The Patient Triage Concept: Right Diagnosis, Right Treatment early diagnosis of patients with RR-/MDR-TB and resistance to key SLDs, followed by timely initiation of effective treatment regimens Susan van den Hof Liverpool 26 October 2016

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Patient Triage Concept: Right diagnosis, Right treatment Rapid molecular tests for TB and resistance (FLD and SLD) Early initiation of effective regimens for rifampicin-resistant (RR) TB patients: Shorter regimens for RR-TB patients without Risk or confirmed resistance to key SLD and/or Intolerance to key SLD Regimens containing new drugs for RR-TB patients with Risk or confirmed resistance to key SLD Severe TB disease KNCV developed the patient triage concept which allows for early diagnosis of patients with RR-/MDR-TB and resistance to key SLDs, followed by timely initiation of effective treatment regimens Effective implementation of KNCV’s patient triage concept means DR-TB patients can be offered the shorter regimen, or a regimen tailored to their needs, applying what is known about local TB drug resistance patterns, and their own previous drug treatment and drug susceptibility test results.

2016 WHO guidance underpins the Patient Triage Concept Use of molecular line probe assays for detection of second-line drug resistance Treatment guidelines for DR-TB Shorter DR-TB treatment regimen (STR) recommended under eligibility criteria Design of individualized treatment regimen uses different grouping of component medicines Using the newly WHO recommended rapid molecular tests for second line drug resistance, patients with rifampicin resistance can be quickly triaged to the most appropriate drug-resistant TB (DR-TB) regimen, either the shorter regimen or an individualized regimen

Patient Triage Concept Linking the bedaquiline donation program with introduction of the shorter DR-TB treatment regimen

Patient with presumptive TB Rifampicin resistant TB # Rapid molecular test (Xpert MTB/RIF) No TB Rif susceptible TB Rifampicin resistant TB # Appropriate referral/ treatment Standard TB treatment with First Line Drugs # Includes patients with high risk of RR-TB such as contacts of RR/MDR-TB patients GO THROUGH DIFFERENT OPTIONS

For Dx algorithm: need to consider: ELIGIBILITY CRITERIA FOR SHORTER DRUG-RESISTANT TB TREATMENT REGIMEN 1) No confirmed resistance to fluoroquinolones (FQ) and/or second-line injectables (SLI) 2) No contact with patient that has resistance to FQ/SLI 3) No exposure to second-line drugs (SLD) for ≥ 1 month 4) No known intolerance to drugs in the shorter regimen 5) Not pregnant 6) No Extra-Pulmonary TB (EPTB)* 7) No other risk of unfavorable outcome ** Rifampicin resistant TB # Initial treatment regimen Shorter DR-TB treatment regimen Eligible Individualized DR-TB treatment regimen Ineligible Send sample for SL DST (genotypic and phenotypic) START TREATMENT AFTER EVALUATION OF FOLLOWING CRITERIA: Diagnostic algorithm designed considering laboratory capacity of respective country For Dx algorithm: need to consider: Availability of SL LPA and/or SL phenotypic DST Transport mechanisms for specimens Information systems for transmission of results   Initiate treatment while awaiting DST result # Includes patients with high risk of rifampicin resistance such as contacts of RR/MDR-TB TB patients * Non-severe forms of EPTB that can be eligible for the shorter regimen include TB pleural effusion (adults and children) and TB lymph node (children) ** Risk of unfavorable outcome includes extensive or advanced TB disease (multiple cavities or extensive parenchymal damage)

No resistance / intolerance Resistance / intolerance Initial treatment regimen Shorter DR-TB treatment regimen Eligible Individualized DR-TB treatment regimen Ineligible Continue shorter DR-TB treatment regimen No resistance / intolerance to SLI and/or FQ Change to individualized DR-TB treatment regimen Resistance / intolerance to SLI and /or FQ Continue individualized DR-TB treatment whilst consulting experts Regimen adjustment based on Second-line drug susceptibility testing results Treatment tolerance Initiate treatment while awaiting DST result Regimen adjustment based on DST results & treatment tolerance Patients will have been on DR-TB regimen when phenotypic DST results come in and may not be possible to switch back to 9-month regimen

Individualized treatment regimens for RR-TB patients ineligible for STR Challenge TB supports inclusion of new drugs in the core DR-TB regimen for patients not eligible for the STR: Bdq and Dlm have strong bactericidal and sterilizing activity Efficacy confirmed in RCTs and is comparable to FLD Tolerability of both new drugs is well documented in RCTs WHO can not yet fully support the inclusion of new drugs as part of the core MDR-TB regimen while phase III trials are still ongoing

CTB/KNCV regimen design steps for RR-TB patients ineligible for STR   Choose new drug Bdq or Dlm STEP 2 Choose a fluoroquinolone Lfx Mfx Gfx STEP 3 Choose an injectable Km Cm Am STEP 4 Choose other core SL agents Pto (Eto), Cs (Trd), Lzd, Cfz STEP 5 Choose first line drugs Z E High-dose isoniazid  STEP 6 Choose other add-on agents PAS, Amx/Clv, Imp/Cln, Meropenem, Thioacetazone FQ or SLI depending on resistance pattern Aim is to design a regimen with ≥5 effective TB drugs during IP

CTB/KNCV documents and tools to support planning and implementation of ND&Rs Implementation planning tool Generic programmatic and clinical guide Generic SOPs (under development) Generic training materials (under development) Implementation planning tool Assists introduction of ND&Rs by highlighting gaps in the existing processes, TA needs, and development of plans Detailed breakdown of activities from the introductory steps to national scale-up, with tentative timelines for each step and set of activities (nationally and per site; can be done in parallel) Generic programmatic and clinical guide Complementary to Implementation planning tool Follows the Patient Triage Concept: early diagnosis of patients with RR-/MDR-TB and resistance to key SLDs, followed by timely initiation of effective treatment regimens To be adapted to the respective country setting

Right diagnosis, right treatment: Benefits Patients – earlier, effective treatment with lowest possible level of side effects. Reduced costs Health systems - shorter diagnostic delay, and less toxic, shorter and cheaper treatment, leading to better success rates Public health - reduced transmission and reduction in creation of additional DR early diagnosis of DR-TB, followed by timely initiation of effective treatment regimens

Thank you! Acknowledgments: Gunta Dravniece Fraser Wares Agnes Gebhard