Multiple Drug-resistant Tuberculosis: a Threat to Global - and Local - Public Health

Transcription

1 Multiple Drug-resistant Tuberculosis: a Threat to Global - and Local - Public Health C. Robert Horsburgh, Jr. Boston University School of Public Health Background Outline Why does drug resistance threaten global TB control? Old and new drugs for MDR-TB Ongoing clinical trials of MDR-TB disease Designing the optimal MDR-TB regimen Southeastern National TB Center 1

2 Tuberculosis (TB): Basic Facts Caused by a bacterium (Mycobacterium tuberculosis) Spread via aerosol route Most who are infected never develop active disease About 10% of infected develop active disease during their lifetime 5% in the first 2 years after infection (primary disease) 5% later in life (reactivation disease) Those with active disease infect an average of 8 to 10 persons if untreated Southeastern National TB Center 2

3 STAGES OF TUBERCULOSIS 70% 30% 5% 95% 5% 95% Southeastern National TB Center 3

4 Magnitude and Dynamics of the World Tuberculosis Problem, MILLION DEATHS 16 MILLION PREVALENT CASES (8.6 Million incident) RELAPSE CURES 4.9 BILLION UNINFECTED EXPOSURE REMAIN UNINFECTED 2.1 BILLION INFECTED 2013 Global TB Report Southeastern National TB Center 4

5 Six-month regimen for newly diagnosed cases of tuberculosis Month of treatment Medication 1-2 (intensive phase) Isoniazid, rifampicin, pyrazinamide,(ethambutol) 3-6 (continuation phase) Isoniazid, rifampicin 100% 5-year Outcome of Tuberculosis Therapy 75% Percent 50% 25% 0% No Poor Good Dead Cured Chronic/Relapse Southeastern National TB Center 5

6 Trends in Global TB Incidence And Deaths over time Global TB Report Annual Incident Global TB Southeastern National TB Center 6

7 Barriers to TB Success Underdiagnosis Stigma Resources Inadequate tools Poor treatment adherence Long course Toxicity Cost WHO Endorses GeneXpert MTB/RIF December 2010 Xpert MTB/RIF-molecular test, detects TB and rifampin resistance directly from sputum Provides diagnosis in < 2 hours Sensitivity sm-pos: 98% (95% CI: 97%-99%) sm-neg: 68% (95% CI: 61%-74%) HIV-pos: 79% (95% CI: 70%-86%) RIF-R: 95% (95% CI: 90%-97%) As of Sept 2013, 95 countries had purchased Xpert MTB/RIF test Southeastern National TB Center 7

8 What do you know about GeneXpert? 2013 Global TB Report Southeastern National TB Center 8

9 Stages of TB with and without HIV 70% HIV - 30% 5% 5% 95% 95% 30% HIV + 70% 40% 45% 60% 55% Trends in Global TB Incidence over time by Region, Lancet 2011;378:59 Southeastern National TB Center 9

10 When a patient has HIV and TB disease but is not on antiretroviral therapy, when should antiretroviral therapy be started? Multidrug-Resistant TB (MDR-TB) Tuberculosis disease caused by M. tuberculosis resistant to Isoniazid and Rifampin (+/- other drugs) Southeastern National TB Center 10

11 MDR-TB - Background Estimated 450,000 new cases last year Less than 25% treated Recommended treatment takes months, cures only ~65%, 15+% mortality No systematic study of currently recommended regimens Second-line drugs are associated with substantial toxicity Emergence of additional resistance in 9-15% Southeastern National TB Center 11

12 Response to of TB % Cured Average Number of Drugs to Which TB was Resistant Southeastern National TB Center 12

13 Have you personally participated in the care of a patient with MDR-TB? WHO Global TB Report 2011 Southeastern National TB Center 13

14 Annual Incident Global MDR-TB Declaration of Cape Town, 2000 Co-sponsors: CDC NIH World Bank International Federation of Pharmaceutical Manufacturers Implementers: Global Alliance for TB Drug Development Global Drug Facility Global Laboratory Initiative Green Light Committee Southeastern National TB Center 14

15 Goals of a New Regimen for MDR-TB Shorten duration of treatment from months Improve on 60% cure proportion Improve tolerability Prevent the emergence of further resistance REPURPOSING OLD DRUGS FOR MDR-TB Southeastern National TB Center 15

16 Potential Repurposable Drugs PZA (WHO Group 1) Moxifloxacin (WHO Group 3) Levofloxacin (WHO Group 3) Linezolid (WHO Group 4) Clofazimine (WHO Group 5) Amoxacillin/Clavulinate (WHO Group 5) Imipenem/Cilastin (WHO Group 5) Clarithromycin (WHO Group 5) Tolerability of 3 rd -Generation Fluoroquinolones Class-specific: Peripheral neuropathy Tendon rupture Hepatotoxicity C. difficile superinfection Moxifloxacin: QT-prolongation Southeastern National TB Center 16

17 Tolerability of Clofazimine Skin discoloration (75-100%) Gastrointestinal intolerance (40-50%) Eosinophilic enteritis Interstitial nephritis Rash, dry skin, ichthyosis QT prolongation A 9-month regimen for MDR-TB in Bangladesh Kanamycin Prothionamide Isoniazid 4-month intensive phase prolonged if still smear-positive after 4 months Fixed 5-month continuation phase Gatifloxacin Ethambutol Pyrazinamide Clofazimine AJRCCM 2010:182: Southeastern National TB Center 17

18 Bangladesh Regimen: Efficacy 206 patients 170 Cures (84.2%) 11 Completions (5.3%) 11 Deaths (5.3%) 12 Defaults (5.8%) 1 Failure (0.5%) 1 Relapse (0.5%) AJRCCM 2010:182: Bangladesh Regimen: Tolerability 206 patients 44 Vomiting (21.4%) 13 Hearing Difficulties (6.3%) 8 Dysglycemia (3.9%) 8 Ataxia (3.9%) 2 Arthralgia (1%) 1 Mental (0.5%) AJRCCM 2010:182: Southeastern National TB Center 18

19 Tolerability of Linezolid in 72 Patients with MDR-TB* Peripheral neuropathy (40%) Anemia (25%) Optic Neuritis (10%) Thrombocytopenia (10%) GI disorders (8%) Neutropenia (2%) *Dose < 600mg/day Eur Resp J 2012;40:1437 Prospective Study of Linezolid in XDR-TB 40 patients with XDR-TB in Korea Randomized to 300mg qd or 600mg qd Further randomized to immediate versus 2 month delayed linezolid (both with OBR) 36/40 converted sputum cultures (mean 90 days) 4 failures were all resistant to linezolid NEJM 2012;367: Southeastern National TB Center 19

20 Linezolid in the of XDR-TB NEJM 2012;367: Tolerability of Linezolid in XDR-TB Trial 22 Patients treated with 600 mg/day Peripheral neuropathy (60%) Myelosuppression (20%) Optic Neuropathy (10%) 16 Patients on 600 mg then 300 mg after 2 months Peripheral neuropathy (50%) Myelosuppression (not seen) Optic Neuropathy (17%) NEJM 2013;367 (on-line supplement) Southeastern National TB Center 20

21 NEW DRUGS FOR MDR-TB Southeastern National TB Center 21

22 New MDR-TB Drugs in Clinical Development, 2014 Drug Class Company Status Bedaquiline Diarylquinolone Tibotec Phase 2 Delamanid Imidazooxazole Otsuka Phase 3 PA-824 Imidazooxazine GATB Phase 2 SQ-109 Ethylene Diamine Sequella Phase 2 Sutezolid Oxazolidinone Sequella Phase 2 AZD-5847 Oxazolidinone AstraZenica Phase 2 Have any patients seen in your program been treated with bedaquiline? Southeastern National TB Center 22

23 Bedaquiline Study C208 (Phase 2) Description: Addition of Bedaquiline to OBT for 6 months, followed by OBT for 18 months Regimens: OBT+Bedaquiline OBT+Placebo Sponsor: Janssen Target population: newly-diagnosed, smear+ MDR-TB, adults, CD4>300 if HIV+ Outcome: Time to sputum culture conversion Size: 200 patients Bedaquiline (TMC-207) Phase 2 MDR-TB Study Time to sputum culture conversion (MITT analysis) Proportion of Culture Positive Patients Time to 50% culture conversion: 12 weeks Placebo TMC207 Time to 50% culture conversion: 18 weeks 58% P = % BAS W 4 W 8 W 12 W 16 W 20 W 24 Time to Culture Conversion (in Days) 46 Diacon, IUATLD Southeastern National TB Center 23

24 Bedaquiline Study C208 Final results Bedaquiline+OBT Placebo+OBT Number 79 patients 81 patients Median Conversion 12 weeks 18 Weeks* Cure at week % 32%** Adverse Events 23% 19% Deaths 13% 2.5%** *p=0.01 **p=0.01 Diacon, IUATLD Nov 2013 Tolerability of Bedaquiline Nausea (~22%) Increased hepatic enzymes (?) QT prolongation NEJM 2009;360: Southeastern National TB Center 24

25 Delamanid Study 204 (Phase 2) Description: Addition of Delamanid (D) to OBT Regimens: OBT+D 100 mg bid OBT+D 200mg bid OBT+Placebo Target population: Adults with pulmonary MDR- TB, CD4>350 if HIV+ Outcome: Sputum conversion at 8 weeks Size: 430 patients NEJM 2012;366:2158 Southeastern National TB Center 25

26 Tolerability of Delamanid QT prolongation NEJM 2012;366:2157 MDR-TB Clinical Trials in Progress AZD-5847 Phase 2 NC-002 (PA-824) STREAM Delamanid Phase 3 Opti-Q Phase 4 Southeastern National TB Center 26

27 PA-824 (NC-002 Trial) Description: 8 week trial of PA-824 in combination with moxifloxacin and PZA Regimens: PA 100 -M-Z for DS-TB PA 200 -M-Z for DS-TB PA 200 -M-Z for MDR-TB (FQ and Z susceptible) HRZE for DS-TB Sponsors: GATB Target population: smear+ MDR-TB, adults Outcome: quantitative sputum cultures Size: 230 patients 100% enrolled Sites: Tanzania and South Africa Expected results: 2014 STREAM Study (Phase 3) Description: Modified Bangladesh regimen (with moxifloxacin in place of gatifloxacin) compared to standard MDR-TB regimen Regimens: 7-drug regimen (9 months) 4-5 drugs (18-24 months) Sponsors: IUATLD, USAID Target population: smear+ MDR-TB, adults Outcome: Failure, relapse, default or death Size: 400 patients 50% enrolled Sites: Ethiopia, Vietnam, South Africa Expected completion: 2016 Southeastern National TB Center 27

28 Delamanid Confirmatory Trial (Phase 3) Description: Addition of D to OBT Regimens:OBT+D 100 mg (D 6 months/obt 18 months) OBT+D 50 mg (D 6 months/obt 18 months) OBT+Placebo (24 months) Sponsor: Otsuka Pharmaceutical Development Target population: Adults with pulmonary MDR-TB, CD4>350 if HIV+ Outcome: Time to sputum conversion through 6 months Size: 430 patients Duration: 2015 Status: 100% enrolled Constructing a new MDR-TB Regimen: Principles At least 3 new drug classes Avoid overlapping toxicities Strive for all-oral regimen Estimate duration based on 2 month sputum culture conversion Southeastern National TB Center 28

29 MDR-TB Drug Menu Class Diarylquinolone: Nitroimidazole: Oxazolidinone: Fluoroquinolone: Riminophenazine: Other: bedaquiline delamanid, PA-824 linezolid, sutezolid, AZD-5847, others? levofloxacin, moxifloxacin, (gatifloxacin) clofazimine PZA MDR-TB Clinical Trials in Preparation Bedaquiline Phase 3 MARVEL (ACTG A5319) Bedaquiline/Delamanid DDI PA-M-Z NiX-TB (for XDR-TB) Southeastern National TB Center 29

30 Conclusions - I New TB drug classes may increase treatment response rates, shorten treatment duration and decrease mortality Tolerability of a number of the new agents remains to be defined, especially when used in combination Combination studies are needed to assure that DDI with other TB drugs and ART will not preclude their concurrent use Conclusions - II Trials currently in progress and under consideration will hopefully clarify DDI and overlapping toxicity issues A major challenge will be preventing the emergence of resistance to the new drugs Increased capacity for MDR-TB clinical trials will also be needed Southeastern National TB Center 30

31 Questions Bedaquiline Confirmatory Trial (Phase 3) Description: Addition of two new arms to STREAM Regimens: SOC 9-month regimen (B + oral OBT) 6-month regimen (B + oral & injectable OBT) Sponsor: USAID Target population: smear+ MDR-TB, adults Outcome: Failure, relapse, default or death Size: TBD Sites: Ethiopia, Vietnam, South Africa, Mongolia Expected completion:? Southeastern National TB Center 31

32 Opti-Q Study Description: levofloxacin in 4 doses + OBT to identify most efficacious tolerable dose of levo for MDR-TB Regimens: Levo at 11, 14, 17 and 20 mg/kg, all plus OBT for 6 months Sponsors: NIH, CDC, Macleods Target population: pulmonary MDR-TB, adults, FQ susceptible Outcome: sputum culture conversion Size: 100 patients Sites: Peru, South Africa Expected completion: month Bangladesh MDR-TB Regimen Am J Respir Crit Care Med 2010 (epub) Southeastern National TB Center 32