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

Restoration of pathogen-specific immunity 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

Wide range of IRIS conditions described 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

ART Paradoxical Patients on TB-IRIS TB treatment ART ART-associated TB Patients not on TB treatment TB-IRIS is characterised by clinical deterioration during ART thought to result from an immunopathological reaction to MTB antigen as MTB-specific immune reposes improve. It may manifest in one of two forms: Patients on TB treatment experience a paradoxical reaction after starting ART. Among patients not on TB treatment when they start ART TB incidence rates remain high especially during the first months of ART in RLS. A subset who manifest with TB that has a particularly exaggerated inflammatory presentation that in the first 3 months of ART are regarded as having unmasking TB-IRIS Unmasking TB-IRIS

OVERVIEW Clinical presentations Diagnosis Neurological TB-IRIS Hepatic TB-IRIS Prolonged TB-IRIS Diagnosis Corticosteroids for treatment ART timing Prevention trial Focus clinical, not pathogenesis

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

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

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

Worsening pulmonary infiltrate and cavitation due to TB-IRIS CXR 3 – one week later Worsening pulmonary infiltrate and cavitation due to TB-IRIS

Massive psoas abscess

(1 litre drained at pericardiocentesis) Pericardial tamponade due to paradoxical TB-IRIS TITLE: LIFE THREATENING COMPLICATIONS ADD MASSIVE TUBERCULOMA CASE SPLENIC RUPTURE 3 weeks on ART (1 litre drained at pericardiocentesis) On TB treatment prior to ART

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 75% no neuroTB prior to ART Pepper Pepper et al, Clin Infect Dis 2009 Marais et al, Clin Infect Dis 2012 Agarwal et al, AIDS Res Ther 2012

TBM diagnosis TBM-IRIS Slide courtesy Suzaan Marais

TBM-IRIS with expressive aphasia Slide courtesy Suzaan Marais

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

CSF Neutrophils and TBM-IRIS Non 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

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 Alk Phos and GGT.

Hepatic TB-IRIS case 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 Low power - several well formed granulomas Medium power - large well formed granuloma High power - Multinucleated epitheloid giant cell with surrounding lcytes, plasma cells and eos

Hepatic TB-IRIS vs DILI 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

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

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? For sterilisation

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

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

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

Other important differential diagnoses Manifestation Differential diagnoses Pulmonary infiltrate Bacterial pneumonia PCP Kaposi’s sarcoma Pleural effusion Bacterial empyema Meningitis Bacterial Cryptococcal Space-occupying lesion Toxoplasmosis Cryptococcoma Primary CNS lymphoma Fever with general deterioration Bacterial sepsis NTM Kaposi’s or lymphoma *Consider and investigate for DR-TB in all scenarios

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

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

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 Given this equipoise we conducted the first treatment in TB-IRIS… We conducted a randomised placebo-controlled trial of prednisone for treating paradoxical TB-IRIS and this was presented at CROI earlier this year. 55 patients were enrolled to each of the two arms - prednisone and placebo. Patients with immediately life threatening TB-IRIS for example neurological involvement were excluded and treated with prednisone Study drug was given for 4 weeks, initially at 1.5 mg/kg/d then half that dose Patients who deteriorated significantly on study drug or relapsed after completing study drug could be switched to open label at physician discretion. Meintjes et al, AIDS 2010;24:2381

Prednisone 1.5mg/kg/day x 2 weeks 0.75mg/kg/day x 2 weeks 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

Primary endpoint Cumulative number of days hospitalized and outpatient therapeutic procedures (counted as 1 additional day), ITT analysis Placebo arm N = 55 Prednisone P-value Total days hospitalized 463 282 - Total number outpatient procedures 28 24 Cumulative primary endpoint (median, IQR) 3 (0-9) 0 (0-3) 0.04 The predefined primary endpoint was a combined endpoint made up of days hospitalisation (463 days in the placebo arm vs 282 in the prednisone arm) and outpatients procedures (31 in the placebo ve 27 in the prednisone arm). Analysis was by intention to treat Counting each outpatient procedure as an additional hospital day (an arbitrarily value we had assigned a priori) there were a median 3 days in the placebo arm and 0 in the prednisone arm. This difference reached statistical significance with a p-value of 0.04. Significant reduction in morbidity associated with prednisone treatment

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 A consistent benefit maximal in the first 4 weeks was also demonstrated across a range of secondary outcome measures: LIST

Adverse events Placebo arm Prednisone P-value Death on study 2 (4%) 2 (4%) 3 (5%) 0.65 Corticosteroid side effects while on study drug* 8 (15%) 0.11 Infections while on study drug 17 (31%) 27 (49%) 0.05 Severe infections** 4 (7%) 0.40 In terms of adverse events, there was no difference in mortality,. Events that could be attributed to steroid side effects such as hypertension, oedema, hyperglyceamia, hypomania and Cushingoid features occurred in similar numbers in both arms. If only steroid side effects that occurred while on study drug are counted there were 3 in the placebo arm and 8 in the prednsione arm but this was not significantlyy different. We analysed infections separately and the number of all infections and severe infections were similar between the arms. Severe infections were classifies as new WHO stage 4 or invasive bacterial infections. There were no cases of Kaposi’s sarcoma * Included BP > 140/90, oedema, hyperglycaemia, hypomania, acne, Cushingoid features, gastritis symptoms ** WHO stage 4 or invasive bacterial infection

Serum IL-6: Placebo vs Prednisone (week 0, 2 and 4) Moving onto the luminex experiments. We found a significant decrease in serum concentrations of interleukin 6 in prednisone-treated participants after correcting for multiple comparisons at both week 2 and week 4 compared with baseline. The reductions in placebo-treated participants were not significant. This is consistent with our finding of a rapid CRP reduction in prednisone treated participants, as IL-6 is the major stimulus of CRP production. This table summarises the luminex findings for all 12 of the cytokines/chemokines that were assayed. Median values are presented by treatment group and time point. After correcting for multiple comparisons significant reductions in TNF alpha, IL12, IL6, IL10 and the chemokine IP10 (also known as CXCL10) were demonstrated at week 2 and week 4 in those on prednisone. For interferon gamma a significant reduction in serum concentrations was seen at week 4 but not 2 in those on prednisone. For all of these cytokines no significant reduction in serum concentrations for those on placebo were seen. For IL-8 and the chemokines MIP 1 a and B no reductions in either treatment group were seen IL2, IL1B and GMCSF serum concentraions were undetectable in most participants. Similar reductions seen in TNFα, IFNγ, IL10, IL12 and CXCL10 on prednisone Meintjes et al, AJRCCM 2012;186:369

Corticosteroids for paradoxical TB-IRIS? Symptom improvement Reduced hospitalisation ? Survival benefit in life threatening cases Potential adverse effects - Kaposi’s - Infections - Metabolic Diagnostic uncertainty Thus we demonstrated that prednisone reduced hospitalisation and improved symptoms, relatively modest benefits. We did not demonstrate a mortality benefit but but one should remember that we excluded patients with life threatening TB-IRIS and switched patients with life threatening deterioration to open label prednisone. Thus it is also possible that there might be a survival benefit in patients with very severe form of TB-IRIS but this has not been studied. This is clearly not the final word on corticosteroids for IRIS. In making the decision regarding using steroids clinicains also need to weigh up the potential side effects, there was an excess of mild infections in our study, may be greater risks in other settings for instance where strongyloides is endemic. But more importantly in settings where diagnostic capability is limited more harm than good could be done by prescribing corticosteroids to patients who do not have TB-IRIS but another OI or have undiagnosed MDR.

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.

Needle aspiration

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

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

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

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)

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

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

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 Others?

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

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

Acknowledgements Robert Wilkinson Gary Maartens Katalin Wilkinson Suzaan Marais Charlotte Schutz Tasnim Bana Maia Lesosky Molebogeng Rangaka Chelsea Morroni Tolu Oni Dominique Pepper Kevin Rebe Rene Goliath Helen van der Plas Marc Mendelson Priscilla Mouton Bob Colebunders Anali Conesa Botella Raylene Titus Keira Skolimowska Kerryn Matthews Rebecca Tadokera Mark Sonderup Finally I wish to acknowledge other investigators who were not listed on my first slide and our funders. Thank you.

Pred-ART funders