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Female Sex Modifies Link Between
Inflammation and Non-AIDS Vascular Events
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CROI 2021, Conference on Retroviruses and Opportunistic Infections, March 6-10, 2021
Mark Mascolini
Female sex appears to affect the link between inflammation and vascular events, according to a longitudinal study of almost 900 people with HIV [1]. The findings may explain why women with HIV appear to lose a general-population advantage over men in cardiovascular risk.
Researchers working with the US Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) reminded colleagues that vascular complications arise in higher proportions of people with than without HIV. This discrepancy can be traced at least partly to systemic inflammation that persists during successful antiretroviral therapy (ART), which predicts both non-AIDS events and mortality. But specific biologic pathways explaining these events remain unmapped, the CNICS team noted, often because research typically lumps non-AIDS events into a single group and fails to distinguish between type 1 and 2 myocardial infarction (MI). Research suggests that sex affects inflammation, but clinical consequences of this impact remain unknown.
To address these issues, the CNICS investigators asked two questions: (1) "What are the immunologic predictors of distinct vascular events during ART-mediated viral suppression?" (2) "How does natal sex affect immune activation and its relationship to clinical outcomes?"
The analysis began with 9430 eligible people with HIV, 979 of them randomly selected to form a subcohort followed through several years of viral suppression below 400 copies. Follow-up continued until a person had an adjudicated vascular event, died, or stopped keeping study visits, or for administrative reasons. The analysis included CNICS members who kept their viral load below 400 copies for at least 1 year and excluded those with acute infection, hospital admission, or immunosuppressive therapy within 3 months of sampling. This case-cohort analysis involved people who had a centrally adjudicated type 1 MI, type 2 MI, ischemic stroke, or venous thromboembolism, comparing them to cohort members without those events. The researchers used Cox proportional hazards models to identify biomarker predictors of a vascular event.
The analysis involved 979 participants with a median age of 47. Most participants (82%) were male at birth, 63% were men who have sex with men, 17% had a drug-injecting history, 29% had a smoking history, and 13% had diabetes. Median current CD4 count stood at 576. The researchers counted 76 people with a centrally adjudicated type 1 MI in a median 3.8 years of follow-up, 56 with type 2 MI in 3.9 years, 30 with ischemic stroke in 3.4 years, 80 with venous thromboembolism in 3.7 years, and 70 who died in 5.4 years.
Analyzing the impact of 13 much-studied biomarkers on vascular events, the CNICS team found that individual biomarkers predicted distinct events. For example the inflammation marker C-reactive protein (CRP) independently predicted type 1 MI, venous thromboembolism, and mortality but did not predict type 2 MI or ischemic stroke. The intercellular adhesion molecule ICAM-1 independently predicted type 2 MI and mortality but not the other three outcomes.
Female sex independently predicted higher levels of 11 inflammation markers, while the remaining 2 markers were not significantly higher in women or men. Eleven inflammation markers were higher in women older than 47 than in younger women, and 8 of these differences were statistically significant. In men 10 of 11 markers were higher after age 47 than in younger men, and 6 of these associations was statistically significant.
Further analysis indicated that sex may modify associations between inflammation and a vascular event. Specifically, the same marker-indicated increase in immune activation may predict an event more strongly in women than in men. But higher marker levels tended to predict venous thromboembolism in men but not women.
The CNICS team cautioned that their analysis may be limited by scant data on sex hormone therapy and transgender participants, and by no data on plasma sex hormones. Also, their sample size could hamper identification of clinically significant differences in biomarkers or interactions.
In this first biomarker analysis of incident (newly occurring) vascular events in people with HIV, distinct biomarkers predicted distinct non-AIDS vascular events. The researchers speculated that the REPRIEVE trial [3] may discern the impact of statins on these interactions, while ACTG A5383 [4] may clarify the impact of the anti-CMV drug letermovir (MK-8228). They believe these findings make it clear that research must aim to identify "specific inflammatory signatures driving discrete disease entities."
The researchers suggested that sex hormones and host genetics could lie behind higher levels of immune activation in women than men with HIV. They proposed that the impact of sex on the association between non-AIDS vascular events and inflammation "may partially explain the ‘loss of the female advantage’" over males in avoiding CVD among people with HIV.
References
1. Schnittman S, Beck-Engeser GB, Shigenaga JK, et al. Sex modifies the association between inflammation and vascular events in treated HIV. CROI 2021, Conference on Retroviruses and Opportunistic Infections, March 6-10, 2021. Abstract 98.
2. Kitahata MM, Rodriguez B, Haubrich R, et al. Cohort profile: the Centers for AIDS Research Network of Integrated Clinical Systems. Int J Epidemiol. 2008;37:948-955. doi: 10.1093/ije/dym231.
3. REPRIEVE: Randomized Trial to Prevent Vascular Events in HIV. https://www.reprievetrial.org/
4. ClinicalTrials.gov. Letermovir (MK-8228) versus placebo in the prevention of clinically-significant cytomegalovirus (CMV) infection in adult, CMV-seropositive allogeneic hematopoietic stem cell transplant recipients (MK-8228-001). ClinicalTrials.gov identifier NCT02137772. https://clinicaltrials.gov/ct2/show/NCT02137772
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