11/14/2016 Disclosures Research grants to my institution from Merck and GSK Tuberculosis: What’s New for the HIV Provider Susan Swindells MBBS University of Nebraska Medical Center Omaha, NE December 2016 Case #1 ARS Question #1 A 34 year man establishes care in your clinic What should you do now? Born in Mexico, he emigrated to the US 6 years ago Rule out active TB and treat him for LTBI as 1. HIV diagnosed 6 months ago during admission indeterminate = “sort of positive” for community acquired pneumonia Perform TB skin testing 2. HIV now well controlled on Repeat QFT when CD4 count higher 3. TAF/FTC/elvitegravir/cobi/ (Genvoya) Repeat QFT until you obtain a definitive result 4. Last CD4 120, VL < 40 You test him for latent TB with an IGRA (in this case, quantiFERON), result is “indeterminate” 1
11/14/2016 Recommendations for LTBI TB Skin Test Interferon –Gamma release Assay Measures immune response to TB in whole Induces DTH response if pt infected testing in HIV blood Risk of progression to TB disease 10x greater in HIV+ CDC recommends testing after HIV diagnosis and then annually if negative and with exposure risk If baseline negative, repeat after initiation of ART 48 to 72 hours later No direct test for LTBI, can use TST or IGRA Neither diagnostic test predicts risk of progression to active TB No benefit to repeating either test once positive ≥ 5 mm positive http://www.cdc.gov/tb/publications/ltbi/diagnosis.htm in HIV+ pts TST/IGRA Comparison Case #1 continued Both tests ~65-70% sensitive in HIV+ After 6 months treatment with TST IGRA TAF/FTC/elvitegravir/cobi CD4 count is 300 Requires 2 visits Single visit Repeat IGRA is positive Interpretation same if pt Unaffected by BCG had BCG vaccine Patient has no signs or symptoms of active TB Result can be positive, negative or indeterminate and has a normal chest xray Indeterminate more common with immunosuppression Result will be negative or (generally CD4 <200) positive in mm induration Blood must be processed Requires training to in 8-30 h administer and interpret Limited data in small Testing for anergy not children, recent TB recommended exposure Cheaper than IGRA 2
11/14/2016 CDC Recommendations for LTBI ARS question 2 Treatment in HIV-infected Patients o How should you treat his LTBI? INH daily or twice weekly for 9 months INH + rifapentine weekly for 12 weeks Rifampin (or rifabutin) daily for 4 months o Treat with 9 months of INH o Treat with weekly INH/RPT o Treatment is not indicated o Don’t treat as needs to be further evaluated for active TB Monitor patients at least monthly for hepatitis and other side effects http://www.cdc.gov/tb/topic/treatment/ltbi.htm RIFAMPIN: A potent inducer of metabolizing enzymes Beware Drug-Drug Interactions This complicates co ‐ treatment of TB and other diseases tremendously RIF PXR RIF PXR RXR RXR Cytoplasm PGP CYP3A4 Phase II MDR1 protein CYP 3A4 regulatory proximal enzyme regulatory XRE gene promoter regulatory genes gene DNA mRNA Nucleus Dooley et al. (2008) JID 198: 948. 3
11/14/2016 Efficacy of IPT in HIV+ Adults: Risk LTBI/HIV Treatment of TB Considerations • 11 randomised trials with 8,130 HIV+ participants Any ART regimen can be used when isoniazid alone is used for LTBI treatment overall reduction in TB = 36%, reduction PPD+ = 62% Only efavirenz or raltegravir based regimens (in combination with either abacavir/lamivudine Relative Risk (Fixed) 95% CI [ABC/3TC] or tenofovir disoproxil 1.0 fumarate/emtricitabine [TDF/FTC]) can be used with Reference 0.64 once-weekly isoniazid plus rifapentine TB incidence • NOTE: TAF contraindicated 0.95 Death Check carefully for DDI with rifamycins • Can use EFV or double dose DTG with rifampin • Can use PI with rifabutin at 150 mg daily or 300 mg 3 times a week https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf http://www.hiv-druginteractions.org/ Woldehanna and Volmink, Cochrane Review 2006 Both have free apps Early ART Prevents TB: Case #2 The Temprano Trial • Patients with CD4 < 800 randomized to 54 year old women is admitted to your hospital with immediate or deferred ART +/ ‐ IPT cough, fever, and weight loss Diagnosed with HIV on admission, CD4+ 70, HIV RNA • Severe HIV morbidity endpoints 120K N=2056 # Events Rate/100 HR P value PY CXR shows pleural thickening and diffuse infiltrate WHO 111 4.9 ART Early ART 64 2,8 0.56 0.0002 No IPT 104 4.7 IPT 71 3.0 0.65 0.005 Sputum AFB smear negative, bronch negative for PCP ART and IPT decreased risk of TB independently Danel, CROI 2015 4
11/14/2016 How To Diagnose or Exclude TB: Novel Diagnostics Now Available XPERT MTBRIF: 2 hour molecular test for M.TB diagnosis and rifampin resistance (1) More sensitive than AFB smear Works in children and extrapulmonary TB Screen for MDR and XDRTB TB Detection: Sensitivity Xpert Ultra in development (2) TB Detection: Sensitivity HAIN MTBDR plus Sensitivity (95% CI) Xpert +/ TB culture + • Diagnosis in 5 Overall 85.8% (78.0, 91.2%) 91/106 hours • Identifies RIF and AFB+/TB culture + 100% ( 94.6, 100%) 67/67 INH resistance TB Diagnostic for 2 Centuries AFB-/TB culture + 61.5% (45.9, 75.1%) 24/39 1. Lawn, Lancet ID, 2013 ;2. Alland, CROI 2015 TB Detection: Specificity Case #2 Continued Specificity (95% CI) Xpert -/ TB culture - Your pt is diagnosed with TB by GeneXpert with Overall 98.9% (97.6, 99.4%) 591/598 culture pending AFB+/TB culture + 100% (51.0, 100 %) 4/4 Started on treatment for TB with isoniazid, AFB-/TB culture + 98.8% (97.6, 99.4%) 587/594 rifampin, ethambutol and pyrazinamide When should you start ART? US only 99.3% (98.0%, 99.8%) 441/444 AFB+/TB culture + 100% (51%, 100%) 4/4 AFB-/TB culture + 99.3% (98.0%, 99.8%) 437/440 Xpert now FDA approved for use in TB infection control Can take pt out of isolation after 1 or 2 negative tests http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm434226.htm 5
11/14/2016 Treatment strategy of immediate TB therapy + early ART (2 vs 8 weeks) saves lives and reduces HIV ARS Question #3 complications Start ART as soon as possible (within 2 weeks) Start ART after 8 weeks (end of induction therapy for TB) Start ART in 6 months at end of TB treatment CAMELIA (Cambodia ) SAPIT (South Africa) STRIDE (multicontinent) Key characteristics of trials of timing of ART during TB treatment Study Setting Key enrollment Median CD4 Primary criteria (IQR) endpoint CAMELIA Cambodia Smear + , 25 (10 - 56) Death (Blanc, ANRS) CD4 < 200 STRIDE Multi-national Clinical TB, 77 (36 – 145) AIDS or (Havlir, ACTG) CD4 < 250 death SAPIT South Africa Smear + , 150 (77 – 254) AIDS or (Abdool-Karim, CD4 < 500 death CAPRISA) NEJM (2011) 365 – Blanc et al. , Havlir et al. , Abdool Karim et al. 6
11/14/2016 Current Guidelines Co-treatment Challenges WHO, ATS and DHHS guidelines all recommend: Need for coordination between HIV and TB programs Challenge of adherence to multidrug therapy for Initiation of ART within 2 weeks for CD4 count both conditions <50 • Less with current compact ART Initiation of ART within 8 weeks for CD4 >50 Overlapping toxicity • Hepatitis, rash, less neuropathy currently • Exception for TB meningitis where increased AE and death Drug-drug interactions reported with early ART in a randomized trial [Torok CID 2011 ] IRIS Do Not Use Rifamycins With TAF HIV/TB co ‐ treatment options for adults ARV* Rifamycin Dose adjustments Other Issues Preferred • TDF has been studied with RIF without significant Efavirenz Rifampin None Watch for CNS toxicity interaction 1 Lopinavir/ Rifabutin Rifabutin 150 mg once daily Monitor for uveitis; • TAF contraindicated with rifamycins in all package Ritonavir Must coordinate care inserts (Darunavir/r) Alternative • Based on modeling data with carbamazepine 2 Raltegravir Rifampin Raltegravir 400 or 800 mg Limited clinical – Carbamazepine reduced TAF exposure 55% twice daily experience Dolutegravir Rifampin Dolutegravir 50 mg twice Awaiting results of trial • TAF more influenced by P-Glycoprotein induction than daily in co-infected patients TDF Nevirapine Rifampin Avoid NVP lead-in Hepatotoxicity – (P-GP = protein that pumps foreign substances out of cells) *All listed antiretroviral drugs should be given together with two NRTI but not with TAF 1 Droste JAH, et al. Antimicrob Agents Chemother 2005 2 Personal communication from Gilead 7
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