Tuberculosis Immune Reconstitution Inflammatory Syndrome in A5221 STRIDE: Timing, Severity and Implications for HIV-TB programs

HIV/AIDS Division, San Francisco General Hospital, University of California, San Francisco Center for Biostatistics in AIDS Research, Harvard School of Public Health College of Medicine, Blantyre, Malawi Center for Biostatistics in AIDS Research, Harvard School of Public Health Faculty of Heath Sciences, University of the Witwatersrand Antiviral Research Center, University of California, San Diego Center for Biostatistics in AIDS Research, Harvard School of Public Health Division of Infectious Diseases, University of Nebraska Medical Center, Omaha, NE Faculty of Health Sciences, University of the Witwatersrand HIV/AIDS Division, San Francisco General Hospital, University of California, San Francisco College of Medicine, Blantyre, Malawi, Adult AIDS Clinical Trials Group A5221 Study Team.
JAIDS Journal of Acquired Immune Deficiency Syndromes (Impact Factor: 4.56). 11/2013; 65(4). DOI: 10.1097/QAI.0000000000000030
Source: PubMed


Earlier initiation of antiretroviral therapy (ART) in HIV-tuberculosis(TB) is associated with increased immune reconstitution inflammatory syndrome (IRIS). The severity, frequency and complications of TB IRIS were evaluated in A5221, a randomized trial of earlier ART (within 2 weeks after TB treatment initiation) vs. later ART (8-12 weeks after TB treatment) in HIV-infected patients starting TB treatment.
In 806 participants, TB IRIS was defined using published clinical criteria. Cases were classified as severe(hospitalization/death), moderate(corticosteroid use/invasive procedure), or mild(no hospitalization/procedures/steroids). Fisher's Exact, Wilcoxon, and log rank tests were used for comparisons.
TB IRIS occurred in 61 (7.6%) patients: 10.4% in earlier vs. 4.7% later ART, 11.5% with CD4 < 50 vs. 5.4% CD4 ≥ 50 cells/mm. The CD4/ART arm interaction was significant, p=0.014, with 44.3% of TB IRIS occurring with CD4 < 50 and earlier ART. TB IRIS occurred sooner with earlier vs. later ART initiation, at a median of 29 vs. 82 days after TB treatment initiation (p<0.001). IRIS manifestations included lymphadenopathy(59.0%), constitutional symptoms(54.1%), and radiographic changes(41.0%); CNS TB IRIS was uncommon (6.6%). TB IRIS was mild in 27.9%, moderate in 41.0%, and severe in 31.1%. No TB IRIS-associated deaths occurred. IRIS management required ≥ 1 invasive procedures in 34.4%, hospitalization in 31.1% and corticosteroids in 54.1%.
TB IRIS was more frequent with earlier ART initiation and CD4 <50 cells/mm. As ART is implemented earlier in HIV-TB co-infection, programs will require the diagnostic capabilities, clinical resources and training necessary to manage TB IRIS.

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Available from: Mulinda Nyirenda, Dec 10, 2014
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    • "The benefit of early HAART (within 30 days) is contingent on increased risk and severity of IRIS accompanied with higher re-hospitalization rate and longer TB treatment duration. We have similar observations with previous studies [8,10,32]. In addition, we found several cases had prolonged hospitalization because of persistent positive sputum smear. "
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    ABSTRACT: Background Optimal timing for initiating highly active antiretroviral therapy (HAART) in HIV-TB coinfected patients is challenging for clinicians. We aim to evaluate the impact of different timing of HAART initiation on TB outcome of HIV-infected adults in Taiwan. Methods A population-based retrospective cohort study was conducted through linking the HIV and TB registries of Taiwan Centers for Disease Control (CDC) during 1997 to 2006. Clinical data of HIV-TB co-infected patients, including the presence of immune reconstitution inflammatory syndrome (IRIS), was collected through medical records review. The outcome of interest was all-cause mortality within 1 year following TB diagnosis. The Cox proportional hazard model was used to explore the probability of death and IRIS after TB diagnosis by adjusting for confounding factors and factors of interest. The probability of survival and TB IRIS were calculated by the Kaplan-Meier method and compared between different HAART initiation timing groups by the log-rank test. Results There were 229 HIV-TB co-infected patients included for analysis and 60 cases (26.2%) died within one year. Besides decreasing age and increasing CD4 lymphocyte count, having started HAART during TB treatment was significantly associated with better survival (adjusted Hazard Ratio was 0.11, 95% CI 0.06–0.21). As to the timing of HAART initiation, there was only non-significant benefit on survival among cases initiating HAART within 15 days, at 16–30 days and at 31–60 days of TB treatment than initiating after 60 days. Cases with HAART initiated after 30 days had lower risk in developing IRIS than cases with HAART initiated earlier. Cases with IRIS had significantly higher rate of re-hospitalization (49% vs. 4%, p < 0.001) and prolonged hospitalization (28 days vs. 18.5 days, p < 0.01). Conclusion The present study found that starting HAART during TB treatment is associated with better one-year survival, although earlier initiation within 60 days of TB treatment did not show statistical differences in survival than later initiation. Initiation of HAART within 30 days appeared to increase the risk of IRIS. Deferring HAART to 31–60 days of TB treatment might be optimal after considering the risks and benefits.
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