The Elimination of Tuberculosis. Richard E. Chaisson, MD. Center for TB Research Center for AIDS Research Johns Hopkins University

Transcription

1 The Elimination of Tuberculosis Richard E. Chaisson, MD Center for TB Research Center for AIDS Research Johns Hopkins University

2 Disclosures Spouse owns Merck stock Consultant: Merck Research funding: NIH, CDC, Gilead Foundation, FDA, USAID, Bill and Melinda Gates Foundation

3 Case Presentation 53 year old white woman with nocturnal dyspnea and mild cough for 4 weeks no fever, weight loss, sputum, pain, orthopnea. Non smoker, no pets, no toxic exposures PMH: Rheumatoid Arthritis,? Asthma, depression, cervical dysplasia, kidney stones PPD+ 6 years ago (Converter), CXR negative, no Rx Meds: etanercept, methotrexate, prednisone (5 mg) Exam: AF, VSS, RR 18, O2 sat 97%, chest clear, heart normal, no adenopathy, no clubbing

4 Case Presentation 2 Labs: CBC normal, LFTs normal, U/A negative, EKG nsr without changes, PFTs normal

5 Case Presentation 2 Labs: CBC normal, LFTs normal, U/A negative, EKG nsr without changes, PFTs normal CXR:

6 Case Presentation 2 Labs: CBC normal, LFTs normal, U/A negative, EKG nsr without changes, PFTs normal CXR: CT: multiple hilar and mediastinal lymph nodes

7 Case Presentation 3 Mediastinoscopy LN biopsy with non-caseating granulomas Dx: sarcoidosis Treated with bronchodilators, immunosuppressants not changed 3 weeks later, cultures from LN biopsy grew M. tuberculosis Started on 4 drug therapy and did well

8 Highlights of this case Immunosuppression (e.g., HIV) a major driver of TB globally Iatrogenic immunosuppression increasingly important in developed world Missed opportunity for prevention PPD conversion, no treatment Diagnosis of sarcoid in patient with positive tuberculin test is at your and patient s peril

9 30,000 Reported TB Cases United States, * 25,000 No. of Cases 20,000 15,000 10,000 5,000 0 *Updated as of June 5, Year

10 Cases per 100, TB Case Rates by Race/Ethnicity,* United States, ** American Indian or Alaska Native Black or African-American White Asian Native Hawaiian or Other Pacific Islander Hispanic or Latino *All races are non-hispanic. **Updated as of June 5, 2015.

11 Trends in TB Cases in Foreign-born Persons, United States, * No. of Cases Percentage % % % % % % % 0 0% Number of Cases Percent of Total Cases *Updated as of June 5, 2015.

12 Countries of Birth of Foreign-born Persons Reported with TB, United States, 2014 Other Countries 39% Mexico (21%) Philippines (12%) Haiti (3%) Guatemala (3%) China (7%) Vietnam (8%) India (8%)

13 Global TB Incidence and Mortality, WHO. Global Tuberculosis Report 2015

14 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

15 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.

16 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 existing 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 Global policies that lack understanding of best epidemiologic approaches

17 Risk of TB infection and disease among exposed individuals Exposure (close contact) No infection 70% Infection ~30%

18 Risk of TB infection and disease among exposed individuals Exposure (close contact) No infection 70% Infection ~30% Early progression (TB <2 years) 5-10% Containment 90-95%

19 Risk of TB infection and disease among exposed individuals Exposure (close contact) No infection 70% Infection ~30% Early progression (recent TB <2 years) 5-10% Containment 90-95% Reactivation greatly increased by HIV and other immunosuppressive states Late progression (reactivation TB) 5% Continued containment 85-90%

20 The Origin of TB Cases: Prevalence of Risk Factors in Patients with Culture-Confirmed Pulmonary TB in Baltimore, MD 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

21 Rangaka, Chaisson, Lancet, 2015 Population dynamics of TB globally

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

23 A Platform for Controlling Global Tuberculosis FIND the TB that is there Passive case detection is not sufficient Intensified (active case finding essential) Improved diagnostic technologies TREAT the TB that is found Treatment success is unacceptably low Treatment for 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

24 Clinical suspicion Symptoms Keys to diagnosis of TB Cough, fever, weight loss, night sweats Epidemiologic risk factors Risk of exposure: e.g., contact of case, spent time in a highburden setting (immigrants, prisoners, HCWs) Biomedical risk factors Immunosuppression (HIV, TNF-inhibitors, cancer Rx), diabetes, silicosis, end-stage renal disease Appropriate clinical and laboratory evaluation AFB smears, nucleic acid amplification, culture Presumptive therapy often appropriate

25 Diagnosis of Tuberculosis Chest x-ray or CT scan (non-specific) Sputum smear Sensitivity 50-60% Specificity varies Sputum culture Sensitivity 95+% Time to detection days Nucleic acid amplification tests Rapid turnaround Sensitivity 70-90%

26 Boehme CC et al. N Engl J Med 2010;363: Cepheid GeneXpert MTB/RIF Test

27 Boehme CC et al. N Engl J Med 2010;363: GeneXpert MTB/RIF Performance Characteristics No. Sputums Tested 3 Sputum Samples Sensitivity, all Smear-positive Smear-negative 1 Sputum Sample Sensitivity, all Smear-positive Smear-negative Sensitivity 97.4% 99.8% 90.2% 92.2% 98.2% 72.5% Sensitivity HIV+ 93.9% Sensitivity HIV- 98.4% Specificity % Sensitivity for RIF-resistance 99.1%

28 Xpert vs. smear to rule out TB in hospitalized patients LH Chaisson, et al, Clin Infect Dis 2014;59:

29 Nahid et al. Clin Infect Dis 2016; 2016 ATS/CDC/IDSA Recommended Drug Regimens for Pulmonary Tuberculosis Caused by Drug-Susceptible Organisms

30 2016 ATS/CDC/IDSA Recommended Drug Regimens for Pulmonary Tuberculosis Caused by Drug-Susceptible Organisms 6 month regimen 2 month intensive phase, 4 month continuation phase Isoniazid/Rifampin/Pyrazinamide/Ethambutol x 2 months Isoniazid/Rifampin x 4 months Daily therapy during intensive phase Daily or 3x weekly therapy during continuation phase Supervised therapy (DOT) and intensive case management Monitor for drug toxicity Nahid et al. Clin Infect Dis 2016;

31 Baltimore City Case with some twists 27 y.o. Mexican male with 2 weeks of cough, bloody sputum, chest pain, breathlessness, and fever presents to local emergency department Recent immigrant with no prior medical problems His brother in Mexico treated for TB 2 years ago Works as laborer and lives with 6 coworkers

32 Meds None Exam: Temp. 38.2, RR 24 Chest exam normal No adenopathy No hepatosplenomegaly Labs CBC: WBC 7.4, Hct. 40 Liver and kidney tests: normal

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34 PPD placed and sputum sent for smear and culture, patient referred to Health Department Clinic for follow up, no treatment given in ED 2 days later, PPD = 35 mm induration AFB smears X 3 Positive, 2-3+ HIV Serology Positive CD4 268 VL 35,000

35 Treatment with INH/RIF/PZA/EMB started by directly observed therapy (DOT) Antiretroviral therapy deferred for first 8 weeks of TB treatment

36 Good response to therapy, improvement in symptoms in 2 weeks Sputum smears negative at 4 weeks Susceptibility test results returned at 3 weeks: Low-level resistance to INH (0.2 mcg/ml) Resistant to RIF Susceptible to PZA, EMB, Streptomycin

37 Treatment changed: RIF stopped, Moxifloxacin and Streptomycin added Treatment given daily by DOT ART started after 2 months Contacts treated with INH preventive therapy

38 Tuberculosis Drug Resistance Acquired drug resistance Selection of innately resistant mutants by inadequate treatment Requires sufficient AFB load for selection of resistant mutants ( organisms) Primary drug resistance Disease with an organism that was resistant when infection was acquired Multi-drug resistant TB (MDR TB) Resistance to at least INH and rifampin extensively-drug resistant TB (XDR TB) MDR TB plus resistance to fluouroquinolones and an injectable agent (amikacin, kanamycin, capreomycin)

39 Treatment of MDR Tuberculosis Principle of treatment: use 3-4 drugs active against the strain Continue treatment for at least months after conversion of cultures to negative Short course regimens (9 months) for selected cases Consider surgical removal of affected segments or lobe(s) after several months of antibiotic therapy

40 Placebo-Controlled Trials of new drugs for MDR-TB Bedaquiline (TMC207) and Delamanid 9% 48% Diacon et al., NEJM 2009;360: Gler et al., NEJM 2012;366:

41 Effect of Linezolid in Patients with Refractory XDR Tuberculosis Lee et al., N Engl J Med 2012, 367:

42 Latent TB Infection 31 y.o. anesthesiologist from South India has pre-employment TST 21 mm induration BCG as infant No TB history or known exposures, though worked in public hospitals in India No symptoms, non-smoker, no other medical problems Medications: Birth control pills (Lo-Estrin) CXR normal What would you do? 1. Repeat TST in 1 month 2. Obtain interferon-gamma release assay (IGRA) 3. Offer treatment for latent TB infection 4. No treatment needed, patient had BCG

43 Stimulate immune cells Allow time for response by immune cells Measure response TST QFT-GIT shake LAB T-SPOT.TB LAB Courtesy of Susan Dorman

44 Diagnosis of latent TB infection Tuberculin skin test >5 mm induration positive for close contacts, immunosuppressed (HIV+) and infants >10 mm for others at risk >15 mm for those with no risk factors for infection Interferon-gamma release assay (IGRA) Quantiferon-gold in tube or T-Spot TB Sensitivity 70-90% Specificity 95+% Exposure to active TB case assume infected if HIV+ or immunocompromised

45 Discordance between TST and IGRAs in patients starting anti-tnf therapy All Patients Positive by Either Test BCG-vaccinated Patients Positive by Either Test Non-BCG-vaccinated Patients Positive by Either Test Hsia et al., ARTHRITIS & RHEUMATISM 2012;64:

46 Reversion of initially positive IGRA tests in health care workers tested serially Dorman et al., AJRCCM 2014;189:77-87.

47 IGRA vs. Tuberculin Skin Test TST Placement and reading require skill and experience Requires return visit in 2-7 days Vast experience, abundant data False positives due to BCG, environmental AFB IGRA Human error reduced Technical errors/problems occur Failure of control mitogen, over-incubation More specific than TST Frequent reversions to negative Both identify populations at risk for TB, but discordance common CDC Guidance: Choose one test and stick with it

48 Groups at risk of progression of latent TB to active disease in low TB incidence countries Patient population Published incidence of active tuberculosis per 1000 Median (range) People living with HIV ( ) TB contacts (adults only) 0.6** Patients receiving tumor necrosis factor 1.4** blockers and other biologics Patients receiving hemodialysis (1.3-52) Patients receiving organ transplantation 5.1** Patients with silicosis 32.1** Prisoners 2.6 ( ) Health care workers 1.3 ( ) Immigrants from high TB burden countries 3.55 ( ) Homeless 2.2 ( ) Illicit drug users 6.0** Adapted from: Getahun, Matteelli, Chaisson, Raviglione. NEJM 2015;372:

49 JAMA 2016;316:

50 Current CDC Guidelines for TB Preventive Therapy in HIV+ Patients Positive TST or IGRA, or high-risk exposure Rule out active TB Regimen Adult Dosage Duration Rating (HIV-) Isoniazid* daily 300 mg/day 9 months A II Isoniazid* daily 300 mg/day 6 months B I Rifampin daily 600 mg/day 3-4 months B II Rifapentine and isoniazid* weekly 900 mg/900 mg once weekly (supervised) 3 months A I *Give pyridoxine mg with INH. 1. MMWR Recomm Rep Jun 9;49(RR-6): MMWR Morb Mortal Wkly Rep. 2011;60:

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52 Weekly RPT/INH x 12 vs INH daily x 9 mos. Clinical and Demographic Characteristics Modified Intent-to-Treat Population Indication for preventive therapy 9INH N=3,745 3RPT/INH N=3,986 Close contact of case 2,609 (70) 2,857 (72) Recent TST converter 972 (26) 953 (24) HIV-infected/PPD+ 74 (2) 87 (2) Fibrosis on CXR 90 (2) 89 (2)

53 Log-rank P-value: 0.06 Cumulative TB Rate Modified ITT

54 Hepatotoxicity Events Toxicity All hepatotoxicity 9-INH 3-RPT/INH P-value N=3,759 N=4, (3.0) 24 (0.6) < Related to drug 103 (2.7) 18 (0.5) < Not related 13 (0.4) 6 (0.2) 0.08

55 Summary Despite global aspirations, TB elimination is unlikely in the next 20 years TB control in the US is attainable Internists and primary care physicians can contribute to TB control through: Diagnosis of active tuberculosis in symptomatic individuals Initiation of appropriate initial therapy and institution of infection control measures Diagnosis and treatment of latent tuberculosis infection in highrisk groups

56 Thank you.