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
+
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
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Mycobacteria
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Cryptococcus
Histoplasmosis
PCP
Dermatophytes
Candida
Aspergillus
Penicillium
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Hepatitis B and C
HSV 1 and 2
HZV
CMV
JC virus
BK virus
Molluscum
Warts
Parvovirus B19
HIV dementia
Acne and folliculitis
Auto-immune and inflammatory conditions
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Bartonella
Other skin conditions
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Schistosoma
Strongyloides
Bacteria
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Toxoplasmosis
Leishmaniasis
Microsporidia
Cryptosporidia
Helminths
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Viruses
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Protozoans
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Fungi
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TB
MAC
Leprosy
BCG
Other NTM
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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
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Kaposi’s sarcoma, lymphoma
ART
Patients on
TB treatment
ART
Patients not on
TB treatment
Paradoxical
TB-IRIS
ART-associated TB
Unmasking TB-IRIS
OVERVIEW
• Clinical presentations
– Neurological TB-IRIS
– Hepatic TB-IRIS
– Prolonged TB-IRIS
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Diagnosis
Corticosteroids for treatment
ART timing
Prevention trial
What is the typical time of onset of
paradoxical TB-IRIS after ART start?
1.
2.
3.
4.
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
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
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 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
TBM and PTB prior to ART
TB-IRIS with enlarging mass lesion/cerebral oedema
Patient died
Non
IRIS
CSF Neutrophils and TBM-IRIS
650
p=0.01
p<0.0001
60
60
Cells/mm3
IRIS
40
20
Marais
CID 2012
0
TBM diagnosis
Day 0
ART Start
Day 14
2 weeks post ART/IRIS
Day 28
Hepatic TB-IRIS is characterised by
which of the following?
1. Severe jaundice on clinical examination
2. Elevation in transaminases more then 10 x
upper limit of normal
3. Non-tender hepatomegaly
4. The most prominent LFT abnormality being
elevation of Alk Phos and GGT.
Hepatic TB-IRIS case
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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
Drug-induced liver injury
• RUQ pain, nausea and
vomiting
• Tender hepatomegaly
• Cholestatic LFT derangement
• +/- mild jaundice
• Usually other TB-IRIS
manifestations
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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
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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.
2.
3.
4.
5.
6.
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 TBIRIS, 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 diagnoses
Manifestation
Differential diagnoses
Pulmonary infiltrate
Bacterial pneumonia
PCP
Kaposi’s sarcoma
Pleural effusion
Bacterial empyema
Kaposi’s sarcoma
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?
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 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
arm
N = 55
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
2
0.40
(7%)
(4%)
* 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)
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
CASE: 49 year old HIV+ man with CD4=29, diagnosed with drugsusceptible 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
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)
50
40
30
ART within 4 weeks
ART 8-12 weeks
20
10
0
All pa ents
CD4 < 50
CD4 ≥ 50
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
TB TREATMENT (and CO-TRIMOXAZOLE)
ART started within 30 days of TB treatment
HIV-infected
ART-naive
CD4 < 100
TB diagnosed
ART
Start ART
+
4 weeks prednisone
Follow-up for 12 weeks
(Visits at weeks 1,2,4,8 and 12)
Start ART
+
4 weeks placebo
Follow-up for 12 weeks
(Visits at weeks 1,2,4,8 and 12)
Informed consent
Randomised 1:1
n = 240
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
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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