The Timing of ART initiation in TB HIV co-infected patients: Impact on IRIS severity
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Transcript of The Timing of ART initiation in TB HIV co-infected patients: Impact on IRIS severity
The Timing of ART initiation in TB HIV co-infected patients: Impact on IRIS severity
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention 20 July 2011
Kogieleum Naidoo; on behalf of Nonhlanhla Yende-Zuma; Nesri Padayatachi; Niraksha Jithoo; Gonasagrie Nair; Sheila Bamber; Santhana
Gengiah; Wafaa El-Sadr; Gerald Friedland; Salim Abdool Karim
Evidence based guidelines now available for Integrated management of TB and HIV
Unanswered questions on IRIS associated morbidity remains an obstacle to widespread integration of TB and HIV care
TB HIV Treatment Integration
Muller M, Wandel S, Colebunders R, Attia S, Furrer H, Egger M. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis 2010;10:251-61.
Lawn SD, Bekker LG, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005;5:361-73.
Is IRIS infrequent or insignificant?
Purpose of study:
To determine IRIS incidence, severity, risk factors, and outcome in a TB-HIV co-infected population randomized to ART initiation during or after TB therapy - sub-study of the CAPRISA 003 SAPiT Trial.
Design: Open-label 3-arm randomized controlled trial:• Arm 1- ART within 4 weeks of starting tuberculosis treatment• Arm 2 - ART within 4 weeks of completing the intensive phase
of tuberculosis treatment• Arm 3 - ART initiated after TB treatment completed
Sample size:
642 HIV-TB co-infected patients
Study Population:
Ambulatory TB smear +ve, HIV +ve (CD4 count < 500 cells/mm3) and on standard TB treatment regimens.
• Cotrimoxazole prophylaxis: provided to all patients• Once daily ART: ddI + 3TC + efavirenz –integrated with TB Rx
• Protocol Definition of IRIS: New onset or worsening symptoms, signs or radiographic features temporally related to ART treatment initiation; together with a CD4+ increase, viral load decrease and upon exclusion of confirmed TB or ART treatment failure, toxicity, non-compliance, or new concurrent opportunistic infections.
~ in accordance with other published case definitions~Cases were retrospectively assessed & found to have
met the 2008 IRIS definition(INSHI) of one major or two minor clinical criteria
IRIS Evaluation
• IRIS evaluated using standardized set of criteria at every clinical visit
• Diagnosis of IRIS verified by an independent trained clinician
• IRIS severity measured by number of IRIS associated: deaths; life-threatening events; hospitalizations and duration of hospitalization events warranting steroid use; and IRIS events that did not resolve or resolved with sequelae at
study exit
SAPiT trial: Randomization, and follow-up of study participants with
suspected IRIS
642 Randomized
IRIS OutcomesResolved=18
Initiated ART164 (76.3%)
18 IRIS Events
215 late Integrated-treatment arm
214 early Integrated-treatment arm
Initiated ART198 (92.5%)
43 IRIS Events
IRIS OutcomesDied=2Resolved=38Not resolved=1Resolved with sequelae=2
213 sequential treatment arm
Initiated ART139 (65.3%)
19 IRIS Events
IRIS OutcomesResolved=16Not resolved=1Resolved with sequelae=1Unknown=1
Variable Developed IRIS (N=80)
Did not develop IRIS (N=562) p-value
Age in years (mean ± SD) 34.3±6.4 34.2±8.5 0.97
Males, % (n) 49 (39) 280 (50) 0.91
BMI (kg/h2) <18.5, % (n) 13 (10) 13 (72) 1.00
CD4 cells/mm3, median (IQR) 91 (36-177) 155 (78-261) <0.0001Log10 HIV RNA, copies/ml, mean± SD 5.5±0.7 5.0±0.9 <0.0001
Baseline characteristics of study participants
Incidence Rate / 100 P-Yr p values
Arm Early Integ Late Integ Sequential Early vs late Early vs sequential
Late vs sequential
All patients
19.5 7.5 8.1 <0.001 <0.001 0.86
IRIS Incidence stratified by CD4+ cell count (cells/mm3)
<50 45.5 9.7 19.7 0.004 0.05 0.19
≥50 15.3 7.1 5.6 0.01 0.003 0.53
IRIS incidence in each study arm in the SAPiT trial
Kaplan-Meier estimates of cumulative probability of IRIS in the 3 SAPIT treatment arms
Months after randomization
0 3 6 9 12 15 18
Early integrated- treatment arm
214 40/156* 42/145 42/141 42/138 43/131 43/123
Late integrated- treatment arm
215 6/188 14/167 16/153 17/143 17/139 18/130
Sequential- treatment arm
213 0/196 1/179 6/152 14/130 15/121 19/114
*number of patients with IRIS/number of patients in follow up
Early integrated- treatment arm
Late integrated- treatment arm
Sequential- treatment arm
Prob
abili
ty o
f IR
ISEarly Integrated vs Sequential arm p < 0.001
Early Integrated vs late Integrated arm p < 0.001
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
Severity of immune reconstitution inflammatory syndrome
Study arm Early- integrated am
Late-integrated arm
Sequential arm
p-value
Number of patients with IRIS
43 18 19
Patients hospitalized for IRIS, %(n)
41.9 (18) 22.2 (4) 5.3(1) 0.01
Patients who received steroids for IRIS,% (n)
9.3 (4) 5.6 (1) 15.8 (3) 0.69
IRIS associated deaths, % (n)
4.7(2) 0 0 1.00
When is IRIS most severe?
Respiratory symptoms
Pulmonary infiltrates
Hepatosplenomegaly
Skin lesions and herpes zoster
Cervical lymphadenopathy
Neurological signs/ symptoms
Thoracic lymphadenopathy
Pleural effusions
Abdominal pain
Fever
0 10 20 30 40 50 60 70 80
Series1Early integrated-treatmentLate integrated-treatmentSequential-treatment
Proportion of patients (n=80)
Clinical signs, symptoms and radiographic features of IRIS
Conclusion
• Initiation of ART early during TB treatment > 2-fold higher risk of IRIS in study patients, however in patients with
CD4< 50, there was a five- fold higher IRIS risk
greater proportion of IRIS being severe cases
More frequent hospitalization• Low IRIS associated mortality• Low rate of steroid use• IRIS occurred at all CD4 strata• Respiratory signs and symptoms accounted for most
clinical presentations of IRIS
Recommendation
Patients with CD4+ counts <50 cells/mm3: Early ART initiation as soon as possible after TB treatment
initiation – with close clinical observation for IRIS
Patients with CD4 counts ≥ 50 cells/mm3: ART initiation can be deferred to start of the continuation phase
of TB treatment to avoid IRIS associated morbidity
Decision on early or late initiation: use clinical judgment, consider capacity to manage IRIS & toxicities
Acknowledgements• The patients in the study• President’s Emergency Plan for AIDS Relief (PEPfAR)• Global Fund & Enhancing Care Initiative• eThekwini Metro & staff of Prince Cyril Zulu clinic• CAPRISA SAPiT Team & Community Support Group• The SAPiT Safety Monitoring Committee• KwaZulu-Natal Provincial Department of Health• KwaZulu-Natal, Yale & Columbia Universities• CAPRISA was established by the Comprehensive
International Program of Research on AIDS of the US National Institutes of Health (grant# AI51794)