Tuberculosis-associated immune reconstitution inflammatory syndrome

(TB-IRIS)

Graeme MeintjesUniversity of Cape Town

Imperial College London

Webinar25 Nov 2013

ART

Viral suppression

(CD4 rise)

Restoration of pathogen-specific immunity

Regression or prevention of opportunistic infections

Inflammatory reactions days tomonths after starting ART = IRIS

+ -

IRIS = Immune Reconstitution Inflammatory SyndromeIRD = 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

Patients on TB treatment

Patients not onTB treatment

ParadoxicalTB-IRIS

ART

ART-associated TBART

Unmasking TB-IRIS

OVERVIEW

• Clinical presentations– Neurological TB-IRIS– Hepatic TB-IRIS– Prolonged TB-IRIS

• Diagnosis• Corticosteroids for treatment• ART timing• Prevention trial

What is the typical time of onset of paradoxical TB-IRIS after ART start?

1. 3-10 days2. 1-4 weeks3. 4-8 weeks4. Around 3 months

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)

Paradoxical TB-IRIS

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

Massive psoas abscess

Pericardial tamponade due to paradoxical TB-IRIS

On TB treatment prior to ART 3 weeks on ART(1 litre drained at pericardiocentesis)

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 2009Marais et al, Clin Infect Dis 2012Agarwal et al, AIDS Res Ther 2012

TBM diagnosis TBM-IRIS

Slide courtesy Suzaan Marais

TBM-IRIS with expressive aphasia

Slide courtesy Suzaan Marais

TBM and PTB prior to ARTTB-IRIS with enlarging mass lesion/cerebral oedema

Patient died

CSF Neutrophils and TBM-IRIS

TBM diagnosisDay 0

ART StartDay 14

2 weeks post ART/IRISDay 28

Non IRIS

Cel

ls/m

m3

IRIS

p=0.01 p<0.0001

MaraisCID 2012

Hepatic TB-IRIS is characterised by which of the following?

1.Severe jaundice on clinical examination2.Elevation in transaminases more then 10 x upper limit of normal3.Non-tender hepatomegaly4.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

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

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?

Key points in TB-IRIS diagnosis

1. Diagnosis of TB confirmed or very likely?

2. Improvement on TB treatment prior to ART?

3. Symptom onset typically 1-4 weeks on ART

4. Deterioration with inflammatory features of TB

5. Consider and exclude differential diagnoses

6. Exclude drug-resistant TB

There is no confirmatory diagnostic test

100 TB-IRIS suspectsscreened usingcase 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

Other important differential diagnosesManifestation Differential diagnoses

Pulmonary infiltrate Bacterial pneumoniaPCPKaposi’s sarcoma

Pleural effusion Bacterial empyemaKaposi’s sarcoma

Meningitis BacterialCryptococcal

Space-occupying lesion ToxoplasmosisCryptococcomaPrimary CNS lymphoma

Fever with general deterioration Bacterial sepsisNTMKaposi’s or lymphoma

*Consider and investigate for DR-TB in all scenarios

Pathogenesis of paradoxical IRIS

Inflammatory reactions directed to antigens of opportunistic infection

Recovery of pathogen-specific immune responses and T-cell activation

Pro-inflammatory cytokines and chemokines

Defective immuneregulatory function

Recovery of innate immunefunction

Prednisone for TB-IRIS: which statement is correct?

1. Prednisone has been shown to reduce the risk of death from TB-IRIS

2. Prednisone should be prescribed to prevent TB-IRIS in high risk patients

3. 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

4. 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

Meintjes et al, AIDS 2010;24:2381

HIV-TB patients recentlystarted ART with

suspected TB-IRIS

Assessed using a clinicalcase definition for TB-IRISand alternative diagnoses

excluded

Inclusion criteriaInformed consent

Randomised

Prednisone1.5mg/kg/day x 2 weeks0.75mg/kg/day x 2 weeks

Identical placebo1.5mg/kg/day x 2 weeks0.75mg/kg/day x 2 weeks

Followed for a total of 12 weeksPrimary endpoint: Total number of days hospitalised + outpatients therapeutic proceduresSecondary endpoints included symptom score, CXR score and steroid side effects

Primary endpointCumulative number of days hospitalized and outpatient

therapeutic procedures (counted as 1 additional day), ITT analysis

Placebo

arm

N = 55

Prednisone

arm

N = 55

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

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

Adverse events

Placebo

arm

Prednisone

arm

P-value

Death on study 2 (4%) 3 (5%) 0.65

Corticosteroid side effects while on study drug*

3 (5%) 8 (15%) 0.11

Infections while on study drug

17 (31%) 27 (49%) 0.05

Severe infections** 4 (7%) 2 (4%) 0.40

* 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)

Meintjes et al, AJRCCM 2012;186:369

Similar reductions seen in TNFα, IFNγ, IL10, IL12 and CXCL10 on prednisone

Corticosteroids for paradoxical TB-IRIS?

Symptom improvementReduced hospitalisation? Survival benefit in life threatening cases

Potential adverse effects- Kaposi’s- Infections- Metabolic

Diagnostic uncertainty

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;21:335Meintjes Lancet Infect Dis 2008;8:516Burman IJTLD 2007;11:1282

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)

EarlierART

DeferredART

ART timing and primary endpoints

Death/AIDSp = 0.45 Death/AIDS

p = 0.73

Deathp=0.00638%

ART timing and primary endpoints in patients with CD4 < 50

Deathp=0.00638%

Death/AIDSp=0.0242%

Death/AIDSp=0.0668%

* 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

HIV-infectedART-naiveCD4 < 100TB diagnosed

n = 240

Informed consentRandomised 1:1

Start ART+

4 weeks prednisone

Start ART+

4 weeks placebo

Follow-up for 12 weeks(Visits at weeks 1,2,4,8 and 12)

Follow-up for 12 weeks(Visits at weeks 1,2,4,8 and 12)

TB TREATMENT (and CO-TRIMOXAZOLE)TB TREATMENT (and CO-TRIMOXAZOLE)

ARTARTART started within 30 days of TB treatment

Dose of prednisone/placebo: 40mg/day x 2 weeks then 20mg/day x 2 weeksPrimary 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

Pred-ART funders