title: MDR-TB Outbreak among HIV-Negative Tunisian Patients followed during 11 Years.
abstract: Multidrug-resistant tuberculosis (MDR-TB) outbreaks that evolve, from the outset, in a context strictly negative for HIV infection deserve special consideration since they reflect the true intrinsic epidemic potential of the causative strain. To our knowledge, the long-term evolution of such exceptional outbreaks and the treatment outcomes for the involved patients has never been reported hitherto. Here we provide a thorough description, over an 11-year period, of an MDR-TB outbreak that emerged and expanded in an HIV-negative context, Northern Tunisia.
  
  
  
  From October 2001 to June 2011, the MDR-TB outbreak involved 48 HIV-negative individuals that are mainly young (mean age 31.09 yrs; 89.6% male) and noninstitutionalized. Drug susceptibility testing coupled to mutational analysis revealed that initial transmission involved an isolate that was simultaneously resistant to isoniazid, rifampicin, ethambutol, and streptomycin. The causative Haarlem3-ST50 outbreak strain expanded mainly as an 11-banded IS6110 RFLP profile (77.1%), from which a 12-banded subclone evolved. After undergoing a 2-year treatment with second-line drugs, 22 (45.8%) patients were cured and 3 (6.2%) completed treatment, thus yielding an overall treatment success rate of 52.1%. Among the patients that experienced unfavorable treatment outcomes, 10 (20.8%) failed treatment, 3 (6.2%) were lost to follow-up, 5 (10.4%) died, and 5 (10.4%) could not be evaluated. Poor adherence to treatment was found to be the main independent predictor of unfavorable outcomes (HR: 9.15; 95% CI 1.72-48.73; P = 0.014). Intriguingly, the evolved 12-banded subclone proved significantly associated with unfavorable outcomes (HR: 4.90; 95% CI 1.04-23.04, P = 0.044). High rate of fatality and relapse was further demonstrated at the long-term, since 70% of those whose treatment failed have died, and 24% among those deemed successfully treated have relapsed.
  
  
  
  Taken together, the data obtained in this study indicate that MDR-TB clinical isolates could become fit enough to cause large and severe outbreaks in an HIV-negative context. Such MDR-TB outbreaks are characterized by low treatment success rates and could evolve towards increased severity, thus calling for early detection of cases and the necessity to raise the bar of surveillance throughout and beyond the treatment period.
authors.affiliation: Unit of Typing & Genetics of Mycobacteria, Laboratory of Molecular Microbiology, Vaccinology, and Biotechnology Development, Institut Pasteur de Tunis, Université Tunis El Manar, Tunis, Tunisia.
authors.forename: Naira
authors.initials: N
authors.lastname: Dekhil
authors.affiliation: Unit of Typing & Genetics of Mycobacteria, Laboratory of Molecular Microbiology, Vaccinology, and Biotechnology Development, Institut Pasteur de Tunis, Université Tunis El Manar, Tunis, Tunisia.
authors.forename: Nedra
authors.initials: N
authors.lastname: Meftahi
authors.affiliation: Unit of Typing & Genetics of Mycobacteria, Laboratory of Molecular Microbiology, Vaccinology, and Biotechnology Development, Institut Pasteur de Tunis, Université Tunis El Manar, Tunis, Tunisia.
authors.forename: Besma
authors.initials: B
authors.lastname: Mhenni
authors.affiliation: Unit of Typing & Genetics of Mycobacteria, Laboratory of Molecular Microbiology, Vaccinology, and Biotechnology Development, Institut Pasteur de Tunis, Université Tunis El Manar, Tunis, Tunisia.
authors.forename: Saloua
authors.initials: S
authors.lastname: Ben Fraj
authors.affiliation: Hôpital Régional de Menzel-Bourguiba, Menzel Bourguiba, Tunisia.
authors.forename: Raja
authors.initials: R
authors.lastname: Haltiti
authors.affiliation: Hôpital Régional de Menzel-Bourguiba, Menzel Bourguiba, Tunisia.
authors.forename: Sameh
authors.initials: S
authors.lastname: Belhaj
authors.affiliation: Unit of Typing & Genetics of Mycobacteria, Laboratory of Molecular Microbiology, Vaccinology, and Biotechnology Development, Institut Pasteur de Tunis, Université Tunis El Manar, Tunis, Tunisia.
authors.forename: Helmi
authors.initials: H
authors.lastname: Mardassi
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use; D004196:Disease Outbreaks; D005260:Female; D018023:HIV Seronegativity; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy / Q000453:epidemiology* / Q000382:microbiology; D014416:Tunisia / Q000453:epidemiology; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents