Whats new in HIV-associated tuberculosis? December 14, 2019 Sarah - PDF document

What’s new in HIV-associated tuberculosis? December 14, 2019 Sarah Puryear, MD MPH 1 Disclosure I have no relevant financial relationships with any companies related to the content of this course. 2 1 | [footer text here]

Objectives § Select and interpret diagnostic tests for latent tuberculosis infection (LTBI) in HIV-infected patients § Design an LTBI treatment plan that accounts for ART drug interactions § Identify appropriate methods to screen for LTBI vs. diagnose active TB § Describe when to start ART in TB and major rifamycin-ART interactions § Manage TB immune reconstitution inflammatory syndrome (IRIS) 3 Tuberculosis: A major global health problem § 2018: - 10.0 million cases/year - 1.5 million deaths/year § #1 cause of death among PLHIV WHO, Global Tuberculosis Report 2019 4 2 | [footer text here]

Epidemiology of TB in the United States Tuberculosis Cases in United States, 1980-2015 Centers for Disease Control (CDC). Reported Tuberculosis in the United States, 2015 Atlanta, GA: U.S. Department of Health and Human Services, CDC; 2016. 5 Epidemiology of TB in California • California reports 20% of TB cases in the US each year • >2000 cases annually • LTBI cases estimated at 2.4 million • 1 in 17 Californians • 1 in 5 foreign-born Californians California Department of Public Health (CDPH). TB Fact Sheet 2017, Sacramento, CA; 2018. 6 3 | [footer text here]

Audience response How many people have you started on latent TB treatment in the past year? A. None. B. <5 C. 5-10 D. Who has time to count!? 0 A B C D 7 Case 1 § A 41 year-old man from San Francisco presents to your clinic for evaluation. Two weeks ago, he was diagnosed with HIV. § Initial labs show: - CD4 120, HIV RNA 75,000 - Interferon gamma release assay (IGRA): Indeterminate § He denies any history of TB infection and does not know of any contacts with TB § He has experienced homelessness and has had brief periods of incarceration in the past 8 4 | [footer text here]

Audience Response 41M from SF with new HIV (CD4 120, VL 75K) and indeterminate IGRA What is the correct interpretation of this indeterminate IGRA result and what is your next step? TB infected; rule out active TB and treat him A. TB exposed, uninfected; do nothing B. TB infection cannot be determined; re-test when CD4 is higher C. TB exposed OR BCG vaccinated; obtain a PPD “tie-breaker” D. TB infection cannot be determined; obtain a PPD “tie-breaker” E. 0 A B C D E 9 Screening for LTBI in HIV § WHO? § WHEN? - All HIV patients, regardless of - At HIV diagnosis or entry into risk factors care - In those with negative LTBI test § WHY? & CD4<200 à repeat after ART - Increased risk of progression to started & CD4>200 active disease - If likely ongoing/repeat - Poor outcomes with active exposure to active TB: Screen disease annually - Effective treatments exist - Recent contact with a known TB case DHHS OI Guidelines, 2019 10 5 | [footer text here]

LTBI Treatment and ART reduce risk of TB disease and death in PLHIV Probability of Death Badje, Lancet Global Health, 2017 11 Testing for LTBI Option 1: Tuberculin Skin Test Option 2: Interferon Gamma Release Assay QuantiFERON-TB Gold-Plus ELISA 48 to 72 hours later T-SPOT. TB ≥ 5 mm positive ELISPOT in HIV+ pts Neither distinguishes between latent and active disease Negative does NOT rule out active disease 12 6 | [footer text here]

TST vs. IGRA Both 65-70% sensitive in PLHIV Diagnostic Strengths Limitations Approach TST § Requires 2 visits § False positives possible with BCG* § Vast experience, § Can remain positive after LTBI, abundant data active TB tx § Cheaper IGRAs § Technical errors § Requires 1 visit § Must be processed in 8-30hrs § Interpretation not § False positives with some other subjective mycobacteria § More specific than TST § Limited data in children, recent TB § Unaffected by BCG exposure, CD4<200 § Can remain positive after LTBI, active TB tx *BCG status should NOT affect PPD interpretation 13 QuantiFERON-TB Gold-Plus § 4 th generation IGRA FDA approved 6/2017 § Advances/Advantages 1 - Adds CD8+ T cell antigens - Option for single tube blood collection - Non-inferior sensitivity § PLHIV 2 - Overall sensitivity not affected by HIV status - Lower sensitivity with severe immunosuppression 1 APHL Press Release, 2018. 2 Telisinghe, IJTLD, 2017. 14 7 | [footer text here]

QuantiFERON-TB: Interpretation Measure Incubate IFN-γ by ELISA 15 QuantiFERON-TB: Interpretation Nil TB1 minus TB2 minus Mitogen QFT-Plus Report/ (IU/ml) Nil (IU/ml) Nil (IU/ml) minus Nil Result Interpretation (IU/ml) ≥0.35 and Any Any Positive M. tuberculosis ≥25% Nil infection likely Any ≥0.35 and ≦ 8.0 ≥25% Nil <0.35 ≥0.5 Negative M. tuberculosis OR infection NOT ≥0.35 and <25% Nil likely <0.5 Indeterminate Likelihood of M. tuberculosis >8.0 Any Any infection cannot be determined Quantitative Qualitative 16 8 | [footer text here]

...but wouldn’t a tie-breaker help? § 294 HIV positive San Franciscans underwent TST & Quanteriferon 1 - 30% did not return for PPD follow up - Concordance of tests: 89.3% “…the predictive value of this approach is not clear, and its § BUT if one test was positive: only 28% had concordance adoption would be more expensive and more difficult to implement. The routine use of both TST and IGRAs to screen for LTBI is not recommended in the United States” 2 1 Luetkemeyer, Am J Respir Crit Care Med, 2007; 2 Mazurek, MMWR, June 2010. 17 Case 1 (continued) 41M from SF with new HIV (CD4 120, VL 75K) and indeterminate IGRA § You start him on Descovy (TAF/FTC) and Dolutegravir § 3 month labs demonstrate: - CD4 is 230, VL undetectable - Repeat QuantiFERON positive § He is asymptomatic § CXR is within normal limits You decide to treat him for LTBI. 18 9 | [footer text here]

Audience Response 41M from SF with new HIV (CD4 230, VL UD) on TAF/FTC/DTG with positive IGRA Which one of the following regimens do you select to treat LTBI in this patient? A. Isoniazid, pyrazinamide, rifampin, ethambutol, and pyridoxine for 2 months Isoniazid and pyridoxine daily for 9 months B. Isoniazid and pyridoxine daily for 6 months C. Isoniazid and pyridoxine plus rifapentine weekly for 3 D. months 0 A B C D 19 LTBI Treatment Options § Preferred H = isoniazid R = R ifampin - 9H: INH x 9 months (with B6) P =Rifa P entine Z =Pyra Z inamide § Alternative - 3HP: INH + Rifapentine weekly (with B6) † - 4R: Rifampin x 4 months - 6H: INH x 6 months (with B6)* - 2RZ: Rifampin + Pyrazinamide x 2 months § **High risk of hepatotoxicity** † Rifapentine and isoniazid recommended only with Efavirenz and Raltegravir + ABC/3TC or TDF/FTC. DHHS OI Guidelines, 2019 20 10 | [footer text here]

Current Guidelines for TB Preventive Therapy Regimen Adult Dosage Durations, Months Evidence Rating in HIV-Positive Pts Isoniazid* daily 300 mg/day 9 A I Isoniazid* daily 300 mg/day 6 C I Rifampin daily 600 mg/day 4 B I Rifapentine + Maximum: isoniazid* † weekly 900 mg/900 mg 3 A II (+/- DOT) *Give pyridoxine 10-50 mg/day with isoniazid to prevent neuropathy in HIV-positive pts. † Rifapentine and isoniazid recommended only with Efavirenz and Raltegravir + ABC/3TC or TDF/FTC. DHHS OI Guidelines, 2019; Borisov, MMWR, 2018. 21 HOT OFF THE PRESS • Multinational study of 6063 patients ( Only 255 PLHIV ) • Completion rate: 78.8% rifampin vs 63.2% INH • Adverse events: 1.5% in rifampin vs. 2.6% INH • TB cases: 0.1/100 person-yrs in RIF vs. 0.11/100 person-yrs in INH à DHHS 2019: 4R recommended in LTBI patients who cannot receive INH Menzies, NEJM, 2018; DHHS OI Guidelines, 2019 22 11 | [footer text here]

HOT 3HP Guidelines Update OFF THE PRESS § 2011: 3HP recommended for LTBI in PLHIV NOT on ART § 2018 CDC updates & 2019 DHHS updates: - As young as 2 years - PLHIV taking ARVs with acceptable drug-drug interactions with RPT - By DOT or self-administered therapy DHHS OI Guidelines, 2019; Borisov, MMWR, 2018; Sterling (PREVENT TB), AIDS, 2016 23 What is an “acceptable drug-drug” interaction with rifapentine? No PIs Rifapentine and Antiretrovirals § Efavirenz (n=87) 1 NRTI Backbone: - 1HP qD TDF/FTC Or - EFV >1mg/L: 98% à 86% (0 à 4 weeks) ABC/3TC - VL undetectable: 93% à 95% (0 à 8 weeks) § Raltegravir (n=16) 2 not TAF - RAL levels measured w/ weekly and daily rifapentine …more on this later - 900mg qweek rifapentine increased raltegravir AUC 89% - 600mg qD rifapentine decreased trough, not Cmax or AUC - No intolerance observed à Weekly rifapentine + RAL acceptable; daily is not § Dolutegravir ? 1 Podany, CID, 2015; 2 Weiner, J Antimicrob Chemotherapy, 2014 24 12 | [footer text here]