HIV and the Immune Reconstitution Inflammatory Syndrome (IRIS): Understanding the Challenges

2. IRIS? No thank you, I prefer Roses Allison Agwu LEAH Adolescent Grand Rounds Advanced HIV Management October 9, 2009

3. Clinical Case 18* year old AA male with a history of AIDS Prior history of candidaesophagitis Two week history of acute onset fevers, headaches and anorexia Associated weight loss Started on HAART one month prior Nadir CD4 count 5 cells/µL, Viral load >750,000 copies/ml *case slightly altered from original

4. History Medications: Efavirenz (Sustiva), Didanosine (Videx), Stavudine (Zerit) , Paxil, Iron, Bactrim, Prilosec Physical Examination Temp 103°F, PR 120bpm, RR 22 cpm, BP 106/90 mmHg Cachectic, acutely ill looking male Tender hepatomegaly with liver edge palpable 4cm below the right costal margin

5. Work-up CBC-WBC 6.6, HCT 24.0, Platelet count 149 BMP- Na 128otherwise WNL Ca 8.2, Alb 2.6, ALT 136, AST 222, Alkphos 360 Lumbar puncture- negative Cultures of blood (including AFB), stool, urine - negative Imaging - Hepatomegaly, contracted gallbladder, no biliary tract dilatation or obstruction

6. Pathology • Liver biopsy- Granulomas and multiple AFB consistent with mycobacteria infection

7. What is Responsible for Patient’s Clinical Presentation ? • Severe immune deficiency secondary to HIV ? • Severe inflammatory reaction after immune reconstitution ? • Drug Toxicity ?

8. HIV and the Immune Reconstitution Inflammatory Syndrome (IRIS) A Challenge to the Recovering Immune System?

9. Objectives • Briefly review our current understanding of the effects of HIV infection on the immune system • Review proposed mechanisms of Immune reconstitution by Highly Active Antiretroviral Therapy (HAART) • Discuss the epidemiology, pathogenesis, common presentations and management of IRIS • Identify gaps in current IRIS knowledge base • Take home points!!!

10. ABP Adolescent Medicine Content Specifications • Identify the major opportunistic infections most commonly encountered in immunocompromised hosts with acquired immunodeficiency syndrome (AIDS) • Understand the importance of close monitoring of adolescents infected with human immunodeficiency virus (HIV) to determine the co-occurrence of opportunistic infections

11. Virologic and Immunologic Dynamics of HIV Infection Fauci AS et al. Ann Intern Med 1996

12. CD4 level and Risk of Opportunistic Infections (OIs)

13. HAART: Current Drugs Fusion Inhibitor Enfuvirtide/T-20 (Fuzeon, SQ inj) Integrase Inhibitors Raltegravir (Isentress) CCR5 Inhibitors Maraviroc (Selzentry) Vicriviroc NNRTIs Efavirenz (Sustiva,) Nevirapine (Viramune) Delavirdine (Rescriptor) Etravirine (Intelence) Protease Inhibitors Ritonavir (Norvir) Saquinavir-HGC (Invirase) Indinavir (Crixivan) Nelfinavir (Viracept) Fosamprenavir (Lexiva) Lopinavir/r (Kaletra) Atazanavir (Reyataz) Tipranavir (Aptivus) Darunavir (Prezista) NRTIs Zidovudine/AZT (Retrovir, Stavudine/d4T (Zerit, Didanosine/ddI(Videx-EC) Lamivudine/3TC (Epivir,) Abacavir/ABC (Ziagen) Zalcitabine/ddC (Hivid) Tenofovir/TDF (Viread) Emtricitabine (Emtriva) AZT/3TC (Combivir) AZT/3TC/abacavir(Trizivir) ABC/3TC (Epzicom) TDF/FTC (Truvada) TDF/FTC/EFV (Atripla)

14. Virologic Response to HAART

15. CD4 Recovery Battegay et al. Lancet Inf Dis 2006

16. Immune Recovery following HAART First Phase (3-6 months) REDISTRIBUTION Release of activated memory CD4 cells trapped in lymphoid tissues and reduction in apoptotic cell death Second phase (6 months- 4years) RECONSTITUTION Naive CD4 cells and memory CD4 contribute to reconstitution

17. Immune Reconstitution Inflammatory Syndrome • A pathologic inflammatory immune recognition of antigens associated with a known or unknown replicating infection or persistent non-replicating antigens from a previous infection • Results in spectrum of presentations ranging from clinical worsening of a treated opportunistic infection (OI), atypical presentation of an unrecognized OI or autoimmune disorders such as Graves’ disease • Occurs in subset of HIV-infected patients on HAART

18. Categories of IRIS Related to underlying opportunistic infection Inflammatory “unmasking” of a previously untreated infection Paradoxical clinical deterioration of an infective process for which patient is on appropriate treatment Autoimmune e.g Graves Disease Malignancies e.g worsening of Kaposi’s sarcoma

19. Historical View of Non-HIV IRIS Paradoxical responses well described among non-HIV infected patients treated for Mycobacterium tuberculosis (MTB) Thought to be linked to reversal of immunosuppression induced by MTB infection Inflammatory reactions during treatment routine in patients with Mycobacterium leprae Recovery of immune cells following bone marrow transplantation or chemotherapy

20. Infections associated with HIV IRIS Mycobacteria Mycobacterium tuberculosis Mycobacterium avium complex M. leprae Cytomegalovirus Herpes Viruses Herpes zoster virus Herpes simplex virus Human Herpes virus-8 associated Kaposi’s Sarcoma Cryptococcus neoformans Bacteria B. Henselae Pneumocystisjirovecii pneumonia Histoplasmacapsulatum Dermatophytosis Toxoplasmosis Hepatitis B virus Hepatitis C virus JC virus-PML Parvovirus B19 Molluscumcontagiosum Strongyloidesstercoralis & other parasitic infections

21. Most Commonly Seen Entities • In a case series and literature review of 182 episodes of IRIS, the most frequently reported associated infections were: • localized herpes zoster (22 percent) • M. tuberculosis (20 percent) • M. avium complex (17 percent) • CMV (12 percent) • Cryptococcus (6.5 percent) • Shelburne, SA etal. Medicine (Baltimore) 2002; 81:213.

22. Non-infectious HIV IRIS Etiologies • Graves Disease • Systemic lupus erythematosus (SLE) • Rheumatoid arthritis • Sarcoidosis • Guillain-Barre syndrome • AIDS related lymphoma

23. Difficulties with Definition of HIV IRIS Wide variety of underlying OIs Need to incorporate both unmasking of clinically silent infections and worsening of previously diagnosed OIs Difficulty in establishing that patient’s clinical presentation is not due to a new microbial process or drug toxicity

24. Proposed Diagnostic Criteria for HIV IRIS HIV positive Receiving HAART Decrease in HIV-1 RNA level from baseline Increase in CD4+ cells from baseline 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 Shelburne et al. Medicine 2002

25. Epidemiology Develops in 15-25% of patients receiving HAART Up to 45% incidence rate in patients with known opportunistic infections Most cases develop within the first 3 months of treatment (median 6-8 weeks) Reports of patients presenting up to 2 years after initiation of treatment

26. Why Do These Inflammatory Reactions Occur?

27. Pathogenesis Not well understood May vary from one infection to the other The trigger for this paradoxical reaction is probably an excessive enhancement of immune response to disease-specific antigens leading to an overproduction of inflammatory mediators. Host genetic susceptibility –carriage of specific HLA alleles

29. HIV IRIS Symptoms Depends on prevailing opportunistic infections in the environment Corresponds to patients’ specific underlying condition and location M. tuberculosis, zoster, M. avium complex, CMV, Cryptococcus Shelburne et al. Medicine 2002

30. Paradoxical HIV Tuberculosis IRIS Recurrent, worsening or new clinical or radiologic manifestations of TB Return of symptoms, fever, enlargement of nodes, worsening radiographic pulmonary infiltrates CNS involvement with tuberculomata or tuberculous meningitis

31. Paradoxical TB IRIS Lymphadenitis Dhasmana et al. Drugs 2008

32. Paradoxical TB IRIS At HAART Initiation 10 Days into TB IRIS Dhasmana et al. Drugs 2008

33. Non-Tuberculous Mycobacteria Usual presentation is pulmonary disease or bacteremic wasting illness associated with fever, gastrointestinal disease and anemia MAC IRIS presents with more focal inflammatory disease Peripheral lymphadenitis with or without abscess formation, intraabdominal disease and involvement of joint, skin, soft tissues and spine

34. MAC IRIS Abdominal lymphadenopathy with evidence of psoas abscess

35. CMV IRIS-Immune Recovery Uveitis • Patients present with visual impairment and floaters • Occurs in patients with prior CMV infection • Distinct from necrotizing retinitis with minimal intraocular inflammation of classic CMV retinitis • High intensity of inflammatory response inducing proliferative vitroretinopathy and posterior subcapsular cataracts • Diagnosis requires a high level of suspicion

36. CMV Retinitis Normal Retina CMV Retinitis

37. Paradoxical Cryptococcal IRIS • Presents with recurrent meningitis symptoms • CSF shows inflammation with marked leukocytosis but fungal cultures typically negative • Neuroimaging shows significant inflammation • Other findings include cryptococcomas, cerebellitis, lymphadenitis, mediastinitis, cavitating pneumonia and skin lesions • Patients typically have raised intracranial pressure requiring serial lumbar punctures. • Mortality up to 66%

38. Neuroimaging in Cryptococcal IRIS

39. Zoster HIV IRIS • Dermatomal varicella zoster comprises 9-40% of IRIS cases in large observational IRIS cohorts • Patients present with typical or atypical dermatomal involvement without dissemination or systemic symptoms • Complications such as encephalitis, myelitis, cranial and peripheral nerve palsies possible but rare.

41. Risk Factors for HIV IRIS?

42. Design: Retrospective cohort identified through a city-wide prospective surveillance program • Method: Retrospective chart review of 180 HIV infected patients on HAART coinfected with Mycobacterium Tuberculosis, Mycobacterium avium complex or Cryptococcus neoformans between 1997-2000 AIDS 2005, 19:399-406

43. Shelburne et al. AIDS 2005

44. CD4 and Viral Load Response as IRIS Risk Factors Shelburne et al. AIDS 2005

45. Determinants of IRIS • 1) extent of CD4+ T-cell immune suppression prior to the initiation of HAART (rapidity of increase) • 2) degree of viral suppression and immune recovery following the initiation of HAART • 3) Prior opportunistic infections (known or unknown)

46. Design: Case-control study • Methods: Patients from Johns Hopkins HIV Clinic who had IRIS were identified and matched with 4 controls without IRIS who initiated HAART within 6 months of the case Journal of Acquired Immune Deficiency Syndrome Dec 2007

47. *BPI- boosted protease inhibitor Manabe et al. J Acquir Immune Defic Syndr 2007

48. Risk Factors for IRIS An active or subclinical OI A nadir CD4 cell count below 100 cells/µl (or 50 cells/µl as reported in other studies) Robust immunologic response to HAART The initiation of HAART within the first 4–8 weeks of starting therapy for an OI Being ART naïve at the time of OI diagnosis

49. Diagnosis Clinical- History! History! History! Investigations to exclude alternative explanations for clinical deterioration Failure of antimicrobial therapy Suboptimal drug concentrations due to non-adherence or malabsorption Adverse drug reaction Alternative infection or malignancy

50. Treatment • No randomized control trials available so largely based on anecdotal reports • Treatment for the underlying pathogen should generally be started or continued in patients who develop IRIS. • For most patients with untreated HIV and known OIs with effective antimicrobial therapies, reasonable to delay HAART for 1-2 months while treating the OIs in an attempt to decrease the likelihood of IRIS. • Continue HAART in the majority of cases. However, if the manifestations of IRIS are considered to be life or organ-threatening, discontinuation of HAART is sometimes necessary. • Corticosteroids or NSAIDS may help decrease the inflammatory response in some patients with IRIS.