1. 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

2.  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

3. 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.

4. 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?

5. 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/mm 3 ) and on standard TB treatment regimens. Cotrimoxazole prophylaxis: provided to all patients Once daily ART: ddI + 3TC + efavirenz –integrated with TB Rx

6. 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

7. 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

8. SAPiT trial: Randomization, and follow-up of study participants with suspected IRIS 642 Randomized IRIS Outcomes Resolved=18 IRIS Outcomes Resolved=18 Initiated ART 164 (76.3%) Initiated ART 164 (76.3%) 18 IRIS Events 215 late Integrated- treatment arm 214 early Integrated- treatment arm Initiated ART 198 (92.5%) Initiated ART 198 (92.5%) 43 IRIS Events IRIS Outcomes Died=2 Resolved=38 Not resolved=1 Resolved with sequelae=2 IRIS Outcomes Died=2 Resolved=38 Not resolved=1 Resolved with sequelae=2 213 sequential treatment arm Initiated ART 139 (65.3%) Initiated ART 139 (65.3%) 19 IRIS Events IRIS Outcomes Resolved=16 Not resolved=1 Resolved with sequelae=1 Unknown=1 IRIS Outcomes Resolved=16 Not resolved=1 Resolved with sequelae=1 Unknown=1

9. Variable Developed IRIS (N=80) Did not develop IRIS (N=562) p-value Age in years (mean ± SD) 34.3±6.434.2±8.50.97 Males, % (n)49 (39)280 (50)0.91 BMI (kg/h 2 ) <18.5, % (n)13 (10)13 (72)1.00 CD4 cells/mm 3, median (IQR)91 (36-177)155 (78-261)<0.0001 Log 10 HIV RNA, copies/ml, mean± SD5.5±0.75.0±0.9<0.0001 Baseline characteristics of study participants

10. Incidence Rate / 100 P-Yr p values ArmEarly IntegLate IntegSequentialEarly vs late Early vs sequential Late vs sequential All patients 19.57.58.1<0.001 0.86 IRIS Incidence stratified by CD4+ cell count (cells/mm 3 ) <5045.59.719.70.0040.050.19 ≥5015.37.15.60.010.0030.53 IRIS incidence in each study arm in the SAPiT trial

11. Kaplan-Meier estimates of cumulative probability of IRIS in the 3 SAPIT treatment arms Months after randomization 0369121518 Early integrated- treatment arm 21440/156*42/14542/14142/13843/13143/123 Late integrated- treatment arm 2156/18814/16716/15317/14317/13918/130 Sequential- treatment arm 2130/1961/1796/15214/13015/12119/114 *number of patients with IRIS/number of patients in follow up Early integrated- treatment arm Late integrated- treatment arm Sequential- treatment arm Probability of IRIS Early 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

12. Severity of immune reconstitution inflammatory syndrome Study arm Early- integrated am Late-integrated arm Sequential arm p- value Number of patients with IRIS 431819 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)001.00 When is IRIS most severe?

13. Clinical signs, symptoms and radiographic features of IRIS

14. 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

15. Recommendation  Patients with CD4+ counts <50 cells/mm 3 :  Early ART initiation as soon as possible after TB treatment initiation – with close clinical observation for IRIS  Patients with CD4 counts ≥ 50 cells/mm 3 :  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

16. 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)