SEIN SEIN THI1, SYLVIE JONCKHEERE1, CHINMAY LAXMESHWAR1, GUSTAVO CORREA1, SARTHAK A RASTOGI1, PARVATI NAIR1, SUYOG S SHETYE1, DINESH P SAWANT1, MRINALINI DAS1, HOMA MANSOOR1, PETROS ISAAKIDIS1,2 1 MÉDECINS SANS FRONTIÈRES, MUMBAI, INDIA 2MÉDECINS SANS FRONTIÈRES, OPERATIONAL RESEARCH UNIT, LUXEMBOURG CITY, LUXEMBOURG Too little, too late; new anti-TB drugs for patients with complex drug-resistant tuberculosis in Mumbai Sarthak A Rastogi MSF OCB, Mumbai, India

Digesting the Alphabet Soup - DR-TB Easier to Treat Difficult to Treat ??? Drug susceptible TB (DS-TB) Multidrug resistant TB (MDR-TB) Extensive drug resistant TB (XDR-TB) Pre-extensive drug resistant TB (PreXDR-TB) Too little, too late; new anti-TB drugs for patients with complex drug-resistant tuberculosis in Mumbai

Scenario facing DRTB community Challenging Time Exciting Time Difficult to treat drug resistant (DR) patterns are emerging DR TB treatment takes longer (~2 yrs), use of toxic drugs which lacks clinical evidence Fewer Drugs to treat (≥4 required) Dismal cure rates – Globally 48%, HIV/ DR TB co infected – 38% New diagnostic tool – after > 100yrs Renewed interest in TB research Reanimation of age old tools – Surgery After a gap of 50yrs since the last TB drug – we have 2 new drugs Too little, too late; new anti-TB drugs for patients with complex drug-resistant tuberculosis in Mumbai

Background - DR-TB New Drugs Only 2 NEW DRUGS (Bedaquilline - Bdq & Delamanid - Dlm) Bdq & Dlm validated by WHO in 2012 & 2013 to be “conditionally used” and “required monitoring of pharmacovigilance” Bdq is registered only in 9/27 high burdened countries (including India, where a Conditional Access Program is about to start) The price of new drugs is still high – Bdq: 900 USD/course, Dlm: 1700 USD /course New drugs are available to only 2% of patients who need them (AC) Too little, too late; new anti-TB drugs for patients with complex drug-resistant tuberculosis in Mumbai

Setting –MSF Clinic in Mumbai Provides free DR TB and HIV treatment services since 2006 1101 HIV and 253 TB/DR TB beneficiaries Increasing proportion of complex DR TB cases (PreXDR and XDR) Access to Bdq through CU in 2013 – Aug 2015, Dlm since June 2015 Counseling and consent prior to introduction of Bdq and Dlm into back-bone regimen Enrolled DR TB patients (2013-2015) Too little, too late; new anti-TB drugs for patients with complex drug-resistant tuberculosis in Mumbai

Method of study Descriptive Study from routinely recorded and collected medical data Retrospective cohort analysis of 12 patients registered for Bdq and 14 patients for Dlm from Feb 2013 to Dec 2015 (~10% of the global cohort on Dlm) This retrospective analysis met the criteria of the MSF Ethics Review Board for exemption from ethics review ©MSF / Anshul Uniyal Too little, too late; new anti-TB drugs for patients with complex drug-resistant tuberculosis in Mumbai

Characteristic of patients Bedaquiline Group (n=12) Delamanid Group (n=14) Age (yrs) 18-37 17-47 Gender (M:F) 4: 8 4: 10 HIV co-infected 2 Type of DR TB (based on 13 drugs Drug Susceptibility Testing) Pre XDR XDR 3 9 12 Prior exposure to 2nd line anti-TB drugs Yes / No 12 / 0 12 / 2 Too little, too late; new anti-TB drugs for patients with complex drug-resistant tuberculosis in Mumbai

No of patients by > 2 and < 2 likely working drugs* Results No of patients by > 2 and < 2 likely working drugs* *likely working drugs is arbitrarily defined as drugs either sensitive in DST-results and/ or less-than 3 month-of-exposure Backbone regimens: XDR: Cm, Lfx, Cs, PAS, Cfz, Lzd, Amx/Cluv PreXDR:Cm,Lfx,Cs,Cfz,Lzd,Amx/Cluv, only 1 case with PAS, 1 case with Z XXDR: Cm, Lfx, Cs, Cfz, Lzd, Amx/Cluv Too little, too late; new anti-TB drugs for patients with complex drug-resistant tuberculosis in Mumbai

Outcome 1 died prior to initiation 1 died after Bdq course 2 cured / completed 12 requests for Bdq CU 11 started on treatment 8 doing well on treatment 14 requests for Dlm CU 12 started on treatment 10 doing well on treatment 1 died prior to initiation 1 no effective regimen 2 died on treatment Too little, too late; new anti-TB drugs for patients with complex drug-resistant tuberculosis in Mumbai

Death during treatment Other severe Adverse Events Results – Major SAE Death during treatment Severe Cardio-toxicity (QTc > 500ms) Other severe Adverse Events Bdq (n=11) 1* 2 Dlm (n=12) 2* 2** * 3 deaths = due to evolution of DR TB, no direct relationship with new drugs ** same patients, cardio-toxicity triggered by other side-effects Cardio-toxicity: no need for permanent discontinuation Despite other cardio-toxic drugs in all patients for 1 case - stopped Bdq for 10 days and stopped Cfz until QTc <500 and reintroduced 100 mg, other case – stopped all drugs for 6 days, reintroduced all when Qtc <500 (chronic diarrhoea grade 3- pre-existing condition, PNP – grade 3, moderate depression (on Mitrazepine) Too little, too late; new anti-TB drugs for patients with complex drug-resistant tuberculosis in Mumbai

Discussion Promising outcomes: sustained culture conversion – 16/18 cases Safe ambulatory treatment with adequate monitoring (clinical, lab & ECG) Limitation: Small cohort but one of the 1st ever documented cohort with a high proportion of ≤ 2 likely working drugs (21/26) v/s 4 drugs required for an effective regimen © Sylvie Jonckheere Too little, too late; new anti-TB drugs for patients with complex drug-resistant tuberculosis in Mumbai

Discussion 21 patients with ≤ 2 likely working drugs, 24/26 with prior exposure to 2nd line drugs They need at least two new drugs to establish efficient treatment Too few drugs available Diagnosed too late Access to these new drugs remains difficult Compassionate Use programs and restrictive protocols for Dlm Conditional Access Programs that has cut down access to Bdq QTc: all with recorded QTc (10): experienced increased QTc, Baseline QTc is high (>450, <480) : 66.7% have >450 ms, 4/6 has prior exposure to Cfz and Mfx, 3 case with QTc <450: 1 no exposure to both Cfz and Mfx, 1 exposure to Cfz, 1 to both All patients are on Lfx and Cfz containing regimen when on Bdq avg increase 45 ms (8-98 ms), Max QTC occurred anytime from w1 to W24, most occurrence within 2 mth, two case with grade 3 QTc: suspended Rx and reintroduce when QTc <500 Too little, too late; new anti-TB drugs for patients with complex drug-resistant tuberculosis in Mumbai

Conclusion Use of new TB drugs should be scaled up - not to be preserved as a last chance in case of multiple failures 2 new drugs is not enough in DR TB management: Urgent need for broader access to Bdq + Dlm combination for patients ≤ 2 likely working drugs, Need for large trial data with new regimens, (not just adding new single molecules) Need to tackle on-going transmission in the community Too little, too late; new anti-TB drugs for patients with complex drug-resistant tuberculosis in Mumbai

Acknowledgement: MSF team in Mumbai/Delhi and Our Patients who endure their difficult life-journey with DR TB to have access to new drugs! ©MSF / Anshul Uniyal Thank You! Too little, too late; new anti-TB drugs for patients with complex drug-resistant tuberculosis in Mumbai