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2. Evolution of TB control and elimination strategies TB and M/XDR-TB: from clinical management to control and elimination May 23-26, 2012 - Bucharest, Romania GB Migliori, WHO CC, Tradate, IT M. Zignol, WHO STB Department, Geneva , CH

3. Aims of this presentation • To review the global burden and state of control of TB, TB/HIV, MDR/XDR-TB • To describe the challenges to further progress of control efforts towards elimination • To propose a multi-dimensional strategy consisting of action on core TB business, health policies, research, and social development that are necessary to make incidence decline rapidly towards elimination

4. The global burden of TB in 2010 Estimated number of cases Estimated number of deaths All forms of TB (men and women) 8.8 million (range, 8.5–9.2 million) 1.1 million* (range, 0.9–1.2 million) All forms of TB (in women) 0.3 million (range, 0.2–0.4 million) 3.2 million (38%) (range, 3.0–3.5 million) HIV-associated TB 0.4 million (range, 0.32–0.39 million) 1.1 million (13%) (range, 1.0–1.2 million) Multidrug-resistant TB 0.65 million** ~0.15million *excluding deaths among HIV+ people ** prevalent cases

5. Americas EMR 3% 7% South- Europe East Asia 4% 34% Africa 30% Western Pacific 21% Most TB cases are still in Asia 55% cases in Asia

6. Global case notification and estimated TB incidence rates, 1990–2010

7. Case notification and estimated TB incidence rates by WHO region, 1990–2010

8. Incidence of TB per 100,000 population, 2010

9. HIV prevalence among TB cases, 2010

10. Impact of HIV on TB in Africa 4/5 of all estimated TB/HIV cases are in Africa Notified cases per 100,000 pop. 1980-2008

11. Drug Resistance in Mycobacterium tuberculosis • Selection of naturally occurring mutations • Established through virtual drug monotherapy due to failures of • Health systems • Health policies • Drug manufacturers and/or regulatory authorities • Prescribers • Patient adherence • Any or all of the above

12. Definitions MDR TB= Strains resistant to at least INH and RIF (most important 1st-line drugs) XDR TB =MDR TB strains with additional resistance to any fluoroquinolone and any of the 3 injectable second-line drugs (amikacin, kanamycin, capreomycin) TB with any drug resistance MDR TB XDR TB

13. Proportion of MDR among new TB cases, 1994-2010

14. Proportion of MDR among previously treated TB cases, 1994-2010

15. Trends of MDR-TB cases in selected settings Estonia Latvia Lithuania

16. Trends of MDR-TB cases in selected settings China, Hong Kong SAR United States of America

17. Trends of MDR-TB cases in selected settings Orel Oblast, Russian Federation Tomsk Oblast, Russian Federation

18. "Why making things simple when they can be made complicated?" XDR-TB is born… XDR = Resistance to at least INH and RIF (MDR) PLUS resistance to any fluoroquinolones, AND any one of the second-line injectable drugs (amikacin, kanamycin, capreomycin) Of 17,690 isolates from 49 countries during 2000-2004 20% were MDR and 2% were XDR XDR found in: USA: 4% of MDR Latvia: 19% of MDR S Korea: 15% of MDR XDR found in Southern Africa associated with HIV

19. Tugela Ferry, KZN: MDR/XDR TB Survey Gandhi NR et al, Lancet 2006; 368:1575-80 1539 isolates 544 (35%) Cx+ M. tuberculosis 995 (65%) Cx Negative 221(41%) MDRTB 323 (59%) Susceptible 53 (10%) XDR-TB (24% of MDR-TB)

20. Tugela Ferry XDR-TB SurveyPatient Characteristics Characteristics of 53 patients No. (%) • No prior TB Treatment 26 (51) • Prior TB treatment • Cure or Completed treatment 14 (28) • Treatment Default or Failure 7 (14) • HIV-infected (44 tested) 44 (100) • Dead (Includes 34% on ARV) 52 (98) • Health care workers 2 • Median survival 16 days • Number of M. tuberculosis strains 4+ Gandhi NR et al, Lancet 2006; 368:1575-80

21. Countries that had reported at least one XDR-TB case by Oct 2011

22. TB Control Global Targets 2015:Goal 6: Combat HIV/AIDS, malaria and other diseases Target 8: to have halted by 2015 and begun to reverse the incidence… Indicator 23: incidence, prevalence and deaths associated with TB Indicator 24: proportion of TB cases detected and cured under DOTS 2015:50% reduction in TB prevalence and deaths by 2015 2050: elimination (<1 case per million population)

23. The global response: Stop TB Strategy & Global Plan • Pursue high-quality DOTS expansion • Address TB-HIV, MDR-TB, and needs of the poor and vulnerable • Contribute to health system strengthening • Engage all care providers • Empower people with TB and communities • Enable and promote research

24. Case detection stagnating globally

25. Treatment success target reached globally: 87% in 2007-8-9 92 88 88 100 82 79 67 80 60 40 20 0 EMR Africa Europe SE Asia W Pacific Americas Successful treatment rate (%) in DOTS cohorts 2007 N= 2.5 million 1994 N= 250,000 But not in the Americas, Africa and Europe

26. TB incidence, prevalence and mortality:global estimates, 1990–2010 Globally on track to achieve the 2015 targets for reductions in incidence and mortality

27. TB incidence: global estimates by WHO Region, 1990–2010

28. The "rare" case of Peru: rapid increase, good DOTS/PHC, rapid decrease (6-7% per year) DOTS introduced Pulmonary TB cases/100,000

29. What are the challenges in 2011? • DOTS quality not uniform; only 65% of all estimated cases reported; diagnosis probably late in most settings • TB/HIV, especially in Africa; MDR-TB, especially in former USSR and China; XDR-TB everywhere we look for it • Weak health systems and services compromising TB care; lack of bold policies on free access to care, drug quality and restriction, labs, human resources, infection control, etc. • Not all practitioners, non-state and even governmental, working at high standard; weak public-private links • Communities often un-aware, un-involved, not mobilised • Research not yet delivering innovative tools, transfer of technology slow, and operational research neglected

30. Challenges specifically in the TB core area of work • Political commitment and funding, both domestic and international aid, uncertain • Early and increased case detection not pursued • Scale-up of links with non-state sector practitioners • TB/HIV:TB and AIDS programmes not working together • Scale-up of MDR-TB care

31. Funding has increased substantiallyin recent years 4.1 2.7 • Data based on ~ 100 countries each year with ~ 94% estimated global cases • Technical assistance and R & D not included

32. But still falls short of Global Plan targets, except in E. Europe All regions except Eastern Europe Eastern Europe 3.8 GP = Global Plan AF = Available Funding US$ billions 2.7 2.2 1.7 1.3 1.2 • Data based on ~ 100 countries each year with ~ 94% estimated global cases • Sources: WHO TB database, Global Plan; technical assistance and R & D not included

33. Early and increased case detection Targeting vulnerable groups: contacts % of all cases yielded by active case finding among contacts of TB cases – Maroc, 1993-2004 Ottmani S et al, 2008

34. Increasing case notifications through public-private schemes Case recovery into the NTP by different care providers, Bangalore, 1999-2005 • Public and private medical colleges (yellow) diagnose a huge number of cases, but many of them are from outside the city and need to be refereed for treatment elsewhere. • The increase in diagnosed cases represents increased notification after medical colleges and other providers started to report to NTP in a standardised way

35. Policy on collaborative TB/HIV activities WHO recommendations A. Establish NTP-NACP collaborative mechanisms • Set up coordinating bodies for effective TB/HIV activities at all levels • Conduct surveillance of HIV prevalence among TB cases • Carry out joint TB/HIV planning • Monitor and evaluate collaborative TB/HIV activities B. Decrease burden of TB among PLHIV (the "3 Is") • Establish intensified TB case finding • Introduce INH preventive therapy • Ensure TB infection control in health care and congregate settings C. Decrease burden of HIV among TB patients • Provide HIV testing and counselling • Introduce HIV prevention methods • Introduce co-trimoxazole preventive therapy • Ensure HIV/AIDS care and support • Introduce ARVs World Health Organization

36. Global implementation of key TB/HIV activities, 2003 – 2010

37. Bottlenecks to scale-up M/XDR-TB prevention and management • Gaps in TB control • Extremely weak M/XDR-TB management and care • Health workforce crisis • Inadequate laboratories • Quality of anti-TB drugs not assured • No restriction or regulation of anti-TB drug use • Absent infection control • Insufficient research • Major financial gaps From the conclusions of the Ministerial Conference on M/XDR-TB, Beijing, 1-3 April 2009

38. Huge challenges to face MDR-TB effectively defined in Beijing & WHA 2009 In addition to proper basic control.. • Remove financial barriers (UHC) • Ensure well trained and sufficient human resources • Establish a network of labs where rapid tests are also available • Ensure availability of quality drugs • Regulate the use of all anti-TB drugs • Introduce infection control • Establish proper surveillance • Promote R&D • Mobilize funds domestically and internationally Document WHA 62.15, 2009

39. 27 high MDR-TB burden countries Progress of MDR-TB care very slow

40. Full implementation of Global Plan: 2015 MDG target reached but TB not eliminated by 2050 10000 1000 Projected incidence 10x lower than today, but 100x bigger than elimination target in 2050 Incidence/million/yr 100 10 Elimination 16%/yr Elimination target: 1 / million / year by 2050 Global Plan 6%/yr Current trajectory 1%/yr 1 2000 2010 2020 2030 2040 2050 Year

41. Traditionalarea of core TB control not enough TB care and control Health systems And policies Development Research Innovative action needed in 4 spheres"Moving beyond the TB box"

42. Thinking a bit in the "R&D box" VACCINE DIAGNOSTIC TREATMENT Sputum smear microscopy Discovered 1882 BCG Developed 1920s 1st-line TB drugs Discovered 1943-1970

43. Limitations of today’s Diagnostics, Drugsand Vaccine - A clear need for new tools Diagnostics - More than 100 years old Smear microscopy detects only half of the cases in patients tested Rapid tests for resistant strains not widely available in the field Particularly ineffective for diagnosing TB in people living with HIV Drugs - Nearly 40 years old Four drugs, taken for at least 6 months Not compatible with some antiretrovirals Treatment for resistant strains lengthy, with low success rates, expensive, toxic Vaccine - More than 85 years old Unreliable protection against infectious pulmonary TB Most widely used vaccine in the world, but no apparent impact on the growing TB epidemic

44. Potential impact of new TB vaccines, diagnostics and drugs in SE Asia Source: L. Abu Raddad et al, PNAS 2009 Add. Effects = effects also on latency and infectiousness of cases in vaccinated • Led & NAAT at microscopy lab level • Dipstick at point of care • Regimen 1 = 4-month, no effect on DR • Regimen 2 = 2-month, 90% effective in M/XDR • Regimen 3 = 10-day, 90% effective in M/XDR

45. Needs for diagnostics in tiered health system

46. TB diagnostic pipeline

47. Evolution since 2007 - Maintaining tiered system approach 2009 2008 2007 Until 2007 Expected 2014 Expected 2010 Expected 2011 • Surveillance • Reference methods • Network supervision LC /DST 15d/45d Reference Labs • Resolution testing • (screening-test negative • drug resistance) SC /DST 30d/60d Regional Labs LPA 2d District Level • Screening • Passive case finding • Detect and treat ZN 2-3d SubDistrict Level Auto NAAT +40% /2h Microscopy Level LED FM +10% Manual NAAT+25% • Clinical • Screening • Primary care Community Level RDT

48. Roll out of Xpert MTB/RIF, 2011

49. Current TB Therapy and Unmet Needs * Rifampin (R), Isoniazid (H), Pyrazinamide (Z), Ethambutol (E) • Need shorter and simpler therapies against both DS and DR-TB

50. The ideal new anti-TB drug Novel mode of action, effective against M(X)DR-TB Shorter therapy against both DS and M(X)DR-TB Suitable for co-administration with ARVs Orally active, once daily or less frequent dosing Adequate safety and tolerability profiles Affordable – low cost of goods • Keep adoption in mind, we must set a higher bar than what is required to get a regimen approved by regulatory agencies