CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

Methods: Retrospective study using Trio Health HIV Network EMR data from federally qualified health centers in US. Eligibility: ≥18 yrs, in care between 1/1/2015-8/15/2023, with BL and 3y wt measures (all); PWH: treatment experienced suppressed at BL and 3y or suppressed on 1st ART with BL≥ 6mo since suppression and ≥ 12mo since ART start. BL characteristics were compared (Χ-square, t-test). Propensity scores (PS) and odds of shifting up BMI class were calculated (logistic regression); groups were matched on site, BL year, gender, age, race, and PS to compare 3y wt and BMI changes, with additional adjustment for imbalanced covariates. Results: Of 68856 qualified individuals, 11888 (17%) were PWH suppressed, 902 (8%) suppressed on 1st ART. PWH and PWoH differed respectively in key BL characteristics (all listed p<.05): age (median 50 vs 54 years), gender (male 77 vs 40%), race (42 vs 48% Black), eGFR <60 mL/min/1.73m 2 (11 vs 6%), obesity (BMI> 30 kg/m 2 ; 29 vs 47%), hyperlipidemia (14 vs 4%), hypertension (24 vs 46%), diabetes (5 vs 2%), neuropsychiatric disorders (26 vs 14%), cardiovascular disease (28 vs 49%), sexually transmitted diseases (10 vs 1%), smoking (11 vs 2%), or substance use (9 vs 6%). PWoH had statistically higher mean [median] BL BMI (all: 30.8 [29.4] vs 28 [26.9], matched: 29.6 [27.5] vs 28.6 [26.9]). In unmatched analyses, PWH gained 0.6 kg (95% CI 0.3-1.0) more at 3y vs PWoH after adjusting for BL differences. After matching, PWH and PWoH did not differ in 3y wt change (0.1 kg CI -0.5-0.7), Figure 1. Despite small differences in wt change, unmatched PWH were 1.3 (CI 1.1-1.5) times more likely to shift up a BMI class (17% vs 10% PWoH); smaller, but similar differences were observed in matched cohorts (17% vs 13%; 1.3 [CI 1.1-1.7]). Conclusion: This is the largest study that matched and compared wt change in suppressed PWH vs PWoH, accounting for return to health, population differences, and geography. After adjusting for differences in BL characteristics, small (unmatched) and no difference (matched) in 3y mean wt change were observed in PWH vs PWoH. A greater proportion of PWH vs PWoH shifted up a BMI class after 3 y, although results may be influenced by higher prevalence of obesity at BL among PWoH. Further examination of drivers of outlier wt gain and the role of ARTs is ongoing. Effect of Obesity on Response to Antiretroviral Therapy in SIV-Infected Rhesus Macaques Kristin Sauter , Diana Takahashi, Melissa A. Kirigiti, Sarah R. Lindsley, Hannah Blomenkamp, Heather Hofmeister, Gabriela Webb, Oleg Varlamov, Jonah Sacha, Charles Roberts, Paul Kievit Oregon Health and Sciences University, Portland, OR, USA Background: Modern antiretroviral therapy (ART) regimens are associated with increased risk of weight gain and overt metabolic disease. Adipokines play a role in adipose tissue dysfunction and are indicators of cardiometabolic disease risk. A reduced adiponectin:leptin ratio (ALR) is a predictive biomarker that correlates with a number of metabolic risk factors, as well as with markers of chronic inflammation. We employed the rhesus macaque model of SIV infection to determine if a modern ART regimen comprised of TDF, FTC, and DTG would elicit metabolic dysfunction with a corresponding decrease in the ALR, and if this effect was exacerbated by pre-existing obesity. Methods: Lean, metabolically healthy (n=6) and western-style diet-induced obese (n=5) adult male macaques were infected i.v. with SIVmac239 and ART was initiated at 5 weeks post-infection and continued for 16 months. Baseline and longitudinal assessments of plasma, adipose tissue morphology, and systemic measures of metabolism were obtained. Results: Unsurprisingly, the obese cohort exhibited a significantly lower ALR at baseline compared to the lean cohort (Obese 0.21±0.06 vs Lean 0.87±0.32, p=0.02). The lean cohort experienced a progressive decrease in ALR that was driven by a decrease in adiponectin, throughout the time course of chronic infection, ART initiation, and full suppression of viremia, that became significant at 56 weeks post-infection (PI) (Lean average 0.30±0.05). The change in ALR was inversely correlated to % change in body weight and fat mass, where animals in the lean group with the largest decrease in their ALR also had the

greatest weight and fat mass gain. Additionally, the change in ALR in all animals was inversely correlated to % change in fasting insulin levels and HOMA-IR. The obese cohort also exhibited significantly elevated circulating C-reactive protein (CRP) and lipopolysaccharide (LPS)-binding protein (LBP) at baseline compared to the lean cohort. The lean cohort exhibited a drastic increase in both CRP and LBP throughout the time course. The ALR was inversely correlated to CRP levels at necropsy. Conclusion: SIV infection and subsequent ART significantly decrease the ALR in lean animals to values similar to those seen in pre-diabetic and dysmetabolic obese animals. Thus, SIV and ART induce an obese phenotype in initially lean animals. Therefore, weight gain and/or increases in BMI in people living with HIV are not adequate measures as cardiometabolic risks may be independent of these factors. Transcriptomics and Proteomics Reveal Differential Pathways in DTG/3TC vs 3DR Regimens in PLHIV Victoria Rios-Vazquez 1 , Wilhelm A. Vos 1 , Marc Blaauw 1 , Louise E. van Eekeren 1 , Albert L. Groenendijk 2 , Quirijn de Mast 1 , Leo Joosten 1 , Mihai Netea 1 , Willem L. Blok 3 , Janneke E. Stalenhoef 3 , Jan van Lunzen 1 , Andre J. van der Ven 1 1 Radboud University Medical Center, Nijmegen, Netherlands, 2 Erasmus University Medical Center, Rotterdam, Netherlands, 3 OLVG, Amsterdam, Netherlands Background: Drug toxicity in people living with HIV (PLHIV) using cART is a concern. Nucleoside analogues are associated with mitochondrial damage. Two-drug regimens (2DR), such as DTG (integrase strand inhibitor) and 3TC may reduce drug toxicity, but the molecular effects remain unclear. Systemic effects of DTG/3TC and triple therapies (3DR) were studied using multi-omics. Methods: Data are used from the 2000HIV (NTC03994835) study that includes discovery (n=1275) and validation (n=212) cohorts of PLHIV with ~11.5 years of cART stratified by treatment regimen. We measured ~2368 plasma proteins (Olink Explore), and ~58347 genes expression by PBMC Bulk RNA-seq. We compared differential gene (DEG) and protein (DEP) expression and enriched pathways between PLHIV using DTG/3TC (n=188) versus 3DR containing INSTI (3DR-INSTI, n=526) or without (3DR-non-INSTI, n=773), and compared 3DR-INSTI versus 3DR-non-INSTI, adjusting for sex, age, ethnicity, and pre-cART conditions. Results: Discovery cohort data showed limited DEG (5 up, 15 down) and DEP (2 up, 27 down) in DTG/3TC compared to 3DR-INSTI (Figure). DTG/3TC and 3DR-non-INSTI comparison showed 21 DEG (14 down) and 131 DEP (119 down). 3DR-INSTI versus 3DR-non-INSTI revealed no DEG and limited DEP (63 up, 83 down). Gene set enrichment analysis on the total summary statistics of genes and proteins ranked by -log 10 (p-value)*sign(log2FC) revealed significant results (p<0.05). DTG/3TC genes compared to 3DR-INSTI revealed the up-regulation of the ATPase complex and down-regulation of the Oxidative stress pathway; meanwhile proteins revealed a down-regulation of the Biological oxidations with ALDH1A1, ACY1, ACY3, and ADH4 DEPs as leading markers. DTG/3TC compared to 3DR-non-INSTI genes showed an up-regulation of the TCA cycle with PC DEG as leading marker and down-regulation of the OXPHOS system with TMEM70 DEG as leading marker of the latest, while proteins revealed a down regulation of the Biological oxidation enzymes and Oxidoreductase activity with ADH4, AKR7L, DCXR, and ADH1B DEPs leading markers. 3DR-INSTI proteins compared 3DR-non-INSTI showed a down-regulation of the Fat digestion and Metabolism with CKMT1A, RBP2, FABP2, and DDC DEPs as leading markers. The direction of our findings was confirmed in the validation cohort. Conclusion: This study suggests that DTG/3TC reduces mitochondrial and oxidative stress in PLHIV compared to 3DR containing NRTIs. We also showed the negative effects on fat metabolism of INSTI compared to non-INSTI based regimens.

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Poster Abstracts

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CROI 2024 248