Second-line Drug Resistance among MDR TB Patients Starting Second-line Treatment in 8 Countries

Transcription

1 Second-line Drug Resistance among MDR TB Patients Starting Second-line Treatment in 8 Countries U.S. National Academy of Sciences, Russian Academy of Medical Sciences, International Science & Technology Center Moscow, Russian Federation May 26, 2010 Peter Cegielski, MD, MPH Team Leader for Drug-Resistant TB International Research and Programs Branch Division of Tuberculosis Elimination

2 Global Trend in MDR TB Estimated Global Incidence 500, , , , , Years

3 Anti-TB Drugs and Evolution of Anti-TB Drug Resistance Drug susceptible Streptomycin, Isoniazid Rifampin & MDR TB Quinolones & XDR TB First availability Widespread resistance 1940s-50s 1960s-70s 1980s-90s 1950s 1980s 2000s

4 Can we preserve the effectiveness of second-line drug treatment of MDR TB? Increasing treatment of MDR TB Increasing Resistance to 2 nd -line drugs

5 Preserving Effective TB Treatment Study (PETTS) Objectives To determine the frequency of and risk factors for acquired resistance to SLD in relation to Program characteristics (GLC) Patient characteristics Mycobacterial characteristics Treatment To determine the effect of acquired SLD resistance on patient outcomes

6 PETTS Overview Prospective follow up study of MDR TB patients in 8 countries Consecutive consenting adults with pulmonary MDR TB, confirmed locally, enrolled at the start of treatment with second-line drugs (SLD) Baseline sputum culture within 30 days of starting SLDs Monthly follow-up with sputum cultures for 2 years or until treatment completed Baseline and monthly follow up cultures shipped to CDC

7 PETTS Overview First and last isolate from each patient tested for susceptibility to 12 drugs If drug susceptibility test (DST) results differ genotyping Same genotype: ACQUIRED RESISTANCE Different genotypes: different strains

8 PETTS Network Estonia Latvia Russia S. Korea CDC/Atlanta Philippines Thailand Peru S. Africa

9 PETTS Enrollment Country Russia Estonia Latvia Peru Philippines South Africa South Korea Thailand TOTAL Patients Baseline DST 119 (90%) 46 (92%) 104 (98%) 202 (96%) 414 (93%) 348 (95%) 110 (94%) 60 (95%) 1398 (94%)

10 Patient Characteristics Clinical Characteristics: 19% HIV-positive (34% HIV unknown) 13% DM 53% inpatients 83% sputum smear positive 61% cavitary disease 16% no previous treatment, 71% first line drugs 71%, 13% 2 nd -line drugs Frequencies differ by site

11 Baseline MDR TB Sample 1492 Patients 1390 Baseline DST Results 1278 Confirmed MDR TB

12 Confirmation of Local DST Results as MDR TB at CDC Lab 5 Countries 3 Countries TOTAL 96%-100% 84%-90% 92%

13 Baseline Resistance to Individual Drugs Drug EMB SM RBT FQ KM AMK CAP ETA PAS % Resistant Range Across Sites (%)

14 Baseline Drug Resistance to Drug Combinations +EMB +STR 1 SLD + 1 INJ + 3 INJ + FQ XDR % Resistant Range (%)

15 Prevalence of Second-line Drug Resistance among MDR TB Patients Starting Second-line Drug Treatment, Color-coded by Site (25 th, 50 th, 75 th percentiles have been interpolated) 25 th %ile 50 th %ile 75 th %ile FQ INJ XDR

16 Can we do better with currently available drugs? Num. (%) resistant at concentration indicated (mcg/ml) INH 1.0: 1278 (100%) RIF 1.0: 1278 (100%) KAN 5.0: 237 (18%) KAN 5.0: 237 (18%) Num. (%) susceptible at concentration indicated (mcg/ml) INH 5.0: 554 (45%) RBT 2.0: 403 (31%) AMK 4.0: 39 (16% of 237) CAP 10.0: 98 (41% of 237)

17 % of Patients who could be treated with indicated number of potentially effective drugs: Pushing the limits of available drugs could increase % of patients treated with at least 4 potentially effective drugs from 75% to 95%, and with at least 5 potentially effective drugs from 26% to 86%. Percent of Patients Number of Effective Drugs "Doing more with available drugs" approach Standard Approach

18 PETTS Preliminary Results: Social Risk Factors for Resistance to Injectable SLDs, Fluoroquinolones (P<0.001) 1 Inj SLD 1 FQ XDR Sex Male Female Unemployment Yes No Hx imprisonment Yes No Homelessness Yes No Alcohol abuse Yes No Tobacco Yes No

19 PETTS Preliminary Results: Medical Risk Factors for Resistance to Injectable SLDs and Fluoroquinolones (P<0.001) 1 Inj SLD 1 FQ XDR TB HIV infection Pos Neg Previous Rx SLD Yes No Previous Rx INJ Yes No Previous Rx FQ Yes No Previous Rx TA Yes No Previous Rx CYS Yes No

20 Baseline Prevalence Data: Summary Among 1278 MDR TB patients starting SLD treatment in 8 countries, range of resistance across countries: 33% - 62% resistance to 1 SLD 2% - 47% resistance to 1 injectable 7% - 24% resistance to FQ 1% - 11% XDR HIV infection not associated with SLD resistance Social factors associated with resistance to injectables, but not FQ or XDR. FQ resistance and XDR associated with any previous SLD treatment, but resistance among injectables associated only with previous treatment with same drugs

21 Follow Up Data Patient follow up ends June 2010 Final shipment of cultures by Sep Clinical database to be finalized Dec Final DST and genotyping to be completed March 2011

22 PETTS Preliminary Results: Drug Susceptibility Test Results of 477 Pairs of Baseline and Final Cultures* Drug Baseline Isolate Susceptible* Final Isolate Resistant* % change FQ Inj PAS ETA SLD XDR * Genotyping of paired isolates not yet completed

23 PETTS Preliminary Results: Cumulative Resistance, Baseline and Final Isolates (n=477 pairs) Drug Baseline Resistance New Resistance During Follow Up Net % Resistance 1 SLD. 222 (46.7) 45 (9.5) 56.2% FQ 69 (14.5) 47 (11.3) 25.8% 1 Inj. 105 (22.1) 81 (18.3) 40.4% 3 Inj. 45 (9.4) 20 (4.2) 13.6% XDR 29 (6.1) 45 (9.4) 15.5% ETA 102 (21.4) 41 (8.6) 30.0% PAS 61 (12.8) 43 (9.0) 21.8%

24 Acknowledgements CDC, Atlanta, Georgia, USA Tracy Dalton* Ken Castro Charles Wells Eugene McCray Julia Ershova* Allison Taylor* Bryan Kim* Gail Starks* Andrey Borisov* Lauren Cowan Lois Diem* Denise Hartline* Dorothy Kaminski* Heather Alexander Beverly Metchock Tom Shinnick David Sikes Kathrine Tan* Peter Cegielski Emory University, Atlanta, Georgia, USA Ekaterina Kurbatova* Charlotte Kvasnovsky* Medical Research Council, Pretoria, S. Africa Martie van der Walt Jeannette Brand Joey Lancaster Ronel Odendaal Karin Weyer Tropical Disease Foundation, Manila, Philippines Thelma Tupasi Janice Campos Caoili* Grace Egos Maricelle Gler Nellie Mangubat Imelda Quelapio Tartu University, No. Estonia Regional Hospital & National TB Registry,,Tallinn, Estonia Kai Kliiman Piret Viiklepp Tiina Kummik Klavdia Levina Vahur Hollo State Centre of TB and Lung Disease, Riga, Latvia Girts Skenders Ingrida Sture Liga Kuksa Vaira Leimane National TB Program, National Inst. of Health, & Socios en Salud Sucursal, Lima, Peru Cesar Boniila Jaime Bayona Luis Asencios Martin Yagui Carmen Contreras Office of Disease Prevention and Control 7th Muang District, Ubon Ratchatani, Thailand: Rattanawadee Akksilp Somsak Akksilp Wanlaya Sitti WanpenWattanaamornkiet Korean Institute of TB, Seoul, and National Masan TB Hospital, Masan, South Korea Woojin Lew Chang-ki Kim Hee Jin Kim Hee Jung Lee Ray Cho Sungkyu Park Nackmoon Sung Russian Federation: Central TB Research Institute, Moscow; Orel Oblast TB Dispensary; Vladimir Oblast TB Dispensary; Northern State Medical University and Arkhangelsk Reg. TB Dispensary; Vladislav Erokhin & CTRI Team, Moscow Andrey Maryandyshev, Nina Nizovtseva, Director Perkhin and team from Arkhangelsk Boris Kazenniy and team from Orel Grigory Volchenkov and team from Vladimir Ministry of Health / National TB Strategy, National Institute of Health, Socios en Salud Sucursal, Lima City & Lima East Health Districts, LIma, Peru Jaime Bayona Carmen Contreras Cesar Bonilla, Oswaldo Jave Martin Yagui Luis Asencios Gloria Yale National Institute of Allergy & Infectious Disease, Bethesda, Maryland, USA Clifton Barry III Laura Via USAID Washington & Moscow Christy Hansen Amy Bloom Nikita Afanasiev WHO Geneva, Copenhagen, Moscow, Lima Mario Raviglione Paul Nunn Melina Abrahan Richard Zaleskis Wieslaw Jakubowiak Mario Valcarcel * Global Coordinating Team