1. Welcome to UW I-TECH HIV/AIDS Clinical Seminar Series Immune Reconstitution Inflammatory Syndrome Dr. G. Manoharan, M.D., Medical Director, I-TECH India

2. 22 Learning Objectives Describe the epidemiology and historical picture of IRIS Review IRIS case studies Review pathogenesis of IRIS Define diagnostic criteria for IRIS Explain the clinical spectrum & differential diagnosis of IRIS Discuss management of IRIS

3. 3 IRIS- epidemiology IRIS is recognized as a potential complication that can occur after potent ART. The frequency of IRIS has not been reported conclusively, but it may be estimated to occur in 10% – 25% of patients who receive ART 23% – 25% of HAART responders developed one or more inflammatory syndromes consistent with IRIS in two large case series from Australia and London Retrospective study of HIV-infected patients in Texas with history of MTB, MAC, and/or cryptococcal infection:  31% developed IRIS  similar rates of IRIS for each pathogen Ref: (1) French MA, Lenzo N, John M, et al. Immune restoration disease after the treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy.HIV Med 2000; 1:107–15 (2) DeSimone JA, Pomerantz RJ, Babinchak TJ. Inflammatory reactions in HIV-1–infected persons after initiation of highly active antiretroviral therapy. Ann Intern Med 2000; 133:447–54. (3)Clin Infect Dis. 2006 Feb 1;42(3):418-27. (4)(4) AIDS 2005 Mar 4;19(4):399-406.

4. 44 Historical Picture of IRIS Paradoxical reactions among HIV-ve patients treated for Mycobacterium Tuberculosis infection Inflammatory reactions occurring in patients on treatment for Mycobacterium Leprae Recovery of immune cells following bone marrow transplantation or chemotherapy Atypical, localized MAC Inflammatory responses in patients when they were treated with AZT monotherapy

5. 5

6. Case studies IRIS

7. 77 Case Study 1 7 yrs old HIV positive male child, presented with mediastinal TB & oral candidiasis Mantoux Test : 0 mm Sputum Smear AFB: Negative  CD4 : 84 Cells (4%) ATT started Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai

8. 88 Case Study 1 (continued) Prior to treatment After 2 months of ATT Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai

9. 99 Case Study 1 (continued) After 2 months of ATT Initiated on ART also 3 weeks after ART (d4T+3TC+EFV) Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai

10. 10 Case Study 1 (continued) 3 weeks after ART After treatment Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai

11. 11 Case Study - 2 A 22 yr old male HIV positive since Feb. 2000, on Cotrimoxazole prophylaxis, found to be eligible for ART in March 2006 08 th March 06: Started on AZT,3TC and NVP 16 th May 06: Presented with cough and grade 4 dyspnoea Dramatic improvement with steroids and Cotrimoxazole (therapeutic dose) in 2 weeks time

12. 12 6 th March 2006 CD4 166 16 th May 2006 CD4 199 31 st May 2006 Source: Dr.Manoharan, I-TECH

13. 13 Case Study - 3 Jan07: 10 yr old girl, sputum positive Pulmonary tuberculosis was started on Category -1 (Rifamycin, Isoniazid, Ethambutol and Pyrazinamide) anti-TB treatment and cotrimoxazole; body weight 10.5 kg March.07: Body weight 11 kg; Hb 8.5gms% and CD4 (317) 9%; Sputum negative ; started on d4T, 3TC & EFV Sept.07: Hospitalised

14. 14 Case study - 3 (continued) Severe dyspnea, pedal edema, & cough Dyspnoeic at rest, tachycardia, pitting pedal edema, cervical adenopathy; Body weight 15 kg CVS: JVP elevated; S1,S2 heard well, S3+, systolic murmur + Respiratory system: Basal rales at both lungs Abdomen: Distended & Liver + Hb:12.9gms% & CD4 33%, sputum negative for AFB

15. 15 Case Study- 3 (continued) Source: GHTM,Chennai

16. 16 Case Study- 3 (continued) Source: GHTM,Chennai

17. 17 Case Study- 3 (continued) What is the clinical diagnosis?

18. 18 Case Study- 3 (continued) Clinical course – 8 months later… May 2008 Weight: 18 Kg Echo findings >> Moderate LV dysfunction, Mild MR, Mild Pulmonary Hypertension, No pericardial effusion, Ejection fraction 48%

19. 19 Case Study- 3 (continued) September 2007 November 2007.

20. 20 Case Study- 3 (continued) Jan. 2008 Feb. 2008.

21. 21 Final diagnosis Probable IRIS- dilated cardiomyopathy

22. Pathogenesis IRIS

23. 23 Immune Reconstitution Inflammatory Syndrome Improved Cell Mediated Immunity with restoration of both memory and naïve CD4 cells Increased CD4/CD8 cells detect hidden pathogens which were ignored with deficiency of immunity previously Result in inflammatory process at the area of occult / sub-clinical infections Usually improves with control of inflammation and specific treatment

24. 24 PML-IRIS:Pathogenesis B C D A

25. 25 MRI pictures of PMLN-IRIS

26. 26 Increase in PPD specific T-cells

27. 27 Categories of IRIS CategoriesAntigen target Infectious-unmaskingViable replicating infective antigen Infectious-paradoxicalDead or dying organisms Auto immuneHost MalignanciesPossible tumor or associated pathogen Other inflammatory conditions Range of antigens Immune Reconstitution Inflammatory Syndrome in HIV-Infected Patients Receiving Antiretroviral Therapy Pathogenesis, Clinical Manifestations and Management Devesh J. Dhasmana, Keertan Dheda, Pernille Ravn, Robert J. Wilkinson and Graeme Meintjes; Drugs 2008; 68 (2): 191-208

28. 28 Defining IRIS Required criterionSupportive criterion Worsening symptoms of inflammation/infection Increase in cd4 cell count of > 25 cells/cu.mm Temporal relationship with starting antiretroviral treatment Biopsy demonstrating well formed granulomatous inflammation or unusually exuberant inflammatory response Symptoms not explained by newly acquired infection or disease or the usual course of a previously acquired disease > 1 log10 decrease in plasma viral load Source: CID J 2006;(1 June) 42: 1639-46

29. 29 Defining IRIS HIV positive Receiving HAART  Decrease in HIV-1 RNA level from baseline  Increase in CD4 cells from baseline (may lag HIV-1 RNA decrease) Clinical symptoms consistent with inflammatory process Clinical course NOT consistent with:  Expected course of previously diagnosed OI  Expected course of newly diagnosed OI  Drug toxicity Source: Journal of Antimicrobial Chemotherapy (2006) 57, 167-170; Samuel A. Shelburne, Martin Montes and Richard J.Hamill

30. 30 Defining IRIS: Major Criteria Previous diagnosis of AIDS Concurrent Antiretroviral Therapy; Increase in CD4 count and Decrease in plasma vireamia by > 1 log copies/ml Atypical presentation of ‘opportunistic infection or tumor’, i.e.:  localized disease or  exaggerated inflammation or  atypical inflammatory response or  worsening of pre existing disease.  Symptoms consistent with infectious/inflammatory condition Symptoms not explained by normal course of previous or new OI or side effect of ART Source: Battegay and Drechsler; Current Opinion in HIV and AIDS; 2006, 1; 56-61

31. 31 Defining IRIS: Minor Criteria Increase in CD4 cell count Increase in measured specific immune response Spontaneous resolution of symptoms without specific therapy Source: Battegay and Drechsler; Current Opinion in HIV and AIDS; 2006, 1; 56-61

32. 32 Practical Definition: NACO “Occurrence or manifestations of new OIs within six weeks to six months after initiating ART; with increase in CD4 count” India’s National AIDS Control Organization, Antiretroviral Therapy Guidelines for HIV- infected Adults and Adolescents Including Post- exposure Prophylaxis. May 2007

33. 33 Onset of IRIS Source: AIDS 2005, Vol 19 No4 ;399-406, Samuel A. Shelburne et al

34. 34 HAART & HIV RNA Levels Source: AIDS 2005, Vol 19 No4 ;399-406, Samuel A. Shelburne et al

35. 35 IRIS & Non-IRIS Response to HAART Source: AIDS 2005, Vol 19 No4 ;399-406, Samuel A. Shelburne et al

36. 36 Clinical Spectrum Heterogeneous Onset; early/delayed Atypical symptoms; generalized/local Varying severity Infectious agents/site of infection

37. 37 Differential Diagnosis Opportunistic infections Drug resistance organisms Drug side effects

38. Risk factors IRIS

39. 39 French: AIDS, Volume 18(12).August 20, 2004.1615-1627

40. 40 Risk of TB-IRIS AIDS 2007, 21:335–341

41. 41 Management Mild form (with ongoing ART)  Observation Localized IRIS (with ongoing ART)  Local therapy such as minor surgical procedures for lymph node abscesses Most of the situations (with ongoing ART)  Unmasking &/or Recognition of ongoing infections >> Antimicrobial therapy to reduce the antigen load of the triggering pathogen;  Reconstituting immune reaction to non-replicating antigens >> no antimicrobial therapy. Short term therapy with corticosteroids or non-steroidal anti inflammatory drugs to reduce the inflammation.

42. 42 Management Temporary cessation of ART has to be considered if potentially life threatening forms of IRIS develop

43. 43 Prevention of IRIS Identify and treat OI’s before the initiation of ART, if possible o How long should ART be deferred?? In patients with a recently treated OI, identify those at risk of “paradoxical” IRIS o Low CD4 cell count o Disseminated infection o Genetic susceptibiltiy

44. 44 Key Points IRIS less likely to occur when ART is initiated early enough HIV infected persons who come late in their disease course are at risk from IRIS Clinicians need to know about this syndrome and its pathophysiology when working up the differential diagnosis of a wide variety of clinical symptoms in HIV-infected patients on ART  Important in countries where ART is prescribed for patients who already have advanced immunodeficiency.

45. Additional slides Illustrations

46. 46 Illustration 1 Before ART: 3.6.2004 4 Months after: 11.10.2004 Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai

47. 47 Illustration 2 Before ART 11 weeks after Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai

48. 48 Illustration 3 10 weeks after Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai

49. 49 Illustration-4 Source: Dr.Rajasekaran, Superintendent, GHTM,Chennai

50. 50 Illustration 5 Source: CMC, Vellore

51. 51 IRIS CMV (Cytomegalovirus) Source: Graeme Meintjes, HIV service, GF jooste Hospital, Department of Medicine, UCT

52. 52 IRIS-Microsporidiosis Multiple granulomas on hyperemic peritoneal wall Granulomas over the peritoneum & the hyperemic bowel

53. Thank you! Next session: December 4 th, 2008 Listserv: itechdistlearning@u.washington.eduitechdistlearning@u.washington.edu Email: DLinfo@u.washington.edu

54. Welcome to UW I-TECH HIV/AIDS Clinical Seminar Series Next session: December 4 th, 2008 Mark Micek Operations Research