Immune Reconstitution Inflammatory Syndrome (IRIS)

1. Immune Reconstitution Inflammatory Syndrome (IRIS) HAIVN Harvard Medical School AIDS Initiative in Vietnam

2. Outline of Presentation • Definition of IRIS • Pathogenesis of IRIS • Clinical presentation of IRIS • IRIS due to TB, Hepatitis B, CMV • Diagnosis of IRIS • Management of IRIS

3. Learning objectives At the end of this presentation, the trainee will be able to describe: • The two forms of the Immune Reconstitution Inflammatory Syndrome (IRIS) • The etiological agents and syndromes of IRIS • The management of IRIS • Commonly encountered forms of IRIS

4. IRIS: Definition • IRIS = IRD: Immune Restoration Disease • IRIS: symptoms or signs consistent with an inflammatory and/or atypical presentation of OIs or tumors • Is not a side effect of ARV, • Occur after initiation, reintroduction, or change of ARV • In patients who have evidence of viral load suppression.

5. IRIS: Definition • IRIS is a pattern of diseases presenting soon after the initiation of ARV. • Typically, it occurs in the first 2-12 weeks after starting ARV. • IRIS is a “paradoxical” overreaction against a foreign antigen (alive or dead) in patients starting ARV.

6. IRIS: Pathogenesis • IRIS is secondary to immunological changes after ARV: • Rapid and potent suppression of HIV viraemia + • Abundant microbial antigen (alive or dead) promotes a greater immune response when it encounters suddenly increased numbers of functionally active antigen-specific cells.

7. IRIS: Clinical presentations • IRIS in patients already receiving therapy for an OI at the time at which ARV is initiated. Clinical deterioration of the disease: “paradoxical reaction”. • IRIS may trigger the presentation of an OI that was sub-clinical prior ARV: “unmasking IRIS”.

8. IRIS: Clinical presentations • Inflammatory response that causes the unexpected worsening of the patient’s condition. • Often there is no detectable evidence of the underlying pathogen. • Mycobacterium Tuberculosis accounts for 1/3 of all IRIS events. • BCG vaccine: very common in infants

9. Common Pathogens All infections have been reported to cause IRIS • Mycobacteria: • TB and MAC, BCG in children • Fungal: • Cryptococcosis, PCP, histoplasmosis, Penicilliosis • Viral: • CMV, VZV, HBV, HCV • Parasites: • Strongyloides stercoralis, cryptosporidium

10. IRIS Risk factors • Low CD4 count before starting ARV • Rapid reduction in HIV viral load with ARV • High pathogen load at the beginning of ARV, i.e. starting ARV therapy in the setting of an active OI • High number of prior OIs • Minor criteria: increase in CD4 count.

11. IRIS TB • Worsening of signs and symptoms of TB in patients being started on anti-TB chemo-therapy • Described in the pre-HIV era but appear to be more frequent in HIV-infected patients • Occur in 7 to 36% of patients • More frequently when HAART is started within 2 months of beginning anti-TB treatment

12. IRIS TB • Factors complicating ARV and TB therapy: • Adherence to heightened pill burden • Overlapping drug toxicities • Drug/drug interactions

13. IRIS TB • “Paradoxical reaction”: • Initial clinical response to TB treatment, • ARV introduction, • New persistent symptoms or signs of TB, • Adequate adherence to ARV and TB treatment.

14. IRIS TBDiagnosis • “Paradoxical reaction”: • Chest X ray/Ultrasound: worsening or new lesions, • Good virological response, • Clear exclusion of other conditions: • TB treatment failure, resistant TB • others OI, • Malabsortion, • Drug reactions.

15. IRIS TBDiagnosis • “Unmasking IRIS”: Unapparent TB at the start of ARV • Insufficient clinical symptoms to justify TB treatment, • Chest X ray: normal • Patients with cough at least 3 sputum: AFB negative

16. IRIS TBDiagnosis • “Unmasking IRIS”: • TB appeared within the first 6 months of ARV • Good virological response to ARV • Adequate adherence to ARV

17. CXR before ARV CXR 3 weeks after ARV

18. 8 months old: • Severe malnutrition • Wt 5 kg; height 58cm • Hepatosplenomegaly • CD4 40.6%; 662 tb/mm3 • PCR + • ARV: D4T/3TC/NVP • enlargement of the axillary lymph nodes.

19. IRIS TBDifferential diagnosis • For patients on TB treatment who develop IRIS after start ARV: “Paradoxical reaction” • Side effects of ARV • drug fevers • TB infection not responding to treatment • Resistant TB • Poor adherence to TB treatment • Other HIV or non-HIV related infections • IRIS is a diagnosis of exclusion !!!

20. Overlapping Side Effects of Antituberculosis and Antiretroviral Drugs

21. Overlapping Side Effects of Antituberculosis and Antiretroviral Drugs

22. IRIS in Thai children • Between May 2002-2004 (3 hospital) • HIV-infected children enrolled: 153 • ARV regimens: • D4T + 3TC + NVP: 81 • D4T + 3TC + EFV: 72 • Mean Age: 8 years old • Mean CD4 baseline: 5% • No active OI The Pediatric Infectious Disease Journal • Volume 25, Number 1, January 2006

23. IRIS in Thai children: results • 153 enrolled children: • 29 children (19%) had 32 episodes of IRIS • Median time: 4 weeks after ARV • IRIS: • Mycobacterial: 14 episodes (43%) • Atypical mycobacteria: 9 • Mycobacterium Tuberculosis: 3 • Mycobacterium Bovis: 2 • Varicella-Zoster: 7 episodes The Pediatric Infectious Disease Journal • Volume 25, Number 1, January 2006

24. IRIS in Thai children: results (cont’) • HSV: 7 episodes • Cryptococcus: 3 • Guillain Barre: 1 The Pediatric Infectious Disease Journal • Volume 25, Number 1, January 2006

25. IRIS in Thai children: outcomes • One patient interrupted 8 weeks ARV during IRIS • 3 patients died of IRIS or its complications The Pediatric Infectious Disease Journal • Volume 25, Number 1, January 2006

26. IRIS in infants(South Africa) • Infants less than 24 months old: 169 • ARV: D4T + 3TC + Aluvia • Median age: 8 months old • IRIS: 34 infants (21%) • Median time: 2 weeks post-ARV • BCG disease: 24/34 (71%) • Local reaction and/or ipsilateral axillary lymph node AIDS 2009, 23:1097–1107

27. IRIS in infants(South Africa) • Tuberculosis: 12 cases (6 co-infected with M. bovis) • Outcomes: • IRIS: 3/34 died (9%) • BCG disease: 2 cases • BCG and TB: 1 case AIDS 2009, 23:1097–1107

28. IRISManagement • Continuation of primary therapy against the pathogen, • Continuation of ARV, • Judicious use of anti-inflammatory agents, • To provide reassurance to the patients: • With appropriate management, IRIS usually does not alter the patients long-term prognosis.

29. IRISManagement • Corticosteroids (1mg/kg/day) might be necessary in case of severe symptoms: • Worsening of meningeal, cerebral or mediastinal disease with compression of vital structure, • Pain, prolonged fever. • In case of life-threatening forms of IRIS, stopping ARV temporarily could be considered. * Rifampicin decrease 50% prednisolone concentrations

30. Managing ARV During IRIS • Continue ARV • Except in life-threatening situations • Adjust for anti-mycobacterial treatment • If rifampin is prescribed: • Switch NVP to EFV • Stop PIs and start EFV or a third NRTI, as appropriate • Super boosted PI

31. Summary and Key Points • Restoration of immunopathological response to antigens of opportunistic pathogens • subclinical infections • treated infections • Usually presents during the first weeks (2-12 weeks) of ARV • Less commonly presents after many months of ARV • The most common agent inducing IRIS in Vietnam is TB/BCG 28

32. Summary and Key Points • IRIS is a diagnosis of exclusion • Treatment consists of antimicrobial + anti-inflammatory therapy or anti-inflammatory therapy alone • IRIS is NOT treatment failure: ARV therapy should be continued • The syndrome will be spontaneously resolved after months

33. Thank you! Questions?