Multidrug resistant Tuberculosis

Multidrug resistant Tuberculosis Pennan Barry, MD, MPH California MDR TB Consult Service Surveillance and Epidemiology Section Curry International Tuberculosis Center Clinical Intensive October 018 Objectives Describe the national and global epidemiology of MDR and XDR TB Recognize who is at higher risk for MDR TB Discuss interpretation of molecular tests for drug resistance List the general principles of MDR/XDR TB treatment Discuss the challenges in managing contacts of MDR/XDR TB Identify resources for education, training, and expert consultation 1 1

Terminology Mono resistant: resistant to only one drug Poly resistant: resistant to more than one drug, but not the combination of INH and RIF Multidrug resistant (MDR): resistant to at least INH and RIF Pre extensively drug resistant (Pre XDR): MDR plus resistance to fluoroquinolone (FQ) or a second line injectable (Amikacin, Kanamycin, or Capreomycin) Extensively drug resistant (XDR): MDR TB plus resistance to a FQ and at least one second line injectable Global MDR Burden 017 Estimate: 8,000 incident cases 47% from China, India, and Russia Surveillance by country and region 017: Data from 8% (160/194) of countries since 1994 Continuous surveillance (91) vs epidemiological surveys (69) National vs subnational National drug resistance surveys ongoing in 1 countries WHO Global Tuberculosis Report, 018 3

Percentage of New TB Cases with MDR TB Overall: 3.% WHO, Global Tuberculosis Report, 018 4 Percentage of Previously Treated Cases with MDR TB Overall: 18% WHO, Global Tuberculosis Report, 018 3

XDR TB 17 countries have reported XDR TB 8.% of MDR TB cases, increase from 6.% in 016 6 Resistant (%) 10 9 8 7 6 4 3 1 0 Primary Anti TB Drug Resistance, United States, 1993 016* Isoniazid MDR TB 1994 1996 1998 000 00 004 006 008 010 01 014 016 Year * As of June 1, 017. Note: Based on initial isolates from persons with no prior history of TB; multidrug resistant TB (MDR TB) is defined as resistance to at least isoniazid and rifampin. 7 4

Primary Isoniazid Resistance Among U.S. Born versus Non U.S. Born Persons, United States, 1993 016* 14 1 10 U.S. born Non U.S. born Resistant (%) 8 6 4 0 1994 1996 1998 000 00 004 006 008 010 01 014 016 Year * As of June 1, 017. Note: Based on initial isolates from persons with no prior history of TB. 8 3 Primary MDR TB Among U.S. Born versus Non U.S. Born Persons, United States, 1993 016* U.S. born Non U.S. born Resistant (%) 1 0 1994 1996 1998 000 00 004 006 008 010 01 014 016 Year * As of June 1, 017. Note: Based on initial isolates from persons with no prior history of TB; multidrug resistant TB (MDR TB) is defined as resistance to at least isoniazid and rifampin. 9

XDR TB* Case Count, Defined on Initial DST, by Year, 1993 016 1 10 8 Case count 6 4 0 1994 1996 1998 000 00 004 006 008 010 01 014 016 Year of diagnosis *XDR TB, extensively drug resistant TB. DST, drug susceptibility test. As of June 1, 017. Note: XDR TB is defined as resistance to isoniazid and rifampin, plus resistance to any fluoroquinolone and at least one of three injectable second line anti TB drugs. Multidrug resistant TB Cases California, 199 017 Number of MDR cases 0 4 40 3 30 0 1 10 0 47 46 4 36 39 34 31 41 33 37 36 34 8 31 33 3 3 14 6 18 3 9 30 199 1996 1997 1998 1999 000 001 00 003 004 00 006 007 008 009 010 011 01 013 014 01 016 017 MDR cases Pct MDR 1. 1 0. 0 Percent of culture pos cases 11 6

Recognition: Who Is At Higher Risk of MDR TB? History of previous TB treatment, particularly if recent Known exposure to MDR TB case HIV (+) Higher incidence of Rifampin mono resistance Poor response to standard 4 drug treatment Culture remains (+) after months treatment Recognition: Who Is At Higher Risk of MDR TB? NonUS born arrived in U.S. within last years Immigration from or recent extended travel to country with > % MDR among cases from that country diagnosed in California/U.S. These countries* are: India Laos Russia and other former Soviet states Korea Peru Central America Burma Ecuador Dominican Republic Other state or locally identified risk groups, including: Hmong refugees Persons of Tibetan origin *California data from 011 01 and U.S. data from 010 013 Current U.S. data are available from the CDC, Division of TB Elimination (DTBE) (www.cdc.gov/tb) 13 7

High risk for MDR: Action Steps Obtain molecular test for drug resistance Xpert MTB/RIF, (pyro)sequencing, Hain line probe test, or other Consider initiation of expanded regimen (rare in era of molecular testing) Contact of MDR TB case with active TB Immigrant with history of extensive treatment for TB in the past and again has active TB Extended time to resistance information/ not clinically stable enough to await results Molecular Testing for Drug Resistance 1 8

Antimicrobial agent Molecular Testing: Drugs/Loci Gene/locus Sensitivity (Sequencing) Specificity (Sequencing) Assays Isoniazid (INH) katg 86.0 99.1 Hain, PSQ, MDDR INH and Ethionamide inha promoter INH ahpc promoter 4. 100 PSQ INH fabg1 PSQ, MDDR Rifampin (RIF) rpob 97.1 97.4 Xpert, Hain, PSQ, MDDR Ethambutol (EMB) embb 78.8 94.3 Hain, MDDR Pyrazinamide (PZA) pnca 86.0 9.9 MDDR Fluoroquinolones gyra 79.0 99.6 Hain, PSQ, MDDR Amikacin (AMK) rrs 90.9 98.4 Hain, PSQ, MDDR Capreomycin (CAP) rrs tlya Lin, et al., Clin Lab Med. 014 Jun;34():97 314. doi: 10.1016/j.cll.014.0.00 http://www.cdc.gov/tb/topic/laboratory/mddrusersguide.pdf Lin, et al., J Clin Micro. 014;:47. 91.0 MDDR 16 Types of mutations Silent (synonymous) Nucleic acid change No amino acid change Not associated with drug resistance generally 14 (TTC TTT) mutation in rpob is the most common silent mutation Missense (nonsynonymous) Nucleic acid change Amino acid change Some are associated with resistance 17 9

10 Molecular Testing for Rifampin (rpob) Rifampin cornerstone of TB treatment Resistance requires a longer duration of therapy Rif resistance without INH resistance rare Rif resistance MDR Xpert Probes: Coverage of rpob 0 8 0 9 1 0 1 1 1 1 3 1 4 1 1 6 1 7 1 8 1 9 0 1 3 4 6 7 8 9 3 0 3 1 3 3 3 Codon # Most common silent mutation (14 TTT) Most common resistance mutation (31 TTG) Location of silent mutation Location of missense mutation

Ct Ct End pt MTBC detected 4 probes up RIF R detected Probe E no signals Δ Ct max > 4: 4.8 0=4.8 Most common MDR mutation: S31L, detected by probe E 0 Xpert Performance Rifampin Resistance Pooled median sensitivity: 9% (9% CrI: 90, 97) Pooled median specificity: 98% (9% CrI: 97, 99) Steingart 014 Cochrane Review (http://tbevidence.org/wp content/uploads/014/01/steingart Cochrane 1 Library Updated Xpert SR.pdf) 11

Number and Proportion MDR TB by Country/Region of Origin, CA 011 01 Country/Region No. % Former Soviet Republics 1. Laos 6.1 Burma 3.4 Japan 1 3. India 1 3.1 Guatemala 3.0 Korea (N&S) 7.9 Peru 1.6 Ethiopia 1.0 Philippines 7 1.7 Vietnam 13 1.4 China (incl Taiwan) 7 1. United States 13 0.8 Cambodia 1 0.7 Mexico 11 0.6 Countries with >0 cases tested for MDR Number and Proportion MDR TB by Country/Region of Origin, CA 011 01 Country/Region No. % PPV PPV (99% spec) (98% spec) Former Soviet Republics 1. 93% 87% Laos 6.1 84% 7% Burma 3.4 77% 63% Japan 1 3. 76% 61% India 1 3.1 7% 60% Guatemala 3.0 7% 60% Korea (N&S) 7.9 74% 9% Peru 1.6 7% 6% Ethiopia 1.0 66% 0% Philippines 7 1.7 6% 4% Vietnam 13 1.4 7% 40% China (incl Taiwan) 7 1. 4% 37% United States 13 0.8 44% 8% Cambodia 1 0.7 40% % Mexico 11 0.6 36% % Countries with >0 cases tested for MDR 3 1

MDR TB Cases by Country/Region of Origin and Years in the US, CA 011 01 Country/Region Total MDR TB cases years in US No. (%) > years in US No. (%) All Countries* (excl U.S.) 103 30 (3.7) 71 (1.) Vietnam* 13 9 (7.9) 3 (0.4) China* (incl Taiwan) 7 (8.8) (0.4) Philippines* 7 8 (4.0) 19 (1.4) * Difference is statistically significant 4 Number and % MDR among foreign born TB patients in the U.S., 010 013 Country of origin Total TB cases* No. % (Top 1 countries) Ukraine 93 1 1.9 Laos 84 1 4. Peru 373 14 3.8 Dominican Republic 96 8.7 Ecuador 307 8.6 Republic of Korea 461 11.4 Burma / Myanmar 46 9.1 India,1 40 1.9 Vietnam,00 3 1.6 China 1,478 3 1.6 Haiti 73 11 1. Philippines 3,068 39 1.3 Ethiopia 63 7 1.1 Guatemala 777 8 1 Mexico,4 37 0.7 Source: Centers for Disease Control and Prevention, Division of Tuberculosis Elimination, National Tuberculosis Surveillance System, Bob Pratt 13

How to interpret results of molecular tests for resistance 6 Case 1 70 yo asymptomatic man from India with abnormal preimmigration CXR, no TB history Domestic CXR with multifocal infiltrates Sputum smear positive x 3 Xpert positive: rifampin resistant What do you do next? Start MDR treatment Order pyrosequencing or MDDR Start RIPE Repeat Xpert on another specimen Start treatment for monorif resistance 7 14

Case 1 Treatment held; PSQ available within days and clinically stable Pyrosequencing: katg mutation: INH R rpob 31TTG mutation: RIF R gyra (FQ): no mutations rrs (amikacin): no mutations What do you do next? Start MDR treatment Order MDDR Start RIPE Repeat Xpert on another specimen Order second line DSTs Cancel DSTs (already have molecular results) 8 Case 70 yo man from Mexico in US x years with 4 weeks of cough, no TB history CXR with multifocal infiltrates Sputum smear positive x 3 Xpert positive, rifampin resistant What do you do next? Start MDR treatment Order pyrosequencing or MDDR Start RIPE Repeat Xpert on another specimen Start treatment for monorif resistance 9 1

RIPE started PSQ: Case katg/inha: no mutation INH Sens rpob: 14TTT silent mutation: RIF Sens 30 How to interpret molecular test for resistance Put into clinical and epidemiologic context! Confirm non sequencing tests (e.g., Xpert) with sequencing test Consider Rif resistance on Xpert to be MDR (not just rifampin monoresistant) Can usually treat based on sequencing test results; follow the growth based DST results 31 16

Limitations / Areas for Caution Molecular tests vs. DST discordance Undescribed mutations outside of loci in current molecular tests resistance Emerging resistance in mixed populations may not be detected Disputed mutations DSTs show susceptible but associated with clinical treatment failure 3 Experts on Xpert: A Laboratorian and a Clinician Discuss Interpretation of Xpert MTB/RIF Results This 90 minute webinar discussed the principles of Xpert MTB/RIF testing, highlighting it as an important tool for the rapid diagnosis of TB and how to best utilize the tool. A laboratorian and a clinician reviewed the rules set by the manufacturer, presented cases that addressed pitfalls in interpretation of test results, and offered expert opinion on how to proceed. The training was created for physicians who diagnose and treat patients with TB. The webinar may also be of interest to microbiologists. The webinar content is more advanced, and does not spend time on the basics. https://www.currytbcenter.ucsf.edu/trainings/experts xpert laboratorian and clinician discussinterpretation xpert mtbrif results 33 17

Basic steps: Choosing a regimen Decision: Begin empiric MDR regimen Ask for help: Expert consultation Empiric (expanded) regimen for MDR: 4 first line + FQ + linezolid (+ consider additional second line drug) How many drugs for MDR? Goal: 4 6 likely effective drugs optimally at least Recent studies suggest better outcomes with at least drugs Expert input: Consider more if extensive disease and/or resistance Four may be sufficient with limited disease and/or limited resistance 18

Building an Individualized Regimen for MDR TB STEP 1 Begin with any First line agents to which the isolate is susceptible Add a fluoroquinolone and an injectable drug based on susceptibilities Use any available First line drugs Pyrazinamide Ethambutol* One of these Levofloxacin Moxifloxacin One of these Injectable agents Amikacin Capreomycin Kanamycin 1 Streptomycin 1. Not available in U.S.. SM: use only if not previously used and if documented susceptibility *WHO 016 Guidelines put EMB in a lower group Building an Individualized Regimen for MDR TB STEP 1 Begin with any First line agents to which the isolate is susceptible Add a fluoroquinolone and an injectable drug based on susceptibilities Use any available First line drugs Pyrazinamide Ethambutol* One of these Fluoroquinolones Fluoroquinolones Levofloxacin Moxifloxacin One of these Injectable agents Amikacin Capreomycin Kanamycin 1 Streptomycin 1. Not available in U.S.. SM: use only if not previously used and if documented susceptibility *WHO 016 Guidelines put EMB in a lower group 19

Step 1 Step Step 3 Step 4 Building a Treatment Regimen WHO 016 Update Group A (one) Levofloxacin Moxifloxacin Gatifloxaxin Group B (one) Kanamycin Amikacin Capreomycin Group C (two) Ethionamide/Prothionamide Clofazimine Cycloserine/Terizidone Linezolid Group D1 Pyrazinamide (include) Ethambutol* High-dose INH* Group D Bedaquiline Delamanid Group D3 Imipemen/Meropenem Amoxacillin/Clavulanate P-aminosalicylic acid drugs, incl. PZA Demoted: PAS and EMB Promoted: Clofazimine, linezolid, INH high dose Not available in the U.S. Step 1 Step Step 3 Step 4 Building a Treatment Regimen WHO 016 Update Group A (one) Levofloxacin Moxifloxacin Gatifloxaxin Group B (one) Kanamycin Amikacin Capreomycin Group C (two) Ethionamide/Prothionamide Clofazimine Cycloserine/Terizidone Linezolid Group D1 Pyrazinamide (include) Ethambutol* High-dose INH* Group D Bedaquiline Delamanid Group D3 Imipemen/Meropenem Amoxacillin/Clavulanate P-aminosalicylic acid drugs, incl. PZA Demoted: PAS and EMB Promoted: Clofazimine, linezolid, INH high dose Not available in the U.S. 0

August 018 http://www.who.int/tb/publications/018/rapid_communications_mdr/en/ 40 Kanamycin and capreomycin removed http://www.who.int/tb/publications/018/rapid_communications_mdr/en/ 41 1

018: MDR Regimen Questions When (if ever) to use injectable? Use Clofazimine in all? Difficult to get FQ, BDQ, CFZ all prolong QTc How long to use BDQ? >6months? What will ATS/CDC/IDSA/ERS MDR Guidelines say? 4 Bangladesh Regimen Short course treatment for MDR Recommended by WHO 016 Observational data impressive (8 90% cure) RCTs ongoing Contraindications: resistance to any drug in regimen, extrapulmonary disease, pregnancy Should this be used in the U.S.? WHO, 016. http://who.int/tb/short_mdr_regimen_factsheet.pdf 43

Short(er) Course Regimen for MDR TB Initial Phase (7 drugs) Continuation Phase (4 drugs) Moxifloxacin* Ethambutol Pyrazinamide Clofazimine Prothionamide Isoniazid* Kanamycin *High dose 0 1 3 4 6 7 8 9+ months Eligibility for Short Course Regimen in California, 009 01 n=171 with full DSTs H (any) H (high) H (low) Drug resistance (%) Eligible for shorter regimen Alternate eligibility for shorter regimen * R SLID 1 FQ Eto E Z No.(%) No.(%) 100 77 18 100 7 9 36 63 46 (1%) 3(1%) *allow for resistance to ETO if INH resistance is low level Clofazimine not tested Analysis by Phil Lowenthal 3

Barriers to Implementing Clofazimine availability Full DST info few qualify by strict criteria How to substitute for adverse events or resistance Why does it work? Other considerations when choosing drugs Beyond susceptibility results, consider: Cross resistance (table page 76) Avoid drugs used previously Side effect profile 4

Treatment Duration Survival Guide Expert consensus for U.S. Setting: Use culture conversion to guide minimum duration Intensive phase: at least 6 mo beyond culture conversion for use of injectable agent Total duration: at least 18 months beyond culture conversion WHO 011 and 016 Guideline: Intensive phase at least 8 months Total duration at least 0 months (if no prior rx for MDR; if prior MDR rx at least 4 months) 003 ATS/CDC/IDSA guidelines: 18 4 mo Treatment regimens Suggestions based on pattern of drug resistance Pre XDR and XDR recommend longer duration (at least 4 mo. post culture conversion) Chapter 4, page 80

Medication Fact Sheets Drug class/trade name Activity against TB Cross resistance Dose (adult, peds, renal) Route of administration Preparation/storage Pharmacokinetics Oral absorbtion/metabolism CSF penetration Special circumstances Adverse reactions/contraindications Monitoring Costs/patient education Regimens for XDR TB Treatment choices are limited Bedaquiline, Linezolid and any remaining injectable become the mainstay of treatment Add whatever oral medications are left to which there is in vitro susceptibility Surgery if disease is localized Nearly all patients are treatable and curable 6

Surgery? No hard and fast rules; WHO: Surgery may be used Metaanalysis suggests success Consider if: Very extensive resistance Residual large cavity Predominantly one sided disease Previous MDR treatment failure Marrone MT, et al. Surgical interventions for drug resistant tuberculosis: a systematic review and meta analysis. Int J Tuberc Lung Dis 013;17(1):6 16. MDR TB Clinical Case Management Seek consultation with MDR TB expert as soon as multidrug resistance known Use daily DOT throughout entire treatment course No intermittent therapy for drug resistance!! Use case management tools (drug o gram) to follow serial changes in drugs, bacteriology, CXR, toxicities Optimize management of underlying medical conditions and nutritional status (i.e. diabetes) 7

8

Cycloserine: Therapeutic Drug Monitoring absorption highly variable therapeutic and toxic levels are very close drug levels are highly recommended Draw hours after dose Injectables: if renal compromise, significantly over or under weight, or elderly Some experts recommend obtaining levels routinely peak and/or trough levels Recommended MDR TB Monitoring for Efficacy Collect sputum monthly throughout End of treatment sputum for smear and culture CXR quarterly and at end of treatment Monitor for years after treatment Quarterly: first year, Q6 months: second year) 9

MDR TB Laboratory Monitoring Second line drug susceptibilities Repeat susceptibilities on cultures that remain positive after 3 months Repeat susceptibility for EMB/PZA if susceptible at baseline and 4 weeks of first line treatment 30

California MDR Outcomes 009 016 All MDR Cases n=19 Off Treatment 13 On Treatment Moved 11 0% 10% 0% 30% 40% 0% 60% 70% 80% 90% 100% Failure (micro)=1 Death=4 Failure(ADR)=4 Default/LTFU= Off Treatment n=13 Cure/Complete 118 0% 0% 40% 60% 80% 100% Includes consult and nonconsult cases by year of MDR Service notification MDR by MDR Service definition: includes molecular susceptibility tests and clinical cases 31

Common Side Effects G.I. symptoms Hearing loss, vestibular toxicity Renal insufficiency/electrolyte Hepatotoxicity Peripheral neuropathy Neuropsychiatric: depression, agitation, psychosis, difficulty concentrating, insomnia QTc prolongation Rash Visual changes Hypothyroidism Headache Chapter 9 Ethionamide, PAS, Quinolones, Clofazimine, Rifabutin, Linezolid Injectables Injectables PZA, PAS, Rifabutin, Ethionamide, Quinolones Linezolid, INH, Quinolones, Ethionamide, Cycloserine Cycloserine, Quinolones, Ethionamide Bedaquiline, Clofazimine, Quinolones All EMB, Rifabutin, Linezolid Ethionamide, PAS Quinolones, Cycloserine, Ethionamide, EMB Prevention Preventing acquired drug resistance DOT and daily therapy as appropriate Preventing transmission of MDR TB to contacts Effective treatment, Isolation until noninfectious Preventing progression to active disease in infected MDR TB contacts MDR LTBI treatment and monitoring 3

Isolation (CDPH/CTCA Guidelines) Patients with pulmonary MDR TB should be considered infectious until: An effective MDR regimen has been initiated and tolerated for weeks AND A favorable clinical response has occurred AND 3 consecutive sputum smears are documented AFB negative Guidelines for the Assessment of Tuberculosis Patient Infectiousness and Placement into High and Lower Risk Settings, 009: http://www.ctca.org/filelibrary/file_.pdf Preventing Progression to Active TB Some published data on LTBI treatment for MDR TB contacts; No randomized trials CDC guidance last in 199 Contact investigation and management principles same as drug susceptible: Drug resistant TB is not more infectious, but duration can be longer and consequences are greater Consider infectiousness of index case, duration/intensity of contact, immune status of contact, LTBI test results Rule out active disease prior to starting LTBI treatment 33

Fluoroquinolones for MDR Contacts Published data from MDR outbreaks in Chuuk: 104 of 119 received LTBI treatment x 1 months Adults: MFX + EMB (n=4) or MFX/LFX alone (n=1) Children: LFX + EMB (N=17) or LFX + Ethionamide (n=1) 11 stopped early; 6 received >6 mos 0 cases in treated vs 3 among 1 refused (36 mo f/u) Bamrah et al, Int J Tuberculosis Lung Dis 014 66 Treatment Regimens for MDR TB Contacts FQ monotherapy FQ + EMB Monitor for years only acceptable FQ + PZA very poorly tolerated PZA + EMB Other combinations? Duration? 34

Resources 68 Resources: COEs Curry International Tuberculosis Center 1 877 390 NOTB or 1 877 390 668 www.currytbcenter.ucsf.edu Heartland National Tuberculosis Center 1 800 TEX LUNG or 1 800 839 864 www.heartlandntbc.org New Jersey Medical School Global Tuberculosis Institute 1 800 4TB DOCS or 1 800 48 367 www.umdnj.edu/globaltb Southeastern National Tuberculosis Center 1 800 4TB INFO or 1 800 48 4636 http://sntc.medicine.ufl.edu Mayo Clinic Center for Tuberculosis 8 360 1466 http://centerfortuberculosis.mayo.edu/ 3

MDR Resources Partners in Health Guide (013): http://www.pih.org/library/pih guide to the medical management ofmultidrug resistant tuberculosis nd WHO MDR Guides: Companion Guide (014): http://apps.who.int/iris/bitstream/1066/130918/1/97894148809_eng.pdf Guideline (016): http://www.who.int/entity/tb/areas of work/drug resistant tb/mdrtbguidelines016.pdf?ua=1 International Union Guide (013): http://www.theunion.org/what we do/publications/technical/english/mdrtbguide_6 19 13_web.pdf CDC Bedaquiline Guideline (013): http://www.cdc.gov/mmwr/pdf/rr/rr609.pdf 70 California Resources MDR TB Service Provides clinical consultation, case management, CI assistance 10 60 3000 CA Microbial Diseases Lab pyrosequencing for drug resistance phenotypic DST for first line drugs and amikacin, moxifloxacin, capreomycin, and ethionamide 36

Acknowledgments Lisa True Lisa Chen Neha Shah Grace Lin Gisela Schecter Janice Westenhouse Marya Husary Leslie Phil Henry Lowenthal Jenny Flood Pennan Barry Neha Shah Gayle Schack (Ret) Kristen Wendorf Lisa True Christy Pak (Ret) Not pictured: Shereen Katrak 7 37