 Anastasiya Shakhmistova 0 Nadezhda Malomanova 0 Yulia Chinkova 0 Svetlana Mironova 0 Ivan Fedorin 0 Francis A. Drobniewski 0 Igor Mokrousov, St. Petersburg Pasteur Institute, Russian Federation 0 1 Queen Mary College, Barts and the London School of Medicine, University of London , London , United Kingdom , 2 Samara Oblast Tuberculosis Dispensary, Samara , Russia Objective and Methods: A long-term observational study was conducted in Samara, Russia to assess the survival and risk factors for death of a cohort of non-multidrug resistant tuberculosis (non-MDRTB) and multidrug resistant tuberculosis (MDRTB) civilian and prison patients and a civilian extensive drug-resistant tuberculosis (XDRTB) cohort. Results: MDRTB and XDRTB rates of 54.8% and 11.1% were identified in the region. Half (50%) of MDRTB patients and the majority of non-MDRTB patients (71%) were still alive at 5 years. Over half (58%) of the patients died within two years of establishing a diagnosis of XDRTB. In the multivariate analysis, retreatment (HR = 1.61, 95%CI 1.04, 2.49) and MDRTB (HR = 1.67, 95%CI 1.17, 2.39) were significantly associated with death within the non-MDR/MDRTB cohort. The effect of age on survival was relatively small (HR = 1.01, 95%CI 1.00, 1.02). No specific factor affected survival of XDRTB patients although median survival time for HIV-infected versus HIV-negative patients from this group was shorter (185 versus 496 days). The majority of MDRTB and XDRTB strains (84% and 92% respectively) strains belonged to the Beijing family. Mutations in the rpoB (codon 531 in 81/92; 88.8%), katG (mutation S315T in 91/92, 98.9%) and inhA genes accounted for most rifampin and isoniazid resistance respectively, mutations in the QRDR region of gyrA for most fluroquinolone resistance (68/92; 73.5%). Conclusions: Alarmingly high rates of XDRTB exist. Previous TB treatment cycles and MDR were significant risk factors for mortality. XDRTB patients' survival is short especially for HIV-infected patients. Beijing family strains comprise the majority of drug-resistant strains. - Funding: The study was partially funded by an EU FP7 Programme (TB-EURO-GEN) grant, the Foundation for Innovative Novel Diagnostics, Switzerland, and the UK Department for International Development. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Multidrug-resistant tuberculosis (MDRTB) is a growing threat to national tuberculosis (TB) programmes world-wide. Extensive drug-resistance (XDR), i.e. additional resistance to fluoroquinolones (FQ) and injectable agents decreases chances of survival and success further [1,2,3,4,5,6,7]. So far co-infection of HIV and XDRTB has been largely fatal [2,8,9,10,11]. The problem of drugresistant tuberculosis is particularly acute in the countries of the Former Soviet Union (FSU) where almost half of all TB cases are resistant to at least one drug and the MDRTB rate among new cases exceed 20% in some countries [12]. The extent and pattern of resistance to second-line drugs (SLD) among MDRTB isolates remain unknown in most FSU countries due to insufficient laboratory infrastructure and testing. Only limited data is available on patient survival in the long term and where reported in Russia, cure rates and short-term survival have been poor regardless of HIV status [13,14]. In Samara Oblast (a region of the Russian Federation with a population of 3.3 million) high rates of MDRTB (20% among new and 43% among previously treated cases) are coupled with a fast growing HIV epidemic (HIV-positive cases reaching 43 000 in December 2010) [15,16]. A drug-resistance survey conducted in 20012002 in this region demonstrated relatively low rates of resistance to second-line drugs with no XDRTB cases [17]. Prolonged hospitalization (minimum 3 months) is compulsory for culture-confirmed patients; HIV-infected patients stay at the same hospitals with other patients including drug-resistant cases. Institutional infection control measures are not fully implemented, i.e. there are no negative-pressure rooms, appropriate protective masks are not worn regularly by staff, there is no strict separation of in-patients with sensitive and resistant tuberculosis and there are opportunities for patients to meet socially. The potential for HIV infected patients to become infected with drug resistant TB is high. The aim of this study was to determine the long-term survival of drug-sensitive (non-MDR), MDRTB and XDRTB patients in the civilian and prison sectors, and to identify risk factors including TB strain type, associated with survival. Materials and Methods Ethics statement The study was approved by Samara Medical University Ethics Committee and received a waiver of informed consent. Study settings and population Results of two independent patient cohorts from the same region of Russia are presented. Patients from a non-MDR/ MDRTB Cohort (N = 880) were prospectively consecutively recruited from the civilian and prison sectors into the study in 20022003 within a pilot DOTS-programme; this 2002-3 TB Cohort was comprised of new (88%) and relapse cases infected with MDRTB and non-MDR strains (including fully-sensitive and mono-/polyresistant) and was followed prospectively until December, 31st 2008 to give long-term survival data. XDRTB Cohort consisted of all civilian patients diagnosed with XDRTB in the same region in 2008 (2008 XDRTB Cohort). All identified XDRTB patients were enrolled into the analysis (n = 92). Basic data on history of TB and survival were collected using routine TB patients register supplemented with detailed epidemiological and clinical data from chart review. Bacteriological methods For all patients, smear microscopy was performed using the Ziehl-Neilsen method with culture on Lowenstein-Jensen media according to standard procedures [18]. Overall, mycobacterial isolates were obtained from 783 patients in the 2002-3 Cohort. First-line drug susceptibility testing (FLD DST) was performed using either conventional solid media (by the absolute concentration method), or the MGIT 960 system using standard techniques [18,19]; second line DST was performed using the MGIT system as described [20,21]. Drug concentrations used for second-line drugs were (mg/ml): Ofloxacin (Ofl): 2.0; Moxifloxacin (Mox): 0.25; Amikacin (Amk): 1.0; Capreomycin (Cap): 2.5; Prothionamide (Pt): 2.5 [20]. Prior to routine implementation of SLD MGIT 960 testing, labora (...truncated)