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Regimens to treat multidrug-resistant tuberculosis: past, present and future perspectives

Emanuele Pontali, Mario C. Raviglione, Giovanni Battista Migliori and the writing group members of the Global TB Network Clinical Trials Committee
European Respiratory Review 2019 28: 190035; DOI: 10.1183/16000617.0035-2019
Emanuele Pontali
1Dept of Infectious Diseases, Galliera Hospital, Genova, Italy
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Mario C. Raviglione
2Global Health Programme, University of Milan, Milan, Italy
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Giovanni Battista Migliori
3Servizio di Epidemiologia Clinica delle Malattie Respiratorie, Istituti Clinici Scientifici Maugeri IRCCS, Tradate, Italy
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Tables

  • TABLE 1

    Historical list of recommended regimens for multidrug-resistant (MDR)/extensively drug-resistant (XDR) tuberculosis (TB)

    NameYearMain features/regimensLength of treatment[Ref.]
    DOTS-PLUS2000
    • Rational use of second-line drugs in resource-limited settings

    • GLC to facilitate access to proven quality second-line anti-TB drugs to overcome difficulties in procurement and cost

    [6, 7]
    Guidelines for the programmatic management of drug-resistant TB2006
    • Management of MDR-TB to be integrated into comprehensive national TB control plans

    • First “modern” categorisation of drugs used to treat MDR-TB into five groups

    • Options for tailoring diagnosis and care to different epidemiological and programmatic conditions worldwide

    18 months after culture conversion[9]
    Guidelines for the programmatic management of drug-resistant TB: emergency update 2008
    • Definition of XDR and acknowledgement of this threat

    • Recommendations on drug resistant management

    • Introduction of rapid DST

    [10]
    WHO guidelines for the programmatic management of drug-resistant TB: 2011 update2011
    • Importance of rapid DST stressed

    • Regimens including at least four, and ideally five, drugs likely to be effective

    • Drugs to be included are a FLQ, an injectable agent, ethionamide or prothionamide, PZA and either cycloserine or para-amniosalicylic acid. Other drugs such as EMB or group 5 drugs could be added, but they should not be counted among the four effective drugs

    20 months (with an 8-month intensive phase)[11]
    WHO consolidated guidelines on drug-resistant TB treatment2019
    • Continued recommendation of using shorter regimen whenever possible

    • If using injectables use amikacin

    • Drugs reclassified into three groups (A, B and C) for the purpose of composing the longer regimen:  Group A includes three drugs to be prioritised and used, if possible, in all regimens: levofloxacin/moxifloxacin, BDQ and LZD  Group B includes two drugs to be possibly added to all regimens (CFZ and cycloserine/terizidone) Group C includes “other” agents (including injectables) to be used as a substitute to complete a regimen of at least four drugs when agents from groups A and B cannot be used

    Longer regimen: may be standardised or individualised; duration 18–20 months, modified depending upon patient response
    Shorter regimen: 9–12 months
    [32]

    WHO: World Health Organization; RR: rifampicin-resistant; GLC: Green Light Committee; DST: drug susceptibility testing; FLQ: fluoroquinolone; PZA: pyrazinamide; EMB: ethambutol; CFZ: clofazimine; BDQ: bedaquiline; LZD: linezolid.

    • TABLE 2

      Innovative ongoing trials for an “all-oral” treatment of multidrug-resistant (MDR)/extensively drug-resistant (XDR) tuberculosis (TB)

      Trial number/nameType of TB (MDR/XDR)Study phaseRegimens studiedPromoterDuration of new regimenStatusPatients n
      1Nix#XDR3Pretomanid, bedaquiline and linezolidTB Alliance6 monthsOngoing>75¶
      2ZeNixXDR3Pretomanid, bedaquiline and linezolid (linezolid treatment dose and duration are double-blinded)TB Alliance26 weeksEnrolling180 (estimated)
      3STREAMMDR3A: local WHO standard
      B: clofazimine, ethambutol, moxifloxacin and pyrazinamide (40 weeks) + isoniazid, kanamycin and prothionamide (first 16 weeks)
      C: bedaquiline, clofazimine, ethambutol, levofloxacin and pyrazinamide (40 weeks) + isoniazid and prothionamide (first 16 weeks)
      D: bedaquiline, clofazimine, levofloxacin and pyrazinamide (28 weeks) + isoniazid and kanamycin (first 8 weeks)
      IUATLD36/56 weeksEnrollingCurrently >300
      4NeXTMDR3Linezolid, bedaquiline, levofloxacin, pyrazinamide + ethionamide or terizidone or high-dose INHSouth African investigators6–9 monthsNot yet recruiting300 (estimated)
      5TB PRACTECALMDR/XDR2–3A: local WHO standard
      B: bedaquiline and pretomanid + linezolid, moxifloxacin
      C: bedaquiline and pretomanid + linezolid, clofazimine
      D: bedaquiline and pretomanid + linezolid
      MSF6 monthsEnrollingCurrently >100 (630 estimated)
      6End TBMDR3A: bedaquiline, linezolid, moxifloxacin, pyrazinamide
      B: bedaquiline, linezolid, clofazimine, levofloxacin, pyrazinamide
      C: bedaquiline, delamanid, linezolid, levofloxacin, pyrazinamide
      D: delamanid, clofazimine, levofloxacin, linezolid, pyrazinamide
      E: delamanid, clofazimine, moxifloxacin, pyrazinamide
      F: local WHO standard, including the possible use of bedaquiline or delamanid
      MSF and PIH9 monthsEnrollingCurrently >170 (750 estimated)
      7SimpliciTBMDR (or single resistance to isoniazid or rifampicin)2Bedaquiline, pretomanid, moxifloxacin, pyrazinamideTB Alliance6 monthsEnrollingCurrently >10 (150 estimated)
      8MDR-ENDMDR2Delamanid, linezolid, levofloxacin and pyrazinamide versus local WHO standardSeoul National University Hospital9–12 monthsEnrolling(238 estimated)

      IUATLD: International Union Against Tuberculosis and Lung Diseases; MSF: Médecins Sans Frontières; PIH: Partners In Health; WHO: World Health Organization; INH: isoniazid: #: definitive results pending; ¶: information reported only for this number of patients.

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      Regimens to treat multidrug-resistant tuberculosis: past, present and future perspectives
      Emanuele Pontali, Mario C. Raviglione, Giovanni Battista Migliori
      European Respiratory Review Jun 2019, 28 (152) 190035; DOI: 10.1183/16000617.0035-2019

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      Regimens to treat multidrug-resistant tuberculosis: past, present and future perspectives
      Emanuele Pontali, Mario C. Raviglione, Giovanni Battista Migliori
      European Respiratory Review Jun 2019, 28 (152) 190035; DOI: 10.1183/16000617.0035-2019
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