State of the State in TB Control Jason Stout, MD, MHS Wake County TB Medical Consultant NC TB Medical Director Division of Infectious Diseases, Duke University Medical Center
Disclosures-Funding NIH (grant) CDC (contract) JHP Pharmaceuticals (grant) Exxon-Mobil (consultant) UpToDate (card author) Novella/NKT Therapeutics (DSMB)
In 2014 TB was subdued, Ebola! Ebola! Ebola! was news. Polio spreads! WHO did cry, And that new virus MERS called for Media Live. Two fatal plane crashes on Malaysian Air Chikungunya popped up all over the West, And D68 pneumonia wasn t the best. All of these problems make people shriek, But TB kills as many in about a week.
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TB News in 2014 Continued decline in cases Continued decline in funding to treat cases Smoking and TB still bad New drugs and making old drugs work better Perspective on contact investigations More info on IGRAs Long-term survival after TB
Lancet 2014; 384: 1005-70
TB in NC US rate (2014) 3.0/100K vs NC 2.0 100/K #29 for incidence rate, #13 for total cases TB is not someone else s problem
# Cases NC TB cases 1993-2014 600 500 400 300 200 100 0 1995 2000 2005 2010 Year
NC Demographics 1990-2014 1000 900 800 700 600 500 400 300 200 100 0 Thousands Asian/Pacific Islander Hispanic Total FB 1990 2014
1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Foreign-born TB Cases in NC 1993-2014 50% 40% 30% 20% 10% 0% Year
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Smoking and TB Smoking is associated with higher rates of both TB infection and disease Smoking has also been associated with worse TB treatment outcomes The reasons for these observations are not clearly understood
Smoking and TB Investigators obtained alveolar macrophages via bronchoscopy from nonsmokers, exsmokers, and smokers Examined how these macrophages responded when challenged with Mycobacterium tuberculosis O Leary SM et al, AJRCCM 2014; 190: 1430-1436
O Leary SM et al, AJRCCM 2014; 190: 1430-1436
O Leary SM et al, AJRCCM 2014; 190: 1430-1436
O Leary SM et al, AJRCCM 2014; 190: 1430-1436
O Leary SM et al, AJRCCM 2014; 190: 1430-1436
Smoking and TB Smoking impairs the macrophage response to TB in the lung May explain part of why smokers get more TB and tend to stay smear-positive longer O Leary SM et al, AJRCCM 2014; 190: 1430-1436
New Drugs Current treatment for MDR TB is 18-24 months Multiple, toxic drugs Suboptimal outcomes
New Drugs Pretomanid (Pa-824) is a nitroimidazole drug active against M. tuberculosis Mechanism of action is not fully understood; probably has several mechanisms Promising therapy for drug-resistant TB as well as perhaps treatment-shortening for drugsusceptible TB
New Drugs Phase 2 study examining a combination of pretomanid, moxifloxacin, and pyrazinamide Evaluated patients from 6 sites in South Africa and 2 sites in Tanzania Pulmonary TB, CD4>200 One group of patients had MDR but had to be susceptible to PZA and moxi Dawson R et al, Lancet 2015; 385: 1738-1747
Dawson R et al, Lancet 2015; 385: 1738-1747
Dawson R et al, Lancet 2015; 385: 1738-1747
Dawson R et al, Lancet 2015; 385: 1738-1747
New Drugs Early data, but drug and regimen have potential Looks good for MDR but many MDR are PZAresistant (67% in the group studied here), so not widely applicable
Optimizing TB Drugs Current TB drugs were developed in the 50s and 60s Dose of rifampin was primarily based on cost Is it the right dose? Mouse studies suggest that more is better
Increasing Rifampin Dose Dose-ranging safety, tolerability, and microbiologic efficacy (phase 2) study Conducted at one of two sites in Cape Town, South Africa Enrolled patients with smear-positive pulmonary TB; if HIV+ had CD4 350 Boeree MJ et al., AJRCCM 2015; 191: 1058-1065
Increasing Rifampin Dose Dose-ranging safety, tolerability, and microbiologic efficacy (phase 2) study Conducted at one of two sites in Cape Town, South Africa Enrolled patients with smear-positive pulmonary TB; if HIV+ had CD4 350 Boeree MJ et al., AJRCCM 2015; 191: 1058-1065
Boeree MJ et al., AJRCCM 2015; 191: 1058-1065
Boeree MJ et al., AJRCCM 2015; 191: 1058-1065
Boeree MJ et al., AJRCCM 2015; 191: 1058-1065
Boeree MJ et al., AJRCCM 2015; 191: 1058-1065
Boeree MJ et al., AJRCCM 2015; 191: 1058-1065
Increasing Rifampin Dose Higher doses appeared to be reasonably safe and well tolerated Higher doses also associated with more microbiologic activity Maximum tolerated dose was not reached may try higher! Boeree MJ et al., AJRCCM 2015; 191: 1058-1065
What About Rifapentine? Longer half-life than rifampin, so exposure is much higher when rifapentine is given at equivalent doses Mouse models also have suggested increased activity at high doses
What About Rifapentine? Phase 2 randomized, controlled trial examining high-dose rifapentine Randomized pulmonary TB patients to one of the following: Rifampin 10 mg/kg daily Rifapentine 10 mg/kg daily Rifapentine 15 mg/kg daily Rifapentine 20 mg/kg daily All subjects got standard HZE Dorman SE et al., AJRCCM 2015; 191: 333-343
Dorman SE et al., AJRCCM 2015; 191: 333-343
Dorman SE et al., AJRCCM 2015; 191: 333-343
Dorman SE et al., AJRCCM 2015; 191: 333-343
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Risk of TB Among Contacts We often tell people that after TB infection, the risk of TB disease is 5-10% ~2.5-5% during the 2 years after infection ~2.5-5% over the rest of a lifetime These estimates are based on old data Are they still true?
Risk of TB Among Contacts Examined contact of pulmonary TB patients in Amsterdam 2002-2011 Followup through October 2012 Definitions: Coprevalent: Dx 180 days from index case Incident: Dx>180 days after index case Sloot R et al, AJRCCM 2014; 190: 1044
Risk of TB Among Contacts Contact investigations performed similar to how we do them TST read 72-96 hours Since 2008, positive TSTs are confirmed with a Quantiferon If no IGRA done, TST of 10 mm or more considered positive Contacts with LTBI are offered 3HR, 4R, or 6H Sloot R et al, AJRCCM 2014; 190: 1044
Risk of TB Among Contacts 9332 contacts identified 74 (0.8%) had coprevalent TB Of these, 68 were contacts to smear-positive cases 36 incident cases Sloot R et al, AJRCCM 2014; 190: 1044
Risk of TB Among Contacts 739/4774 (16%) screened contacts had LTBI 57 of these had coprevalent TB not really LTBI 5-year risk of incident or coprevalent TB=9.5% 372/681 contacts with LTBI did not start rx 5-year risk of LTBI in this group 2.4% (95% CI 1.2-4.7%) Sloot R et al, AJRCCM 2014; 190: 1044
Risk of TB Among Contacts Most of the TB found was coprevalent Major benefit of contact investigation is to find these Incidence of TB lower than previously estimated Protective effect of LTBI rx probably limited by adherence Sloot R et al, AJRCCM 2014; 190: 1044
IGRAs in TB Contacts The tuberculin skin test has traditionally been used to screen TB contacts, but has a number of limitations Limited published data have supported the use of IGRAS to screen TB contacts Especially in an era of declining resources, we need to understand how these tests perform
TBNET Contact Study Multicenter study examining TB contacts in Western Europe Prospective, observational Either a QFT or a TSPOT was done, at the discretion of the site Further evaluation and f/u done per local protocols Zellweger J-P et al, AJRCCM 2015; 191: 1176-1184
Zellweger J-P et al, AJRCCM 2015; 191: 1176-1184
TBNET Contact Study Overall 27.2% were IGRA+; only 0.5% indeterminate results Extent of contact correlated with proportion with positive IGRA Birthplace outside of Europe also associated with positive IGRA Zellweger J-P et al, AJRCCM 2015; 191: 1176-1184
Zellweger J-P et al, AJRCCM 2015; 191: 1176-1184
Zellweger J-P et al, AJRCCM 2015; 191: 1176-1184
TBNET Contact Study Changing the test cutoffs didn t seem to make a huge difference in ability to predict future TB Latent TB treatment among persons with a positive IGRA was associated with significant reduction in future TB (compared with no treatment) We probably need better tests Zellweger J-P et al, AJRCCM 2015; 191: 1176-1184
IGRAs in Immunocompromised TBNET authors examined the relative performance of TST and both IGRAs Recruited patients from 17 centers in 11 European countries Patients were adults (18+) with HIV, chronic renal failure, rheumatoid arthritis, or transplant Also recruited low-risk, immunocompetent controls Sester M et al, Am J Respir Crit Care Med 2014; 190: 1168
Sester M et al, Am J Respir Crit Care Med 2014; 190: 1168
Sester M et al, Am J Respir Crit Care Med 2014; 190: 1168
Sester M et al, Am J Respir Crit Care Med 2014; 190: 1168
IGRAs in Immunocompromised 11 patients developed active TB during median 1.8 yrs f/u (IQR 0.2-3.0) 10 of these had HIV (median CD4 302, all with detectable VL), 1 was a solid-organ transplant recipient All patients who developed TB were born in a medium or high incidence country and had not received LTBI rx Sester M et al, Am J Respir Crit Care Med 2014; 190: 1168
IGRAs in Immunocompromised Incidence of active TB after 2 years among persons with positive test and no LTBI rx: TST 1.15/100 person-years QFT 0.71/100 person-years TSPOT 0.88/100 person-years Much lower in persons with negative tests (0.15, 0.11, and 0.17/100 p-y for TST, QFT, TSPOT, respectively) Sester M et al, Am J Respir Crit Care Med 2014; 190: 1168
IGRAs in Immunocompromised None of the available tests perform well in these populations IGRAs were not superior to TST in this study All patients who developed TB had a risk factor for TB exposure Testing low-risk persons because of immune compromise probably not a great idea Sester M et al, Am J Respir Crit Care Med 2014; 190: 1168
Long-term mortality from TB A small proportion of people with TB die from it acutely In NC 1993-2003 3.4% of TB cases died before starting rx 5.7% died in the first 8 weeks 4.4% died prior to completing rx Nguyen LT et al, IJTLD 2011; 15: 257-262
Nguyen LT et al, IJTLD 2011; 15: 257-262
Mortality After TB Treatment TB can cause long-term damage to the lungs People who get TB may systematically differ from the rest of the population Does having had TB affect long-term survival?
Mortality After TB Treatment TBESC examined this question among patients in TX, MA, and Seattle Compared 2 groups: Patients with active TB dx 1993-2002 who completed TB therapy (N=3853) Comparison group with LTBI during the same 10 year period as the cases (N=7282) Used National Death Index to assess mortality as of 2008 Am J Pub Health 2015; 105: 930-937
Am J Pub Health 2015; 105: 930-937
Mortality After TB Treatment As of 2008, 20.7% of TB survivors vs. 3.1% of LTBI patients dead Death among TB survivors associated with white race and HIV+ status After adjustment for age, gender, race, HIV status, foreign birth, TB survivors were 7.6 times more likely to die than LTBI patients Am J Pub Health 2015; 105: 930-937
Mortality After TB Treatment What does this mean? Unlikely that most of the mortality effect is actually due to late effects of TB EP TB not much different than pulmonary TB Long-term effects of lung damage, for example, may be contributing to mortality TB probably a marker for high risk Am J Pub Health 2015; 105: 930-937
A Little Story Accinelli RA et al, AJRCCM 2015; 191: 1202
A Little Story Intervention started in 1985 TB screening with sputum and CXRs DOT for active TB patients LTBI treatment Physician-directed program integrated with community resources Accinelli RA et al, AJRCCM 2015; 191: 1202
Accinelli RA et al, AJRCCM 2015; 191: 1202