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"Use of integrase inhibitors is an independent risk factor for immune reconstitution inflammatory syndrome (IRIS) in HIV-1 late presenters: an ATHENA cohort study"
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Raltegravir But Not DTG or EVG May Pose IRIS Risk in Late Presenters
16th European AIDS Conference, October 25-27, 2017. Milan
Mark Mascolini
People starting raltegravir (RAL) with a CD4 count below 200 and an opportunistic infection in the Dutch ATENA cohort ran a tripled risk of immune reconstitution inflammatory syndrome (IRIS) [2]. Beginning therapy with dolutegravir (DTG) or elvitegravir (EVG) posed no IRIS risk.
Starting an integrase inhibitor results in rapid viral load drops and quick CD4 gains--factors linked to development of IRIS, which the researchers defined as "an excessive, pathological inflammatory response against (antigens of) opportunistic infections." Late presenters--people starting antiretrovirals with a sub-200 CD4 count or an active opportunistic infection--run an especially high risk of IRIS. Whether starting an integrase inhibitor heightens IRIS risk remains uncertain because phase 3 studies of these drugs included few late presenters.
ATHENA investigators conducted this retrospective study to test the hypothesis that starting an integrase inhibitor is an independent IRIS risk factor in late presenters. Cohort members were eligible for the analysis if they began antiretroviral therapy after March 2009 with a CD4 count below 200 AND an opportunistic infection before or after starting treatment AND/OR corticosteroid use within 12 months of starting treatment AND/OR died within 12 months. Follow-up continued until a person died, dropped out of care, or switched their first regimen. The researchers defined IRIS in one of two ways--by criteria proposed by Australian researchers (French et al) [2] or by the clinician noting IRIS. The researchers used adjusted logistic regression to identify independent IRIS predictors.
The analysis included 155 people starting an integrase inhibitor and 517 starting a regimen without an integrase inhibitor. Median pretreatment viral load was high in both groups (5.5 log10 copies, about 316,000 copies) and median starting CD4 counts were in the 30s in both group. IRIS incidence was higher in people starting an integrase inhibitor than in the comparison group by the French definition (17.0% versus 9.3%, odds ratio [OR] 2.06, 95% confidence interval [CI] 1.24 to 3.43, P = 0.0083) or the French definition plus clinical judgment (30.3% versus 18.0%, OR 1.96, 95% CI 1.30 to 2.95, P = 0.0016).
When the researchers looked at IRIS risk with individual integrase inhibitors they found a tripled risk with RAL in an adjusted analysis (hazard ratio [HR] 3.2, 95% CI 2.0 to 5.0) but no risk with DTG (HR 1.1, 95% CI 0.6 to 1.9) or EVG (HR 1.2, 95% CI 0.4 to 3.2). The integrase inhibitor group did not differ significantly from the comparison group in steroid use for IRIS; hospital admission after HIV diagnosis; hospital admission for HIV, an opportunistic infection, or IRIS; mortality after antiretrovirals began; or IRIS-related mortality (1.3% versus 1.2%, P = 0.896).
The ATHENA team concluded that starting an integrase inhibitor "is a risk factor for development of IRIS in HIV-1 late presenters," but this risk is limited to people starting RAL. They believe their findings underline the need for an adequately powered trial that randomizes late presenters to an integrase inhibitor or a regimen without an integrase inhibitor. If such a trial confirms the ATHENA results, "use of integrase inhibitors as part of the initial [antiretroviral regimen] may have to be revisited in HIV-1 late presenters."
In another study presented at EACS 2017, analysis of several DTG trials found no greater IRIS risk with DTG than with other antiretrovirals [3]. But the researchers noted that these trials excluded people with AIDS diseases.
References
1. Wijting IEA, Wit FWNM, Rokx C, et al. Use of integrase inhibitors is an independent risk factor for immune reconstitution inflammatory syndrome (IRIS) in HIV-1 late presenters: an ATHENA cohort study. 16th European AIDS Conference. October 25-27, 2017. Milan. Abstract PS13/2.
2. French MA, Price P, Stone SF. Immune restoration disease after antiretroviral therapy. AIDS. 2004;18:1615-1627.
3. Hill A, Mitchell N. Meta-analysis of the safety of DTG versus other ARVs in randomised trials: analysis of cardiovascular, CNS and IRIS endpoints. 16th European AIDS Conference. October 25-27, 2017. Milan. Abstract PE12/17.
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