Translating the observed differences in interleukin-6 levels between some antiretroviral regimens into potential long-term risk of serious non-AIDS events: A modeling study

Abstract

IntroductionVariable levels of systemic inflammation are observed in people with HIV (PWH), but the clinical significance of differences among antiretroviral therapy (ART) regimens on associated levels of inflammatory markers is unclear. Based on data from previous epidemiologic studies that defined the predicted change in risk of serious non-AIDS events (SNAEs)/death by changes in interleukin-6 (IL-6) and D-dimer, we modeled the effects of differences in these markers between specific ART regimens on the long-term risk of clinical outcomes.MethodsWe used a Markov model to compare the risk of SNAEs/death with differences in IL-6 and D-dimer levels associated with remaining on specific three-drug regimens versus switching to specific two-drug ART regimens over 5 years of treatment. We used IL-6 and D-dimer data based on trajectories over time from the randomized TANGO and observational AIR studies. Age at model entry was set at 39 years. The primary endpoint was the number needed to treat for one additional SNAE/death.ResultsOver 144 weeks, PWH on one of the three-drug regimens studied were predicted to spend 22% more time in the low IL-6 quartile and 13% less time in the high IL-6 quartile compared with those on one of the two-drug regimens. Over 144 weeks, the predicted mean number of SNAEs/deaths per 100 PWH was 5.6 for a three-drug regimen associated with lower IL-6 levels versus 6.8 for a two-drug regimen associated with higher IL-6 levels. The number needed to treat for one additional SNAE/death among PWH receiving a two-drug versus three-drug regimen for 240 weeks was 43. Approximately 2,900 participants would be required for a 240-week clinical study to evaluate the accuracy of the model.ConclusionsOur Markov model suggests that higher IL-6 levels associated with switching from specific three- to two- drug ART regimens may be associated with an increase in the risk of SNAEs/death. Clinical studies are warranted to confirm or refute these results.

Long-term effects on immunological, inflammatory markers, and HIV-1 reservoir after switching to a two-drug versus maintaining a three-drug regimen based on integrase inhibitors

“…We planned this study given the potential clinical implications of the data, first reported by Serrano-Villar et al. ( 18 ) and later published in 2022 ( 7 , 8 ) endorsed by other expert opinions ( 5 , 6 ), suggesting that switching to 2DR was associated with a worse long-term inflammatory profile.…”

Beyond Undetectable: Modeling the Clinical Benefit of Improved Antiretroviral Adherence in Persons With Human Immunodeficiency Virus With Virologic Suppression

“…This approach was selected as we assumed that most PWH who achieve viral suppression are highly adherent to ART at some point during the course of their treatment (eg, early stage of treatment initiation) [ 24 , 25 ], but that a decrease in adherence—without the development of viremia—is expected in some patients [ 2 , 3 ]. To achieve this, we used a simplified version of the Markov model developed by Serrano-Villar et al [ 26 ], where we inputted the change in biomarkers available in the literature to estimate the number of PWH who would need to reduce adherence before an additional SNAE or death is observed. This model relied on previously published Kaplan-Meier curves illustrating the cumulative number of participants with an event by IL-6 quartile [ 20 ], with separate Weibull distributions fit to each quartile specific curve, from which in-year probabilities of a SNAE or death were derived.…”

“…This model relied on previously published Kaplan-Meier curves illustrating the cumulative number of participants with an event by IL-6 quartile [ 20 ], with separate Weibull distributions fit to each quartile specific curve, from which in-year probabilities of a SNAE or death were derived. In addition to the model by Serrano-Villar et al [ 26 ], we utilized least squares optimization to fit gamma distributions to IL-6 quartiles published by Grund et al [ 20 ], and subsequent movement between quartiles was based on previously reported elevated plasma IL-6 levels for those with <100% ART adherence. We assumed a one-time increase in plasma IL-6 with subsequent events predicted over a 3- or 5-year follow-up.…”