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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.

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The Timing of ART initiation in TB HIV co-infected patients: Impact on IRIS severity

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  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. TB HIV Treatment Integration • 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

  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. Is IRIS infrequent or insignificant? 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.

  5. 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

  6. 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

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

  8. Baseline characteristics of study participants

  9. IRIS incidence in each study arm in the SAPiT trial

  10. Kaplan-Meier estimates of cumulative probability of IRIS in the 3 SAPIT treatment arms 0.35 Early Integrated vs Sequential arm p < 0.001 0.30 Probability of IRIS 0.25 Early integrated- treatment arm 0.20 Early Integrated vs late Integrated arm p < 0.001 0.15 Late integrated- treatment arm 0.10 Sequential- treatment arm 0.05 0.00 *number of patients with IRIS/number of patients in follow up

  11. When is IRIS most severe?

  12. Clinical signs, symptoms and radiographic features of IRIS

  13. 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

  14. 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

  15. 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)

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