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

5. Most TB cases are still in Asia South- East Asia 34% Africa 30% Western Pacific 21% EMR 7%7% Europe 4% Americas 3% 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 Notified cases per 100,000 pop. 1980-2008 4/5 of all estimated TB/HIV cases are in Africa

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) MDR TB XDR TB TB with any drug resistance

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 Lithuania Latvia

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. 1539 isolates 544 (35%) Cx+ M. tuberculosis 995 (65%) Cx Negative 221(41%) MDRTB323 (59%) Susceptible 53 (10%) XDR-TB (24% of MDR-TB) Tugela Ferry, KZN: MDR/XDR TB Survey Gandhi NR et al, Lancet 2006; 368:1575-80

20. Tugela Ferry XDR-TB Survey Patient Characteristics Characteristics of 53 patientsNo. (%) No prior TB Treatment26 (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 survival16 days Number of M. tuberculosis strains4+ 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: 50% reduction in TB prevalence and deaths by 2015 2050 : elimination (<1 case per million population) 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

23. The global response: Stop TB Strategy & Global Plan 1.Pursue high-quality DOTS expansion 2.Address TB-HIV, MDR-TB, and needs of the poor and vulnerable 3.Contribute to health system strengthening 4.Engage all care providers 5.Empower people with TB and communities 6.Enable and promote research

24. Case detection stagnating globally

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

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) Pulmonary TB cases/100,000 DOTS introduced

29. What are the challenges in 2011? 1.DOTS quality not uniform; only 65% of all estimated cases reported; diagnosis probably late in most settings 2.TB/HIV, especially in Africa; MDR-TB, especially in former USSR and China; XDR-TB everywhere we look for it 3.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. 4.Not all practitioners, non-state and even governmental, working at high standard; weak public-private links 5.Communities often un-aware, un-involved, not mobilised 6.Research not yet delivering innovative tools, transfer of technology slow, and operational research neglected

30. Challenges specifically in the TB core area of work 1. Political commitment and funding, both domestic and international aid, uncertain 2. Early and increased case detection not pursued 3. Scale-up of links with non-state sector practitioners 4. TB/HIV:TB and AIDS programmes not working together 5. Scale-up of MDR-TB care

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

32. But still falls short of Global Plan targets, except in E. Europe All regions except Eastern Europe 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 Eastern Europe US$ billions 3.8 1.7 2.7 1.3 GP = Global Plan AF = Available Funding 2.2 1.2

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

34. 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 Case recovery into the NTP by different care providers, Bangalore, 1999-2005 Increasing case notifications through public- private schemes

35. 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 Policy on collaborative TB/HIV activities WHO recommendations

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.. 1.Remove financial barriers (UHC) 2.Ensure well trained and sufficient human resources 3.Establish a network of labs where rapid tests are also available 4.Ensure availability of quality drugs 5.Regulate the use of all anti-TB drugs 6.Introduce infection control 7.Establish proper surveillance 8.Promote R&D 9.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. 1 10 100 1000 10000 200020102020203020402050 Year Incidence/million/yr Elimination 16%/yr Global Plan 6%/yr Current trajectory 1%/yr Full implementation of Global Plan: 2015 MDG target reached but TB not eliminated by 2050 Elimination target: 1 / million / year by 2050 Projected incidence 10x lower than today, but 100x bigger than elimination target in 2050

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

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

43. Limitations of today’s Diagnostics, Drugs and 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 SubDistrict Level Microscopy Level Community Level Reference Labs Regional Labs District Level Surveillance Reference methods Network supervision Resolution testing (screening-test negative drug resistance) Screening Passive case finding Detect and treat Clinical Screening Primary care Auto NAAT +40% /2h LED FM +10% Manual NAAT+25% LC /DST 15d/45d LPA 2d RDT SC /DST 30d/60d ZN 2-3d

48. Roll out of Xpert MTB/RIF, 2011

49. Current TB Therapy and Unmet Needs * Rifampin (R), Isoniazid (H), Pyrazinamide (Z), Ethambutol (E) Patient PopulationCurrent TherapyUnmet Needs Drug-Susceptible DS-TB 4 drugs; ≥6 month therapy (2RHZE + 4RH) Shorter, simpler therapy Drug-Resistant M(X)DR-TB Few drugs (including injectables); ≥18 months; poorly tolerated Totally oral, shorter and safer therapy TB/HIV Co-Infection Drug-drug interactions (DDI) with ARVs No or low DDI, co- administration with ARVs Latent TB Infection 6-9 months HShorter, safer therapy ► 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

51. New TB Drug Pipeline - 2011 Preclinical Development Phase IPhase IIPhase III Gatifloxacin Moxifloxacin Linezolid Rifapentine Existing drugs repurposed or redeveloped for TB Meropenem/ Clavulanate TMC207 OPC-67683 PA-824 LL3858 SQ109 PNU-100480 New drugs developed for TB AZD-5847 BTZ-043 CPZEN-45 DC-159a SQ609 SQ641

52. Global Clinical Portfolio - New TB Drugs in Registration Programs Bayer, TB Alliance Oflotub, TDR Tibotec, TB Alliance Otsuka TB Alliance Sequella Lupin Pfizer Phase IPhase IIPhase III

53. November 2007 TB Vaccine Candidates Under Development

54. Elimination of TB by 2050 requires synergistic interventions Dye C & Williams BG, J.R. Soc. Interface 2007 NOT by preventing infection & treating active TB (both act on cutting transmission) But by treating latent infection and active TB or by preventing and treating latent infection (cutting transmission and reactivation)

55. TB death decline in England and Wales started much before antibiotics First drugs: contributed <5% of reduction in TB deaths 1840-1970 M. tuberculosis discovered in 1882

56. - more crowding? -higher prevalence of HIV, smoking, malnutrition, alcoholism, social marginalization etc? -poor access to health services, diagnostic delays, prolonged infectiousness in poor communities? TB incidence rates & socio-economic level, New York, 1973 (SE level estimated on the basis of education, occupation and income) Hinman AR et al, Am J Epidem 103:490, 1976 "The possibility of eradicating TB in a country is essentially a function of its economic level" (G. Canetti, 1962)

57. The lower the GNI, the higher the incidence of TB Relationship Gross National Income/capita and TB incidence

58. Vision: Action in 4 spheres 1.TB core: Expand all aspects of the Stop TB Strategy Prioritize early and active case detection among high-risk & vulnerable populations Engage non-state sector and communities Scale-up MDR-TB management and further accelerate TB/HIV collaboration Measure impact and improve M&E Innovative diagnostic policies and implementation, including clear standard setting 2.Health system and policies: Pursue UHC to abolish financial barriers, drug quality and rational use, integrated lab networks with rapid molecular tests, infection control etc Examine risk factors such as smoking, diabetes, etc and assess feasibility of interventions to prevent, diagnose early and treat TB linking with NCD 3.Research Promote research: fundamental and pipeline for new tools essential for elimination Study carefully transfer of technology for new tools 4.Development: Make TB a development crisis: advocate for social protection, urban planning, food security, support to migrants, refugee assistance, poverty reduction strategies Assess interventions on social and economic determinants such as malnutrition, alcohol abuse, poor housing, indoor air pollution etc

59. Eradication of tuberculosis: Will it be feasible? " The possibility of eradicating tuberculosis in a country is essentially a function of its economic level… …There are three major weapons which can be used in a policy of eradication: chemotherapy, vaccination, and chemoprophylaxis. …In realising this objective, the developed countries can give developing ones considerable help"

60. Many thanks to all Acknowledgements: WHO, FIND Diagnostics, The Global Alliance for TB Drug Development