Immune Reconstitution Inflammatory Syndrome Dr. Lesego Mawela
TOPICS FOR DISCUSSION IRIS Case Epidermiology Pathogenesis of IRIS Risk factors for IRIS Epidemiology of IRIS Health system burden of IRIS Timing and manifestations of IRIS TB-IRIS Management/prevention of IRIS
CASE PRESENTATION 24 year old female, HIV positive, CD4 31. Brother has been on TB treatment for 12 months Diagnosed with TB for and just completed the intensive phase of TB therapy for pulmonary TB in 8/09; converted to sputum negative after intensive phase; (no cough/fevers/night sweats/ongoing weight loss) Started ART regimen (TDF/3TC/EFZ) in same day; after 2 weeks of ARVs, presented to clinic with persistent cough, new fevers and night sweats Sputum is negative; CXR from 9/09 with unchanged right lower lobe infiltrate and hilar lymphadenopathy
PHYSICAL EXAM Febrile; mild distress with cough No thrush or enlarged lymph nodes Rales, dullness to percussion in right lower lung field No organomegaly No rash or jaundice Bloods: HB: 12 ALT 53 AST 61 ALP 450 GGT 510
IRIS: CASE DEFINITION
EPIDEMIOLOGY OF IRIS: INCIDENCE Incidence of IRIS has been reported as 23%, 17%, and 25% among unselected patients starting ARVs in the UK (CID 2006; 42(3):418-27), Serbia (HIV Medicine 2005; 6(2):140-3), and Australia (HIV Medicine 2000; 1(2):107-15) South African study followed 423 ARV-naïve HIV+ patients during the first 6 months of therapy, and found 44 patients (10.4%) experienced IRIS, for an overall incidence rate of 25.1 cases/100 patient years (AIDS 2008; 22:601-10) For TB-IRIS, one study showed paradoxical clinical worsening in 35% of patients with HIV and TB coinfection after initiation of ARVs while on TB therapy (Archives of Internal Medicine 2002; 162:97-9)
IRIS: HISTORICAL BACKGROUND Leprosy patients (Mycobacterium leprae) may present with inflammation-induced skin and nerve damage up to several years after initiating mycobacterial therapy HIV negative patients treated for pulmonary TB may develop fevers, increasing LAD, pleural effusions, or CNS tuberculomas while on anti-tb drugs (CID 1994; 19:1092-9) With introduction of AZT, reports from Australia described atypical presentations of OIs occurring during AZT therapy (AIDS 1992; 6:1293-7) Introduction of protease inhibitors in 1995 led to more widespread reports of disorders of immune reconstitution: Localized MAC lymphadenitis (4 th CROI, 1997; abstract 351) Severe hepatitis with clearance of chronic hepatitis B infection (Lancet 1997; 349:995-6) Worsening PTB/EPTB infection (Lancet 1998; 351:252-55)
RISK FACTORS FOR IRIS Lower CD4 count at the initiation of therapy (<200) High antigenic load, i.e. MTB, cryptococcal infections (CID 2005; 40(7):1049-52; Thorax 2004; 59(8):704-7) Better virologic response to HAART (Archives of Internal Medicine 2002; 162:97-9) Starting ARVs within 6 weeks of TB diagnosis (Thorax 2004; 59:704-07) In the case of TB, disseminated or extrapulmonary disease when starting ARVs (JID 2006; 53:357-63) Black ethnic origin (Int Journal of Tuberc Lung Disease 2007; 11:1282-89) Polymorphisms in human leukocyte antigen (HLA) and cytokine-related genes (AIDS 2002; 16 (15):2043-7)
TIME OF ONSET OF IRIS IRIS associated with Mycobacterium tuberculosis occurs within 2 months of starting antiretroviral therapy, usually within the first 2-3 weeks (French et al, AIDS 2004, 18:1615 1627) But a recent case series suggested a broader range on time of onset (Shelburne et al. AIDS 2005, 19:399 406)
Shelburne et al. AIDS 2005;19:399-406
IRIS: CATEGORIES OF IRIS Dhasmana, D, et al. IRIS in HIV-infected patients Receiving ART. Drugs 2008; 68(2): 191-208
TYPE 1 IRIS
TYPE 2 IRIS
SPECIFIC IRIS MANIFESTATIONS
TB IRIS
TB-IRIS MANIFESTATIONS Paradoxical: recurrent, worsening, or new clinical or radiological manifestations of TB Return of fever or respiratory symptoms Enlargement of lymph nodes Worsening of pulmonary infiltrates, LAD, or effusions Increasing size of CNS tuberculomas or worsening meningeal signs/symptoms Abdominal pain/obstructive jaundice Cold abscesses Osteitis
TB-IRIS
PARADOXICAL TB-IRIS Important to rule out: Failure of antimicrobial therapy due to resistance Suboptimal drug concentration due to non-adherence or malabsorption Adverse drug reaction Alternative opportunistic infection, especially in smear (-) PTB/EPTB without microbiologic confirmation Malignancy
TB-IRIS: MANAGEMENT Dependent on the presentation and disease severity Continue ARV s! Unmasking: initiate appropriate anti-tb therapy Paradoxical: continue anti-tb therapy, reassure patient Steroids: reserve for severe IRIS cases: tracheal compression from LAD; refractory or debilitating lymphadenitis; or severe respiratory symptoms, such as stridor or ARDS Dosing: IV methylprednisolone of 40 mg q 12 hours, or oral prednisone 20-70 mg/day for 5-12 weeks
Intervention In Cases Of Inflammatory Disease In Hiv-infected Individuals
Timing Of ARVs with TB Therapy
-Prospective, randomized, open-label, two-armed trial with no placebo - superiority trial to answer the question of the best timing for the introduction of HAART -severely immunosuppressed (CD4 200/mm 3 ) HIV-infected adult patients with newly diagnosed TB in Cambodia - 2 arms: late introduction of ART (reference arm: 8 weeks) vs. early (2 weeks) introduction of the same HAART - Primary endpoint: survival at the end of the trial (intent-to-treat analysis) ANRS 1295/12160 - CIPRA KH001/10425 study
Risk of death reduced by 39%
INCIDENCE OF IRIS
Guidelines for Initiating ART in TB/HIV Coinfected Patients Clinical Scenario CD4+ count < 50 cells/mm 3 CD4+ count 50 cells/mm 3 with clinical disease of major severity* Other patients with CD4+ count 50 cells/mm 3 Drug-resistant TB HIV-infected pregnant women with active TB Recommendation Start ART within 2 wks of starting TB therapy Start ART within 2-4 wks of starting TB therapy Can delay ART initiation until 2-8 wks after starting TB therapy Start ART within 2-4 wks after confirmation of resistance, initiation of second-line TB therapy Start ART as early as feasible *Low Karnofsky score, low body mass index, low hemoglobin, low albumin, organ system dysfunction, extent of disease
BACK TO OUR CASE PRESENTATION 24 year old female, HIV positive, CD4 31. Brother has been on TB treatment for 12 months She has been Diagnosed with TB and just completed the intensive phase of TB therapy for pulmonary TB in 8/09; converted to sputum negative after intensive phase; (no cough/fevers/night sweats/ongoing weight loss) Started ART regimen (TDF/3TC/EFZ) in same day; after 2 weeks of ARVs, presented to clinic with persistent cough, new fevers and night sweats Sputum is negative; CXR from 9/09 with unchanged right lower lobe infiltrate and hilar lymphadenopathy
PHYSICAL EXAM Febrile; mild distress with cough No thrush or enlarged lymph nodes Rales, dullness to percussion in right lower lung field No organomegaly No rash or jaundice Bloods: HB: 12 ALT 53 AST 61 ALP 450 GGT 510
How will you manage the patient Will you stop ART
DIAGNOSIS? Recurrent/reinfection TB MDR TB Unmasking TB Paradoxical TB Further tests pending: sputum gram stain and culture for sensitivities Gene Xpert: resistant to Rifampicin Recommendations: start MDR-TB therapy; continue ARVs
TAKE HOME POINTS IRIS is common, but most often manageable IRIS should not be a barrier to ARV initiation ARV initiation should occur within two weeks of TB therapy initiation, and saves lives
Thank You Dr. Dave Spencer Prof. Graeme Mentjies
Dr. Lesego Mawela 0826576782 Lesego@aquah.org www.aquah.org