CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

902

HIV and Antiretrovirals Have Unique In Vivo Effects on Insulin Resistance in HIV Theodoros Kelesidis 1 , Ravikanth Nanduri 1 , Leila Fotoohabadi 1 , Arnaud Kombe Kombe 1 , Pratik Lama Tamang 1 , Philip Hamid 2 , Athanassios Kossyvakis 2 , Shubhendu Sen Roy 2 , Alka Khaitan 3 , Emily Sims 3 , Samir K. Gupta 4 1 University of Texas Southwestern Medical Center, Dallas, TX, USA, 2 University of California Los Angeles, Los Angeles, CA, USA, 3 Indiana University Health, Indianapolis, IN, USA, 4 Indiana University, Indianapolis, IN, USA Background: Diabetes mellitus (DM) is more common in antiretroviral drug-treated (ART) people with HIV (PWH) compared with people without HIV(PWOH), even without obesity. Emerging epidemiologic data suggests that PWH not on ART has a lower DM risk than PWOH. We have shown that measures of pancreatic beta cell function were higher (i.e., better function) and markers of beta cell stress were lower (i.e., reduced stress) in ART-naive PWH compared with ART-treated PWH and PWOH in PWH who have not initiated ART (PMID: 35134838). However, in vivo data on the role of HIV-1 per se versus ART in chronic HIV infection are lacking because observational human studies cannot dissect the differential effect of HIV-1 versus ART on signatures of insulin resistance (IR) in tissues not readily accessible. To address these gaps in knowledge, we used a mechanistic humanized mouse model of chronic HIV infection to dissect in vivo the direct impact of HIV-1 versus ART on IR. Methods: TKO C57Bl6 humanized mice that are not prone to Graft versus Host disease (GVHD), were infected with HIV-1 (that infects only human immune cells) and treated with FTC/TDF/RAL (that impacts both mouse and human cells) for 3 months, as previously (PMID: 33306550). Plasma glucose, insulin (I), proinsulin (pro-I) and Pro-I to I ratio (high ratio indicates IR) were determined in the plasma of mice from 3 groups: A) HIV uninfected (HIV-, n=8), B) HIV+: HIV-1 viremic not on ART (n=5), C: infected but treated with ART (HIV+/ART+, n=15). Results: Compared to HIV- mice, HIV-1 consistently tended to decrease plasma glucose levels (p=0.07) and reduced plasma levels of the mouse (m) insulin (I), Pro-I, and Pro-I/I ratio (p<0.05 for all comparisons). Compared to HIV+ and HIV- mice, ART per se in the HIV+/ART+ mice increased plasma levels of glucose, I, Pro-I, and Pro-I/I ratio (p<0.05 for all comparisons) (Figure). Conclusions: Our study dissected in vivo complex effects of HIV-1 per se versus ART on IR in vivo . We confirmed that HIV-1 per re reduces rather than increases IR in vivo. We have hypothesized that the protective effect against DM may be related to the inherent immune dysregulation associated with untreated HIV. ART rather than HIV increased IR and compromised murine pancreatic beta cell function. Large longitudinal studies of PWH with molecular signatures of immune dysregulation and IR before and after ART initiation are needed to clarify further the role of HIV, ART, and immune dysregulation on diabetes mellitus in PWH.

Methods: From 2006-2019, 373 virally suppressed WWH and 300 WWOH from the Women’s Interagency HIV Study who were non-pregnant and did not have hepatitis C virus infection or DM at baseline were included in the analysis. Participants were WWH who switched to an INSTI (INSTI+), WWH who did not switch (INSTI-), and WWOH from a similar time window, or index visit. Linear mixed effect models first evaluated the change in insulin resistance estimated through log HOMA-IR across five years of follow-up by HIV status and time varying menopausal phase. We then compared trajectories by INSTI group. We used anti-Müllerian hormone, a biomarker of ovarian reserve, to categorize women into premenopause, early peri-, late-peri-, and postmenopause. Models were adjusted for demographics, time-varying waist circumference, socio behavioral factors, comorbidities, and HIV-related factors. Results: At the index visit, 67% identified as Black and 37% were premenopausal, 11% early peri-, 25% late peri-, and 27% postmenopausal. Compared to WWOH, WWH were older (median age: 47 vs. 44 years) and had higher median HOMA-IR (1.9 vs 1.7 mg/dL), respectively. Among WWH, 76% were on tenofovir DF at the index visit. Figure shows HOMA-IR trajectories by HIV and INSTI status in late peri- and postmenopause. When adjusted for waist circumference, there was little difference in HOMA-IR trajectories by HIV status in premenopausal women. By contrast, in late perimenopause and menopause, WWH had 6.0% (95%CI:-0.2,12.6) and 8.6% (95%CI:1.8,15.8) faster increases in HOMA-IR/year, respectively, compared to WWOH. When compared to INSTI-, the percent change in HOMA-IR/year for INSTI+ was -3.1 (95%CI:-11.5,6.1) and -1.3 (95%CI:-9.1,7.2), in late perimenopause and postmenopause, respectively. Conclusions: WWH in late perimenopause and menopause have faster increases in insulin resistance when compared to WWOH, even after adjustment for waist circumference. Switching to an INSTI did not further accelerate increases in insulin resistance. Our findings suggest that DM screening and prevention in midlife WWH is imperative.

Poster Abstracts

904

Obstructive Sleep Apnea and Prevalent Diabetes Mellitus in the Multicenter AIDS Cohort Study Wassim A. Bouhsane 1 , Naresh M. Punjabi 2 , Sanjay R. Patel 3 , Valentina Stosor 4 , Joshua H. Cho 5 , Gypsyamber DSouza 6 , Joseph Margolick 7 , Todd Brown 7 , for the MACS/WIHS Combined Cohort Study (MWCCS) 1 The Johns Hopkins University, Baltimore, MD, USA, 2 University of Miami Miller, Miami, FL, USA, 3 University of Pittsburgh, Pittsburgh, PA, USA, 4 Northwestern University, Chicago, IL, USA, 5 University of California Los Angeles, Los Angeles, CA, USA, 6 The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA, 7 The Johns Hopkins University School of Medicine, Baltimore, MD, USA Background: Obstructive sleep apnea and diabetes are common among people with HIV (PWH). Cardinal features of obstructive sleep apnea such as intermittent hypoxia and sleep fragmentation have been associated with the development of diabetes in the general population. Among PWH, HIV associated inflammation and the use of certain ART medications have also been associated with the development of diabetes. We examined whether HIV status modifies the association between obstructive sleep apnea and diabetes in a cohort of men with HIV (MWH) and without HIV (MWOH). Methods: Obstructive sleep apnea was assessed using in-home polysomnography in 779 men participating in the Multicenter AIDS Cohort Study (438 MWH, 341 MWOH). The apnea-hypopnea index (AHI), the number of apneas and hypopneas per hour of sleep, was used to classify participants by obstructive sleep apnea severity (none: < 5 events/h; mild: 5 - 15 events/h; moderate: 15 - 30 events/h; severe: > 30 events/h). Diabetes was defined as meeting at least one of the following criteria: (1) a fasting blood glucose ≥ 126 mg/dL after ≥ 6 hours of fasting; (2) a self-reported diagnosis of diabetes;

903

Menopause Is Associated With Faster Increases in Insulin Resistance in Women With HIV Rebecca Abelman 1 , Yifei Ma 1 , Cyra C. Mehta 2 , Qian Yang 2 , James B. Brock 3 , Maria L. Alcaide 4 , Anjali Sharma 5 , Michelle Floris-Moore 6 , Elizabeth F. Topper 7 , Kathleen M. Weber 8 , Seble Kassaye 9 , Deborah Gustafson 10 , Cecile D. Lahiri 2 , Phyllis Tien 1 1 University of California San Francisco, San Francisco, CA, USA, 2 Emory University, Atlanta, GA, USA, 3 University of Mississippi Medical Center, Jackson, MS, USA, 4 University of Miami Miller, Miami, FL, USA, 5 Albert Einstein College of Medicine, Bronx, NY, USA, 6 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 7 The Johns Hopkins University, Baltimore, MD, USA, 8 Hektoen Institute of Medicine, Chicago, IL, USA, 9 Georgetown University, Washington, DC, USA, 10 SUNY Downstate Medical Center, Brooklyn, NY, USA Background: Women with HIV (WWH) are at increased risk for developing diabetes mellitus (DM) compared to women without HIV (WWOH). In WWOH, the transition to menopause is associated with metabolic changes that increase DM risk. Whether HIV and menopause are associated with faster increases in insulin resistance, and whether switching to an integrase strand transfer inhibitor (INSTI) modifies this association, is unknown.

CROI 2025 281