Management of Drug-resistant TB author ESCMID Courseby 27.9.19

Dr CynthiaeLibrary Chee TB Control Unit, Tan Tock Seng Hospital

ESCMID © Since effective (“short-course”) chemotherapy became available in the 1970s

• 1985 – 1992: Global emergence of Multidrug-resistant TB (MDR-TB) defined as TB resistant to at least Rifampicin andauthor Isoniazid by • 1993: WHO DECLARED TB “A GLOBAL EMERGENCY”

• 2006 : Global emergence of Extensively drug-resistant TB (XDR-TB) defined as MDR-TB plus resistance to any fluoroquinolone and second-line injectable agent eLibrary

• “Totally drug resistant TB” : resistance to all tested drugs beyond XDR- TB (yet to be defined)

• 2017 : “ProgrammaticallyESCMID incurable TB” © WHO Global Tuberculosis Report 2018 author In 2017 MDR-TB / RRby-TB XDR-TB

3.5% of new cases 8.5% of MDRTB 18% of previously treated cases cases

Estimated number of new cases 558,000 eLibrary(82% MDR)

Number notified 160,684 8,014

Number enrolled for treatmentESCMID 139,114 8,511

* In May 2016, WHO© issued guidance that people with TB resistant to Rif, with or without resistance to other drugs, should be treated with an MDR-TB treatment regimen WHO Global Report 2018 Treatment Outcome (2015 cohort)

MDR-TBauthorXDR-TB N=99,165 N=6,904 by Treatment success rate 55%* 34%*

Died 15% 26%

Treatment failure eLibrary8% 19%

Lost to follow-up 14% 21%

No outcome information 7% ESCMID

• Global treatment success© rate for cases started on first-line treatment regimen in 2016 was 82% WHO MDR treatment guidelines

Conventional 20-month authorKey changes to regimen based longer regimen on IPD MA of based on IPD MA 9,153 patients. by of 12,030 patients. Ahuja et al. Ahmad et al. PLOS 2012 Lancet 2018

2011 2016 2019 eLibrary MDR-TB treatment recommended for RR-TB regardless of confirmation of INH resistance Shorter 9-11 month regimen for eligible patients based on 5 observational studies [1,205 patients, success rate of ESCMIDpooled studies =84%] Medicines in longer regimen re- © grouped WHO 2011 conventional 20-month MDR-TB regimen (updated 2016)

A. Fluoroquinolones Levofloxacin, Moxifloxacin, Gatifloxacin

B. Second-line injectable Amikacin, Capreomycinauthor, Kanamycin agents (Streptomycin) by

C. Other core second-line Ethionamide / Prothionamide agents Cycloserine / Terizidone Linezolid Clofazimine eLibrary D. Add-on agents D1 : Pyrazinamide, Ethambutol, High-dose (not part of the core MDR-TB Isoniazid regimen) D2 : Bedaquiline, Delamanid

ESCMID D3 : PAS, Imipenam-cilastin, Meropenam, © Amoxycillin-clavulanate, (Thioacetazone) Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis Ahmad N et al. Lancet 2018:392:821-34 author • 12,030 patients, 25 countries, 50 studiesby • Treatment success associated with use of linezolid, levofloxacin, carbepenams, moxifloxacin, bedaquiline, clofazimine • Use of linezolid, levofloxacin,eLibrary moxifloxacin or bedaquiline associated with reduced mortality • Kanamycin and capreomycin associated with worse outcomes

• Optimal numberESCMID of drugs : 5 in initial phase, 4 in continuation phase © WHO 2011 20-month regimen WHO 2019 long regimen (updated 2016) (Rapid communication Aug 2018) Group A Levofloxacin, Moxifloxacin, Levofloxacin / Moxifloxacin Gatifloxacin Bedaquiline Linezolidauthor Group B Amikacin, Capreomycin, Kanamycin, Clofazimine (Streptomycin) Cycloserineby / teridozine

Group C Ethionamide / Prothionamide Ethambutol Cycloserine / Terizidone Delamanid Linezolid Pyrazinamide Clofazimine Imipenam-cilastin; meropenam Amikacin (streptomycin) eLibraryEthionamide / Prothionamide PAS Group D D1 : Pyrazinamide, Ethambutol, High-dose Isoniazid Kanamycin and capreomycin no D2 : Bedaquiline, Delamanid longer recommended D3 : PAS, Imipenam-cilastin, Meropenam,ESCMID Amoxycillin -clavulanate, (Thioacetazone)© WHO 2019 Guidelines Major Implications

• Affordability of bedaquiline, linezolid to TBauthor programmes – In Singapore bedaquiline costs US$162 per tablet; linezolid costs US$36 per 600 mg tablet by

• XDR- TB definition no longer relevant eLibrary • Urgent need to develop and standardise DST methods for bedaquiline, linezolid, cycloserine, clofazimine

ESCMID © Bedaquiline (Sirturo) Janssen / Johnson & Johnson

• Di -aryl quinoline, ATPase inhibitor; bacteriocidal andauthor sterilizing properties • Dec 2012: first new TB drug from a new drug class to receive FDA approval in 40 years by

• Tiered pricing structure : US $900, $3,000 and $30,000 for low, medium and high income countries respectively • Donation programme by JansseneLibrary and USAID from 2014-2019 • Post-donation programme: US $400 per course for South Africa and through Global Drug Facility

• Singapore : used in 5 patients (1 XDR-TB, 3 pre-XDRTB, and one with drug hypersensitivity reactionESCMID to second -line drugs) © WHO 2019 Updated Guidelines (Rapid Communication Aug 2018)

Group A Regimen to comprise all Gp A Medicines to be Levofloxacin / Moxifloxacin and at least one Gp B agent prioritized Bedaquiline (at leastauthor 4 drugs) Linezolid Must include at least 3 drugs byfor rest of regimen after Bdq Group B is stopped after 6 months Medicines to be Clofazimine added next Cycloserine / teridozine If one or two drugs in Gp A used, both Gp B drugs must Group C eLibrary be included Medicines to be Ethambutol Delamanid included to Gp C drugs to be used when complete the Pyrazinamide regimens when Imipenam-cilastin; meropenam an effective regimen cannot agents from Gps Amikacin (streptomycin) be constituted using Gp A and A and B cannot EthionamideESCMID/ Prothionamide Gp B drugs be used PAS © Duration: 18-20 months WHO shorter standardized MDR treatment regimen 2016 update for pulmonary TB, regardless of age or HIV status

Intensive phase author 4 – 6 months Gatifloxacin (or Moxifloxacin) Clofazimine by Extended to up to 6 months in Pyrazinamide cases of lack of sputum smear Ethambutol conversion at 4 months Kanamycin Prothionamide HigheLibrary-dose isoniazid

Continuation phase Gatifloxacin (or moxifloxacin) 5 months Clofazimine ESCMID Pyrazinamide © Ethambutol WHO 9-11 month MDR-TB Regimen Exclusion criteria

• Confirmed resistance or suspected ineffectiveness to a medicine in the shorter MDR-TB regimen (except isoniazid) author • Exposure to ≥1 second-line medicines in theby shorter MDR-TB regimen • Intolerance to ≥1 medicines in the shorter MDR-TB regimen or risk of toxicity (eg. drug-drug interaction) • Pregnancy • Extrapulmonary TB (2019 - DisseminatedeLibrary or CNS TB; all PLHIV with extrapulmonary disease) • At least one medicine in the shorter MDR-TB regimen not available in the programme ESCMID © WHO 9-11 month MDR-TB regimen Drug dosages

Drug < 30 kg 30-50 kg author> 50 kg by Gatifloxacin 400 mg 600 mg 800 mg Moxifloxacin 400 mg 600 mg 800 mg Clofazimine 50 mg 100 mg 100 mg Ethambutol 800 mg 800 mg 1200 mg Pyrazinamide 1000 mg eLibrary1500 mg 2000 mg Isoniazid 300 mg 400 mg 600 mg Prothionamide 250 mg 500 mg 750 mg Kanamycin + 15 mg / kg body weight (max 1 kg) ESCMID + : for adults ©> 59 years of age, dose reduced to 10 mg/kg (max 750 mg) A Trial of a Shorter Regimen for Rifampicin-Resistant Tuberculosis (STREAM study) Nunn AJ et al. N Engl J Med March 28 2019

• 424 participants with Rif Resistant TB (5.8% INH-susceptible) without resistance to FQ and SLI randomized in 2:1 ratio to short regimen (9-11 month)author or long WHO 2011 (20- month) regimen by • Primary efficacy outcome was favourable status at 132 weeks: – Cultures that were negative at 132 weeks after randomization and at one previous occasion during the trial period, with no intervening positive culture or unfavourable outcome

• Non inferiority of short regimen demonstrated – Favourable status at 132 weeks : 78.8% in short regimen group vs 79.8% in long regimen group – Death : 8.5% vs 6.4% eLibrary – Acquired resistance to FQ or SLI : 3.3% vs 2.3% – Unfavourable bacteriologic outcomes : 10.6% vs 5.6%

• Safety – AE of grade 3 or higher in 48.2% vs 45.4% – QT prolongation to 500 msec 11% vs 6.4% – Hepatobiliary disordersESCMID 8.9% vs 5.7% © WHO 2019 Guidelines Shorter MDR-TB regimen • Based on STREAM study and IPD MA: author – Higher risk of treatment failure and relapse in patients with baseline resistance to PZA and ethionamide by

• Recommendations: – Emphasis on DST for FQ and SLI, as well as other drugs in regimen (eg PZA, mutations associated with INH and ethionamide resistance) before start of RxeLibrary

– Contraindicated if resistant mutations to FQs or SLI on MTBDRsl, presence of both inhA and katG mutations on MTBDRplus; resistance to PZA – KanamycinESCMID should be replaced by amikacin © Eligibility for WHO shorter regimen Patients from SE Asia – Singapore sample, 2002-2016

Country of birth No of cases Resistance to at least one of the 6 drugs in WHO regimen excludingauthor INH Bangladesh 4 3by (75%) China 37 23 (62.2%) India 7 6 (87.5%) Indonesia 76 57 (75%) Myanmar eLibrary56 40 (71.4%) Philippines 18 10 (55.6%) Vietnam 15 12 (80%) Singapore/Malaysia 54 39 (72.2%) ESCMID Overall © 267 190 (71.2%)

Eur Resp J 2017 Singapore experience WHO Shorter 9-11 month regimen author • 8 patients commenced by – All had GI symptoms; hypokalemia – 3 had Hepatotoxicity – 3 had prolonged QTc – 2 had rash eLibrary • Poorly tolerated • 3 patients completed Rx, 3 left country, 2 had to convert to long regimen (renal impairment, hepatoxicity) ESCMID © MDRTB Treatment Outcome Singapore citizens/PRs 2007-2017 author 14 Treatmentby N=63 12 Outcome 10 Success 56 (89%) 8 Died 5 (8%) 6 eLibraryLost to follow- 2 (3%) 4 up / left country 2 0 Infectious Disease Act served =15

2007 2008 2009 2010 ESCMID2011 2012 2013 2014 2015 2016 2017 Completed© Died Lost to f/up Formulating an MDR-TB treatment regimen

• Careful medication history, noting drugs previouslyauthor received • Consider DST of source case (if any) by

• Consider recent representative surveillance data

• Perform rapid genotypic DSTeLibrary (Genotype MTBDRplus and MTBDRsl)

• Regimen further optimized according to patient’s MTC phenotypic DST results when subsequently available ESCMID © Drug toxicity Group A Levofloxacin / Moxifloxacin Tendinitis, insomnia, QT prolongation Bedaquiline QT prolongation Linezolid Peripheral neuropathy,author myelosuppression, optic neuritis, lactic acidosis by Group B Clofazimine Skin discolouration, QT prolongation Cycloserine / teridozine Neuropsychiatric effects

Group C eLibrary Ethambutol Optic neuritis Delamanid QT prolongation Pyrazinamide Arthralgia, hepatitis Imipenam-cilastin; meropenam Amikacin (streptomycin) Ototoxicity, nephropathy Ethionamide / ProthionamideESCMIDNausea / vomiting, hypothyroidism PAS © GI disturbance, hypothyroidism Monitoring during treatment

Response to treatment Active TB drugauthor safety monitoring and management (aDSM) by Symptoms Renal Weight Liver Sputum bacteriology Full blood count Chest radiography eLibraryThyroid function ECG Audiometry

ESCMID © Monitoring patient response to MDR-TB treatment using culture

• In MDR/RR-TB patients on longer regimens, the performance of sputum culture in addition to sputum smear microscopy is recommendedauthor to monitor treatment response. It is desirable for bysputum culture to be repeated at monthly intervals (strong recommendation, WHO 2019 )

• WHO analysis of a subset of 3,762 patients with monthly smear and cultures done showed that, in order to detect non-response as early as possible: eLibrary – Monthly culture had higher sensitivity than monthly smear microscopy – Monthly culture had higher sensitivity than two-monthly culture

• May be burdensome and unrealistic for many programmes ESCMID © MDR-TB Management Dealing with drug side-effects

•Close attention to symptoms of toxicity andauthor reports of discomfort are essential in maintaining the patient’s goodwill and cooperation with the regimen by

–Patient has to be primed to expect medication side-effects and accept long duration of therapy

– Side-effects may require adjustmenteLibrary of dosage, timing of medications, Vitamin B6, use of anti-emetics (eg ondansetron)

–When to reassure vs when to discontinue/change drug is a challenge ESCMID © Adherence-promoting measures • Strong TB programme • Psycho social and financial support author by • DOT vs SAT (WHO 2019 systematic review) – Persons on DOT had better rates of treatment success, adherence and 2-month sputum culture conversion; slightly lower rates of loss to f/up and acquired drug resistance. But patients on DOT had a slightly higher relapse rate – HIV -positive TB patients benefit moreeLibrary from DOT Community or home-based DOT recommended over health facility-based DOT or unsupervised treatment DOT administered by trained lay-providers or health-care workers recommended over DOT by family members or unsupervised treatment ESCMID Conditional recommendation, WHO 2019 © Starting of ART in patients on second-line anti-TB regimens • ART is recommended for all patientsauthor with HIV and DR-TB requiring second-lineby anti-TB drugs irrespective of CD4 cell count, as early as possible (within the first 8 weeks) following initiation of anti-TB eLibrarytreatment

Strong recommendation, WHO 2019 ESCMID © Surgery for patients on MDR –TB treatment

In patients with RR-TB or MDR-TB, elective partial lung resection (lobectomy or wedge resection) may be used alongsideauthor a recommended MDR-TB regimen (conditional recommendation, WHO 2019) by

Surgery as an Adjunctive Treatment for MDR-TB: an individual patient data meta-analysis. Fox et al. CID 2016 • Partial lung resection, but not pneumonectomy associated with improved treatment success. • Treatment success more likely when eLibrarysurgery was performed after culture conversion

• Patients with high-grade drug resistance (ie. XDR or FQ resistant MDR-TB) with few chemotherapeutic options; those with previous history of ineffective treatment or with high risk of relapse • Localised disease • Good pulmonary reserve • Skilled surgical teamESCMID • Surgery timed© when bacterial load has decreased in response to chemotherapy The good news

• 14 Aug 2019 : Pretomanid (PA 824) approvedauthor by FDA for use with bedaquiline and linezolid for treatment of XDR-TB or treatment intolerant/non-responsive MDRby -TB

– Nix-TB trial in 3 sites in S Africa – 109 patients with XDR or treatment intolerant or non-responsive MDR-TB eLibrary – Successful outcome in 95/107 patients who received BPaL for 6 months

ESCMID © The bad news Bedaquiline resistance • Reported within 5 years of its use – appeared rapidly after treatment and in patients thatauthor have never been treated. Veziris et al. Eur Resp J 2017 by • Currently known mechanisms: mutations within the atpE, Rv0678, and pepQ genes

• M utations in Rv0678 encodingeLibrary the Mmpl5 efflux pump repressor generate low level Bdq resistance and clofazimine cross resistance

• BDQ has a terminal half life of 4.5 to 5 months – Acquired resistance may occur when it is the only efficacious drug in circulation ESCMIDif companion medications are stopped within this period. © The Future

Phase 3 trials author STREAM Stage 2 by Otsuka 23 NeXT NiX-TB eLibrary STAND endTB China PZA

F-S 1 Trial The global rise of extensively drug-resistant ESCMID tuberculosis: is the time to bring back sanatoria now © overdue? Dheda K, Migliori G. Lancet Oct 26 2011