Can TB Be Eliminated?

Transcription

1 Can TB Be Eliminated? Richard E. Chaisson, MD Center for AIDS Research Center for TB Research Johns Hopkins University

2 The Global Burden of TB All forms of TB HIV-associated TB MDR TB / RR TB Estimated number of cases 10.4 million ( million) (IR=142/100,000) 1.2 million (11%) ( million) 580,000 (520, ,000) Estimated number of deaths 1.8 million* ( ) *1.4 million among HIV negative 390,000 (22%) (320, ,000) 250,000 (160, ,000) WHO Global Tuberculosis Report 2016

3 WHO Global Tuberculosis Report 2016

4 TB is now leading infectious cause of death WHO Global Tuberculosis Report 2016

5 Vision, goal, targets, milestones Vision: A world free of TB Zero TB deaths, Zero TB disease, and Zero TB suffering Goal: End the Global TB epidemic

6 Eradication, elimination or control? Eradication complete absence of the disease from the planet. Elimination ending the disease as a public health problem. Defined as TB incidence of <1 per million and TB deaths <1 per 10 million Control making it a much smaller problem than it currently is.

7 Tools to Control of Tuberculosis Why hasn t TB already been eliminated? Global failure to apply biomedical tools effectively Weaknesses in health systems Lack of political will and commitment Inadequacies of most widely used tools Smear detection of cases ~50% Adherence to regimens is poor and MDR TB regimens are toxic and weak BCG vaccine does not prevent adult TB Changing epidemiological situation HIV epidemic MDR Migration Global policies that lack understanding of best epidemiologic approaches

8 Latent TB (Global ~ 2 billion) Reduce and treat individual drivers (HIV) Case finding and treatment of active TB Active TB (Global ~6-7 million/year) Uninfected/Susceptible (5 billion) Vaccination TB Preventive Rx Primary TB (~2-3 million/year)

9 Modeled approaches to reaching TB elimination Dye, et al., Ann Rev Publ Health 2013

10 A Platform for Controlling Global Tuberculosis FIND the TB that is there Passive case detection is not sufficient Improved diagnostic technologies very important Better case finding strategies essential TREAT the TB that is found Improved treatment outcomes essential M/XDR is abysmal New drugs and treatment strategies urgently needed PREVENT the TB that hasn t occurred yet Preventive therapy essential for high risk populations Infection (transmission) control critical Control susceptibility (antiretrovirals, diabetes control) New vaccine

11 TB Case Detection: Missed Cases Drive Transmission and Mortality WHO Global Tuberculosis Report 2013

12 Adults dying at home, no specific diagnosis (18% excluded, known to have TB) Consent from family Bilateral axillary Tru-Cut biopsy Modified bronchoalveolar lavage

13 Tuberculosis found at limited autopsy in adults dying at home from natural causes Omar et al., Int J Tuberc Lung Dis 2015,19: Post-Mortem Diagnosis N=85 (%) TB on 1 lab test 27 (32) TB on 2 lab tests 18 (21) Biopsy with TB (N=20) Histology 14/20 (70) AFB positive (ZN) 7/20 (35) Xpert 17/20 (63) MGIT 18/29 (62.1) BAL with TB (N=22) AFB+ (Auramine) 9/22 (41) Xpert 20/22 (91) MGIT 19/29 (86)

14 New Tools for Diagnosing TB Xpert MTB/RIF Ultra Omni Xpert Platform Abbott BD Max New tools are exciting and attractive, but do they make a difference in incidence of disease or death?

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16 Southern Africa Zambia Western Cape K m Western Cape Zambia K

17 ZAMSTAR Interventions: Enhanced Case finding vs. Household Contact Screening Enhanced case finding (ECF) Community Mobilization and sputum collection School intervention Open Access at the clinic Household intervention (HH) Visit all households of new TB patients Offer TB screening, HIV testing and referral to appropriate care to entire household

18 Impact of Household Contact Evaluations for New TB Patients or Community Active TB Case (ECF) Finding in High Burden Areas % 55% Household Evaluations: Impact on TB prevalence Household Evaluations: impact on transmission in children 1.09 ECF impact on TB prevalence 1.36 ECF impact on transmission in children Risk ratios (for prevalence) and Rate ratios (for transmission) H. Ayles, et al., Lancet, 2013

19 Impact of Improving Case Finding and Treatment on Tuberculosis Control: A Mathematical Model Annual Decline in TB Incidence (%) Case Detection Rate: 20% 40% 60% 70% 80% Years After Stabilization of Case Detection Rate Effect of case-finding plateaus eventually Dowdy and Chaisson, Bull WHO 2009, 87:

20 PERÚ: TASA DE MORBILIDAD E INCIDENCIA DE TUBERCULOSIS * TASA POR HABITANTES * MORBILIDAD INCID TBC INCID TBP FP * Información preliminar Fuente: ESNPCT /DGSP /MINSA /PERU Fecha de Elaboración.: 17-MAR-2015

21 CDC, 2016

22 Cavalcante et al., Int J TB Lung Dis 2010:14:203-9 Contact evaluation: combining TB case finding and TB preventive therapy: DOTS Ampliado (Enhanced DOTS) Cluster-randomized trial in 8 neighborhoods in central Rio de Janeiro comparing standard DOTS to DOTS Ampliado DOTS Ampliado: Identification of all household contacts (household visits) Evaluation with PPD, x-ray and clinical exam 4% of contacts had active TB 72% of contacts had latent TB ~70% of contacts treated with preventive therapy

23 Community-Randomized Trial of Household Contact Evaulation and Preventive Therapy (DOTS-A) vs DOTS in Rio de Janeiro TB Incidence/100, Year 15% difference p=0.04, 1999 vs DOTS DOTS-A Cavalcante et al., Int J TB Lung Dis 2010:14:203-9

24 Preventive Interventions in TB Prevent Infection Reduce Chemoprophylaxis Susceptibility TB and HIV vaccines obvious additional strategies, but not currently available

25 Prevalence of latent tuberculosis infection in rural China Tuberculin Skin Test >10 mm Quantiferon test positive Tuberculin Skin Test >10 mm Quantiferon test positive Gao, et al. Lancet Infect Dis 2015:15;310-9

26 Preventive Interventions in TB: Impact of ART on TB Incidence in HIV+ People Reduce Susceptibility A.B Suthar, et al. PLoS Medicine, 2012

27 TB-HIV in Rio (THRio): Improving the uptake of TB screening and INH preventive therapy (IPT) in people receiving care of HIV infection in Rio de Janeiro Control Intervention Month

28 Intervention Training for 2 clinics every other month Implementation of TB screening and TST policy for all HIV-infected patients TST to be done for all eligible clinic patients No prior TB history No prior IPT No prior +TST IPT x 6 months for all TST+ without active TB and all contacts of active TB cases 28

29 Clinic-level Outcome Cases Crude HR (95% CI) p-value TB ( ) 0.24 TB or Death ( ) <0.001 Adjusted HR* (95% CI) 0.73 ( ) 0.69 ( ) p-value 0.04 <0.001 *Adjusted for age, sex, ART and CD4 count at enrollment Lancet Infect Dis. 2013;10:852-8

30 Long term efficacy of IPT in HIV-infected persons in a medium TB burden setting: Rio de Janeiro Cumulative probability of tuberculosis Did not start IPT Started IPT Number at risk (events) Did not start IPT Started IPT 1 mo 1 yr 2 yr 3 yr 4 yr 5 yr 6 yr 7 yr Years since PPD (58) 400 (14) 318 (9) 241 (1) 168 (2) 123 (2) 84 (0) (7) 1470 (12) 1506 (12) 1437 (2) 1149 (5) 790 (3) 414 (0) 189 Golub, et al. CID, 2015

31 TEMPRANO: Immediate vs Deferred ART Initiation and IPT Delivery for African Patients Not Eligible for ART Cumulative Probability of Death or Severe HIV-Related Illness (%) Mo Probability, % Deferred ART 14.1 Deferred ART + IPT 8.8 Immediate ART 7.4 Immediate ART + IPT Mos From Randomization TEMPRANO ANRS Study Group. N Engl J Med. 2015

32 Poor Global Uptake of IPT for People with HIV WHO. Global TB Report, 2016

33 The Cascade of Care for Latent TB 31% start PT 18.8% complete PT Alsdurf et al., Lancet ID, 2016

34 TEKO Study Interferon Gamma Release Assay Blood Test vs Tuberculin Skin Test to Screen HIV+ People for TB IGRA Clinics Eligible 1214 (76%) Standard-of-Care (TST) Eligible 990 (78%) Enrolled n = 1169 (96%) Enrolled n = 933 (94%) Valid Result Obtained 903 (76%) Valid Result Obtained 83 (6%) Martinson and Golub, IUATLD 2016

35 Cluster-Randomized Trial of Nurse-initiated IPT based on symptom screening vs TST-based screening 16 Matlosana Sub-district Primary Care Clinics Restricted Randomization -Mean No. TB cases/month -Distance from Hospital Koombi fare Salazar-Austin, CROI clinics: TSTbased Screening Symptombased Screening Endpoint: Proportion of child contacts started on IPT

36 Screening and provision of INH preventive therapy to child contacts in Matlosana Health District, October 2015 March 2016 Cascade of Child Contact Evaluation Estimated INH Coverage for Child Household Contacts = 22% Salazar-Austin, CROI # TB Index Cases # EstimatedContacts < 5 yr # IdentifiedContacts < 5 # ScreenedContacts < 5 # Contacts Initiated Treatment

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38 1 month of daily rifapentine/inh (HP) vs 9 months of daily INH ACTG A5279 Study Design: Multicenter, randomized, open-label, phase III clinical trial Study Population: 3000 HIV-infected participants >12 years old in 13 countries Stratification 1) CD4+ cell count at entry (<100, , and >250 cells/mm 3 ) 2) ART use at entry (Yes/No 50% on ART at entry) Duration: 3 years (156 weeks) after the last participant is enrolled R. Chaisson and S. Swindells, Co-Chairs

39 Target Populations for TB Control in Developed Countries Active case finding and preventive therapy Immigrants and refugees from high-burden countries Immunosuppressed patients HIV TNF and cytokine inhibitors Transplant and chemotherapy Injection drug users Prisoners Homeless Comorbidities: smoking, diabetes, end-stage renal disease

40 Understanding Local Drivers of TB Risk Factors in Patients with Culture-Confirmed Pulmonary TB in Baltimore Characteristic No. (Total = 139) % Foreign born 12 9% HIV Infection 31 24% IDU 28 20% Diabetes 18 14% Renal Failure 12 9% Recent Cancer 8 6% Steroid Use 7 6% Oursler et al., CID 2002;34:729-9

41 How to improve TB control globally Increase case finding Better diagnostic tests Active case finding, especially in household contacts Initiate treatment early and improve outcomes Reduce early losses to follow up Better regimens Prevent TB in high-risk populations Preventive therapy for those at increased risk Better regimens sterilizing regimens in high-burden settings Reduce susceptibility, e.g., ART

42 Can TB be eliminated? Probably not by 2035 or even Can TB be controlled? Yes, with investment in epidemiologically sound strategies and tools and greatly improved delivery.

43 JHU/PHRU Jonathan Golub Neil Martinson David Dowdy Larry Moulton Nicole Salazar-Austin Silvia Cohn Bonnie King Grace Link Barnes Anne Efron Susan Dorman Jenny Hoffmann Chris Hoffmann Acknowledgements ZAMSTAR Peter Godfrey-Faussett Helen Ayles Nulda Beyers Richard Hayes THRio Solange Cavalcante Betina Durovni Valeria Saraceni ACTG Sue Swindells TBTC Tim Sterling Elsa Villarino Marcus Conde Funders: Fogarty Int l Center NIDA NIAID/NIH CDC FDA Bill and Melinda Gates Foundation