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Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS)

Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS). Graeme Meintjes University of Cape Town Imperial College London. Webinar 25 Nov 2013. ART Viral suppression (CD4 rise) Restoration of pathogen-specific immunity. -. +.

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Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS)

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  1. Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) Graeme Meintjes University of Cape Town Imperial College London Webinar 25 Nov 2013

  2. ART Viral suppression (CD4 rise) Restoration of pathogen-specific immunity - + Regression or prevention of opportunistic infections Inflammatory reactions days to months after starting ART = IRIS IRIS = Immune Reconstitution Inflammatory Syndrome IRD = Immune Restoration Disease

  3. Mycobacteria TB MAC Leprosy BCG Other NTM Fungi Cryptococcus Histoplasmosis PCP Dermatophytes Candida Aspergillus Penicillium Viruses Hepatitis B and C HSV 1 and 2 HZV CMV JC virus BK virus Molluscum Warts Parvovirus B19 HIV dementia Protozoans Toxoplasmosis Leishmaniasis Microsporidia Cryptosporidia Helminths Schistosoma Strongyloides Bacteria Bartonella Other skin conditions Acne and folliculitis Auto-immune and inflammatory conditions Guillain-Barre syndrome Sarcoidosis Grave’s Peyronie’s Rheumatological conditions (SLE, RA, Reiter’s) Tattoo pigment and foreign body reactions Cerebral vasculitis TTP LIP Tumours Kaposi’s sarcoma, lymphoma Wide range of IRIS conditions described

  4. ART Paradoxical TB-IRIS Patients on TB treatment ART-associated TB ART Patients not on TB treatment Unmasking TB-IRIS

  5. OVERVIEW • Clinical presentations • Neurological TB-IRIS • Hepatic TB-IRIS • Prolonged TB-IRIS • Diagnosis • Corticosteroids for treatment • ART timing • Prevention trial

  6. What is the typical time of onset of paradoxical TB-IRIS after ART start? • 3-10 days • 1-4 weeks • 4-8 weeks • Around 3 months

  7. Paradoxical TB-IRIS Patient diagnosed with TB and started on TB treatment Improving on TB treatment then starts ART Recurrence of TB symptoms and new or recurrent clinical manifestations of TB (Usually 1-4 weeks after starting ART)

  8. Paradoxical TB-IRIS characteristics • Incidence 8 – 54% (15.7% in meta-analysis) • Onset of symptoms: Median 14 days from ART start • Focal and systemic inflammatory features • Fever, tachycardia, weight loss • Hospitalisation in up to 48% • Median duration 2-3 months • Mortality infrequent • Meta-analysis 3.2% (substantially higher if CNS IRIS) Meintjes Lancet Infect Dis 2008;8:516, Muller Lancet Infect Dis 2010;10:251, Agarwal AIDS Res Ther 2012;9:17, Meintjes Clin Infect Dis 2009;48:667, Burman IJTLD 2007;11:1282

  9. Worsening pulmonary infiltrate and cavitation due to TB-IRIS

  10. Massive psoas abscess

  11. Pericardial tamponade due to paradoxical TB-IRIS 3 weeks on ART (1 litre drained at pericardiocentesis) On TB treatment prior to ART

  12. Neurological TB-IRIS • 12% with paradoxical TB-IRIS have CNS involvement • Up to 47% of TBM patients starting ART develop IRIS • Features • Meningitis • Tuberculoma/s • Radiculomyelopathy • Occurs in patients with or without CNS TB prior to ART • Outcomes • 13% mortality and 18% loss to follow-up in one series • 25% and 75% mortality in other series • Neurological disability Pepper et al, Clin Infect Dis 2009 Marais et al, Clin Infect Dis 2012 Agarwal et al, AIDS Res Ther 2012

  13. TBM diagnosis TBM-IRIS Slide courtesy Suzaan Marais

  14. TBM-IRIS with expressive aphasia Slide courtesy Suzaan Marais

  15. TBM and PTB prior to ART TB-IRIS with enlarging mass lesion/cerebral oedema Patient died

  16. Non IRIS IRIS CSF Neutrophils and TBM-IRIS p=0.01 p<0.0001 Cells/mm3 Marais CID 2012 TBM diagnosis Day 0 ART Start Day 14 2 weeks post ART/IRIS Day 28 P=0.007

  17. Hepatic TB-IRIS is characterised by which of the following? • Severe jaundice on clinical examination • Elevation in transaminases more then 10 x upper limit of normal • Non-tender hepatomegaly • The most prominent LFT abnormality being elevation of AlkPhos and GGT.

  18. 4 months treatment for drug-sensitive pericardial TB Clinically improved, then started ART 3 weeks later presented with fever and hepatomegaly LFT: Bil 52, CBil 31, Alk Phos 1081, GGT 1468, ALT 82, AST 88 CD4 rise from 64 to 221 Biopsy AFB- and TB culture - Case courtesy of Mark Sonderup Hepatic TB-IRIS case

  19. Hepatic TB-IRIS vs DILI Hepatic TB-IRIS • RUQ pain, nausea and vomiting • Tender hepatomegaly • Cholestatic LFT derangement • +/- mild jaundice • Usually other TB-IRIS manifestations Drug-induced liver injury • Similar symptoms • Typically not hepatomegaly • Transaminitis +/- jaundice • Absence of other TB-IRIS features Patients may present with clinical picture between these two - Biopsy or treat as DILI Two conditions may co-exist

  20. Prolonged TB-IRIS • Typically suppurative lymphadenitis & abscesses • Systemically well • Tuberculomas & cerebral abscesses • TB-IRIS duration (n = 176) • Median: 70 days • IQR: 41-111 days • IRIS > 90 days: 36% Bana, unpublished

  21. Prolonged TB-IRIS: Management • Often repeated aspirations required • Avoid surgical drainage • Repeat TB culture and susceptibility testing • Corticosteroids for > 4 months questionable unless CNS involved • Experimental therapies • Thalidomide and TNF-α blockers • Consider prolonging TB treatment • How adequate is drug penetration?

  22. Key points in TB-IRIS diagnosis • Diagnosis of TB confirmed or very likely? • Improvement on TB treatment prior to ART? • Symptom onset typically 1-4 weeks on ART • Deterioration with inflammatory features of TB • Consider and exclude differential diagnoses • Exclude drug-resistant TB There is no confirmatory diagnostic test

  23. 100 TB-IRIS suspects screened using case definition KEY FINDING Undiagnosed rifampicin resistance in 10.1% of patients (95% CI 3.9-16.4%) presenting with TB-IRIS, after exclusion of known rifampicin resistance and alternative opportunistic diseases Meintjes Clin Infect Dis 2009;48:667

  24. Lymph node enlargement Differential diagnoses • Lymphoma • Kaposi’s • Castleman’s disease Consider malignancy particularly when LN remains firm • NTM IRIS • Cryptococcal IRIS

  25. Other important differential diagnoses *Consider and investigate for DR-TB in all scenarios

  26. Pathogenesis of paradoxical IRIS Recovery of pathogen-specific immune responses and T-cell activation Recovery of innate immune function Inflammatory reactions directed to antigens of opportunistic infection Pro-inflammatory cytokines and chemokines Defective immune regulatory function

  27. Prednisone for TB-IRIS: which statement is correct? • Prednisone has been shown to reduce the risk of death from TB-IRIS • Prednisone should be prescribed to prevent TB-IRIS in high risk patients • When prednisone is used to treat TB-IRIS it has been shown to have modest benefits in terms of reducing symptoms and duration of hospitalisation • It should not be used because of its side effects in HIV positive patients

  28. Rationale for steroid trial • Anecdotal reports of symptomatic response • Potential risks in patients with advanced HIV • 110 participants (55 each arm) • Life-threatening TB-IRIS was an exclusion • Open-label prednisone at physician discretion if clinical deterioration/relapse Meintjes et al, AIDS 2010;24:2381

  29. HIV-TB patients recently started ART with suspected TB-IRIS Assessed using a clinical case definition for TB-IRIS and alternative diagnoses excluded Inclusion criteria Informed consent Randomised Prednisone 1.5mg/kg/day x 2 weeks 0.75mg/kg/day x 2 weeks Identical placebo 1.5mg/kg/day x 2 weeks 0.75mg/kg/day x 2 weeks Followed for a total of 12 weeks Primary endpoint: Total number of days hospitalised + outpatients therapeutic procedures Secondary endpoints included symptom score, CXR score and steroid side effects

  30. Primary endpointCumulative number of days hospitalized and outpatienttherapeutic procedures (counted as 1 additional day), ITT analysis Significant reduction in morbidity associated with prednisone treatment

  31. Secondary endpoints • Consistent benefit, maximal in first 4 weeks, across a range of secondary outcome measures • Symptom score • Karnofsky performance score • MOS-HIV questionnaire (quality of life assessment) • Chest radiology score • C-reactive protein • 10/55 in prednisone arm relapsed after completing study drug and required re-initiation of prednisone • 4 weeks appeared to be too short for these patients

  32. Adverse events * Included BP > 140/90, oedema, hyperglycaemia, hypomania, acne, Cushingoid features, gastritis symptoms ** WHO stage 4 or invasive bacterial infection

  33. Serum IL-6: Placebo vs Prednisone (week 0, 2 and 4) Similar reductions seen in TNFα, IFNγ, IL10, IL12 and CXCL10 on prednisone Meintjes et al, AJRCCM 2012;186:369

  34. Corticosteroids for paradoxical TB-IRIS? Potential adverse effects - Kaposi’s - Infections - Metabolic Diagnostic uncertainty Symptom improvement Reduced hospitalisation ? Survival benefit in life threatening cases

  35. CASE: 49 year old HIV+ man with CD4=29, diagnosed with drug-susceptible PTB. Started ART 2 weeks after TB treatment. 2 weeks later developed recurrent TB symptoms, worsening of pulmonary infiltrate and new pleural effusion. MANAGEMENT: Antibiotic, aspiration of pleural effusion, prednisone. TB cultures of sputum and effusion were negative at TB-IRIS.

  36. Needle aspiration

  37. Major TB-IRIS risk factors • Low CD4 count • Short interval between TB treatment and ART • Disseminated TB Lawn AIDS 2007;21:335 Meintjes Lancet Infect Dis 2008;8:516 Burman IJTLD 2007;11:1282

  38. Earlier ART Deferred ART Risk of HIV disease progression Risk of IRIS MORTALITY MORTALITY When to start ART after recent diagnosis of TB? 3 recent large RCTs (SAPIT, STRIDE, CAMELIA)

  39. ART timing and primary endpoints Death p=0.006 38%  Death/AIDS p = 0.45 Death/AIDS p = 0.73

  40. ART timing and primary endpoints in patients with CD4 < 50 Death p=0.006 38%  Death/AIDS p=0.02 42%  Death/AIDS p=0.06 68%  * CAMELIA data represents all patients in trial, majority had CD4 < 50 (median CD4 =25)

  41. SAPiT IRIS incidence(IRIS cases/100 person years) Naidoo, Annals Intern Med 2012

  42. Implications • In patients with CD4 < 50: start ART at 2 weeks • Even though more likely to develop IRIS with early ART • Benefit most from early ART in terms of survival and preventing AIDS events • In patients with CD4 > 50 • ART can be deferred ~ 8 weeks to reduce risk of IRIS • Except patients with severe clinical disease, organ system dysfunction, low performance score, low BMI or Hb as these are associated with higher mortality

  43. Preventing TB-IRIS in high-risk patients: Randomized placebo-controlled trial of prednisone(Pred-ART trial) Graeme Meintjes, Lut Lynen, Robert J Wilkinson, Gary Maartens, Bob Colebunders, Charlotte Schutz, Shaheed Mattee, Funeka Bango, Jan Kuehne, Zuhoor Dadeker, Christiana Noestlinger, Harry van Loen, Joris Menten, Jozefien Buyze, Edwin Wouters, Bill Burman, Raffaella Ravinetto, Friedrich Thienemann, Liz Blumenthal, Cari Stek, Amanda Jackson, Lorraine Swanepoel, Rene Goliath, Amy Nair

  44. TB TREATMENT (and CO-TRIMOXAZOLE) ART ART started within 30 days of TB treatment Start ART + 4 weeks prednisone Follow-up for 12 weeks (Visits at weeks 1,2,4,8 and 12) HIV-infected ART-naive CD4 < 100 TB diagnosed n = 240 Informed consent Randomised 1:1 Start ART + 4 weeks placebo Follow-up for 12 weeks (Visits at weeks 1,2,4,8 and 12) Dose of prednisone/placebo: 40mg/day x 2 weeks then 20mg/day x 2 weeks Primary endpoint: Development of paradoxical TB-IRIS ClinicalTrials.gov NCT01924286

  45. Paradoxical TB-IRIS only occurs in ART naïve patients starting first line ART. TRUE or FALSE?

  46. Acknowledgements • Robert Wilkinson • Gary Maartens • Katalin Wilkinson • Suzaan Marais • Charlotte Schutz • TasnimBana • Maia Lesosky • MolebogengRangaka • Chelsea Morroni • ToluOni • Dominique Pepper • Kevin Rebe • Rene Goliath • Helen van der Plas • Marc Mendelson • Priscilla Mouton • Bob Colebunders • AnaliConesaBotella • Raylene Titus • KeiraSkolimowska • Kerryn Matthews • Rebecca Tadokera • Mark Sonderup

  47. Pred-ART funders

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