State of the State in TB Control

Transcription

1 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

2 Disclosures-Funding NIH (grant) CDC (contract) JHP Pharmaceuticals (grant) UpToDate (card author) Novella/NKT Therapeutics (DSMB)

3 In 2016 our TB was high, Ten percent increase, cases weren t shy. In the US the decline was said to have stalled, Not much of a drop in the cases at all. Molecular tools made life much better, Despite interference from hurricane weather. High workload offset by Skyping the meds, Though rising addiction fills us with dread. TB nurses are sorely required, Though many are saying I just retired!

4 TB News in 2016 Case numbers higher in NC Spotlight on latent TB in the US More evidence for rifamycin-based LTBI rx TB outbreaks near and far New tools for understanding TB TB and pregnancy

5 TB Incidence in the US MMWR 2017; 66: 289

6 NC TB cases # Cases Year

7 Latent TB in the US CDC conducts NHANES survey about every 10 years Information about many population health parameters Most recent estimate 4.2% of population in 2000 Had declined by ~60% during the previous 28 yrs Data from recently analyzed

8 Latent TB in the US NHANES Population-based sample Did both TST and QFT-IT in participants age 6 and older (prior years only did TST) Estimates based on population-weighted results Mancuso et al., AJRCCM 2016; 194: 501

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15 Mancuso et al., AJRCCM 2016; 194: 501

16 Mancuso et al., AJRCCM 2016; 194: 501

17 LTBI Gets Its Due USPTF reviewed the evidence on screening for latent TB in primary care This is important because under ACA, screening tests with an A or B rating are paid for Consider benefits, harms, but not cost JAMA 2016; 316: 962

18 LTBI Gets Its Due Populations at increased risk: Foreign-born in high-prevalence country Current or former residence in congregate setting Homeless shelter Correctional facility Estimated risk/benefit: TB cases prevented per 100,000 screened 7-67 cases of hepatotoxicity per 100,000 screened JAMA 2016; 316: 962

19 LTBI Gets Its Due LTBI screening received a B rating Moderate certainty of a moderate net benefit in screening asymptomatic persons for LTBI JAMA 2016; 316: 962

20 Rifamycins for LTBI INH still listed as first-line in CDC guidelines In NC, have been moving toward short-course regimens 4 mos rifampin 12 weeks isoniazid/rifapentine Better completion rates and tolerability But how does efficacy compare?

21 Rifamycins for LTBI Network meta-analysis examining current LTBI regimens Conventional meta-analysis: Summarize all studies comparing A to B Network meta-analysis: Combine studies comparing different treatments So if A is better than B and B is better than C, A is probably better than C

22 Annals Int Med 2017; 167: 248

23 Annals Int Med 2017; 167: 248

24 Annals Int Med 2017; 167: 248

25 Rifamycins for LTBI Large RCT comparing 4 mos RIF with 9 mos INH for efficacy was recently completed Results hopefully available in 2018 For now, even more confidence that RIF works

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27 Atlanta Outbreak Longstanding issue with homeless shelters in Atlanta Lots of HIV+ persons not on treatment hanging out at shelters Guess what? Powell et al, Public Health Reports 2017; 132: 231

28 Powell et al, Public Health Reports 2017; 132: 231

29 US TB Outbreaks CDC did a retrospective evaluation of TB outbreaks for which they provided on-site assistance Defined an outbreak as 3 or more cases related by transmission (genotype and epi links) Mindra et al, Public Health Reports 2017; 132: 157

30 US TB Outbreaks Mindra et al, Public Health Reports 2017; 132: 157

31 US TB Outbreaks Mindra et al, Public Health Reports 2017; 132: 157

32 US TB Outbreaks Mindra et al, Public Health Reports 2017; 132: 157

33 Atlanta Outbreak Almost all cases were homeless 100% INH-monoresistant High prevalence of HIV 56% HIV+ initial phase 35% quiescent phase 30% recrudescent phase Of those with HIV, most not on meds Powell et al, Public Health Reports 2017; 132: 231

34 Atlanta Outbreak 12 patients died, 10 of TB All but 2 of remainder completed treatment 59% unable to name any contacts County health dept evaluated 1360 homeless people plus 916 known contacts 1/14-6/ had LTBI 58 of these either were receiving or completed 4 mos rifampin Powell et al, Public Health Reports 2017; 132: 231

35 Atlanta Outbreak Powell et al, Public Health Reports 2017; 132: 231

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37 If you think that s bad Widespread epidemic of XDR TB ongoing in South Africa Cases have increased since 2002 Not entirely clear why

38 XDR in South Africa Prospective study of 404 XDR patients diagnosed in KwaZulu-Natal province, South Africa Did interviews and reviewed medical records Also did genotyping of TB isolates NEJM 2017; 376: 243

39 XDR in South Africa KZN has population of 10.3 million Majority live in rural areas Estimated that about half the XDR burden in S Africa is in this province Highest rates of TB (1076 per 100,000) and HIV (16.9% prevalence) in South Africa NEJM 2017; 376: 243

40 NEJM 2017; 376: 243

41 XDR in South Africa Majority of XDR was transmitted 124 with acquired resistance 280 with transmitted Majority of patients (77%) had HIV Median CD4 in 300s About 60% on antiretroviral meds 60% of pts with transmitted resistance had a history of prior TB treatment, mostly for DS NEJM 2017; 376: 243

42 XDR in South Africa Transmitted in both hospital and community settings Epi links noted in 30% of participants Lots of little networks NEJM 2017; 376: 243

43 XDR in South Africa NEJM 2017; 376: 243

44 Genes and TB Meningitis TB meningitis is a bad disease ~30% mortality Many who survive are disabled Corticosteroids are routinely recommended Reduce inflammation Seem to improve survival Steroids may not benefit everyone equally

45 Genes and TB Meningitis Leukotriene A(4) hydrolase (LTA4H) gene controls balance of pro- and antiinflammatory eicosanoids A single nucleotide polymorphism in the promoter for this gene regulates its activity Tobin et al, Cell 2012; 148(3): 434

46 Tobin et al, Cell 2012; 148(3): 434

47 Tobin et al, Cell 2012; 148(3): 434

48 Genes and TB Meningitis New prospective study to examine this association further Enrolled 764 Vietnamese adults into a randomized trial of intensified TB treatment All patients received dexamethasone Prospectively genotyped all patients Thuong et al, J Inf Dis 2017; 215: 1020

49 Thuong et al, J Inf Dis 2017; 215: 1020

50 Thuong et al, J Inf Dis 2017; 215: 1020

51 Genes and TB Meningitis Both LTA4H genotype and HIV influence the amount of inflammation in spinal fluid and mortality from TB meningitis Practical implication: If we could rapidly genotype patients, maybe we could select which patients would benefit from steroids Thuong et al, J Inf Dis 2017; 215: 1020

52 Computers Taking Over

53 Computers Taking Over

54 maybe not yet But computers may be able to help out Deep learning is a form of machine learning in which computers simulate the networks in human brains Basis for self-driving cars, for example Can this type of technology help with TB care?

55 Deep Learning and Chest Radiography Used publicly available datasets of TB CXRs from Thomas Jefferson University, NIH, Shenzhen, China, and Belarus Downloaded films and examined them using two deep convolutional neural net architectures AlexNet GoogLeNet Radiology 2017; 284: 574

56 Deep Learning and Chest Radiography Total of 1007 posteroanterior films Split films into training, validation, and test sets 150 films in test set, of which 75 had TB, 75 did not In cases where the two classifiers disagreed, an independent radiologist reviewed the films Radiology 2017; 284: 574

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58 Deep Learning and Chest Radiography Radiology 2017; 284: 574

59 Deep Learning and Chest Radiography Neural net performance improved with training Test scenario designed to operate in TBendemic regions and differentiate normal from abnormal films Not ready for prime time, but could be useful in areas with limited radiologist availability Radiology 2017; 284: 574

60 Late Positive Smears Seem to be encountered with some frequency Do we have to put these patients back on isolation?

61 Late Positive Smears Retrospective cohort of 1611 patients with drug-susceptible pulmonary TB in South Korea Received standard TB treatment from January 2009-February 2014 Compared 41 patients (2.5%) who were smear-positive after 5 months of treatment to 123 age- and sex-matched controls Kang et al., Medicine 2016; 95: 31 (e4540)

62 Kang et al., Medicine 2016; 95: 31 (e4540)

63 Late Positive Smears Patients with late-positive smears were More likely to have prior TB (24.4% vs 12.2%) More likely to have presented with cough and dyspnea More likely to have initial positive smears (68% vs 44.7%) More likely to have cavity/bilateral disease and pleural effusions Kang et al., Medicine 2016; 95: 31 (e4540)

64 Late Positive Smears Kang et al., Medicine 2016; 95: 31 (e4540)

65 Late Positive Smears Only 1/41 (2.4%) of patients with late positive smears actually grew TB from culture 7 (17.1%) grew NTM The rest (80.5%) had negative cultures (although 6 patients had subsequent growth of NTM in other specimens) Kang et al., Medicine 2016; 95: 31 (e4540)

66 Late Positive Smears Only 1 patient (2.4%) was characterized as treatment failure, no acquired resistance The rest completed treatment successfully Prior studies reported % of pulmonary TB patients were smear-positive at month 5 Few culture positive These studies included some drug-resistant pts Kang et al., Medicine 2016; 95: 31 (e4540)

67 Late Positive Smears Most patients with late positive smears are not failing treatment No need in most cases to re-isolate In cases of suboptimal clinical response or known drug resistance, can consider more aggressive actions Kang et al., Medicine 2016; 95: 31 (e4540)

68 TB in Pregnancy Emerging Problem? Whether pregnancy increases risk of TB reactivation is debated TB has been associated with increased rates of pregnancy complications Treatment of TB in pregnancy is a bit more challenging because in US we avoid PZA

69 TB in Pregnancy Emerging Problem? Examined the Nationwide Inpatient Sample databases from % stratified sample of all discharges from US community hospitals About 7 million admissions from >1000 hospitals El-Messidi et al, Am J Obstet Gynecol 2016; 217: 797.e1-6

70 TB in Pregnancy Emerging Problem? Used ICD codes to identify deliveries and TB Also used these codes to identify comorbidities and obstetric outcomes 2064 births to women with TB identified during the 9 year study Women with TB more likely to be Hispanic (34.6% vs 19.1%) and HIV-infected (1.8% vs 0.1%) El-Messidi et al, Am J Obstet Gynecol 2016; 217: 797.e1-6

71 TB in Pregnancy Emerging Problem? El-Messidi et al, Am J Obstet Gynecol 2016; 217: 797.e1-6

72 TB in Pregnancy Emerging Problem? El-Messidi et al, Am J Obstet Gynecol 2016; 217: 797.e1-6

73 TB in Pregnancy Emerging Problem? Women with TB were more likely to have pregnancy complications: Chorioamnionitis Postpartum anemia Pulmonary complications (pneumonia/ards) Mortality (adjusted OR 6.27, 95% CI ) El-Messidi et al, Am J Obstet Gynecol 2016; 217: 797.e1-6

74 TB in Pregnancy Emerging Problem? Women with TB were more likely to have babies with congenital anomalies (adjusted odds ratio 1.80, 95% CI ) No difference in fetal growth, preterm birth, or stillbirth El-Messidi et al, Am J Obstet Gynecol 2016; 217: 797.e1-6

75 TB in Pregnancy Emerging Problem? TB and pregnancy a bad combination Not clear why the reported rise in the setting of otherwise falling US TB rates Screening high-risk women of reproductive age for TB and treatment for LTBI seems like a good idea El-Messidi et al, Am J Obstet Gynecol 2016; 217: 797.e1-6

76 Conclusions Lots of interesting new information in TB Treatment of latent TB is an important focus to move toward elimination New high-tech tools may help us move forward Old problems like TB in pregnancy still persist