The effects of food insecurity on hepatic steatosis and fibrosis in people with HIV.

BACKGROUND & AIMS: Food insecurity (FI) is a risk factor for nonalcoholic fatty liver disease (NAFLD) and advanced fibrosis in the general population, but its impact on liver disease in people with HIV (PWH) is unknown. METHODS: We examined the association of FI with prevalence of NAFLD and fibrosis in a diverse cohort of PWH. PWH aged ≥18 years on antiretroviral therapy, HIV RNA<200 copies/mL, and without other known liver diseases were screened for NAFLD (CAP≥263 decibels/meter) and advanced fibrosis (LSM≥11 kilopascals) by vibration controlled transient elastography at eight US centers. Participants were categorized as food insecure using the Six-Item Short Form Household Food Security Survey. We used multivariable logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) of NAFLD and advanced fibrosis by FI status. RESULTS: Among 654 PWH, NAFLD was present in 348 (53%) and advanced fibrosis in 41 (6%). FI was present in 203 (31%) of participants, including 97/348 (28%) with NAFLD and 18/41 (44%) with advanced fibrosis. In multivariable analysis, FI was associated with lower odds of NAFLD (OR=0.57,95%CI:0.37-0.88) and a greater, but nonsignificant, odds of advanced fibrosis (OR=1.38,95%CI:0.65-2.90). We identified a significant interaction between FI and diabetes (p=0.02) on fibrosis risk, with a greater odds of fibrosis among food insecure PWH and diabetes (OR=3.83,95%CI:1.15-12.73) but not among food insecure nondiabetics (OR=1.12,95%CI:0.47-2.98). CONCLUSIONS: FI is highly prevalent among PWH and associated with lower odds of NAFLD, and among PWH with diabetes, a greater odds of advanced fibrosis. FI may contribute to hepatic fibrosis through mechanisms other than steatosis in PWH.

Microfluidic Isolation of Neuronal-Enriched Extracellular Vesicles Shows Distinct and Common Neurological Proteins in Long COVID, HIV Infection and Alzheimer's Disease.

Long COVID (LongC) is associated with a myriad of symptoms including cognitive impairment. We reported at the beginning of the COVID-19 pandemic that neuronal-enriched or L1CAM+ extracellular vesicles (nEVs) from people with LongC contained proteins associated with Alzheimer's disease (AD). Since that time, a subset of people with prior COVID infection continue to report neurological problems more than three months after infection. Blood markers to better characterize LongC are elusive. To further identify neuronal proteins associated with LongC, we maximized the number of nEVs isolated from plasma by developing a hybrid EV Microfluidic Affinity Purification (EV-MAP) technique. We isolated nEVs from people with LongC and neurological complaints, AD, and HIV infection with mild cognitive impairment. Using the OLINK platform that assesses 384 neurological proteins, we identified 11 significant proteins increased in LongC and 2 decreased (BST1, GGT1). Fourteen proteins were increased in AD and forty proteins associated with HIV cognitive impairment were elevated with one decreased (IVD). One common protein (BST1) was decreased in LongC and increased in HIV. Six proteins (MIF, ENO1, MESD, NUDT5, TNFSF14 and FYB1) were expressed in both LongC and AD and no proteins were common to HIV and AD. This study begins to identify differences and similarities in the neuronal response to LongC versus AD and HIV infection.

Sexual network characteristics, condomless anal intercourse, and the HIV care cascade among MSM living with controlled versus uncontrolled HIV infection in Lima, Peru: a population-based cross-sectional analysis.

Background: Despite high rates of HIV transmission among men who have sex with men (MSM) in Lima, Peru, limited data exist on the sexual network characteristics or risk factors for secondary HIV transmission among MSM with uncontrolled HIV infection. We report the frequency of serodiscordant, condomless anal intercourse (CAI) and associated sexual network characteristics among MSM in Lima with detectable HIV viremia and compare to those with undetectable viremia. Methods: This cross-sectional analysis includes MSM who tested positive for HIV-1 during screening for a trial of partner management and STI control (June 2022-January 2023). Participants were tested for HIV, gonorrhoea, chlamydia, and syphilis, and completed questionnaires on their demographic characteristics, sexual identity and behaviour, sexual network structures and engagement in HIV care. Findings: Of 665 MSM, 153 (23%) had detectable (>200 copies/mL) viremia. 75% (499/662) of men living with HIV were previously diagnosed, with 94% (n = 469/499) reporting that they were on ART, and 93% (n = 436/469) virally suppressed. 96% (n = 147/153) of men with detectable viremia reported serodiscordant CAI with at least one of their last three sexual partners, and 74% (n = 106/144) reported the same with all three of their recent partners. In contrast, 62% (n = 302/489) of men with undetectable viral load reported serodiscordant CAI with all of their last three partners (p < 0.01). Interpretation: 23% of men living with HIV in Peru had detectable viremia, of whom almost all (96%) reported recent serodiscordant CAI. The primary gap in the HIV care cascade lies in awareness of HIV serostatus, suggesting that improved access to HIV testing could be a key prevention strategy in Peru. Funding: Funding for this study was provided by NIH/NIMH grants R01 MH118973 (PI: Clark) and R25 MH087222 (PI: Clark).

Diagnostic Ability of Simple Noninvasive Blood Tests to Predict Increased Liver Stiffness in People Living With HIV and Steatotic Liver Disease.

INTRODUCTION: Steatotic liver disease is common in people with HIV (PWH). Identifying those with advanced fibrosis (AF, bridging fibrosis or cirrhosis), F3-4, is important. We aimed to examine the performance of FIB-4 and nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS) in PWH to identify those with AF assessed by liver stiffness measurement (LSM). METHODS: We prospectively collected data on adults participating in 2 National Institute of Health-sponsored HIV NAFLD networks. All had HIV on antiretroviral therapy (ART) ≥6 months with HIV RNA <200 copies/mL. Those with viral hepatitis, other liver disease, excessive alcohol use, or hepatic decompensation were excluded. Vibration-controlled transient elastrography for LSM was performed, and AF defined as ≥11 kPa was compared with FIB-4 and NFS at predefined thresholds (<1.3 and >2.67 for FIB-4 and <-1.455 and >0.675 for NFS). RESULTS: A total of 1,065 participants were analyzed: mean age 51.6 years, 74% male, 28% White, 46% Black, 22% Hispanic, with 34% overweight (body mass index 25-29 kg/m 2 ) and 43% obese (body mass index ≥30 kg/m 2 ). Features of the metabolic syndrome were common: hyperlipidemia 35%, type 2 diabetes 17%, and hypertension 48%. The median CD4 + T-cell count was 666 cells/mm 3 , 74% had undetectable HIV RNA, and duration of HIV-1 was 17 years with most taking a nucleoside reverse transcriptase inhibitor (92%) and an integrase inhibitor (83%). The mean LSM was 6.3 kPa, and 6.3% had AF. The area under the receiver characteristic curve for FIB-4 and NFS to identify AF were 0.70 and 0.75, respectively. While both had high negative predictive values (97%-98%), the sensitivity at low thresholds and specificity at high thresholds were 64% and 97% for FIB-4 and 80% and 96% for NFS, respectively. Neither FIB-4 nor NFS at either threshold had good positive predictive value to detect AF. DISCUSSION: FIB-4 and NFS have excellent specificity and negative predictive value for detecting AF, and thus can be used as screening tools in PWH to exclude those with AF who do not need further testing (LSM) or referral to hepatologist.

Delivering integrated strategies from a mobile unit to address the intertwining epidemics of HIV and addiction in people who inject drugs: the HPTN 094 randomized controlled trial protocol (the INTEGRA Study).

BACKGROUND: Persons with opioid use disorders who inject drugs (PWID) in the United States (US) face multiple and intertwining health risks. These include interference with consistent access, linkage, and retention to health care including medication for opioid use disorder (MOUD), HIV prevention using pre-exposure prophylaxis (PrEP), and testing and treatment for sexually transmitted infections (STIs). Most services, when available, including those that address substance misuse, HIV prevention, and STIs, are often provided in multiple locations that may be difficult to access, which further challenges sustained health for PWID. HPTN 094 (INTEGRA) is a study designed to test the efficacy of an integrated, "whole-person" strategy that provides integrated HIV prevention including antiretroviral therapy (ART), PrEP, MOUD, and STI testing and treatment from a mobile health delivery unit ("mobile unit") with peer navigation compared to peer navigation alone to access these services at brick and mortar locations. METHODS: HPTN 094 (INTEGRA) is a two-arm, randomized controlled trial in 5 US cities where approximately 400 PWID without HIV are assigned either to an experimental condition that delivers 26 weeks of "one-stop" integrated health services combined with peer navigation and delivered in a mobile unit or to an active control condition using peer navigation only for 26 weeks to the same set of services delivered in community settings. The primary outcomes include being alive and retained in MOUD and PrEP at 26 weeks post-randomization. Secondary outcomes measure the durability of intervention effects at 52 weeks following randomization. DISCUSSION: This trial responds to a need for evidence on using a "whole-person" strategy for delivering integrated HIV prevention and substance use treatment, while testing the use of a mobile unit that meets out-of-treatment PWID wherever they might be and links them to care systems and/or harm reduction services. Findings will be important in guiding policy for engaging PWID in HIV prevention or care, substance use treatment, and STI testing and treatment by addressing the intertwined epidemics of addiction and HIV among those who have many physical and geographic barriers to access care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04804072 . Registered on 18 March 2021.

Incident Proteinuria differs by HIV Serostatus among Men with Pre-diabetes: The Multicenter AIDS Cohort Study.

BACKGROUND: Pre-diabetes is associated with proteinuria, a risk factor for chronic kidney disease. While people living with HIV (PWH) have a higher risk of proteinuria than people without HIV (PWOH), it is unknown whether incident proteinuria differs by HIV serostatus among pre-diabetic persons. METHODS: Urine protein-to-creatinine ratio (PCR) was measured at semi-annual visits among men in the Multicenter AIDS Cohort Study since April 2006. Men with pre-DM on or after April 2006 and no prevalent proteinuria or use of anti-diabetic medications were included. Pre-diabetes was defined as fasting glucose (FG) of 100-125 mg/dL confirmed within a year by a repeat FG or hemoglobin A1c 5.7-6.4%. Incident proteinuria was defined as PCR > 200 mg/g, confirmed within a year. We used Poisson regression models to determine whether incident proteinuria in participants with pre-diabetes differed by HIV serostatus and, among PWH, whether HIV-specific factors were related to incident proteinuria. RESULTS: Between 2006 and 2019, among 1276 men with pre-diabetes, 128/613 PWH (21%) and 50/663 PWOH (8%) developed proteinuria over a median 10-year follow-up. After multivariable adjustment, the incidence of proteinuria in PWH with pre-diabetes was 3.3 times [95% CI: 2.3-4.8 times] greater than in PWOH (p < 0.01). Among PWH, current CD4 count <500 cells/mm3 (p < 0.01) and current use of protease inhibitors (p = 0.03) were associated with incident proteinuria, while lamivudine and integrase inhibitor use were associated with a lower risk. CONCLUSION: Among men with pre-DM, the risk of incident proteinuria was 3 times higher in PWH. Strategies to preserve renal function are needed in this population.

Cannabis Use and Biomarkers of Inflammation, Immune Activation, and Microbial Translocation in Persons with HIV.

Background: The relationship between cannabis and inflammation among persons with HIV (PWH) remains unclear. We examined whether the cannabis metabolite 11-nor-9-carboxy THC (THC-COOH) is associated with lower levels of plasma biomarkers of inflammation, immune activation, and microbial translocation in PWH. We hypothesized that cannabis use would be associated with lower levels of plasma inflammatory biomarkers than noncannabis use. Methods: We quantified THC-COOH in plasma, with THC-COOH levels between 5.1-69.9 µg/L and ≥70 µg/L being classified as moderate and heavy cannabis use, respectively, with noncannabis use defined as undetected THC-COOH. We measured a panel of plasma biomarkers of inflammation (interleukin [IL]-1-ß, tumor necrosis factor-alpha, IL-18, IL-6, and C-reactive protein), immune activation (CD14 and CD163), and microbial translocation (iFABP2 and lipopolysaccharide binding protein [LBP]), with all biomarkers collected on the same day. We used a cross-sectional design and linear regression models to test whether cannabis use is associated with lower biomarker levels. Results: Participants were (N=107) sexual minority men with HIV (median age=32 years, IQR=28, 38), of whom 65% were virally suppressed; 36%, 44%, and 20% were classified as nonuse, moderate, and heavy cannabis, respectively. In linear regression models adjusted for viral suppression, stimulant use, and CD4 counts, heavy cannabis use was significantly associated with lower levels of log10 LBP (ß=-0.14, 95% confidence interval: -0.24 to -0.04; false discovery rate=0.0029; partial eta squared=0.07) than noncannabis users. No precise associations were observed for other biomarkers (all p>0.05). Conclusions: Our findings suggest that cannabis use may be associated with lower plasma LBP. Further work is needed to clarify the relationship between cannabis use and biomarkers of microbial translocation in PWH.

Pharmacogenetics of weight gain following switch from efavirenz- to integrase inhibitor-containing regimens.

BACKGROUND: Excessive weight gain affects some persons with HIV after switching to integrase strand transfer inhibitor (INSTI)-containing antiretroviral therapy (ART). We studied associations between CYP2B6 genotype and weight gain after ART switch among ACTG A5001 and A5322 participants. METHODS: Eligible participants switched from efavirenz- to INSTI-containing ART, had genotype data, and had weight data at least once from 4 weeks to 2 years post-switch. Multivariable linear mixed effects models adjusted for race/ethnicity, CD4, age, BMI and INSTI type assessed relationships between CYP2B6 genotype and estimated differences in weight change. RESULTS: A total of 159 eligible participants switched ART from 2007 to 2019, of whom 138 had plasma HIV-1 RNA < 200 copies/mL (65 CYP2B6 normal, 56 intermediate, 17 poor metabolizers). Among participants with switch HIV-1 RNA < 200 copies/mL, weight increased in all 3 CYP2B6 groups. The rate of weight gain was greater in CYP2B6 poor than in CYP2B6 normal metabolizers overall, and within 9 subgroups (male, female, White, Black, Hispanic, dolutegravir, elvitegravir, raltegravir, and TDF in the pre-switch regimen); only in Hispanic and elvitegravir subgroups were these associations statistically significant ( P  < 0.05). Compared to normal metabolizers, CYP2B6 intermediate status was not consistently associated with weight gain. CONCLUSION: CYP2B6 poor metabolizer genotype was associated with greater weight gain after switch from efavirenz- to INSTI-containing ART, but results were inconsistent. Weight gain in this setting is likely complex and multifactorial.

Energy balance and body composition after switch between integrase strand transfer inhibitors and doravirine among people with HIV.

BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are associated with excessive weight gain among a subset of persons with HIV (PWH), due to unclear mechanisms. We assessed energy intake (EI) and expenditure (EE) following switch off and onto INSTIs. METHODS: PWH with >10% weight gain on an INSTI-based regimen switched INSTI to doravirine for 12 weeks, then back to INSTI for 12 weeks while keeping their remaining regimen stable. Twenty-four-hour EE, EI and weight were measured on INSTI, following switch to doravirine, and upon INSTI restart. Mixed models analysed changes over time. RESULTS: Among 18 participants, unadjusted 24 h EE decreased by 83 (95% CI -181 to 14) kcal following switch to doravirine, and by 2 (-105 to 100) kcal after INSTI restart; energy balance (EE-EI) increased by 266 (-126 to 658) kcal from Week 0 to Week 12, and decreased by 3 (-429 to 423) kcal from Week 12 to Week 24. Trends toward weight loss occurred following switch to doravirine [mean -1.25 (-3.18 to 0.69) kg] and when back on INSTI [-0.47 (-2.45 to 1.52) kg]. Trunk fat decreased on doravirine [-474 (-1398 to 449) g], with some regain following INSTI restart [199 (-747 to 1145) g]. Fat-free mass decreased on doravirine [-491 (-1399 to 417) g] and increased slightly after INSTI restart [178 (-753 to 1108) g]. CONCLUSIONS: Among PWH with >10% weight gain on an INSTI, switch to doravirine was associated with a trend towards decreases in 24 h EE, weight, trunk fat mass and fat-free mass. Observed changes were not significant, but suggest a mild weight-suppressive effect of doravirine among PWH.

Weight Gain After Antiretroviral Therapy Initiation and Subsequent Risk of Metabolic and Cardiovascular Disease.

BACKGROUND: Weight gain following initiation of antiretroviral therapy (ART) is common. We assessed the impact of changes in weight in the year following ART initiation with subsequent cardiometabolic disease among AIDS Clinical Trials Group (ACTG) participants. METHODS: Linear regression models were fit to examine the association between change in weight/waist circumference (WC) in weeks 0-48 and change in metabolic parameters in weeks 0-48 and 48-96. Cox proportional hazard models were fit to examine the association between changes in weight/WC in weeks 0-48 and diabetes mellitus (DM), metabolic syndrome, or cardiometabolic and cardiovascular events after week 48. RESULTS: Participants (N = 2624) were primarily male (81%) and non-White (60%). Mean weight gain from 0-48 weeks was 3.6 kg (SD 7.3); 130 participants developed DM; 360 metabolic syndrome; 424 any cardiometabolic event; 28 any cardiovascular event, over 480 weeks of follow-up. In adjusted models, total cholesterol increased by 0.63 mg/dL (95% confidence interval [CI] [.38, .089]) and LDL by 0.39 mg/dL (0.19, 0.59) per 1 kg increase in weight from weeks 0 to48. Participants who experienced >10% weight gain (vs -5% to 5%) had an increased risk of DM (hazard ratio [HR] 2.01, 95% CI [1.30, 3.08]), metabolic syndrome (HR 2.24, 95% CI [1.55, 2.62]), and cardiometabolic outcomes (HR 1.54, 95% CI [1.22, 1.95]). Participants who lost more than 5% of their baseline weight had a lower risk of incident metabolic syndrome (HR 0.67, 95% CI [0.42, 1.07]). Trends for WC were similar. CONCLUSIONS: Weight and body composition changes in the first year following ART initiation are associated with contemporaneous changes in metabolic parameters and subsequent cardiometabolic disease.

Proprotein convertase subtisilin/kexin 9 levels decline with hepatitis C virus therapy in people with HIV/hepatitis C virus and correlate with inflammation.

BACKGROUND: Proprotein convertase subtisilin/kexin 9 (PCSK9) raises low-density lipoprotein cholesterol (LDL-C) levels and is associated with inflammation, which is elevated in HIV and hepatitis C virus (HCV) infection. We compared PCSK9 levels in people with co-occurring HIV and HCV (HIV/HCV) vs. HIV alone, and evaluated the impact of HCV direct-acting antiviral (DAA) therapy on PCSK9. DESIGN: A prospective, observational cohort study. METHODS: Thirty-five adults with HIV/HCV and 37 with HIV alone were evaluated, all with HIV virologic suppression and without documented cardiovascular disease. Circulating PCSK9 and inflammatory biomarkers were measured at baseline and following HCV treatment or at week 52 (for HIV alone) and compared using Wilcoxon tests and Spearman correlations. RESULTS: At baseline, PCSK9 trended higher in HIV/HCV vs. HIV alone (307 vs. 284 ng/ml, P  = 0.06). Twenty-nine participants with HIV/HCV completed DAA therapy with sustained virologic response. PCSK9 declined from baseline to posttreatment 1 (median 7.3 weeks after end of therapy [EOT]) and posttreatment 2 (median 43.5 weeks after EOT), reaching levels similar to HIV alone; median within-person reduction was -60.5 ng/ml ( P  = 0.003) and -55.6 ng/ml ( P  = 0.02), respectively. Decline in PCSK9 correlated with decline in soluble (s)E-selectin and sCD163 ( r  = 0.64, P  = 0.002; r  = 0.58, P  = 0.008, respectively), but not with changes in LDL-C or other biomarkers. No significant change in PCSK9 occurred in the HIV alone group over 52 weeks. CONCLUSION: PCSK9 declined with DAA therapy in participants with HIV/HCV, correlating with declines in several inflammatory biomarkers but not LDL-C. Elevated PCSK9 with HCV may be linked to particular HCV-associated inflammatory pathways more so than cholesterol homeostasis.

Adipose Tissue Dysfunction and Energy Balance Paradigms in People Living With HIV.

Over the past 4 decades, the clinical care of people living with HIV (PLWH) evolved from treatment of acute opportunistic infections to the management of chronic, noncommunicable comorbidities. Concurrently, our understanding of adipose tissue function matured to acknowledge its important endocrine contributions to energy balance. PLWH experience changes in the mass and composition of adipose tissue depots before and after initiating antiretroviral therapy, including regional loss (lipoatrophy), gain (lipohypertrophy), or mixed lipodystrophy. These conditions may coexist with generalized obesity in PLWH and reflect disturbances of energy balance regulation caused by HIV persistence and antiretroviral therapy drugs. Adipocyte hypertrophy characterizes visceral and subcutaneous adipose tissue depot expansion, as well as ectopic lipid deposition that occurs diffusely in the liver, skeletal muscle, and heart. PLWH with excess visceral adipose tissue exhibit adipokine dysregulation coupled with increased insulin resistance, heightening their risk for cardiovascular disease above that of the HIV-negative population. However, conventional therapies are ineffective for the management of cardiometabolic risk in this patient population. Although the knowledge of complex cardiometabolic comorbidities in PLWH continues to expand, significant knowledge gaps remain. Ongoing studies aimed at understanding interorgan communication and energy balance provide insights into metabolic observations in PLWH and reveal potential therapeutic targets. Our review focuses on current knowledge and recent advances in HIV-associated adipose tissue dysfunction, highlights emerging adipokine paradigms, and describes critical mechanistic and clinical insights.

Prevalence of steatotic liver disease, MASLD, MetALD and significant fibrosis in people with HIV in the United States.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) has recently been proposed as a replacement term for NAFLD. AIMS: To assess the effects of this new nomenclature on the prevalence and distribution of different SLD categories in people with HIV (PWH) and identified factors associated with MASLD and clinically significant fibrosis (CSF). METHODS: PWH were prospectively enrolled from 9 US centres and underwent clinical evaluation and vibration-controlled transient elastography for controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). SLD was defined as CAP ≥ 263 dB/m, CSF as LSM of ≥8 kPa, and advanced fibrosis (AF) as LSM ≥ 12 kPa. The prevalence of SLD, MASLD, metabolic dysfunction and alcohol-associated liver disease (MetALD), ALD, cryptogenic (cSLD), CSF and AF were determined. Uni- and multivariate logistic regression models were used to assess factors associated with MASLD and CSF risk. RESULTS: Of 1065 participants, 74% were male, mean (SD) age 51.6 ± 11.9 years, 46% non-Hispanic Black and 74% with undetectable HIV RNA. The prevalence of SLD was 52%, MASLD 39%, MetALD 10%, ALD 3%, CSF 15% and AF 4%. Only 0.6% had cSLD. Black race was protective whereas obesity, ALT and AST levels were associated with increased risk of MASLD and CSF in MASLD. HIV or antiretroviral therapy did not affect MASLD risk. CONCLUSIONS: MASLD and MetALD are the dominant causes of SLD in PWH, affecting almost half. Application of the new nomenclature resulted in minimal change in the proportion of patients with MASLD who would have been diagnosed previously with NAFLD.

Sexual network characteristics and partnership types among men who have sex with men diagnosed with syphilis, gonorrhoea and/or chlamydia in Lima, Peru.

OBJECTIVES: Sexual networks are known to structure sexually transmitted infection (STI) transmission among men who have sex with men (MSM). We sought to estimate the risks of STI diagnosis for various partnership types within these networks. METHODS: Our cross-sectional survey analysed data from 1376 MSM screened for a partner management intervention in Lima, Peru. Participants were tested for HIV, syphilis, gonorrhoea (NG) and chlamydia (CT) and completed surveys on their demographics, sexual identity/role, HIV status, partnership types and sexual network from the prior 90 days. χ2 and Wilcoxon rank-sum tests compared participants without an STI to those diagnosed with (1) syphilis, (2) NG and/or CT (NG/CT) and (3) syphilis and NG/CT coinfection (coinfection). RESULTS: 40.8% (n=561/1376) of participants were diagnosed with an STI (syphilis: 14.9%, NG/CT: 16.4%, coinfection: 9.5%). 47.9% of all participants were living with HIV and 8.9% were newly diagnosed. A greater proportion of participants with syphilis and coinfection were living with HIV (73.5%, p<0.001; 71.0%, p<0.001) compared with those with NG/CT (47.8%) or no STI (37.8%). Participants with syphilis more often reported sex-on-premises venues (SOPVs) as the location of their last sexual encounter (51.7%, p=0.038) while those with NG/CT tended to meet their last sexual partner online (72.8%, p=0.031). Respondents with coinfection were the only STI group more likely to report transactional sex than participants without an STI (31.3%, p=0.039). CONCLUSIONS: Sexual networks and partnership types of Peruvian MSM are associated with differential risks for STIs. Participants diagnosed with syphilis tended to meet single-encounter casual partners at SOPV, while MSM with NG/CT were younger and often contacted casual partners online. Coinfection had higher frequency of transactional sex. These findings suggest the potential importance of public health interventions through combined syphilis/HIV screening at SOPV, syphilis screening at routine clinic appointments for MSM living with HIV and directed advertisements and/or access to NG/CT testing through online platforms.

Both/And: Mixed methods analysis of network composition, communication patterns, and socio-economic support within social networks of transgender women involved in sex work in Lima, Peru.

INTRODUCTION: Social networks contribute to normative reinforcement of HIV prevention strategies, knowledge sharing, and social capital, but little research has characterized the social networks of transgender women (TW) in Latin America. We conducted a mixed methods analysis of three network clusters of TW in Lima, Peru, to evaluate network composition, types of support exchanged, and patterns of communication. METHODS: We recruited TW residing in or affiliated with three "casas trans" (houses shared among TW) in Lima between April-May 2018. Eligible participants were 18 or older, self-reported HIV-negative, and reported recent intercourse with a cis-male partner. Participants completed demographic questionnaires, social network interviews, and semi-structured interviews to assess egocentric network structures, support exchanged, and communication patterns. Quantitative and qualitative data were analyzed using Stata v14.1 and Atlas.ti, respectively. RESULTS: Of 20 TW, median age was 26 years and 100% reported involvement in commercial sex work. Respondents identified 161 individuals they interacted with in the past month (alters), of whom 33% were TW and 52% family members. 70% of respondents reported receiving emotional support from family, while 30% received financial support and instrumental support from family. Of the 13 (65%) respondents who nominated someone as a source of HIV prevention support (HPS), the majority (69%) nominated other TW. In a GEE regression analysis adjusted for respondent education and region of birth, being a family member was associated with lower likelihood of providing financial support (aOR 0.21, CI 0.08-0.54), instrumental support (aOR 0.16, CI 0.06-0.39), and HPS (aOR 0.18, CI 0.05-0.64). In qualitative interviews, most respondents identified a cis-female family member as their most trusted and closest network member, but other TW were more often considered sources of day-to-day support, including HPS. CONCLUSION: TW have diverse social networks where other TW are key sources of knowledge sharing and support, and family members may also represent important and influential components. Within these complex networks, TW may selectively solicit and provide support from different network alters according to specific contexts and needs. HIV prevention messaging could consider incorporating network-based interventions with TW community input and outreach efforts for supportive family members.

Social Networks Play a Complex Role in HIV Prevention Knowledge, Attitudes, Practices, and the Uptake of PrEP Through Transgender Women Communities Centered Around Three "Casas Trans" in Lima, Peru: A Qualitative Study.

Transgender women's (TW) social networks may facilitate HIV prevention information dissemination and normative reinforcement. We conducted a qualitative study of social networks among 20 TW affiliated with 3 "casas trans" (houses shared among TW) in Lima, Peru, using diffusion of innovations theory to investigate community-level HIV prevention norms. Participants completed demographic questionnaires, social network interviews, and semistructured in-depth interviews. Median age was 26 and all participants engaged in sex work. Interviews revealed high HIV prevention knowledge and positive attitudes, but low engagement in HIV prevention. Respondents primarily discussed HIV prevention with other TW. Network members' opinions about pre-exposure prophylaxis (PrEP) frequently influenced respondents' personal beliefs, including mistrust of healthcare personnel, concern that PrEP efficacy was unproven, fear of adverse effects, and frustration regarding difficulty accessing PrEP. Patterns of influence in TW networks may be leveraged to improve uptake of HIV prevention tools, including PrEP.

Ramipril for the Treatment of COVID-19: RAMIC, a Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

INTRODUCTION: Retrospective studies report that angiotensin-converting enzyme inhibitors (ACEIs) may reduce the severity of COVID-19, but prospective data on de novo treatment with ACEIs are limited. The RAMIC trial was a randomized, multicenter, placebo-controlled, double-blind, allocation-concealed clinical trial to examine the efficacy of de novo ramipril versus placebo for the treatment of COVID-19. METHODS: Eligible participants were aged 18 years and older with a confirmed diagnosis of SARS-CoV-2 infection, recruited from urgent care clinics, emergency departments, and hospital inpatient wards at eight sites in the USA. Participants were randomly assigned to daily ramipril 2.5 mg or placebo orally in a 2:1 ratio, using permuted block randomization. Analyses were conducted on an intention-to-treat basis. The primary outcome was a composite of mortality, intensive care unit (ICU) admission, or invasive mechanical ventilation by day 14. RESULTS: Between 27 May 2020 and 19 April 2021, a total of 114 participants (51% female) were randomized to ramipril (n = 79) or placebo (n = 35). The overall mean (± SD) age and BMI were 45 (± 15) years and 33 (± 8) kg/m2. Two participants in the ramipril group required ICU admission and one died, compared with none in the placebo group. There were no significant differences between ramipril and placebo in the primary endpoint (ICU admission, mechanical ventilation, or death) (3% versus 0%, p = 1.00) or adverse events (27% versus 29%, p = 0.82). The study was terminated early because of a low event rate and subsequent Emergency Use Authorization of therapies for COVID-19. CONCLUSION: De novo ramipril was not different compared with placebo in improving or worsening clinical outcomes from COVID-19 but appeared safe in non-critically ill patients with COVID-19. TRIAL REGISTRATION: Clinicaltrials.gov NCT04366050.

Both/And: Mixed methods analysis of network composition, communication patterns, and socio-economic support within social networks of transgender women in Lima, Peru.

Introduction: Social networks contribute to normative reinforcement of HIV prevention strategies, knowledge sharing, and social capital, but little research has characterized the social networks of transgender women (TW) in Latin America. We conducted a mixed methods analysis of three network clusters of TW in Lima, Peru, to evaluate network composition, types of support exchanged, and patterns of communication. Methods: We recruited TW residing in or affiliated with three "casas trans" (houses shared among TW) in Lima between April-May 2018. Eligible participants were 18 or older, self-reported HIV-negative, and reported recent intercourse with a cis-male partner. Participants completed demographic questionnaires, social network interviews, and semi-structured interviews to assess egocentric network structures, support exchanged, and communication patterns. Quantitative and qualitative data were analyzed using Stata v14.1 and Atlas.ti, respectively. Results: Of 20 TW, median age was 26 years and 100% reported involvement in commercial sex work. Respondents identified 161 individuals they interacted with in the past month (alters), of whom 33% were TW and 52% family members. 70% of respondents reported receiving emotional support from family, while 30% received financial support and instrumental support from family. Of the 13 (65%) respondents who nominated someone as a source of HIV prevention support (HPS), the majority (69%) nominated other TW. In a GEE regression analysis adjusted for respondent education and region of birth, being a family member was associated with lower likelihood of providing financial support (aOR 0.21, CI 0.08-0.54), instrumental support (aOR 0.16, CI 0.06-0.39), and HPS (aOR 0.18, CI 0.05-0.64). In qualitative interviews, most respondents identified a cis-female family member as their most trusted and closest network member, but other TW were more often considered sources of day-to-day support, including HPS. Conclusion: TW have diverse social networks where other TW are key sources of knowledge sharing and support, and family members may also represent important and influential components. Within these complex networks, TW may selectively solicit and provide support from different network alters according to specific contexts and needs. HIV prevention messaging could consider incorporating network-based interventions with TW community input and outreach efforts for supportive family members.

Aging-Related Comorbidity Burden Among Women and Men With or At-Risk for HIV in the US, 2008-2019.

Importance: Despite aging-related comorbidities representing a growing threat to quality-of-life and mortality among persons with HIV (PWH), clinical guidance for comorbidity screening and prevention is lacking. Understanding comorbidity distribution and severity by sex and gender is essential to informing guidelines for promoting healthy aging in adults with HIV. Objective: To assess the association of human immunodeficiency virus on the burden of aging-related comorbidities among US adults in the modern treatment era. Design, Setting, and Participants: This cross-sectional analysis included data from US multisite observational cohort studies of women (Women's Interagency HIV Study) and men (Multicenter AIDS Cohort Study) with HIV and sociodemographically comparable HIV-seronegative individuals. Participants were prospectively followed from 2008 for men and 2009 for women (when more than 80% of participants with HIV reported antiretroviral therapy use) through last observation up until March 2019, at which point outcomes were assessed. Data were analyzed from July 2020 to April 2021. Exposures: HIV, age, sex. Main Outcomes and Measures: Comorbidity burden (the number of total comorbidities out of 10 assessed) per participant; secondary outcomes included individual comorbidity prevalence. Linear regression assessed the association of HIV status, age, and sex with comorbidity burden. Results: A total of 5929 individuals were included (median [IQR] age, 54 [46-61] years; 3238 women [55%]; 2787 Black [47%], 1153 Hispanic or other [19%], 1989 White [34%]). Overall, unadjusted mean comorbidity burden was higher among women vs men (3.4 [2.1] vs 3.2 [1.8]; P = .02). Comorbidity prevalence differed by sex for hypertension (2188 of 3238 women [68%] vs 2026 of 2691 men [75%]), psychiatric illness (1771 women [55%] vs 1565 men [58%]), dyslipidemia (1312 women [41%] vs 1728 men [64%]), liver (1093 women [34%] vs 1032 men [38%]), bone disease (1364 women [42%] vs 512 men [19%]), lung disease (1245 women [38%] vs 259 men [10%]), diabetes (763 women [24%] vs 470 men [17%]), cardiovascular (493 women [15%] vs 407 men [15%]), kidney (444 women [14%] vs 404 men [15%]) disease, and cancer (219 women [7%] vs 321 men [12%]). In an unadjusted model, the estimated mean difference in comorbidity burden among women vs men was significantly greater in every age strata among PWH: age under 40 years, 0.33 (95% CI, 0.03-0.63); ages 40 to 49 years, 0.37 (95% CI, 0.12-0.61); ages 50 to 59 years, 0.38 (95% CI, 0.20-0.56); ages 60 to 69 years, 0.66 (95% CI, 0.42-0.90); ages 70 years and older, 0.62 (95% CI, 0.07-1.17). However, the difference between sexes varied by age strata among persons without HIV: age under 40 years, 0.52 (95% CI, 0.13 to 0.92); ages 40 to 49 years, -0.07 (95% CI, -0.45 to 0.31); ages 50 to 59 years, 0.88 (95% CI, 0.62 to 1.14); ages 60 to 69 years, 1.39 (95% CI, 1.06 to 1.72); ages 70 years and older, 0.33 (95% CI, -0.53 to 1.19) (P for interaction = .001). In the covariate-adjusted model, findings were slightly attenuated but retained statistical significance. Conclusions and Relevance: In this cross-sectional study, the overall burden of aging-related comorbidities was higher in women vs men, particularly among PWH, and the distribution of comorbidity prevalence differed by sex. Comorbidity screening and prevention strategies tailored by HIV serostatus and sex or gender may be needed.

Hepatic steatosis and nonalcoholic fatty liver disease are common and associated with cardiometabolic risk in a primary prevention cohort of people with HIV.

BACKGROUND: Hepatic steatosis, including nonalcoholic fatty liver disease (NAFLD), is common among people with HIV (PWH). We present baseline steatosis prevalence and cardiometabolic characteristics among REPRIEVE substudy participants. METHODS: REPRIEVE is an international, primary cardiovascular disease prevention, randomized, controlled trial of pitavastatin calcium vs. placebo among 7769 PWH ages 40-75 years on antiretroviral therapy (ART) and with low-to-moderate cardiovascular risk. A subset of participants underwent noncontrast computed tomography, with hepatic steatosis defined as mean hepatic attenuation less than 40 HU or liver/spleen ratio less than 1.0, and NAFLD defined as steatosis in the absence of frequent alcohol use or viral hepatitis. RESULTS: Of 687 evaluable persons, median age was 51 years, BMI 27 kg/m 2 , CD4 + T-cell count 607 cells/µl; 17% natal female sex, 36% Black, 24% Hispanic, and 98% HIV-1 RNA less than 400 copies/ml. Hepatic steatosis prevalence was 22% (149/687), and NAFLD 21% (96/466). Steatosis/NAFLD prevalence was higher in men and with older age, non-Black race, and higher BMI and waist circumference. Both were associated with BMI greater than 30 kg/m 2 , metabolic syndrome components, higher atherosclerotic cardiovascular disease (ASCVD) risk score, HOMA-IR, LpPLA-2 and hs-CRP, and lower high-density lipoprotein cholesterol. Of HIV-specific/ART-specific characteristics, only history of an AIDS-defining illness was more common among persons with steatosis/NAFLD. After adjusting for age, sex and race/ethnicity, BMI greater than 30 kg/m 2 , HOMA-IR greater than 2.0, Metabolic syndrome and each of its components were associated with NAFLD prevalence. CONCLUSION: In this cohort with controlled HIV and low-to-moderate cardiovascular risk, hepatic steatosis and NAFLD were common and associated with clinically relevant metabolic and inflammatory disturbances but not current HIV-related or ART-related factors.