XDR-TB and management options Ninth Technical Advisory Group and National TB Programme Managers Meeting TB Control in the Western Pacific Region, Manila, Philippines, 9-12 December 2014 CHIANG Chen-Yuan MD, MPH, DrPhilos

Global estimates of MDR-TB 3.5% (95% CI: 2.2–4.7%) among new cases 20.5% (95%CI: 13.6–27.5%)of previously treated cases (range: ‒ ) new MDR-TB cases worldwide (range: – ) MDR-TB cases among patients with pulmonary TB notified in % (95% CI: 6.5–11.5%) of MDR-TB cases have XDR-TB Global Tuberculosis Report 2014

Fluoroquinolone-resistant MDR-TB Without previous treatment of MDR-TB – use of fluoroquinolone in the treatment of lower respiratory tract infection – use of fluoroquinolone in the treatment of non- MDR tuberculosis, such as HREZ + fluoroqunolone (+ injectable) for retreatment TB cases With previous treatment of MDR-TB

Transition from drug-resistant TB to XDR-TB INH-resistant TB INH- and Quinolone-resistant TB XDR-TB Use of quinolone in the treatment of community acquired pneumonia Failure to successfully treat MDR-TB using second line drugs MDR-TB MDR-TB plus Quinolone resistance Failure to successfully treat TB using first line drugs Chiang C-Y, et al. Expert Rev Resp Med 2008;2:47-54

Resistance to anti-tuberculosis drugs by multidrug-resistant tuberculosis (MDR-TB) patient group 5 Falzon D, et al Eur Respir J 2013; 42: 156–168

Treatment outcomes for patients diagnosed with MDR- TB by WHO region, 2007–2011 cohorts 6 WHO. Global Tuberculosis Report 2014

Short Standardized Treatment of Multidrug- resistant Tuberculosis Intensive phase: GEZC KHP 4 months, extended till sputum conversion Continuation phase: GEZC 5 months Kanamycin (K) Prothionamide (P) Isoniazid (H)* Gatifloxacin (G)* Clofazimine, C Ethambutol, E Pyrazinamide, P 7 *high dose Van Deun A, et al. Am J Respir Crit Care Med 2010;182:684–692

GenoType® MTBDRplus test procedure 1)DNA Extraction From NALC/NaOH Processed sputum 2) Amplification by PCR 3) Hybridization Reverse hybridization of amplified nucleic acids to specific DNA probes bound on strips 4) Evaluation

Genetic Mutations Associated with M. tuberculosis Resistance to Amikacin, Kanamycin and Capreomycin: A Systematic Review gene mutations believed to confer resistance to the injectable drugs: the rrs and tlyA genes, and the eis promoter. Georghiou SB, et al. PLoS ONE 7(3): e doi: /journal.pone

Performance Assessment of the GenoType MTBDRsl Test for Detection of Second-Line and Ethambutol Drug Resistance among MDR-TB Patients high levels of specificity: 95.8 to 100%. the sensitivities of resistance detection using the GenoType MTBDRsl test were – Fluoroquinolone 85.1% – kanamycin 43.2%, – amikacin 84.2%, – capreomycin 71.4% – Ethambutol 56.2% with the inclusion of an extra gene, eis, in sequencing, the sensitivity reached 70.3% for detection of KM resistance. Huang W-L. et al. 2011

Forest plots of MTBDRsl sensitivity and specificity when performed indirectly or directly for fluoroquinolone resistance detection and using phenotypic culture-based DST as a reference standard

The diagnostic accuracy of the GenoType® MTBDRsl assay As a test for fluoroquinolone resistance measured against culture-based DST Pooled sensitivity (95% CI ) Pooled specificity (95% CI ) Direct test85.1% (71.9% to 92.7%) 98.2% (96.8% to 99.0%) Indirect test83.1% (78.7% to 86.7%) 97.7% (94.3% to 99.1%) Cochrane Database of Systematic Reviews 2014, Issue 10. Art. No.: CD DOI: / CD pub2.

Forest plots of MTBDRsl sensitivity and specificity when performed indirectly for the detection of resistance to amikacin (Ak), kanamycin (Kn) and capreomycin (Cm) using culture as a reference standard.

The diagnostic accuracy of the GenoType® MTBDRsl assay As a test for second-line injectable drugs (amikacin,kanamycin and capreomycin) resistance measured against culture-based DST when performed indirectly Pooled sensitivity (95% CI ) Pooled specificity (95% CI ) SLIDs76.9% (61.1% to 87.6%)99.5% (97.1% to 99.9%) amikacin87.9% (82.1% to 92.0%)99.5% (97.5% to 99.9%) kanamycin66.9% (44.1% to 83.8%)98.6% (96.1% to 99.5%) capreomycin79.5% (58.3% to 91.4%)95.8% (93.4% to 97.3%) Cochrane Database of Systematic Reviews 2014, Issue 10. Art. No.: CD DOI: / CD pub2.

Clofazimine 18 Study designed and supervised by: Jacques Grosset, MD And conducted by: Sandeep Tyagi, BS, Si-yang Li, BS, Deepak Almeida, PhD, Paul Converse, PhD

Long-term outcomes of patients with extensively drug-resistant tuberculosis in South Africa: a cohort study predictors of net culture conversion – no history of multidrug-resistant tuberculosis (p=0·0007) – use of clofazimine (p=0·0069). predictors of survival – net culture conversion (p<0·0001) – treatment with clofazimine (p=0·021). – Antiretroviral therapy in patients with HIV (p=0·003). Pietersen E, et al. Lancet 2014; 383: 1230–39

Linezolid for Treatment of Chronic XDR-TB 21 N Engl J Med 2012;367:

Clinical use of the meropenem- clavulanate combination for XDR-TB 23 Int J Tuberc Lung Dis 2012;16:558–560

Mechanisms of action of new compounds in clinical development for tuberculosis Ma Z, et al. Lancet 2010; 375: 2100–09

Diacon AH, et al. N Engl J Med 2014;371: phase 2b trial, Bedaquiline

Multidrug-Resistant Tuberculosis and Culture Conversion with Bedaquiline In this phase 2b trial, Bedaquiline – reduced the median time to culture conversion from 125 days to 83 days (hazard ratio 2.44 (95% CI ) – Increased the rate of culture conversion at 24 weeks (79% vs. 58%, P = 0.008) and at 120 weeks (62% vs. 44%, P = 0.04). The overall incidence of adverse events was similar in the two groups. There were 10 deaths in the bedaquiline group and 2 in the placebo group, with no causal pattern evident. Diacon AH, et al. N Engl J Med 2014;371:723-32

Diacon AH, et al. N Engl J Med 2014;371:723-32

Mean changes from baseline in QTcF* over time among patients treated with bedaquiline plus background regimen † (BR) versus placebo plus BR, Study C208 (Stage 2) MMWR / October 25, 2013 / Vol. 62 / No. 9

WHO Companion Handbook the QT interval needs to be adjusted (corrected) for the heart rate 2.the Fredericia method (QTcF): dividing the QT interval by the cubed root of the interval in seconds between the peak of two successive R waves (RR)

Flowchart of intent-to-treat patients in delamanid (DLM) Trial 204, Trial 208 and Study 116 Eur Respir J 2013; 41: 1393–1400

Long-term (24 month) treatment outcomes after treatment with delamanid in combination with an optimised background treatment regimen: MDR- and XDR-TB patients Eur Respir J 2013; 41: 1393–1400

Cascade of regimens RifampicinQuinoloneTreatment approach SusceptibleFirst line anti-TB treatment ResistantSusceptibleSecond line anti-TB treatment (9-month regimen) Resistant New drugs and potential group 5 drugs

In Summary Globally, 9.0% (95% CI: 6.5–11.5%) of MDR-TB cases have XDR-TB. Rapid diagnosis of resistance to rifampicin, fluoroquinolone and second line injectables will be helpful in the choice of regimens. Do not add a new drug to a failing MDR-TB regimen. Evidence is emerging that proper use of clofazimine, linezolid, meropenem, and new drugs improves the outcome of XDR-TB. However, experience is insufficient in terms of the type of drugs, the number of drugs and the duration required for the treatment of XDR-TB. Would countries be interested in using a standardized protocol for the treatment of quinolone-resistant TB and XDR-TB?