Global epidemiology of drug-resistant tuberculosis. Factors contributing to the epidemic of MDR/XDR-TB. CHIANG Chen-Yuan MD, MPH, DrPhilos

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1 Global epidemiology of drug-resistant tuberculosis Factors contributing to the epidemic of MDR/XDR-TB CHIANG Chen-Yuan MD, MPH, DrPhilos

2 By the end of this presentation, participants would be able to describe Principles of Global drug resistance surveillance Epidemic of drug-resistant TB Factors contributing to the emergency of drugresistant TB Burden of transmitted multidrug resistance Potential impact of up-front drug sensitivity Testing

3 Principles of Global drug resistance surveillance the sample was representative of all TB cases in the setting under evaluation; new patients were clearly distinguished from those with previous treatment; optimal laboratory performance was assured and maintained through links with a supranational reference laboratory (SRL). WHO/TB/

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5 Estimated global tuberculosis burden 2015 an estimated 10.4 million incident cases of TB 1.0 million (10%) among children 1.2 million (11%) among people living with HIV 480,000 new cases of MDR-TB worldwide, and an additional 100,000 rifampicin-resistant TB (RR-TB) India, China and the Russian Federation accounted for 45% of the combined total of cases. Global TB Report 2016

6 Global estimates of MDR-TB 3.9% (95% CI: %) of new cases (Viet Nam 4.1%) 21% (95%CI: 15 28%) of previously treated cases (Viet Nam 25%) There were about (range, ) deaths from MDR/RR-TB in Globally in 2015, there were an estimated (range, ) MDR/RR-TB cases among notified TB patients. Global Tuberculosis Report 2016

7 Global Tuberculosis Report 2016

8 Global Tuberculosis Report 2016

9 WHO Global Tuberculosis Report 2016

10 WHO Global Tuberculosis Report 2016

11 Prevalence of resistance to second-line tuberculosis drug among multidrug-resistant tuberculosis patients in Viet Nam, 2011 WPSAR Vol 7, No 2, 2016 doi: /wpsar

12 Zignol M,et al. Lancet Infect Dis

13 Factors contributing to the epidemic of MDR- and XDR-TB Drug resistant tuberculosis emerged during antituberculosis treatment Selective multiplication of wild type mutant of tuberculosis bacilli Transmission of drug-resistant tuberculosis

14 Genetics of drug resistance in M. tuberculosis So far no single mutation has been found to cause MDR-TB MDR phenotype is caused by sequential accumulation of mutations in different genes involved in individual drug resistance Susceptible Resistant to one drug (acquired) Zhang Y,et al Resistant to an additional drug (amplification)

15 Within host acquired and amplified resistance Between host transmission Between host transmission Susceptible INH-resistant MDR-TB Fluoroquinoloneresistant MDR-TB XDR-TB

16 Within host: factors associated with the emergence of anti-tb drug resistance Inadequate dosing Poor drug quality Poor adherence to treatment Inappropriate regimen 1. Exposure to (functional) mono-therapy 2. Continuously administer a failing regimen 3. Inadequate modification of a failing regimen

17 Recent bioequivalence studies on fixed-dose combination (FDC) anti-tuberculosis drug formulations available on the global market In seven of 10 FDC formulations, the AUC and Cmax for rifampicin was not found to be bioequivalent to the reference administered as loose (separate) formulations. Pillai G, et al. Int J Tuberc Lung Dis 1999;3:s309-s316

18 Prescription practice of Rifampin, Taipei, 2003 Number of Adequate Dosage too Dosage too patients dosage low high Total % 31.6% 5.6% Liver disease Yes % 46.2% 7.7% No % 30.8% 5.5% Renal Disease Yes % 50.8% 6.6% No % 28.8% 5.5% Chiang C-Y, et al. Int J Tuberc Lung Dis 2010

19 Improved Consistency in Dosing Anti-Tuberculosis Drugs in Taipei, Taiwan PLoS ONE 7(8):e doi: /journal.pone

20 Poor compliance: how drug resistance emerges as a result Bactericidal effects during initial killing Monotherapy during sterilisation of special populations Sub-inhibitory drug concentrations during re-growth Bacteriopausal effects during regrowth Mitchison DA. Int J Tuberc Lung Dis 1998; 2:10-15.

21 Development of acquired drug resistance in recurrent tuberculosis patients in Thailand Regimen 2HRZE/4HR Originally susceptible cases, n=31 Pattern of resistance among retreatment Susceptible 87% INH resistance 10% MDR-TB 3% Yoshiyama T, et al. Int J Tuberc Lung Dis 2004; 8:31-38.

22 Development of acquired drug resistance in recurrent tuberculosis patients Regimen 2HREZ/4HR Originally INH-resistant, n=8 Pattern of resistance among retreatment INH resistant 13% MDR-TB 88% Yoshiyama T, et al. Int J Tuberc Lung Dis 2004; 8:31-38.

23 New TB cases The Burden of Isoniazid Resistant Tuberculosis, Retreatment TB cases Jenkins HE, et al (2011) PLoS ONE 6(7): e doi: /journal.pone

24 Treatment of isoniazid-resistant tuberculosis with firstline drugs: a systematic review and meta-analysis Gegia M, et al. Lancet Infect Dis 2017;17:

25 Gegia M, et al. Lancet Infect Dis 2017;17:

26 Acquired rifamycin monoresistance in patients with HIV-related tuberculosis Adults with culture-positive, drug-susceptible pulmonary tuberculosis 2 months of four drug (isoniazid, rifampin, pyrazinamide, ethambutol) treatment (induction phase), then randomly assigned 900 mg isoniazid and 600 mg rifapentine once weekly, or 900 mg isoniazid and 600 mg rifampin twice weekly. Vernon A, et al. Lancet 1999; 353:

27 Acquired rifamycin monoresistance in patients with HIV-related tuberculosis Relapsed Five of 30 patients in the once-weekly isoniazid/rifapentine group three of 31 patients in the twice weekly isoniazid/rifampin group (p=0 41). Monoresistance to rifamycin four of five relapses in the once-weekly isoniazid/rifapentine group none of three in the rifampin group (p=0 05). Vernon A, et al. Lancet 1999; 353:

28 Acquired rifamycin monoresistance the occurrence of acquired rifamycinmonoresistance suggests that the activity of the companion drug, isoniazid, was inadequate to prevent the selection of rifamycin-resistant Mycobacterium tuberculosis Weiner M, et al. Am J Respir Crit Care Med 2003;

29 MDR-TB and XDR-TB: the result of sequential mutations MDR-TB: INH-resistance RMP-resistance XDR-TB: INH-resistance RMP-resistance Fluoroquinolone-resistance Kanamycin- /Amikacin- /Capreomycin-resistance

30 Evolution of the Extensively Drug-Resistant F15/LAM4/KZN Strain of Mycobacterium tuberculosis in KwaZulu-Natal, South Africa Ca, capreomycin; E, ethambutol; Et, ethionamide; F, fluoroquinolones; I, isoniazid; K, kanamycin/amikacin; R, rifampicin; S, streptomycin; T, thiacetazone. Pillay M, et al. Clin Infect Dis 2007; 45:

31 Development of Extensively Drug-resistant Tuberculosis during Multidrug-resistant Tuberculosis Treatment 6% of MDR-TB patients developed XDR-TB while on MDR-TB treatment Presence of bilateral and cavitary lesions, adjusted hazard ratio [HR], 3.47 Prior exposure to a second line injectable antibiotic, adjusted HR, 3.65 Each additional month in which a patient failed to take at least 80% of their prescribed drugs, adjusted HR, 1.17 Shin SS, et al. Am J Respir Crit Care Med 2010;182:

32 Acquired Resistance to Fluoroquinolones Among 832 Adults With Pulmonary Multidrug-Resistant Tuberculosis Starting Treatment With Second-line Drugs, , in 9 Countries Of those without baseline resistance to specific second-line drugs, 68 (8.9%) acquired extensively drug-resistant (XDR) tuberculosis, 79 (11.2%) acquired fluoroquinolone (FQ) resistance, and 56 (7.8%) acquired resistance to second-line injectable drugs Cegielski JP, et al. Clin Infect Dis 2014;59:

33 Acquired Resistance to Fluoroquinolones Among 832 Adults With Pulmonary Multidrug-Resistant Tuberculosis Starting Treatment With Second-line Drugs, , in 9 Countries Baseline DST Ethambutol Resistance susceptible kanamycin Resistance susceptible Ethionamide Resistance susceptible Acquired FQ resistance 17.4% 7.9% 36.8% 6.0% 11.5% 12.1% RR (95% CI) 1.86 ( ) ( ) ( ) 1 Cegielski JP, et al. Clin Infect Dis 2014;59:

34 Fluoroquinolone-resistant MDR-TB Without previous treatment for MDR-TB use of fluoroquinolone in the treatment of lower respiratory tract infection use of fluoroquinolone in the treatment of tuberculosis With previous treatment for MDR-TB

35 Transition from drug resistant TB to XDR-TB INH-resistant TB MDR-TB Use of quinolone in the treatment of community acquired pneumonia INH- and Quinolone-resistant TB Failure to successfully treat TB using first line drugs MDR-TB plus Quinolone resistance Failure to successfully treat MDR-TB using second line drugs Chiang C-Y, et al. Expert Rev Resp Med 2008;2:47-54 XDR-TB

36 Increasing incidence of fluoroquinolone-resistant Mycobacterium tuberculosis in Mumbai, India Agrawal D, et al. Int J Tuberc Lung Dis 2009;13:79-83

37 WHO 2014 Contributing factors to the development of drug-resistant TB

38 Exogenous Reinfection as a Cause of Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis in Rural South Africa 23 patients who developed MDR- or XDR-TB after being treated for less resistant TB. Both initial and follow-up isolates were available for spoligotyping for 17 of these patients. In all cases, the follow-up isolates spoligotypes differed from those of the initial isolate, indicating exogenous reinfection. Andrews JR, et al. J Infect Dis 2008; 198:1582 9

39 High rates of multidrug-resistant and rifampicin-resistant tuberculosis among re-treatment cases: where do they come from? Ragonnet et al. BMC Infectious Diseases (2017) 17:36 DOI /s

40 Burden of transmitted multidrug resistance in epidemics of tuberculosis Global estimates of 3 5% MDR tuberculosis prevalence among new tuberculosis notifications and 20 5% among re-treatment notifications translate into an estimate that resistance transmission rather than acquisition accounts for a median 95 9% (95% uncertainty range [UR] ) of all incident MDR tuberculosis, and 61 3% ( ) of incident MDR tuberculosis in previously treated individuals. Kendall EA, et al Lancet Respir Med 2015;3:

41 Burden of transmitted multidrug resistance in epidemics of tuberculosis Kendall EA, et al Lancet Respir Med 2015;3:

42 Estimating the future burden of multidrug-resistant and extensively drug-resistant tuberculosis Sharma A, et al. Lancet Infect Dis 2017

43 Estimating the future burden of multidrug-resistant and extensively drug-resistant tuberculosis Sharma A, et al. Lancet Infect Dis 2017

44 Notification of tuberculosis, Taiwan, Number Notification rate Courtesy: Taiwan CDC 44

45 Courtesy: Taiwan CDC

46 Potential Impact of Up-Front Drug Sensitivity Testing on India s Epidemic of Multi-Drug Resistant Tuberculosis Sachdeva KS, et al. PLoS ONE 10(7): e

47 Sachdeva KS, et al. PLoS ONE 10(7): e