HIV/TB Sylvia LaCourse MD, MPH Department of Medicine, Division of Allergy & Infectious Disease TB Clinical Intensive Seattle, WA June 16-17, 2016
Roadmap for today s talk HIV/TB Epidemiology Global US HIV LTBI->TB Latent TB infection (LTBI) Active TB disease (TB) TB Screening/diagnosis Treatment ART/TB medication interactions IRIS LTBI Diagnosis IGRA, TST Treatment
Background 9.6 new cases of TB in 2014 Died From TB 1.2 million were HIV+ 400,000 were HIV+ 1/4 global deaths among HIV+ due to TB TB is the leading cause of death among HIV+ globally WHO 2015
Global TB Epidemiology WHO 2015
Global TB/HIV Epidemiology TB and HIV are co-epidemics WHO 2015
Global TB/HIV epidemiology: over time WHO 2015
US TB Epidemiology Reported TB Cases United States, 1982 2013 30,000 No. of Cases 25,000 20,000 15,000 10,000 5,000 0 HIV epidemic contributed to TB resurgence in late 80s Year CDC 2014
70 US TB/HIV Epidemiology Estimated HIV Coinfection in Persons with TB, 1993 2014 % Coinfection 60 50 40 30 20 10 Proportion of TB cases with HIV decreasing 0 All Ages Aged 25-44 CDC 2015
US TB/HIV Epidemiology: global = local Estimated HIV/TB Coinfection US vs Foreign Born Proportion of TB cases with HIV decreasing except among foreign born Albarak, Arch Intern Med 2007
Question 1 Which of the following is false? A. Globally, TB incidence is declining B. In the US, TB incidence is declining C. Globally, incidence of TB among HIV+ is declining D. In the US, proportion of new TB cases with HIV is declining E. In the US, proportion of new TB cases with HIV who are foreign born is declining
Latent TB (LTBI) and active TB HIV- 10% over lifetime greatest risk in 1st 2 years HIV+ 10% per year Small, NEJM 2001
HIV kills TB-specific CD4 cells Impairs macrophage activation Fewer lung-homing CD4 cells Defective granuloma formation Loss of control of infection Geldmacher, Curr Opin HIV AIDS, 2012
MTb infection TB disease Although ART significantly decrease risk of TB in HIV+, risk is still much higher than among HIV- Lawn, Clin Dev Immunology 2011
Clinical Manifestations of TB in HIV+ Clinical presentation influenced by degree of immunosuppression However, risk of TB still higher among well controlled HIV+ w/ CD4>500 vs. HIV- Most still present with pulmonary disease Upper lobe fibronodular infiltrates +/- cavitation Advanced HIV (CD4 < 200) Can have pulmonary TB (+ AFB/cx) w/ nml CXR Smear often negative->paucibacillary Extrapulmonary/disseminated disease more common (20%-50%) Lymphadenitis, pleuritic, pericarditis, meningitis, sepsis DHHS 2015
Of 72 EPTB pts 35 (49%) abnml CXR Of 57 w/ sputum collected 5 Sm+, 12 Cx+ No significant difference of Cx+ between patients with abnml vs. nml CXR 7/30 (23%) vs 5/27 (19%), p = 0.656 2/5 (40%) HIV+ had nml CXR, but Cx+ Parimon, CHEST 2008
Of 72 EPTB pts 35 (49%) abnml CXR Of 57 w/ sputum collected 5 Sm+, 12 Cx+ Abn CXR common w/ EPTB Nml CXR does not rule out pulm involvement in EPTB No significant difference of Cx+ between patients with abnml vs. nml CXR 7/30 (23%) vs 5/27 (19%), p = 0.656 2/5 (40%) HIV+ had nml CXR, but Cx+ Parimon, CHEST 2008
Question 2a Which of the following is false? A. HIV significantly increases the risk of progression from LTBI to TB B. ART significantly decreases the risk of TB among HIV+ C. Once on ART, risk of TB among HIV+ is similar to HIV- D. Most common presentation of TB among HIV+ is extrapulmonary E. A & C F. C & D
Question 2b 25 y/o woman from Eritrea, HIV+ not yet on ART with CD4 100 presents with 2-3 month history of enlarging cervical lymph node, fever and weight loss. She denies obvious cough. You are concerned for extrapulmonary TB. Which of the following should be part of the workup for extrapulmonary TB in this HIV+ patient? A. Lymph node biopsy including AFB smear and culture B. CXR C. Sputum AFB smear and culture D. All of the above E. A & B
Challenges in TB treatment in HIV+ Adherence polypharmacy Side effects overlapping side effects of anti-tb and ART Immune reconstitution inflammatory syndrome (IRIS) Drug-drug interactions What to start, and when to start?
TB treatment in HIV+ Anti-TB regimen generally the same for non-hiv Initial phase: INH, RIF, PZA, EMB x 2 months Continuation phase: INH, RIF x 4 months Extended to 7 months if initial CXR + cavitation & Cx + at end of 2 months of initial phase. Initial phase caveats w/ HIV+: INH, RIF, PZA, EMB should be given daily Continuation phase caveats w/ HIV+: INH/RIF once weekly contraindicated INH/RIF twice weekly not recommended w/ CD4<100 (given 3 times weekly INH/RPT not recommended ATS, CDC, IDSA, MMRW 2003 DHHS 2015
Drug(s) Duration Interval Comment Initial phase INH, RIF, PZA, EMB Continuation phase TB treatment in HIV+ 2 months Daily Recommended INH/RIF 4 months Daily Recommended INH/RIF 4 months 3 x week Alternative (BII) INH/RIF 4 months Twice weekly Not recommended for HIV+ with CD4 <100 INH/RPT 4 months Once weekly Contraindicated ATS, CDC, IDSA, MMRW 2003 DHHS 2015
TB treatment in HIV+ (cont.) Culture-negative pulmonary TB 6 months total treatment (vs. 4 months HIV-) Extra-pulmonary (same as HIV-) 6-9 months Meningitis (same as HIV-) 9-12 months Adjunctive corticosteroids CNS, pericardium involvement ATS, CDC, IDSA, MMRW 2003 DHHS 2015
Basic Principles in ART and TB treatment Rifamycin-based TB treatment is cornerstone of effective TB treatment Efavirenz-based ART preferred Most drug-drug interactions for anti-tb tx and ART are due to Rifampin Rifampin potent inducer of P450 enzyme 3A sometimes requires ART dose adjustment (typically dose) Rifabutin less potent inducer If take with other drugs that induce or inhibit CYP3A, can effect rifabutin concentration Sometimes requires rifabutin dose adjustment (can be or dose) Important: if ART dc d, rifabutin likely subtherapeutic CDC 2013
Why start ART? ART associated with decreased mortality in HIV+ TB patients Primarily w/ CD4 < 50 Study Patients ARV timing Outcome Blanc (Cambodia) N = 661 Median CD4 = 25 2 Vs 8 weeks HR for death 0.62 (for early ARVs) Havlir (Africa, Asia, NA, SA) N = 809 Median CD4 = 77 Median of 10 Vs 70 days Death rate: Overall 12.9% Vs 16.1% (NS) CD4 < 50: 15.5% Vs 26.6% (P=0.02) Karim (S. Africa) N = 642 Median CD4 = 150 Median of 21 Vs 97 days AIDS or Death: Overall: No difference CD4 < 50: 8.5 Vs 26.3 per 100 py (P=0.06) ART associated with decreased risk of TB among HIV START trial early ART vs. deferred risk of TB (0.09 vs. 0.28, HR 0.29 [0.12 0.73] p =0.008) Blanc, NEJM, 2011 Havlir, NEJM 2011 Karim, NEJM 2011 START, NEJM, 2015
Timing of ART and TB treatment ART is recommended for all HIV+ with TB For ART-naïve CD4 < 50 start ART within 2 weeks CD4 > 50 start by 8-12 weeks Caution with early ART and meningitis, though still recommended If already on ART, continue May require medication adjustment DHHS 2015
ARV ARV dose change RIF dose change Comments NNRTIs Efavirenz ART and RIF recommended dose adjustments None; some 800mg if >50kg No change Preferred Regimen Nevirapine Rilpivirine Etravirine Protease inhibitors Atazanavir (single agent or ritonavir boosted) Darunavir/r Fosamprenavir/r Saquinavir/r Lopinavir/ritonavir (Kaletra ) Super-boosted lopinavir/ritonavir (Kaletra ) lead-in dose 200 mg twice daily, continue as maintenance dose Contraindicated Contraindicated No change Lopinavir 800 mg plus No change ritonavir 200 mg twice daily (double dose) Lopinavir 400 mg plus No change ritonavir 400 mg twice daily (super boosting) Avoid lead-in 200mg once daily, assoc w/ virologic failure Consider therapeutic drug monitoring. Significant decrease in Rilpivirine Significant decrease in PIs, Increased PI doses associated +/- hepatotoxicity Hepatotoxicity in healthy volunteers Better-tolerated among HIV+ already on LPV/r Hepatotoxicity in healthy volunteers CDC 2013
ART and RIF recommended dose adjustments (cont.) CCR-5 receptor antagonists ARV dose change RIF dose change Comments Maraviroc Maraviroc to 600 mg twice-daily Integrase inhibitors Raltegravir Raltegravir to 800 mg twice daily Dolutegravir Dolutegravir to 50 mg twice daily No change No change No change Use with caution, as there is no reported clinical experience with increased dose of maraviroc with rifampin Raltegravir trough concentrations still decreased, follow VL carefully follow VL carefully Elvitegravir, cobicistat, tenofovir, and emtricitabine (Stribild ) Stribild and rifampin should not be used together Marked decrease in elvitegravir and cobicistat concentrations predicted based on metabolic pathways of these drugs CDC 2013
ART and RFB recommended dose adjustments ARV ARV dose change RFB dose change Comments NNRTIs Efavirenz No change 600 mg (daily or thrice-weekly) Nevirapine No change No change RIF preferred Rilpivirine Contraindicated Significant decrease in Rilpivirine Etravirine No change No change Conc of both decreased Protease inhibitors Atazanavir (single agent or ritonavir boosted) Darunavir/r Fosamprenavir/r Saquinavir/r No change 150 mg daily No pub clinical experience Monitor closely for potential rifabutin toxicity uveitis, hepatotoxicity, and neutropenia No change 150 mg daily Monitor closely for potential rifabutin toxicity uveitis, hepatotoxicity, and neutropenia Lopinavir/ritonavir (Kaletra ) No change 150 mg daily Hepatotoxicity in healthy volunteers Better-tolerated among HIV+ already on LPV/r CDC 2013
ART and RFB recommended dose adjustments (cont.) ARV dose change RFB dose change Comments CCR-5 receptor antagonists Maraviroc No change No change No clinical experience; a significant interaction is unlikely, but this has not yet been studied Integrase inhibitors Raltegravir No change No change RAL conc Dolutegravir No change No change DOL conc Elvitegravir, cobicistat, tenofovir, and emtricitabine (Stribild ) Stribild and rifabutin should not be used together Marked elvitegravir, cobicistat conc Marked rifabutin CDC 2013
ART and TB treatment: Overlapping toxicities Adverse effect ART Anti-TB therapy Gastrointestinal AZT, ddi, PIs R,I,P, ethionamide, PAS, Clofazamine, linezolid Hepatotoxicity NVP, EFV, PIs, NRTIs R,I,P, ethionamide, quinolones, PAS Neuropathy D4T, ddi I, ethionamide, cycloserine, linezolid Renal dysfunction TDF Aminoglycosides and capreomycin Neuropsychiatric EFV Cycloserine, ethionamide, quinolones, INH Rash NVP, EFV, ABC R,I,P,E, streptomycin, quinolones, PSA, clofzamine Cytopenia AZT, 3TC R,I, Linezolid, rifabutin Cardiac conduction PIs Pancreatitis D4T, ddi Linezolid Lactic acidosis D4T, ddi Linezolid Bedaquiline, quinolone, clofazamine Lawn, BMC Medicine, 2013
ART and TB treatment: management of toxicities Upon re-challenge >90% patients tolerate medications without a recurrence of the adverse effect Hepatotoxicity Rates among HIV+ similar to HIV- Stop anti-tb tx if ALT > 3 x ULN + clinical sx, or if ALT > 5 x ULN even if no sx when ALT < 2 X ULN: restart RIF, then INH; +/- PZA depending on severity of hepatitis Consider other causes (HBV, HCV, etc.) ATS, Am J Respir Crit Care Med, 2006
Question 3a Which of the following are true in the management of TB in an HIV+ individual? A. Rifamycins should be avoided due to multiple ART and anti- TB medication interactions B. In an ART-naïve HIV+ patient, ART initiation should be deferred until after TB treatment is completed in order to avoid ART and anti-tb medication interaction D. Efavirenz requires dose adjustment when co-administered with rifampin E. Rifabutin requires dose adjustment when co-administered with Efavirenz
Question 3b 42 y/o HIV+ homeless man is diagnosed with pulmonary TB and started on RIPE. He has a history of significant mental health issues worsened on Atripla (efavirenz + truvada). Because of this (and in line with current US HIV-guidelines) you had previously switched his efavirenz to raltegravir last year. At his next follow-up visit, his viral load (previously undetectable) is now >1000. Assuming he has no new HIV resistance, and he has been adherent to both his ART and anti- TB therapy, you should A. Decrease his dose of rifampin B. Increase his dose of raltegravir from 400 mg PO BID to 800 mg PO BID C. Consider switching rifampin for rifabutin D. B or C
Question 3c 30 y/o HIV+ F has a h/o IVDU and ART medication adherence issues in the past, is being treated with a ritonavir-boosted protease inhibitor-based ART regimen. She develops cough, weight lost, and is found to have pulmonary TB. She does not want to change her ART regimen, and so you decide to initiate her anti-tb treatment with rifabutin instead of rifampin. You remember from your TB intensive course that her rifabutin needs to be dosed at 150 mg PO q day. Her life becomes chaotic and she discontinues her ART, but continues her anti-tb tx w/ DOT. In order to ensure that her anti-tb tx remains therapeutic, you should A. Increase her rifabutin from 150 to 300 mg PO Q day B. Switch her rifabutin to rifampin if she is not going to be taking ART C. Decrease her rifabutin from 150 to 75 mg PO Q day D. A or B
Immune Reconstitution Inflammatory Syndrome: IRIS IRIS: collection of inflammatory disorders Paradoxical worsening of preexisting infectious processes Following ART initiation in HIV-infected individuals Assoc w/ immune recovery ( CD4, VL) Risk Factors: CD4 and VL pre- ART, short time between TB tx and ART inititiation, but TB IRIS can occur at CD4 >200 Meintjes, Lancet ID, 2010
Immune Reconstitution Inflammatory Syndrome: associated OIs Paradoxical Tuberculosis 17% (8-45%) Cryptococcus 20% (4-49%) PML 17% KS 7-31 % Unmasking Tuberculosis 1-5% Cryptococcus 1-2% Haddow, PLoS One, 2012 Muller, Lancet Infectious Diseases, 2010
Immune Reconstitution Inflammatory Syndrome: associated OIs Muller, Lancet ID, 2010
TB IRIS Clinical manifestations Pulmonary TB Sx: fever, malaise, weight loss, and worsening respiratory symptoms Worsening CXR: new parenchymal opacities and progressive intrathoracic lymph node Extrapulmonary Worsening lymphadenitis, new pleural effusions, intracranial tuberculomas, worsening of meningitis or radiculomyelopathy cold abscesses Meintjes, Lancet ID, 2010
Immune Reconstitution Inflammatory Continue ART unless life-threatening Steroids RCT 4 wks prednisone vs. placebo for TB IRIS symptoms, improved CXR, hospitalization NSAIDS Syndrome: Treatment Meintjes, AIDS, 2010
Question 4a 23 y/o F from Ethiopia presents with weight, loss, fever, and cough. CXR shows RUL opacity. Sputum smear is neg, but she is initiated on RIPE due to concerns for PTB (NAAT does return positive for Mtb). As part of her TB w/u she is tested for HIV and found to be positive w/ CD4 48. Which of the following are true? A. ART should be initiated within 2 weeks B. ART should be initiated after she has completed initial phase of TB treatment C. ART should be initiated after she has completed continuation phase of TB treatment D. TB treatment should be stopped until after she has initiated ART and her VL is undetectable
Question 4b She initiates ART treatment and continues w/ RIPE. After 2 weeks she develops fever, and her CXR now shows worsening pulmonary infiltrates You should A. Stop ART B. Collect sputum looking for MDR TB and add moxifloxacin and amikacin while waiting C. Stop ART therapy and start prednisone D. Continue anti-tb tx and ART, evaluate the patient for other infections, failed TB therapy and drug toxicity and consider starting prednisone
TB and HIV
LTBI and HIV
LTBI diagnostics in HIV+ TST TST+ > 5 mm (HIV+) Sensitivity 34-82% Specificity 56 95% False positive: BCG, NTM False negative: anergy with lower CD4 IGRA IGRA+ TB ag - nil > 0.35 IU/mL (+/- HIV) Sensitivity 58-74% Specificity 92 97% False positive: NTM (though less crossreactivity) Indeterminates w/ lower CD4 Pai, CMR, 2014 Cattamanchi, JAIDS, 2011 Santin, PloSONE, 2012
LTBI diagnostics TST Both TST/IGRA are indirect measures of M. tuberculosis infection. Require both infection and a functioning immune system for a positive test. Both may take 2-10 weeks to become positive after an exposure IGRA
LTBI diagnostics TST IGRA Either TST or IGRA can be used to diagnose LTBI in HIV+ Decision should be based on context for testing, test availability, and overall cost effectiveness of testing IGRA preferred if low rates of TST return for read, previous BGC vaccination Important to repeat testing when CD4 >200 False negatives due to anergy (immunosuppression) MMRW 2010 DHHS 2015
Question 5a Which of the following are true? A. IGRA is the recommended LTBI diagnostic of choice for HIV+ in the US B. TST and IGRA are direct measures of M. tuberculosis infection C. IGRA LTBI testing should be repeated if initially negative once CD4 >200 D. BCG can cause false positive IGRA E. There are separate cut-offs of a positive QFT for HIV+
Question 5b In a person with advanced HIV, a TST can be negative in the setting of A. Anergy (immunosuppression) B. Lack of infection with M. tuberculosis C. Recent infection within past few weeks D. All of the above
LTBI treatment in HIV+ Drug(s) Duration Interval Comment Isoniazid 9 months Daily Recommended Twice weekly Isoniazid + Rifapentine 3 months Once weekly Not on ART only Rifampin 4 months Daily Drug interactions May required dose adjustment Rifabutin 4 months Daily Drug interactions May required dose adjustment Rifampin + Pyrazinamide 2 months Daily Contraindicated
Why start ART + IPT? ART+IPT vs. ART Reduced risk of death or severe HIV-related illness ahr 0.65 (0.48-0.88) Similar for CD4 >500 TEMPRANO, NEJM 2015
3HP and HIV? Sterling, AIDS 2016
3HP and HIV? 3HP non-inferior to 9H completion rates discontinuation due to hepatotoxicity Sterling, AIDS 2016
Question 6 You are seeing a 45 year old HIV+ male HCW well controlled on ART w/ CD4>500 who recently converted his TST after a medical mission trip in Haiti. TB symptom screen and CXR is negative, and you recommend initiating LTBI therapy. He s heard about a new short course LTBI treatment that you only have to take once a week and wants to know what his options are. Based on CDC/ATS/DHHS guidelines you recommend: A. INH x 9 months (daily) B. RIF x 4 months (daily) C. RIF + PZA x 2 months (daily) D. INH + RPT x 3 months (weekly)
HIV/TB take home points HIV/TB global co-epidemics, HIV significantly increase risk of TB Screening and diagnosis similar to non-hiv, but atypical presentations of PTB, EPTB and disseminated TB TB treatment similar to non-hiv, but Daily Initial phase w/ RIPE, and at least 3 x week Maintenance w/ IR Rifamycin-based anti-tb therapy is key, EFV-base ART preferred Rifabutin may have ART interaction, but requires dose adjustment Important to monitor for drug-drug interactions and side effects IRIS typically managed w/ NSAIDS, steroids if severe Concerns for TB-IRIS should not delay HAART initiation
HIV/LTBI take home points Either IGRA or TST can be used to diagnose LTBI in HIV Consider local factors, cost, risk of not returning Repeat test once CD4 >200 (if initial test negative) Preferred LTBI treatment is INH x 9 months 3 HP should be used only in HIV+ not on ART due to concerns for drug-drug interactions (though guidelines may change in future)
Resources Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the CDC, NIH, HIVMA, IDSA. Updated May 3, 2016. http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Mycobacterium tuberculosis Infection and Disease. Updated May 7, 2013. https://aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent-oi-prevention-and-treatment-guidelines/325/tb CDC. Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis. 2013. http://www.cdc.gov/tb/tb_hiv_drugs/default.htm Curry International Tuberculosis Center. TB Prevention in the HIV-infected Patient: Screening, Testing, and Treatment of Latent TB Infection online course. http://www.currytbcenter.ucsf.edu/ Andersen P, Munk ME, Pollock JM, Doherty TM. Specific immune-based diagnosis of tuberculosis. Lancet. 2000 Sep 23;356(9235):1099-104. CDC. Treatment of Tuberculosis. ATS, CDC, IDSA. MMWR 2003;52(No. RR-11). http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.htm CDC. Updated Guidelines for Using Interferon Gamma Release Assays to Detect Mycobacterium tuberculosis Infection, United States. (PDF) MMWR 2010; 59 (No.RR-5). http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5905a1.htm?s_cid=rr5905a1_e Cattamanchi A, Smith R, Steingart KR, Metcalfe JZ, Date A, Coleman C, Marston BJ, Huang L, Hopewell PC, Pai M. Interferon-gamma release assays for the diagnosis of latent tuberculosis infection in HIV-infected individuals: a systematic review and meta-analysis. J Acquir Immune Defic Syndr. 2011 Mar 1;56(3):230-8. WHO. Global Tuberculosis Report 2015. http://www.who.int/tb/publications/global_report/en/
Additional Slides
TB symptom screening in HIV: a global perspective WHO recommends that all PLWHIV be screened for TB Negative sx - unlikely to have active TB and should be offered isoniazid preventive therapy Positive sx require further evaluation WHO TB symptom screen Cough Fever Weight loss Night sweats WHO 2011
WHO TB symptom screen in HIV+ Meta-analysis of 8,148 HIV+ 4 sx: cough, fever, night sweats, or weight loss 80% sensitive, 50% specificity Getahun, PlosMed 2011
TB rapid diagnostics Xpert MTB/RIF DNA PCR probes detect wild type sequence rpob gene RIF resistance = MDR proxy WHO 2013
TB screening and diagnostic tests: a global perspective Culture Symptom screen Smear Xpert DNA PCR Cost $$$ $ $ $$ Resource ++++ - + ++ requirement Sensitivity Gold variable Low in HIV High standard Results 3 weeks 5 mins <24 hrs 2 hours Resistance testing Yes No No Yes Optimal test: inexpensive, rapid, accurate culture smear Xpert
TB diagnostic performance in HIV+ 100 80 99 99 79 Xpert improved sensitivity compared to smear in HIV+ 60 50 40 20 0 Smear Xpert Sensitivity Specificity Sensitivity Specificity Steingart, Cochrane 2014 Lawn, BMC ID 2013 Drain, Lancet ID 2014
Xpert MTB/RIF WHO recommends Xpert should be used as the initial test rather than microscopy, culture MDR-TB suspects HIV associated TB in both adults and children Can be used All adult/child TB suspects Follow-up test in smear negative TB suspects WHO 2013
Supplemental Question The WHO recommends which of the following as the first-line TB diagnostic in HIV+ in low-resource settings? A. Smear microscopy B. Xpert C. Culture D. TB-sniffing African giant pouched rat smear Xpert culture African giant pouched rat
Optimal length of IPT in high WHO now recommends 36 months of IPT for HIV+ in high TB/HIV settings BOTUSA 2011 Significant risk of TB with 36 vs. 6 months IPT HR 0 57 (33 0 99), p=0. 047) burden settings?