Drug resistant TB: Lisa Chen, MD University of California, San Francisco Curry Interna:onal TB Center Sea=le, June 2016

Transcription

1 Drug resistant TB: Lisa Chen, MD University of California, San Francisco Curry Interna:onal TB Center Sea=le, June 2016

2 Drug- Resistant TB: De1initions Mono- resistant: Resistance to a single drug Poly- resistant: Resistance to more than one drug, but not the combina:on of isoniazid and rifampicin Mul0drug- resistant (MDR): Resistance to at least isoniazid and rifampicin Extensively drug- resistant (XDR): MDR plus resistance to fluoroquinolones and at least 1 of the 3 injectable drugs (amikacin, kanamycin, capreomycin)

3 MDR Care = team sport

4 Drug resistant TB in US What s the likelihood of caring for a case in your clinic?

5 Primary MDR TB, United States, * Number of cases Percentage total cases MDR (67 cases primary) in % of primary MDR were foreign-born 2 cases of XDR (range 0-10 per year) No. of Cases Percentage 3% 2% 1% 0% * Updated June 2015

6 10 Primary Anti- TB Drug Resistance, United States, * 5 INH resistant 9.8% MDR 1.3% 0 Isoniazid MDR- TB * Updated June 2015

7 Case scenario when should we suspect drug-resistance?

8 Case 1 Case: Gisela Schecter, MD 21-year-old Filipina woman with Type I DM recently emigrated from the Philippines No TB screening at the time of immigration History of treatment for TB with INH +/- RIF as a child and, more recently, with INH, RIF, PZA and EMB given by SAT last year Presented with cough x 5 months, progressive SOB/DOE x 6 weeks, pleuritic chest pain and fever to 101 degrees

9 Case 1 Case: Gisela Schecter, MD

10 Case 1 Case: Gisela Schecter, MD

11 Case 1 Case: Gisela Schecter, MD

12 Case 1 Case: Gisela Schecter, MD

13 Case 1 Case: Gisela Schecter, MD

14 Case 1 Case: Gisela Schecter, MD 21-year-old Filipina woman with Philippines Type I DM recently emigrated from the Philippines No TB screening at the time of immigration Where are the high risk areas in the world? History of treatment for TB with INH +/- RIF as a child and, more recently, with INH, RIF, PZA and EMB given by SAT last year Presented with cough x 5 months, progressive SOB/DOE x 6 weeks, pleuritic chest pain and fever to 101 degrees

15 MDR cases among noti1ied TB cases WHO report 2014 Number of MDR cases estimated to occur among notified pulmonary TB cases, 2014

16 Estimated global incidence and proportion of MDR among TB cases 2014 Es:mated: 480,000 new cases of MDR 3.3% of all new cases and 20% of previously treated cases have MDR Of no:fied cases - more than half are from India, China, and the Russian Federa:on Propor:on of previously treated cases with MDR up to 49-69% in some countries (Belarus, Estonia, Kazakhstan, Kyrgyzstan, Lithuania, Republic of Moldova, Russian Federa:on, Tajikistan, Ukraine, Uzbekistan) WHO 2015 report

17 Distribution of XDR Number of patients with laboratory confirmed XDR started on treatment in countries had reported at least one XDR-TB case by cases XDR reported in 2014 (survey data estimate 9.7% of MDR have XDR) WHO 2015

18 Transmission of DR- TB Biological Fitness of the Mtb organism is not generally worsened by resistance Studies have shown robust growth among RIF resistant and MDR strains Once created, drug resistant TB can spread to other people è The majority of global MDR TB (>70%) is among new pa:ents (i.e. was transmi=ed and not acquired)

19 Case 1 Case: Gisela Schecter, MD 21-year-old Filipina woman with Type I DM recently emigrated from the Philippines No TB screening at the time of immigration History of of treatment for for TB TB with with INH INH +/- +/- RIF RIF as a child and, more recently, with with INH, INH, RIF, RIF, PZA and EMB given by by SAT SAT last last year year Presented with cough x 5 months, progressive SOB/DOE x 6 weeks, pleuritic chest pain and fever to 101 degrees

20 Drug- Resistant Tuberculosis MDR-TB is a manmade problem It is costly, deadly, debilitating and is a major threat to our current control strategies.

21 More bugs, more drugs M. Narita MD Random Naturally Occurring Resistance in Bacterial Population I INH = 1 in 10 6 E I E RIF = 1 in 10 8 R EMB = 1 in 10 6 Strep =1 in 10 6 INH and RIF = 10 6 X 10 8 = 1 in 10 14

22 I patient-related factors I E provider-related factors E R program-related factors

23 Clinical Suspicion for MDR Recogni:on of risk factors: Foreign- born from countries or ethnici:es with high prevalence of MDR Ex. Hmong refugees, Tibetan ancestry Former USSR, China, Korea, Peru, Honduras are dispropor:onately MDR History of prior therapy (most powerful predictor) or failing current 1 st - line rx Known contact to DR case Presence of RIF resistance predicts MDR HIV+ (higher incidence of RIF mono- resistance)

24 High- risk MDR: Action Steps Obtain rapid molecular test for drug sensi:vity Xpert RIF/Mtb (RIF only) WA state: DRSS [INH (katg, inha); RIF(rpoB); PZA (pnca)] CA state: Pyrosequencing [INH (katg, inha); RIF(rpoB); FQ (gyra); Injectables x3 (rrs)] CDC Molecular Detec:on of Drug Resistance (MDDR) program - above drugs plus ethambutol (embb), PZA (pnca), capreomycin (tlya), kanamycin (eis) Others: HAIN line- probe (include SL LPA), MODS Order both first/second- line conven:onal DST Consider ini:a:on of expanded regimen

25 Genes Associated with Resistance RIF resistance rpob core region (> 95%) INH resistance katg, inha (85%) ahpc, ndh, and unknown (10-15%) FQ resistance gyra (>90%) Injectable resistance (amikacin, capreomycin, kanamycin) rrs (70-90%)

26 Case 1 Case: Gisela Schecter, MD Started on a four drug standard regimen plus moxifloxacin 400 mg po qd x1 week (is this wise?) Three sputum specimens for AFB smear were positive and the sediment was sent for molecular beacon (MB) testing MBs found mutations conferring both INH + RIF resistance

27 What would you do next? 1. Wait for phenotypic DSTs for first and second-line drugs 2. Continue RIPE and moxifloxacin 3. Begin an empiric MDR-TB regimen 33% 33% 33% 1 2 3

28 Case 1 Case: Gisela Schecter, MD After MDR-TB service consultation, the patient was placed on: Amikacin 870 mg IV five times weekly Moxifloxacin 400 mg po qd Cycloserine 500 mg po qd PAS 4 gm po bid EMB 15 mg/kg po qd PZA 25 mg/kg Vitamin B6 50 mg

29 Case 1 Case: Gisela Schecter, MD Susceptibility results show resistance to all first-line drugs Quinolones: CDC: Res: Oflox, Cipro MDL: Borderline (2.0) Res: Levo NJM: Intermediate (1.0) Res: Moxi Was there a mechanism for acquired fluoroquinolone resistance? Role for continuing moxifloxacin? Treatment regimen?

30 CITC Warmline Consultation Curry Interna:onal Tuberculosis Center NOTB or

31 How many drugs for MDR? Goal: 4-6 likely effec:ve drugs (and op?mally at least 5) Recent studies suggest be=er outcomes with at least 5 drugs (we used to say at least 4 ) Expert input: Consider more if extensive disease and/or resistance Four may be sufficient with limited disease and/or limited resistance [WHO 2016 at least 5 effec:ve drugs including PZA] CITC DR-TB: A Survival Guide for Clinicians v3 2016

32 Building an Individualized Regimen for MDR- TB STEP 1 Use any available One of these PLUS PLUS One of these Begin with any First- line agents to which the isolate is susceptible Add and an injectable drug based on susceptibilities First- line drugs Pyrazinamide Ethambutol Fluoro- quinolones Levo@loxacin Moxi@loxacin Injectable agents Amikacin Capreomycin Kanamycin 1 Streptomycin 2 1. Not available in U.S. 2. SM: use only if not previously used and if documented susceptibility

33 Building an Individualized Regimen for MDR- TB (2) STEP 1 This case: Use any available First- line drugs Pyrazinamide Ethambutol One of these PLUS PLUS Fluoro- quinolones Levo@loxacin Moxi@loxacin? One of these Injectable agents Amikacin Capreomycin Kanamycin 1 Streptomycin 2 1. Not available in U.S. 2. SM: use only if not previously used and if documented susceptibility

34 Building an Individualized Regimen for MDR- TB (3) STEP 2 Add second- line drugs until you have 4-6 drugs (optimally at least 5) to which the isolate is susceptible (and preferably which have not been used to treat the patient previously) Pick one or more of these Oral second- line drugs Cycloserine Ethionamide PAS Linezolid 3 3. Although considered a thirdline drug, many experts now use LZD as a second-line drug option

35 Building an Individualized Regimen for MDR- TB (4) STEP 3 If there are not 4-6 drugs available in the above categories, consider third- line drugs in consultation with an MDR- TB expert Bedaquiline Delamanid 4 Clofazimine Imipenem Consider use of these Third- line drugs Meropenem/ Clavulanate Amoxicillin/ Clavulanate Clarithromycin High- dose INH 4. Awaiting FDA approval

36 MDR- TB Treatment Principles Seek expert consulta:on Never add a single drug to a failing regimen When choosing drugs: Consider cross- resistance Consider side- effects Avoid drugs used previously to treat pa:ent s TB

37 Cross- resistance for First- line Agents Drug INH, specifically low level resistance (InhA) RIF PZA EMB Cross Resistance Ethionamide (up to 70%) All rifamycins* None None * There might be some excep0ons for rifabu0n

38 Cross- resistance for Second- line Agents Drug Streptomycin Capreomycin Amikacin Levofloxacin Cycloserine PAS Linezolid Cross Resistance None Possibly amikacin Kanamycin* All fluoroquinolones** None None None *Some Km muta0ons w/o cross- resistance to Am ** Some excep0ons with moxifloxacin

39 Common Adverse Effects G.I. complaints Hepatotoxicity (early symptoms are anorexia and malaise, then abdominal pain, vomiting, jaundice) Ethionamide Cycloserine PAS Fluoroquinolones Clofazimine Rifabutin INH Rifampicin/rifabutin Ethionamide PZA PAS Fluoroquinolones

40 Common Adverse Effects Peripheral neuropathy Rash Headache Seizures INH Ethionamide Cycloserine Linezolid Ethambutol All Fluoroquinolones Isoniazid Cycloserine Ethionamide Ethambutol Cycloserine

41 Common Adverse Effects Hypothyroidism Hearing loss, Vestibular toxicity Behavioral changes Visual changes Renal failure Hypokalemia, Hypomagnesemia Ethionamide, PAS Aminoglycosides, Capreomycin Cycloserine, Ethionamide, Isoniazid, Fluoroquinolones Ethambutol, Rifabutin, Isoniazid, Linezolid Aminoglycosides, Capreomycin

42 Case 1: Gisela Schecter, MD Clinically did well and smear-converted EMB, PZA, discontinued Moxifloxacin increased to 600 mg qd Linezolid 600 mg qd added Repeat CXR

43 Case 1: Gisela Schecter, MD

44 Treatment Duration 2003 ATS/CDC/IDSA guidelines: mo WHO 2011 (based on individual pa:ent meta- analysis: 32 studies, over 9000 pts. Ahuja et al, PLoS Med 2012); Intensive phase at least 8 months Total dura:on at least 20 months (if no prior rx for MDR; if prior MDR rx at least 24 months) Survival Guide v3 Expert consensus: U0lize culture conversion to help guide minimum dura0on within U.S. high- resource sevng Intensive phase: at least 6 mo beyond culture conversion for use of injectable agent Total dura0on: at least 18 months beyond culture conversion

45 MDR- TB Treatment Principles Use case management and DOT (7 days/wk op:mal, but 5 days/wk acceptable) Use daily, not intermi=ent therapy (some excep:ons: renal, later injectables, HD INH) Drug ramping for CS, ETA, PAS to improve ini:al tolerance Helpful tool: Drug- o- gram MDR/XDR- TB è seek expert consulta:on

46 Linezolid (Zyvox) Increasing experience Excellent ac:vity against M. tb in vitro Dose mg po qd (case series using 300mg daily) Cost of therapy high Side effects myelosuppression, peripheral neuropathy, op:c neuropathy Avoid tyramine containing foods, soy products, SSRIs, tricyclic an:depressants and OTC meds containing pseudoephedrine and phenylpropanolamine à serotonin syndrome

47 Regimens for XDR- TB In the face of quinolone and injectable drug resistance, treatment choices are limited Linezolid and any remaining injectable become the mainstay of treatment, along with whatever oral medica:ons are lex to which there is in vitro suscep:bility Consider Bedaqualine Dura:on at least 24 mo post- culture conversion Surgery if disease is localized Some pa:ents may not be treatable

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49 Bedaquiline (Janssen) Class diarylquinoline Mechanism of ac:on - novel ATP synthase inhibitor Ac:vity In vitro bactericidal (replica:ng and dormant) Animal bactericidal and sterilizing ac:vity Early bactericidal ac:vity similar to isoniazid or rifampicin

50 Bedaquiline (TMC207) for MDR- TB Phase 2, randomized, controlled trial 47 pa:ents with MDR- TB randomized to TMC207 or placebo plus standard five- drug regimen Results Reduced :me to conversion Increased propor:on that converted (48% vs 9%) Mild to moderate AEs with nausea more common with TMC207 (26% vs 4%) Diacon AH, et al. NEJM 2009;360:2397

51 Mortality in Bedaquiline: Phase II Studies Bedaquiline No. of deaths Control Study Design No. (%) No. (%) C202 C208 (Stage 1) C208 (Stage 2) C209 Randomized, open- label, dose ranging EBA study Double- blind, randomized, placebo- controlled superiority trial Double- blind, randomized, placebo- controlled superiority trial Noncompara:ve, single- arm open label trial 2/ / / / / / No control No control Total 30/ / Black box warning increase risk of death CDC MMWR 2013;62;1-12

52 CDC Provisional Guidelines for Use of Bedaquiline (Sirturo) When an effec:ve treatment regimen cannot be provided: BDQ may be used for 24 weeks of treatment in adults with laboratory- confirmed pulmonary MDR- TB BDQ may by used on a case- by- case basis in children, HIV infected persons, pregnant women, extrapulmonary MDR- TB, and pa:ents with comorbid condi:ons BDQ may be used on a case- by- case basis for dura:ons longer than 24 weeks (5.5 mo. ½ life) DOSE: 400 mg once daily for 2 weeks, then 200 mg three :mes a week for 22 weeks, taken with food CDC MMWR 2013;62;1-12

53 CDC Provisional Guidelines: Bedaquiline No dose adjustment with mild/mod renal impairment Drug interac:ons metabolized through CYP3A Hepatotoxicity AST, ALT, bilirubin, alkaline phosphatase monthly Cardiac toxicity Baseline ECG and then 2, 12, and 24 weeks Baseline K, Ca, Mg levels Discon:nue if QTcF >500 ms or ventricular arrthymias CDC MMWR 2013;62;1-12

54 Updated MDR Guidelines WHO 2016 Guidelines: Add to WHO 2011 guide - addi:onal meta- analysis of individual pa:ent data (32 studies), >9000 pa:ents (XDR- TB excluded) New ATS/CDC/IDSA MDR guideline in progress New DR- TB Survival Guide April 2016 (!) h=p://

55 Short course Bangladesh regimen Nine (to twelve) month MDR regimen: 4 mo: Kanamycin, ga:floxacin, prothionimide, high- dose INH, clofazamine, ethambutol, PZA; then 5 mo: ga:floxacin, clofazamine, ethambutol, PZA : Treatment success 84.5% (n=515); KJM Aung et al. Int J Tuberc Lung Dis 2014 ;18(10) Ongoing mul:- country observa:onal study Separate STREAM trial [randomized 9 mo (except uses Moxi) vs standardized regimen]; adds BDQ arm (6 and 9 month regimens) Endorsed for use in WHO 2016 guidelines

56 Patient- centered DOT Pa:ent- centered care: more than watching pa:ents swallow their pills

57 TO 28: Personal Impact Source: Suzanne Marks, CDC/Division of Tuberculosis Elimination Findings from TBESC Task Order 28 Presentation at NTCA, 6/12/2014 Published: Emerging Infectious Diseases May 2014

58 The public sector covered: 80% of MDR and 100% of XDR costs Source: S. Marks, CDC/DTBE Findings from TBESC Task Order 28 Presentation at NTCA, 6/12/2014

59 Comparison of Direct Costs: Disease Cost in 2010 Dollars MDR TB episode $134,000 XDR TB episode $430,000 Pneumococcal Disease episode $47,000 Breast Cancer, life0me $20,000- $100,000 HIV Infec0on, life0me $380,000 Marks S., Emerging Infectious Diseases, May 2014

60 TO 28: MDR Outcomes random sample MDR cases from CA, TX, NYC (N=135, of total US 370) 21% Acquired resistance (any) 90% Ambulatory care (>80% doses done as outpt) 73% were hospitalized 1-6 :mes during course 90% assigned case managers 81% documented expert consulta:on 97% culture conversion if eligible (median 2 mos) 78% Treatment comple:on 9% died during treatment, 2% lost to follow- up Marks S., Emerging Infectious Diseases, May 2014

61 Management of Drug- Resistant TB Summary: Treatment of MDR- TB is complex and costly It is much easier to prevent than to treat Expert consulta:on should be obtained whenever possible when MDR- or XDR- TB is suspected Preventable, Treatable, Curable