1. ©2013 MFMER | slide-1 TB-Associated Immune Reconstitution Inflammatory Syndrome (IRIS) Wisconsin TB Summit; April 24, 2014 John W. Wilson, MD Associate Professor of Medicine Division of Infectious Diseases Mayo Clinic, Rochester MN Mayo Clinic Center for Tuberculosis

2. ©2013 MFMER | slide-2 TB-IRIS: General concepts The paradoxical worsening of signs, sx’s and/or radiologic features of TB after starting antiretroviral therapy (ART) for HIV infection In setting of initial clinical improvement after starting TB-drug therapy Incidence of TB-IRIS in HIV(+) patients is variable = 8-43% Can occur in HIV (-) patients as well, but less common E.g. CNS tuberculomas, cervical LNs Thorax 2004. 59:704-707 Clin Infect Dis 2006. 39:1709-12

3. ©2013 MFMER | slide-3 Immunologic Reconstitution Inflammatory Syndrome (IRIS): principles - I Associated with increased functional immunologic & inflammatory responses - Examples: a.HIV (+) patient: Recovery of CD4 T-cells after recent start of antiretroviral therapy (HAART, ART) b.Leukemia, BMT patient: Recovery of neutrophils after myeloablative chemotherapy or hematopoietic stem cell transplantation (HSCT) engraftment c.Solid organ trnplt pt: Reduction in pharmacologic immunosuppressive therapy

4. ©2013 MFMER | slide-4 Immunologic Reconstitution Inflammatory Syndrome (IRIS): principles - II IRIS results from a rapid restoration of pathogen specific immune responses to opportunistic infections – causing either: a.The deterioration of a treated infection via worsening symptoms, or b.The new presentation of a previously subclinical infection Inflammatory response also augmented by increased MTB antigen loads released by dead or dying bacilli (Antivir Therap 2005, 10:417-22)

5. ©2013 MFMER | slide-5 Immunologic Reconstitution Inflammatory Syndrome (IRIS): principles -III Timing of IRIS onset: During the first few months of ART Generally sooner after myeloablative neutrophil recovery IRIS can be associated with a wide array of pathogens - examples: M. tuberculosis Cryptococcus neoformans (e.g. meningitis) Herpes viruses IRIS not always limited to HIV (+) pts – e.g.: Invasive filamentous fungal diseases (heme)

6. ©2013 MFMER | slide-6 IRIS common with other HIV-associated opportunistic infections Meta-analysis of immunologically advanced HIV (+) pts developing IRIS after starting ART: 13,100 pts among 54 cohort studies Incidence of IRIS s/p ART start: Cytomegalovirus (CMV) – 37.7% Cryptococcus meningitis – 19.5% PML – 16.7% Tuberculosis 15.7% Herpes zoster – 12.2% Kaposi's sarcoma – 6.4% Müller et al. Lancet Inf Dis 2010;10:251-61

7. ©2013 MFMER | slide-7 CNS VZV–IRIS (non-TB) 37 yo HIV (+) woman with VZV lesions - T7 dermatome Treated with acyclovir 6 weeks prior to admission HAART was initiated 2 weeks PTA Double vision was followed by severe weakness in her legs 1–2 days PTA Post el at. Am J Neuroadiol. 2013 Jul;34(7):1308-18

8. ©2013 MFMER | slide-8 IRIS common with other HIV-associated opportunistic infections - II Deaths in patients developing IRIS: 20.8% in pts with cryptococcal meningitis 3.2% pts in pts with TB Lower CD4 counts at time of ART start – associated with high risk of IRIS Especially when CD4 < 50 cells/uL Müller et al. Lancet Inf Dis 2010;10:251-61

9. ©2013 MFMER | slide-9 Distinguishing between: 1 - TB-associated IRIS and 2 - ART-associated TB Meintjes et al. Lancet Infect Dis 2008; 8: 516–23

10. ©2013 MFMER | slide-10 Diagnosing TB-associated IRIS *No single laboratory or confirming test for TB-IRIS IRIS is a clinical diagnosis – based on Timing of TB and/or HIV therapies and case definitions Clinical signs, pt. symptoms with supportive radiologic studies and laboratory information Underlying risk & predisposing patient factors towards IRIS (e.g. low CD4 before starting ART) Must exclude other diagnoses including: Other opportunistic or community-based infections Negative tissue stains, cultures, PCR; serologies, etc. for alternative pathogen(s) Aseptic causes of inflammation Malignancies Other processes

11. ©2013 MFMER | slide-11 Symptoms and Clinical findings of TB-IRIS - can be quite variable - I Clinical examples: New or recurrent fever (may be most common) New or recurrent cough New or worsening lymphadenopathy New skin lesions New soft tissue abscess New or recurrent seizure (e.g. CNS tuberculoma)

12. ©2013 MFMER | slide-12 Symptoms and Clinical findings of TB-IRIS - can be quite variable - II Radiologic examples: New intraabdominal adenopathy New pulmonary infiltrate *Worsening CXR infiltrate → can still be IRIS; but must r/o drug-resistant TB or non-TB cause New pleural effusion

13. ©2013 MFMER | slide-13 Paradoxical TB-associated IRIS Meintjes et al. Lancet Infect Dis 2008; 8: 516–23 36 yo HIV (+) pt; baseline CD4 of 39 cells with culture (+) pulmonary TB A.Cervical LN enlargement (1 week after starting ART) B.Chest wall cold abscess C.Right psoas abscess (CT scan) D.Worsening cough with sputum AFB staining (+); but culture (-)

14. ©2013 MFMER | slide-14 Presentations of miliary TB-IRIS after starting HAART A. Miliary Pulmonary B. TB C. Cerebral tuberculomas with meningeal TB D. Choroid tubercles Sharma et al. Indian J Med Res 135, May 2012, pp 703-730

15. ©2013 MFMER | slide-15 Presentations of miliary TB-IRIS after starting HAART Sharma et al. Indian J Med Res 135, May 2012, pp 703-730

16. ©2013 MFMER | slide-16 Timing of TB-IRIS onset Generally presents within the first 3 months Usually within the first 2 months or even first few weeks after starting ART Journal of Infection (2006) 53:357-63 Bangkok, Thailand: 167 patients 21 (12.6% developed TB- IRIS)

17. ©2013 MFMER | slide-17 Case definition for paradoxical TB-IRIS - 3 components to case definition: A. Antecedent requirements Both of the 2 following requirements must be met: 1.Diagnosis of TB: the TB diagnosis was made before starting ART and this should fulfil WHO criteria for diagnosis of smear-positive PTB, smear-negative PTB or extrapulmonary TB 2.Initial response to TB treatment: the patient’s condition should have stabilized or improved on appropriate TB treatment before ART initiation – e.g. cessation of night sweats, fevers, cough, weight loss. (Note: this does not apply to patients starting ART within 2 weeks of starting TB treatment since insufficient time may have elapsed for a clinical response to be reported.) B. Clinical criteria The onset of TB-IRIS manifestations should be within 3 months of ART initiation, re-initiation, or regimen change because of treatment failure. Of the following, at least 1 major criterion or 2 minor clinical criteria are required: Major criteria 1.New or enlarging lymph nodes, cold abscesses or other focal tissue involvement – e.g. tuberculous arthritis 2.New or worsening radiological features of TB (found by chest X-ray, abdominal USS, CT or MRI) 3.New or worsening central nervous system TB (meningitis or focal neurological deficit – e.g. caused by tuberculoma) 4.New or worsening serositis (pleural effusion, ascites, or pericardial effusion) Minor criteria 1.New or worsening constitutional symptoms such as fever, night sweats, or weight loss 2.New or worsening respiratory symptoms such as cough, dyspnea, or stridor 3.New or worsening abdominal pain accompanied by peritonitis, hepatomegaly, splenomegaly, or abdominal adenopathy C. Exclude alternative explanations for clinical deterioration 1.Failure of TB treatment due to TB drug resistance 2.Poor adherence to TB treatment 3.Another opportunistic infection or neoplasm (it is particularly important to exclude an alternative diagnosis in patients with smear- negative PTB and extrapulmonary TB where the initial TB diagnosis has not been microbiologically confirmed) 4.Drug toxicity or reaction Lancet Infect Dis 2008;8(8):516-523

18. ©2013 MFMER | slide-18 ART-associated TB “Unmasking” tuberculosis-associated IRIS Meintjes et al. Lancet Infect Dis 2008; 8: 516–23 48 yo HIV (+) pt; baseline CD4 of 10 cells with dry cough (no sputum collected) A.Baseline CXR clear B.10 days after starting ART – (+) fever and worsening productive cough. Sputum (+) AFB The rapid development of pulmonary symptoms and infiltrated attributed to the ‘unmasking of TB- associated IRIS Chest wall cold abscess

19. ©2013 MFMER | slide-19 Case definition for ART-associated TB - 3 components to case definition: Lancet Infect Dis 2008;8(8):516-523 Case Rep Infect Dis. 2013; 2013:1-7 1.Patient is not receiving TB treatment when ART is started Active TB has not yet been diagnosed (when ART started) 2.Active TB is diagnosed after ART has been started 3.Diagnosis of TB should meet WHO criteria for AFB smear (+), smear ()-) or extrapulmonary TB

20. ©2013 MFMER | slide-20 Presentations of ART-associated TB - “unmasking” IRIS Pulmonary TB most common Other sites periodically encountered: Spinal TB Spondylodiscitis Paraspinal abscess(s) – in up to 50% cases Psoas abscess AFB stains and cultures may be positive – e.g. Sputum – pulmonary source Needle aspiration Tissue biopsies Case Rep Infect Dis. 2013; 2013:1-7

21. ©2013 MFMER | slide-21 Risk factors for TB-associated IRIS development in HIV (+) pts: Baseline low CD4 cell count (e.g. CD4 < 100 cells/uL) Rise in CD4 count with effective ART during first 3 months of therapy Disseminated TB (extrapulmonary TB) More common in advanced HIV (+) pts Earlier start of ART Balancing potential reductions in AIDS-related mortality risk vs. IRIS morbidity & mortality risks No effect on IRIS Latent TB infection (much lower MTB load) - ↓↓ risk (if any) Type if ART therapy used Michailidis et al. Antivir Therap 2005, 10:417-22

22. ©2013 MFMER | slide-22 Associations between pre-ART clinical and laboratory characteristics with subsequent TB-IRIS events Narendran et al. PLoS One. 2013; 8(5): e63541

23. ©2013 MFMER | slide-23 Pre-ART plasma levels of IL-6 or CRP distinguish individuals at higher risk for TB-IRIS Narendran et al. PLoS One. 2013; 8(5): e63541

24. ©2013 MFMER | slide-24 Not every HIV-TB pt with low CD4 cell counts develops TB-IRIS Reasons for such discordance among patients is not overly clear - examples: a.Complex interplay of immune responses and/or severity of immunosuppression b.Inter-patient genetic predisposition E.g. humoral immune response – abnormalities in IL-12 and IFN- γ c.Higher MTB bacilli burden; antigen load E.g. rise of antigen release after treatment started d.Anatomic location of MTB infection e.Other??

25. ©2013 MFMER | slide-25 When to start HIV antiretroviral therapy (ART) in patient with active TB? Considerations: Curr Opin HIV AIDS. Jan 2010; 5(1): 61–69

26. ©2013 MFMER | slide-26 Early vs. Late introduction of ART CAMELIA study (Cambodia) Patients who had CD4 counts <200 cells/mm3 were randomized to initiate ART at 2 wks or 8 wks after start of TB treatment. Enrolled pts with advanced HIV disease, median CD4 of 25, low BMI, high rates of disseminated TB Compared with ART started at 8 wks, ART started at 2 wks resulted in a 38% reduction in mortality (P = 0.006) N Engl J Med. Oct 20 2011;365(16):1471-1481

27. ©2013 MFMER | slide-27 Early vs. Late introduction of ART CAMELIA study (Cambodia) However, pts starting ART earlier (at 2 weeks) had a higher incidence of IRIS (36%) compared to pts starting ART at 8 weeks (16%) Most frequent IRIS findings: Progressive adenopathy Fever Abdominal pain HSM TB-assoc. IRIS was very manageable Low mortality (3.9%) Laureillard et al. AIDS 2013, 27:2577–2586

28. ©2013 MFMER | slide-28 Laureillard et al. AIDS 2013, 27:2577–2586 CAMELIA Trial: Kaplan–Meier estimates of occurrence of TB- associated IRIS by study arm

29. ©2013 MFMER | slide-29 The ACTG 5221 (STRIDE) trial Multinational study, randomized ART-naive patients with confirmed or probable TB and CD4 counts <250 cells/mm 3 Earlier (<2 weeks) ART or later (8–12 weeks) ART Overall rates of mortality and AIDS diagnoses were not different between the earlier and later arms – However: Higher rates of IRIS were seen in the earlier ART arm A significant reduction in AIDS or death was seen in the subset of patients with CD4 <50 cells/mm 3 who were randomized to the earlier ART arm Havlir et al. N Engl J Med. Oct 20 2011;365(16):1482-1491

30. ©2013 MFMER | slide-30 Basic TB and HIV Treatment Principles – Summary (DHHS) All HIV-infected patients with diagnosed active TB should be started on TB treatment immediately (AI) TB has the priority in timing All HIV-infected patients with diagnosed active TB should be treated with antiretroviral therapy (ART) (AI) Timing of starting ART depends upon patient factors, including: a.CD4 count b.Clinical severity of HIV disease 2013 DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents http://aidsinfo.nih.gov/guidelines on 4/14/2014http://aidsinfo.nih.gov/guidelines on 4/14/2014

31. ©2013 MFMER | slide-31 Basic TB and HIV Treatment Principles – Summary (DHHS) – II In pts with CD4 counts <50 cells/mm 3, ART should be initiated within 2 weeks of starting TB treatment (AI) In pts with CD4 counts ≥50 cells/mm 3 who present with clinical disease of major severity (e.g. low Karnofsky score, low body mass index, low Hgb, low albumin, organ system dysfunction, etc), ART should be initiated within 2 to 4 weeks of starting TB treatment Strength of this recommendation varies on the basis of CD4 cell count: CD4 count 50 to 200 cells/mm 3 (BI) CD4 count >200 cells/mm 3 (BIII) 2013 DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents http://aidsinfo.nih.gov/guidelines on 4/14/2014http://aidsinfo.nih.gov/guidelines on 4/14/2014

32. ©2013 MFMER | slide-32 Basic TB and HIV Treatment Principles – Summary (DHHS) – III In pts with CD4 counts ≥50 cells/mm 3 who do not have severe clinical disease, ART can be delayed beyond 2 to 4 weeks of starting TB therapy but should be started within 8 to 12 weeks of TB therapy initiation. The strength of this recommendation also varies on the basis of CD4 cell count: CD4 count 50 to 500 cells/mm 3 (AI) CD4 count >500 cells/mm 3 (BIII) In all HIV-infected pregnant women with active TB, ART should be started as early as feasible, both for maternal health and for prevention of mother-to-child transmission (PMTCT) of HIV (AIII) In HIV-infected patients with documented MDR- or XDR-TB, ART should be initiated within 2 to 4 weeks of confirmation of TB drug resistance and initiation of second-line TB therapy (BIII) 2013 DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents http://aidsinfo.nih.gov/guidelines on 4/14/2014http://aidsinfo.nih.gov/guidelines on 4/14/2014

33. ©2013 MFMER | slide-33 The End Questions?