MDR-TB Update

Kevin L. Winthrop M.D., M.P.H. Professor, School of Public Health Division of Infectious Diseases Oregon Health and Science University Global TB Epidemiology

Definitions

MDR-TB: TB isolate that is resistant to both isoniazid and rifampin XDR-TB: MDR + resistance to fluoroquinolone and 1 of the 3 injectable drugs (amikacin, kanamycin, capreomycin)

• Primary drug resistance: – Infected with TB which is already drug resistant • Secondary (acquired) drug resistance: – drug resistance develops during treatment Random Naturally Occurring Resistance

• INH = 1 in 106 • RMP = 1 in 108 I I 6 • EMB = 1 in 10 E • Strep =1 in 106 E R Multidrug therapy: Drug-resistant mutants in No bacteria resistant to all 3 drugs large bacterial population INH RIF PZA

Monotherapy: INH-resistant bacteria proliferate

INH Spontaneous mutations develop as bacilli proliferate to >108 INH resistant bacteria multiply to large numbers INH RIF INH

INH mono-resist. mutants killed, RIF-resist. mutants proliferate  MDR TB Drug Resistant Mutants Selected by:

• Non-adherence • Malabsorption • Inadequate drug regimen Emergence of Resistance with Single Drug Therapy of Active TB

Start INH alone 8 7 6 5 INH-S 4 INH-R

3 Log Log cfu 2 1 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Weeks TB Drugs

• First-line – Isoniazid (INH), ethambutol (EMB) , rifampin (RIF), pyrazinamide (PZA) • Others – Moxifloxacin, aminoglycosides, capreomycin, kanamycin, ethionamide, cylcoserine, PAS, – Clofazimine, bedaquiline Mechanism of Drug Resistance • Amikacin – ribosomal changes 16S rRNA • Capreomycin – ribosomal changes 16S RNA • Clofazimine – No resistance known • Ethambutol – embA or embB mutation • Ethionamide – Mutations in coding for drug activation enzymes (cross resistance common with INH) • Gatifloxacin, moxifloxacin – DNA gyrase mutation (gyrA or gyrB) Mechanism of Drug Resistance • INH – inhA or activating enzyme KatG • Kanamycin, streptomycin – ribosomal changes 16S rRNA • Linezolid – Rare and mechanism unknown • Pyrazinamide – converting enzyme PZAase • Rifamycin – RIF-resistant determining region (RDR) mutations, a 81 bp stretch of the rpoB gene http://www.currytbcenter.ucsf.edu/products/drug-resistant-tuberculosis-survival-guide-clinicians-3rd-edition/chapter-4-treatment MDR-TB Challenges

• Enormous resource sink for patient and program • Large cost incurred (drugs, hospitalization, isolation, DOT, lab testing) • Prolonged treatment/monitoring required • Major impact to individual health • Pool of clinical experts diminishing • Increasingly complex healthcare systems to navigate • No proven therapy for contacts $$$$$$$$$$$$

Cost of a single MDR-TB case in the U.S. ranges from $ 28,217 - $ 1,278,066

Source: Rajbhandaw SS et al, JTDL 2004:204 Tuberculosis Epidemiology https://www.cdc.gov/tb/statistics/surv/surv2016/default.htm Number and Percentage of TB Cases Among Non-U.S.–Born Persons, United States, 1993–2016 TB Case Rates,* United States, 2016

NYC

DC

*Cases per 100,000; as of June 21, 2017. ≤2.9 (2016 national average) DC, District of Columbia; NYC, New York City (excluded from New York state) >2.9

https://www.cdc.gov/tb/statistics/surv/surv2016/default.htm Primary Anti-TB Drug Resistance,

United States, 1993–2016* Resistant (%)

Year

* As of June 21, 2017. 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.

https://www.cdc.gov/tb/statistics/surv/surv2016/default.htm Primary MDR-TB, United States, 1993–2016*

* As of June 21, 2017. 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. Primary* Multidrug-Resistant TB Among U.S.-Born and Non-U.S.–Born Persons, United States, 1993–2016

Non-U.S.–Born

U.S.-Born

* Based on initial isolates from persons with no prior history of TB; multidrug-resistant TB is resistance to at least isoniazid and rifampin. XDR-TB* Case Count, Defined on Initial DST,†

by Year, 1993–2016§ Case count Case

Year of diagnosis * XDR-TB , extensively drug-resistant TB. † DST, drug susceptibility test. § As of June 21, 2017. 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. Percent of New Cases MDR

Zignol M et al NEJM 2016

Treatment of MDR-TB Duration of Therapy

8 months 20 + months

Intensive Continuation

WHO 2011 Update Global Alliance http://www.currytbcenter.ucsf.edu/products/drug-resistant-tuberculosis-survival-guide-clinicians-3rd-edition/chapter-4-treatment http://www.currytbcenter.ucsf.edu/products/drug-resistant-tuberculosis-survival-guide-clinicians-3rd-edition/chapter-4-treatment Nathanson E et al. IJTLD 2004 Treatment of Contacts

Bamrah S et al. IJTLD 2014 Bamrah S et al. IJTLD 2014 Treatment of Contacts

Bamrah S et al. IJTLD 2014 WHO Policy Recommendation Shorter Course MDR-TB Regimen

Recommendation:

In patients with RR or MDR-TB • who have not been treated with second-line drugs and • in whom resistance to FQNs and SLI agents has been excluded or is considered to be highly unlikely a shorter MDR-TB regimen of 9-12 mos may be used instead of a conventional regimen

(conditional recommendation, very low certainty in the evidence)

WHO 2016 Update Other Shorter Course Regimens Injectable Free! Clinical trial Regimen Duration (wks) Completed NiX-TB Bdq, Pa, Lzd 24-36 Yes MDR END Dlm, Lzd, Lfx, Z 36-52 Ongoing STREAM 2 # C Bdq, Cfz, E, Z, Lfx, H, Pto 16 Ongoing followed by Bdq, Cfz, E, Z, Lfx 24 PRACTECAL # Bdq, Pa, Lzd 36 Ongoing 1 PRACTECAL # Bdq, Pa, Lzd, Cfz 36 Ongoing 2 PRACTECAL # Bdq, Pa, Lzd, Mfx 36 Ongoing 3 endTB # 1 Bdq, Lzd, Mfx, Z 36 Ongoing endTB # 2 Bdq, Cfz, Lzd, Lfx, Z 36 Ongoing endTB # 3 Bdq, Dlm, Lzd, Lfx, Z 36 Ongoing endTB # 4 Dlm, Cfz, Lzd, Lfx, Z 36 Ongoing endTB # 5 Dlm, Cfz, Mfx, Z 36 Ongoing

Bdq – bedaquiline, Cfz – clofazimine, Dlm – delamanid, E – ethambutol, H – isoniazid, Lfx – levofloxacin, Lzd – linezolid, Mfx – moxifloxacin, Pa – pretomanid, Z - pyrazinamide Courtesy: KJ Seung Short Course Regimens

http://www.who.int/tb/challenges/mdr/MDR-RR_TB_factsheet_2017.pdf?ua=1 • 2.6% to 61.5% of persons with MDR-TB treated with aminoglycosides have documented hearing loss

• Even with shorter course regimens (4 months of injectable), hearing loss as high as 44% has been reported

• Risk factors: • Most important is cumulative dose • Other possible RF include age, HIV infection, exposure to loud noises and genetic risks We need injectable free regimens!

Reuter A, et al. IUATLD 2017;21:1114 New Grouping of MDR-TB Drugs

Group A Group B Group C Group D Fluoroquinolo Second-line Other Core Add-on agents ne injectable Second-line Levofloxacin Amikacin Ethionamide/ D1: Pyrazinamide Moxifloxacin Prothionamid Ethambutol e Gatifloxacin Capreomycin High-dose INH Cycloserine/ Kanamycin D2: Bedaquiline (Streptomyci Terizidone Delamanid n) Clofazimine D3: P-aminosalicylic acid Linezolid Imipenem/meropenem Amoxacillin/Clavulanate (Thioacetazone) Cross Resistance Among Fluoroquinolones

Zignol M, et al. Lancet 2016;16:1185-1192 https://www.cdc.gov/nchhstp/newsroom/docs/factsheets/costly-burden-dr-tb-508.pdf Acknowledgments

• Friends and collaborators within: – CDC – ACR – EULAR – OHSU – Oregon Health Authority – UAB

Comparison of Countries with the Highest Rates of TB to Most Common Countries of Birth Among Non-U.S.–Born Persons with TB, United States, 2016

Top 10 countries with highest rates of TB worldwide

WHO Number of patients WHO Number of patients Country Country from country diagnosed Country Country from country diagnosed Rate* in the U.S. Rate* in the U.S.

South Africa 781 7 Mexico 22 1,192 Lesotho 724 0 Philippines 554 790 Kiribati 566 0 India 211 589 Philippines 554 790 Vietnam 133 494 Mozambique 551 6 China 64 383 North Korea 513 23 Guatemala 24 189 Timor-Leste 498 0 Haiti 188 168 Gabon 485 1 Ethiopia 177 151 Namibia 446 0 Honduras 40 148 Papua New Guinea 432 1 Myanmar 361 125

2 World Health Organization. 2017 Global Tuberculosis Report. Geneva: WHO; 2017. Rate per 100,000 population in country of birth.

Top 10 countries of birth for non-U.S.–born persons with TB in the United States Mechanism of Action (MOA)

• Isoniazid • inhibits InhA (mycolic acid synthesis) • Ethambutol • inhibits arabinosyl transferases (cell wall synthesis) • Rifamycin • inhibits RNA polymerase acting early in transcription • Pyrazinamide • inhibits functions at acid pH like fatty acid synthesis/transport Mechanism of Action (MOA)

• amikacin, kanamycin, streptomycin (Aminoglycoside) – inhibits protein synthesis, binds 16S rRNA in the 30S ribosomal subunit • Clarithromycin/azithromycin (macrolide) – inhibits protein synthesis, binds 50S ribosomal subunit • Gatifloxacin, levofloxacin, moxifloxacin – DNA gyrase inhibitor • Capreomycin (polypeptide antibiotic) – inhibits protein synthesis, binds ribosome presumably • Clofazimine – unknown • Cycloserine – inhibits alanine racemase (cell wall synthesis) • Ethionamide – inhibits InhA gene by katG-independent mechanism • Linezolid (oxazolidinone) – inhibits protein synthesis binding to 23S rRNA • PAS – DHFR inhibitor

Tuberculosis

• Mycobacterium tuberculosis, the causative agent is spread by droplet aerosol from TB patients to exposed contacts – Complex includes M. bovis, M. canettii, M. africanum, M. microti (voles), M. pinnipedii (seals)

• Unusual modes: transplantation, bronchoscopy, raw milk ingestion from infected cattle (M. bovis or M. tuberculosis)