Scaling up LTBI Treatment with Short Course Regimens to Eliminate TB

August 2016 Scaling up LTBI Treatment with Short Course Regimens to Eliminate TB Carol Dukes Hamilton, MD, MHS Director, Scientific Affairs and Leader, TB Portfolio, FHI 360 Professor of Medicine, Duke University Durham, North Carolina

Disclosures past 12 months No financial disclosures Will be discussing off-label use for rifampin for treatment of latent TB infection (LTBI) Investigator/author on 2 referenced studies Sterling et al; N Engl J Med 2011;365:2155-66 TB Trials Consortium Holland et al; PLoS ONE, vol 6; 2011; e22276 Investigator with the TB Trials Consortium

Scaling Up Treatment of LTBI Objectives: Recognize how LTBI treatment enables TB elimination Consider how short-course regimens may increase uptake and completion of treatment of LTBI Understand how new LTBI guidelines may enhance scale-up of treatment for LTBI

Scaling up : Market and Public Health Create demand How our lives will be better with XYZ! Understand the price point Affordable for the target audience Market the product Why is it better than competitors? Systematize if possible E.g., getting on the hospital or Medicare formularies Measure sales, uptake, % of market Ensure steady supply

Scaling up : Market and Public Health Create demand [for scaling up short-course Tx LTBI] Articulate the rationale, projected impact Understand the price point Do the cost benefit analysis, work with pharma Market the product Why shorter might be better than longer treatment Rx Systematize if possible Guidelines Measure sales, uptake: CDC Program Evals Ensure steady supply: Work with pharma

Scope of Problem: Enormous Reservoir of Latent TB ~ 1/3 world s population with LTBI Progress to Active TB

Spillover to active TB can be. Modest.think Mexico, much of Latin America

Spillover to active TB can be. Frequent, potentially accelerating. Think countries of former Soviet Union eastern Europe, parts of Asia Overwhelming. Southern Africa coinciding with HIV/AIDS epidemic 8

Impact of Addressing the Reservoirs US & Canada: Scope & Impact of Treating LTBI Studied LTBI practices in 2002* 79% of LTBI identified and treated in public health clinics Immigrant/refugee clinics (6.4%), correctional/detention centers 6.1% Drying up the reservoir! Extrapolated to estimate that between 4-11,000 future TB cases prevented by activities that year *Sterling, TB Epi Consortium; AJRCCM, 2006, 927-931

Most Effective Interventions? Or, where to spend the $$? Number of cases Number of deaths Treating LTBI Treating LTBI TB Morbidity TB Morality Abu-Raddad et al; PNAS 106: 13980-13985; 2009

Latent TB Infection (LTBI) Active TB Continuum from exposure to infection to latency to active disease Opportunity to intervene

Latent TB Infection (LTBI): Not Really Latent Trends in Microbiology, Young, 2009, 183-189

Latent TB Infection (LTBI) Active TB Continuum from exposure to infection to latency to active disease Opportunity to intervene Certain populations EXTREMELY vulnerable Recent close contacts to a case, especially infants and children <4 years HIV/AIDS; other immunosuppressed (TNF-inhibitors) Newly arriving immigrants with abnormal chest x-rays Identifying vulnerable populations can lead to efficient targeted testing for LTBI

Evidence for Long-course treatment LTBI with INH Isoniazid (INH) 1952: Rapidly bactericidal in animal models and humans disease 1965: Recommended INH for prevention of TB 1970: Hepatotoxicity recognized with INH, especially among individuals > age 35

Evidence for Long-course treatment LTBI with INH Large scale clinical trials of INH to prevent TB Union (IUAT) trials of 27,830 subjects with TST+ and fibrotic lesions on CXR in eastern Europe Placebo-controlled randomized clinical trial (INH versus placebo) Compared 12-week to 24 weeks to 52 weeks INH/placebo

Evidence for Long-course treatment LTBI with INH Completion: Shorter is better 87% completed 12 weeks 78% completed 24 weeks 68% completed 52 weeks Bull WHO 60:555-564; 1982

Evidence for Long-course treatment LTBI with INH Efficacy: Longer is better 21% reduction in TB cases with 12 weeks treatment 65% reduction.. with 24 weeks treatment 75% reduction.. with 52 weeks treatment Bull WHO 60:555-564; 1982

Long-course treatment LTBI with INH: Limitations TBESC study (Colson et al, 2013, IJTLD) 29% eligible for TLTBI refused to participate in study Of those enrolled in study, 89% agreed to TLTBI Completion of 6-9 month INH 20-60% range Boston study, mostly foreign-born population, 29% finished 6 months INH (Shieh et al; 2006, AJRCCM) Multi-site study of close contacts, 63% completed (Fiske et al, 2014, IJTLD) Commonly sited reasons for discontinuation: Side effects, time away from work or family, resistance to taking medicine when not sick

Scaling up : Current Approach Not Working NEED A SHORTER DRUG REGIMEN THAN 9 months IPT! Is there EVIDENCE that shorter course regimens might work?

PREVENT TB*: RCT 9H versus 3HP 9 INH Arm INH 300 mg Self-administered Daily, 9 months 3HP Arm INH 900 mg + RPT 900 mg DOT Weekly, 3 months TB Trials Consortium study: US, Canada, Brazil, Spain & Hong Kong 2001-2010 enrolled high risk adults and children with LTBI (e.g., recent contacts to a case, recent conversions), (children > age 2) and HIV-infected (not on ARV) Followed each for 2 years after end of treatment *Sterling et al; N Engl J Med 2011;365:2155-66 (adults); pediatric data in press; HIV data CROI

PREVENT TB: RCT 9H versus 3HP Conclusions for all populations studied (adults, children, HIV+): Weekly 3HP by DOT was at least as effective as 9H by selfadministration Met non-inferiority criteria 3HP TB rate was approximately half that of 9H in adult, non-hiv The 3HP completion rate was significantly higher than 9H 3HP was safe relative to 9H Lower rates of any adverse event, and less hepatotoxicity attributable to study drug ClinicalTrials.gov: NCT00023452

Subsequent Studies show it is safe and effective in: *children down to age 2 *persons living with HIV/AIDS (caution RPT drug-drug-interaction) *self-administered

Scaling up : Market and Public Health Create demand How our lives will be better with XYZ! Understand the price point Affordable for the target audience Market the product Why is it better than competitors? (including safety) Systematize if possible E.g., getting on the hospital or Medicare formularies Measure sales, uptake, % of market Ensure steady supply

Overview Toxicities of All LTBI Treatment Regimens Hepatotoxicity Less if regimen excludes daily INH Drug-drug interactions Many if regimen w/rif or RPT Syncope/hypersensitivity syndrome: Unique to 12 HP Requires counseling and education Serious episodes rare, but potential for harm Mild: Dizziness, rash can try a second dose Moderate to severe (syncope) or allergic reactions: bronchospasm/wheezing, urticarial, angioedema No further doses; manage as other allergy/anaphylaxic

Reported Symptoms for Patients on 3HP and Treatment Completion 600 500 15% 400 300 200 100 0 [CELLRANGE] 12% [CELLRANGE] 8% 7% 6% 6% 6% [CELLRANGE] [CELLRANGE] 5% 4% 4% [CELLRANGE] [CELLRANGE] [CELLRANGE] [CELLRANGE] 4% [CELLRANGE] [CELLRANGE] [CELLRANGE] [CELLRANGE] 0.7% [CELLRANGE] [CELLRANGE] [CELLRANGE] [CELLRANGE] [CELLRANGE] [CELLRANGE] [CELLRANGE] [CELLRANGE] [CELLRANGE] 3% [CELLRANGE] 5% 8% Completed Tx Discontinued Tx Other symptoms reported by one or more patients include: Dermatological-related Symptom, Gastro-Intestinal related Symptoms, Cough, Mental Health Symptom, Weight Loss, Blurred Vision, Flu-like Symptoms, Breathing Problem, Back Pain, Gynecological-related Symptoms, Chest Pain, Diaphoresis, Angioedema, Bleeding, Palpitation, Ease Bruising, Edema, Neurologic Symptoms, Hypotension, Flushing, Red Eyes, URI, Genitourinary Symptoms, Other Eye Symptom, Black Stool, Pain, Pneumonia, and Sepsis. *Patients can have more than one symptom

Scaling up : Market and Public Health Create demand How our lives will be better with XYZ! Understand the price point Affordable for the target audience Market the product Why is it better than competitors? (including safety) Systematize if possible E.g., getting on the hospital or Medicare formularies Measure sales, uptake, % of market Ensure steady supply

Scaling up : Affordability of 3 HP Expense of PRIFTIN Started at $52/32-tablet blister pack 2011 2014: $32/pack (need 2.25 packs per course, adults) 2016: Course of treatment Rifapentine & INH $ 22.60 + $1.00* *California FAQ sheet estimates total $147/month with clinic visit and DOT Modeling study** showed that even at $52/pack and with DOT, 3-month HP more cost effective than 9H Fewer TB cases because of greater uptake, completion, less toxicity **Holland et al; PLoS ONE, vol 6; 2011; e22276

Scaling up 3 HP: DOT and the iadhere Study iadhere randomized participants into selfadministered, with or without SMS reminders, compared to DOPT Recognizing that DOPT is almost certainly going to result in higher completion rates, but affordable, sustainable? Therefore planned on a non-inferiority statistical approach, i.e., will SA no more than than 15% lessgood than DOPT

Belknap R et al; CROI 2015, manuscript in preparation iadhere: Comparable Completion Rates Selfadministered Compared to DOPT

Near-final data, with permission, Ho, Nwana, et al, CDC Field Services Branch, Presentation 2015 Union meetings, Cape Town Post-marketing 3HP Surveillance Project Patients Started on 3HP, June 2011 December 2013 3,327 patients started on 3HP 39 Ineligible to complete Index-case resistant: 20 QFT negative/not LTBI: 2 Active TB case: 1 Pregnant: 14 HIV + receiving HAART: 2 3,288 patients eligible to complete treatment 421 (12.8%) discontinued treatment 2,867 (87.2%) completed treatment 246 (7.5%) discontinued with symptoms 175 (5.3%) discontinued due to other reasons

Post-marketing Project Objectives Monitor for adverse events with 3HP in non-research settings Track number of patients started on regimen Note if certain populations, risk factors or settings are associated with adverse effects (AE) more often Assess compliance and treatment completion Assess impact of 3HP on programs Staffing Costs Match patients with TB registry at 2 years Observational measurement of effectiveness Surveillance for drug-resistant TB after LTBI treatment Near-final data, with permission, Ho, Nwana, et al, CDC Field Services Branch, Presentation 2015 Union meetings, Cape Town

Treatment Completion Rate (%) Range of Treatment Completion Across 16 U.S. Sites, June 2011 December 2013 100 90 80 70 60 50 40 30 20 10 0 100 81 * 83 84 85 85 87 88 88 90 91 91 91 92 95 97 L E J A F D I N K H O P C B G M Participating Site Number of participants at each site ranged from 14 to 1,018 Completion ranged from 81-100% Discontinuation while reporting symptoms ranged from 0 16% * Proportion completing treatment among those eligible to complete at that site Near-final data, with permission, Ho, Nwana, et al, CDC Field Services Branch, Presentation 2015 Union meetings, Cape Town

Demographic Factors and Treatment Reasons Associated with Discontinuation of 3HP, N=3,288 Discontinued Multivariate Completed Univariate N p-value arr N (%) RR (%) p-value Age (years) 1.01 <.001 (2-17) 155 9 (94.5) (5.5) 0.44.014 0.55.077 >=65 Race/Ethnicity Non-Hispanic White Treatment Reason Contact Corrections Homeless Student 154 (78.6) 595 (82.5) 751 (91.5) 451 (87.4) 147 (81.2) 123 (94.6) 42 (21.4) 126 (17.5) 70 (8.5) 65 (12.6) 34 (18.8) 7 (5.4) 1.72 <.001 1.52.009 1.60.001 1.22.199 0.60 <.001 0.68.005 0.98.878 1.43.013 1.51.011 1.72.001 0.41.016 0.45.044

Scaling up: Getting There? Education, Systemization California TBCB 3 HP FAQ Sheet

Shorter Treatment Options for LTBI? 2 months rifampin and pyrazinamide Efficacy similar to INH But significant hepatotoxicity outside HIV+ populations INH and rifampin for 3 months 5 trials, total of 1,926 adults (meta-analysis)* Hong Kong, Spain, Uganda Estimated similar efficacy to INH, also similar toxicity Rifampin for 3 months One study (silicosis + TST+) showed 63% efficacy Less toxicity than INH Rifampin for 4 months RIF 4 months has become default regimen in many places due to higher uptake, low toxicity, despite very limited data Currently being evaluated in RCT (Menzies et al) *Ena, Valls; CID 40:670-6; 2005

http://www.cdc.gov/tb/topic/treatment/ltbi.htm

Updating LTBI Testing and Treatment Guidelines Updating the 2000 LTBI Guidelines In process since 2011 Co-sponsored by ATS (MTPI Assembly), CDC and IDSA and in-kind author support from institutions Working with NTCA to create companion how-to document

Updating LTBI Testing and Treatment Guidelines Recommending short-course regimens as preferred over longer course treatment on basis of effectiveness (efficacy + greater completion + less toxicity, probably greater uptake) Discussion of the how (SAT versus DOT) awaiting iadhere data and CDC recommendations Finalizing and approvals hopefully 2016

Concluding Points Targeted testing and treatment of high-risk individuals is necessary for TB Elimination in the US We now have important new tools IGRAs more specific, may help with FB populations Shorter regimens higher acceptance and completion Agreement across international normative bodies embracing short-course regimens ATS/CDC/IDSA LTBI treatment guideline update in progress Canada, WHO embrace

Acknowledgements Conveners of Annual North Carolina TB RD Jason Stout, Myra Allen Jason Stout, David Holland Research collaborators CDC s ongoing support for TB Trials Consortium & TBESC Ken Castro, Andy Vernon Tim Sterling, Elsa Villarino and all other TBTC investigators for Study 26/PREVENT TB Chistine Ho, Nwana, et al, CDC Field Services Branch, for generously sharing their data

THANK YOU! And here s hoping that short-course treatment of LTBI will scale-up as rapidly as SELFIES have!