Many faces of TB: Drug resistant it ttbs Survival lgid Guide v3 P B L Ch G Sh t L T P. Barry, L. Chen, G. Schecter, L. True Curry International TB Center/CTCA April 20, 2016
Real case Practical Walk through New Survival Guide
0 yo man with diabetes Philippines to US late 1990 s Hemoptysis x several weeks Works in banking Tobacco hx Travelled to PI 4 years ago
0 yo man with diabetes Philippines to US late 1990 s Hemoptysis x several weeks Works in banking Tobacco hx Travelled to PI 4 years ago Let s talk about risk factors
TB Rate by Diabetes, Age, and Nativity California, 2010 2012 2012 (Persons aged 18) Case Rat te per 100 0,000 100 80 60 40 20 Diabetes No Diabetes 0 18 44 4 64 6 74 7+ 18 44 4 64 6 74 7+ United States or Canada Foreign born Demlow et al, BMC Public Health 201 Sources: Denominator: 2011 2012 California Health Interview Survey Numerator: CA TB Registry
What is the added value of NAAT? For AFB smear ( ): 0 70% of smear /culture + cases will be + by NAAT start treatment (earlier) If NAAT ( ), the likelihood of TB lower Release from isolation earlier (2 Xpert results finds all smear +) Stillstart treatmentif suspicion ishigh For AFB smear (+): NAAT can confirm TB quickly If NAAT negative, prevent falsely diagnosing TB (likely NTM if inhibitors are ruled out and result repeated) Luetkemeyer Clin Infect Dis 2016 6
Xpert MTB/RIF Test Performance Compared with Culture, U.S. patients Sensitivity i i Specificity i 1 Xpert 2 Xperts Smear (+) 96.7% 100% (9/61) (62/62) Smear ( ) 9.3% 71.4% (16/27) (20/28) 99.2% Luetkemeyer Clin Infect Dis 2016 7
Case: CXR Hemoptysis, cough x weeks No weight loss, fevers, or night ih sweats Admitted d and isolated Next tests?
Initial diagnostic tests Smear positive x3 (cultures sent) Xpert MTB/RIF: Positive for Mtb and RIF resistance
Benefits of Molecular Tests for Drug Resistance Reduced dtime to detection of resistance Time from empiric (first line) treatment to MDR treatment 40 days less (median) Less transmission Less acquired resistance while DSTs pending Less ineffective LTBI treatment given to contacts Banerjee et al, J Clin Micro, 2010 10
Xpert Performance Rifampin Resistance Pooled median sensitivity: iii 9% (9% CrI: 90, 97) Pooled median specificity: 98% (9% CrI: 97, 99) Steingart 2014 Cochrane Review (http://tbevidence.org/wpcontent/uploads/2014/01/steingart Cochrane Library Updated Xpert SR.pdf) 11
Chapter 3, page 3
Xpert Probes: Coverage of rpob Xpert Probes: Coverage of rpob 0 8 0 9 1 0 1 1 1 2 1 3 1 4 1 1 6 1 7 1 8 1 9 2 0 2 1 2 2 2 3 2 4 2 2 6 2 7 2 8 2 9 3 0 3 1 3 2 3 3 Codon # Most common Most common i silent mutation (14 TTT) resistance mutation (31 TTG) Location of silent mutation Location of missense mutation
Number and Proportion MDR TB by Country/Region of Origin, CA 2009 2013 2013 Country/Region No. % Former Soviet Republics 8 14. Laos 4.3 Korea, North and South 11 4.1 Burma 2 3.4 India 10 2.6 Central America 9 2.2 Peru 1 2.0 Ethiopia 1 1.9 Vietnam 17 1.9 Philippines 2 1.6 Kampuchea 2 1.4 China (incl Taiwan) 7 1.2 Mexico 16 0.8 United States 8 0. Countries with >0 cases tested for MDR 14
Number and Proportion MDR TB by Country/Region of Origin, CA 2009 2013 2013 PPV PPV Country/Region No. % (99% spec) (98% spec) Former Soviet Republics 8 14. 94% 89% Laos 4.3 81% 68% Korea, North and South 11 4.1 80% 67% Burma 2 34 3.4 77% 63% India 10 2.6 72% 6% Central America 9 2.2 68% 2% Peru 1 20 2.0 66% 0% Ethiopia 1 1.9 6% 48% Vietnam 17 1.9 6% 48% Philippines 2 16 1.6 61% 44% Kampuchea 2 1.4 7% 41% China (incl Taiwan) 7 1.2 4% 37% Mexico 16 08 0.8 44% 28% United States 8 0. 33% 20% Countries with >0 cases tested for MDR 1
MDR TB Cases by Country/Region of Origin and dyears in the US, CA 2009 2013 2013 Country/Region Total MDR TB cases <= 2 years in US No. (%) >2 years in US No. (%) All Countries (excl US)* 123 29 (3.3) 93 (1.) Former Soviet Republics 8 3 (33.3) (10.9) Vietnam* 17 8 (7.1) 8 (1.1) China (incltaiwan)* 7 4 (6.4) 3 (0.6) Philippines* 2 7 (3.6) 18 (1.4) Central America 9 2 (3.) 7 (2.1) India 10 2 (2.2) 2) 8 (2.9) All Other Countries 20 3 (1.7) 17 (1.9) Mexico 16 0 (0.0) 16 (0.9) Korea, North and South 11 0 (0.0) 11 (4.) * Difference is statistically significant. 16
Increased Risk for MDR TB? Foreign born patients from countries or groups with high prevalence of MDR In California: Hmong refugees Tibetan ancestry Immigrants from former USSR, Laos, Burma, Korea, Peru, Central America, India Recent immigrants (e.g., within 2 years) especially from China, Vietnam, Philippines
Increased Risk for MDR TB History of previous TB treatment, particularly if recent Poor response to standard 4 drug treatment Culture remains (+) after 2 months treatment Known exposure to MDR TB case HIV (+) Higher incidence of Rifampin mono resistance
Chapter 3, page 48
Initial diagnostic tests Smear positive x3 (cultures sent) Xpert MTB/RIF: Positive for Mtb and RIF resistance PSQ: rpob mutation No gyra, rrs, inha, or katg
Molecular Testing for Rifampin (rpob) Rifampin cornerstone of TB treatment Resistance requires a longer duration of therapy Rif resistance without INH resistance rare ~90% (114of129) 129) Rif resistant cases MDR (California, 2011 201) 201) MDR Rif mono R 0% 20% 40% 60% 80% 100% Rif resistance MDR
Basic steps: Choosing a regimen Decision: Begin empiric MDR regimen Ask for help: Expert consultation Empiric (expanded) regimen for MDR: 4 first line + FQ + injectable (+ consider additional second line drug) This case (Xpert, then PSQ results)?
How many drugs for MDR? Goal: 4 6 likely eyeffective ect edugs drugs (and 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 [WHO 2011 tl at least t4 likely l effective drugs ]
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 One of One of available these these First line Fluoro o Injectable e drugs quinolones agents Pyrazinamide Levofloxacin Amikacin Ethambutol Moxifloxacin Capreomycin Kanamycin 1 Streptomycin 2 1. Not available in U.S. 2. SM: use only if not previously used and if documented susceptibility
Building an Individualized Regimen for MDR TB STEP 1 This case: st e (INH) Use any One of One of available these these First line Fluoro o Injectable e drugs quinolones agents Pyrazinamide Levofloxacin Amikacin Ethambutol Moxifloxacin Capreomycin Kanamycin 1 Streptomycin 2 1. Not available in U.S. 2. SM: use only if not previously used and if documented susceptibility
Building a Regimen for MDR TB () (2) STEP 2 Add second line drugs until you have 4 6 drugs (optimally at least ) 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 third-line drug, many experts now use LZD as a second-line drug option
Building a Regimen for MDR TB (3) 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 Consider use of these Third line drugs Bedaquiline Meropenem/ Delamanid 4 Clavulanate Amoxicillin/ Clofazimine Clavulanate consultation with Imipenem Clarithromycin High dose INH 4. Awaiting FDA approval
Classification: U.S. vs. WHO Chapter 4, page 6
Other considerations when choosing drugs Beyond susceptibility Beyond susceptibility results, consider: Cross resistance (table page 76) Avoid drugs used previously Side effect profile
Treatment Duration 2003 ATS/CDC/IDSA guidelines: 18 24 mo WHO 2011 (based on individual patient metaanalysis: 32 studies, over 9000 pts. Ahuja et al, PLoS Med 2012); Intensive phase at least 8 months Total duration at least 20 months (if no prior rx for MDR; if prior MDR rx at least 24 months) Survival Guide v3 Expert consensus: Utilize culture conversion to help guide minimum duration within U.S. high resource setting Intensive phase: at least 6 mo beyond culture conversion for use of injectable agent Total duration: at least 18 months beyond culture conversion
Treatment regimens Suggestions based on pattern of drug resistance Pre XDR and XDR recommend longer duration (at least 24 mo. post culture conversion) Chapter 4, page 80
Good resource to know: Ui Using the Medication Mdi Fact tsheets 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
New Medication Fact Sheets Bedaquiline Delaminid Meropenam Rifapentine Clarithromycin New drugs in the pipeline
Monitoring and case management Isolation issue can he go home? Planningfor outpatient injections/infusions Patient education and concerns (cost, anxiety) Monitoring for toxicities
Question: When to discharge from hospital? Pt is still smear positive On expanded MDR regimen Lives at home with wife and 2 adult daughters (all IGRA negative) Pt very concerned about high deductible and big hospital bill
**A patient may be considered for placement in a lower risk setting without meeting these criteria if no previously unexposed persons will be present (see section: Home isolation) Chapter 8, page 230
Home Isolation Many patients t with drug resistant ttbd do not require hospitalization and may be on home isolation at the start of treatment. Some patients may be hospitalized to initiate treatment and become ready for discharge prior to becoming non infectious.
Providing the Injectable Agent Chapter 8, page 21
Patient Education: Communicating Effectively Recognize and address the patient s fears and concerns. Patients areless likely to comprehend treatment information if they are fearful or preoccupied with worries about their jobs or family members.
Monitoring for Toxicities Chapter 8, page 23
Comorbidities: DR TB and diabetes Slower response to treatment Potential lower drug levels Increased risk of acquired drug resistance Poorer outcomes in treatment MDR TB
Recommendations for treating TB in the presence of DM Follow oo renal function Decrease frequency of injectable if impaired Treat GI symptoms aggressively Manage neuropathy Change meds if possible Add tricyclics or gabapentine Consider TDM If initially INH resistant, don t use intermittent treatment and strongly consider RIF & EMB levels
Drug level monitoring When to order: Injectable (especially impairedrenal renal functionor or age 60+) Cycloserine to establish safe and effective dose for patient Malabsorption Lack of expected tdclinical i l response Few effective drugs in regimen to optimize Drug drug interactions, e.g. rifamycins and HIV antiretrovirals Renal impairment e.g., EMB Where to send: National Jewish or University of Florida Amikacin often done locally How/when to collect: See pages 7 and 8
Next set of DST results CDC MDDR results: Confirmed PSQ results No pnca mutation embb mutations identified (silent and neutral mutation so not associated with resistance) Get these results soon after start any changes?
Chapter 3, pages 46 47
Update: first month of rx Frequent nursing calls..
DR TB Contacts Rx options Duration 6 12 months Two drug combo or fluoroquinolone l alone Avoid PZA (risk vs. benefit) Observation/clinical monitoring option
Update ( weeks into rx): Phenotypic DST: sensitive to INH, EMB, PZA (confirms RIF mono resistant)
Regimen options for mono/poly DR Case: RIF mono resistant Case: RIF mono resistant INH, EMB, PZA, Levo (Treatment Chap table 1, pg 70)
Update ( weeks into rx): Phenotypic DST: sensitive to INH, EMB, PZA (confirms RIF mono resistant) Last update on management. Last update on management. Rx for contacts? Patient education?
More MDR resource tips: Pediatric DR TB New chapter in Survival Guide Sentinal Project International/WHO Companion Handbook New US and WHO DR TB guidelines underway!
The end. Here to help :) California DPH MDR TB Service 1 10 620 304 Warmline (Western region) Curry International Tuberculosis Center 1 877 390 NOTB or 1 877 390 6682 www.currytbcenter.ucsf.edu t