Effect of metabolic status on response to SIV infection and antiretroviral therapy in nonhuman primates.

Current antiretroviral therapy (ART) regimens efficiently limit HIV replication, thereby improving life expectancy of people living with HIV, but also cause metabolic side effects. The ongoing obesity epidemic has resulted in more people with metabolic comorbidities at the time of HIV infection, yet the impact of pre-existing metabolic dysregulation on infection sequelae and response to ART is unclear. Here, to investigate the impact of preexisting obesity and insulin resistance on acute infection and subsequent long-term ART, we infected a cohort of lean and obese adult male macaques with SIV and administered ART. The responses of lean and obese macaques to SIV and ART were similar with respect to plasma and cell-associated viral loads, ART drug levels in plasma and tissues, SIV-specific immune responses, adipose tissue and islet morphology, and colon inflammation, with baseline differences between lean and obese groups largely maintained. Both groups exhibited a striking depletion of CD4+ T cells from adipose tissue that did not recover with ART. However, differential responses to SIV and ART were observed for body weight, omental adipocyte size, and the adiponectin/leptin ratio, a marker of cardiometabolic risk. Thus, obesity and insulin resistance had limited effects on multiple responses to acute SIV infection and ART, while several factors that underlie long-term metabolic comorbidities were influenced by prior obesity and insulin resistance. These studies provide the foundation for future investigations into the efficacy of adjunct therapies such as metformin and glucagon-like peptide-1 receptor agonists in the prevention of metabolic comorbidities in people living with HIV.

Trends in Bundled Outpatient Behavioral Health Services in VA-Direct Versus VA-Purchased Care.

The Veterans Health Administration (VA) increasingly purchases community-based care (CC) to improve healthcare access, including behavioral health. In 2018, VA introduced standardized episodes of care (SEOCs) to guide authorization and purchase of CC services for specific indications in a defined timeframe without bundling payment. In this retrospective cross-sectional study, we describe trends in VA and CC behavioral healthcare utilization using the VA Outpatient Psychiatry SEOC definition. Counts of Outpatient Psychiatry SEOC-allowable service and procedure codes during fiscal years 2016-2019 were organized according to four SEOC-defined service types (evaluation and management, laboratory services, psychiatry services, transitional care) and measured as percentages of all included codes. Trends comparing behavioral healthcare utilization between Veterans using any CC versus VA only were analyzed using a linear mixed effects model. We identified nearly 3 million Veterans who registered 60 million qualifying service and procedure codes, with overall utilization increasing 77.8% in CC versus 5.2% in VA. Veterans receiving any CC comprised 3.9% of the cohort and 4.7% of all utilization. When examining service type as a percent of all Outpatient Psychiatry SEOC-allowable care among Veterans using CC, psychiatry services increased 12.2%, while transitional care decreased 8.8%. In regression analysis, shifts in service type utilization reflected descriptive results but with attenuated effect sizes. In sum, Outpatient Psychiatry SEOC-allowable service utilization grew, and service type composition changed, significantly more in CC than in VA. The role of SEOCs and their incentives may be important when evaluating future behavioral healthcare quality and value in bundled services.

Pitavastatin is Well-Tolerated with no Detrimental Effects on Physical Function.

BACKGROUND: Little is known about the potential benefits or harms of statins on physical function among people with HIV (PWH). METHODS: REPRIEVE was a double-blind randomized controlled trial evaluating pitavastatin for primary prevention of major adverse cardiovascular events (MACE) in PWH. Time to complete ten chair rises, 4-meter gait speed, grip strength, and a modified short physical performance test were assessed annually for up to 5 years in the ancillary study PREPARE and analyzed using linear mixed models. FINDINGS: Of 602 PWH, 52% were randomized to pitavastatin and 48% to placebo. Median age was 51 years; 18% were female at birth; 2% transgender; 40% Black, and 18% Hispanic. Median PREPARE follow-up was 4.7 (4.3, 5.0) years. Muscle symptoms (grade ≥3 or treatment-limiting) occurred in 5% of both groups. There was no evidence of decline in chair rise rate in either treatment group, and no difference in the pitavastatin group compared to placebo (estimated difference -0.10 [95% CI: -0.30, 0.10] rises/min/year; p=0.31). Small declines over time were observed in other physical function tests in both treatment groups, with no apparent differences between groups. INTERPRETATION: We observed minimal declines in physical function over 5 years of follow-up among middle-aged PWH, with no differences among PWH randomized to pitavastatin compared to placebo. This finding, combined with low prevalence of myalgias, supports the long-term safety of statin therapy on physical function, when used for primary prevention of MACE among PWH.

CROI 2024: Metabolic and Other Complications of HIV Infection.

Comorbid conditions have a major impact on the health, quality of life, and survival of people with HIV (PWH), particularly as they age. The 2024 Conference on Retroviruses and Opportunistic Infections (CROI) featured many excellent reports related to specific comorbidities, most notably cardiovascular disease, cancer, fatty liver disease, and hypertension. Major themes included hypertension management strategies used in low- and middle-income countries, important insights from the REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) study that focused on cardiometabolic outcomes, studies investigating metabolic-associated fatty liver disease, and the use of glucagon-like peptide-1 receptor agonists in PWH. This review focuses on the abstracts presented at CROI 2024 that discussed these areas, highlighting those with the most clinical impact.

The impact of diabetes mellitus on HIV virologic control: results of the MACS/WIHS combined cohort study.

OBJECTIVE: Diabetes mellitus (DM) is associated with lower antiretroviral (ART) drug exposure among persons with HIV (PWH) compared to PWH without DM. The association between DM and virologic control in PWH, however, remains unknown. METHODS: We included participants in the Multicenter AIDS Cohort Study/Women's Interagency HIV Study Combined Cohort Study (MWCCS) who had initiated ART between 1999 and 2020 and had a suppressed HIV viral load (≤200 copies/mL) within 1 year of ART initiation. We compared the frequency of incident HIV viremia (HIV-1 RNA >200 copies/mL) between adult PWH with and without DM. Poisson regression was used to examine the rate of incident viremia based on the diagnosis of DM among PWH. DM was defined as two consecutive fasting glucose measurements ≥126 mg/dL, use of anti-diabetic medications, pre-existing DM diagnosis, or a confirmed HbA1c >6.5%. RESULTS: 1,061 women (112 with DM, 949 without DM) and 633 men (41 with DM, and 592 without DM) were included in the analysis. The relative rate (RR) of incident HIV viremia for women with HIV and DM was lower when compared to women without DM (0.85 [95% CI: 0.72-0.99]; p = 0.04). The RR of incident viremia for women with uncontrolled DM (HbA1c>7.5%) was higher when compared to women with controlled DM (HbA1c <7.5%) (1.46 [95%CI: 1.03-2.07]; p = 0.03). In contrast, the RR of incident viremia for men with HIV and DM was not statistically different compared to men without DM (1.2 [95%CI: 0.96- 1.50]; p = 0.12). The results were stratified by adherence levels (100%, 95-99%, and less than 95% based on self-report). CONCLUSIONS: Women with DM who are highly adherent to ART (100% self-reported adherence) have a lower risk of viremia compared to women with HIV without DM. However, women with poorly controlled DM were at higher risk of HIV viremia than women with controlled DM. Further research is necessary to understand the impact of sex, DM, and ART adherence on HIV viremia.

Effects of Semaglutide on Muscle Structure and Function in the SLIM LIVER Study.

BACKGROUND: Semaglutide, a GLP-1 receptor agonist, is highly effective for decreasing weight. Concomitant loss of muscle mass often accompanies weight loss and may have consequences on muscle function. METHODS: This is a secondary analysis from the SLIM LIVER (ACTG A5371) study, a single-arm study of semaglutide in people with HIV (PWH) with metabolic dysfunction-associated steatotic liver disorder (MASLD). Participants received subcutaneous semaglutide for 24 weeks (titrated to 1 mg/week by week 4). Psoas volume and fat fraction were assessed from liver magnetic resonance imaging and physical function by 10-time chair rise test and 4m gait speed. Mean change from baseline to week 24 was estimated with linear regression modeling. RESULTS: 51 PWH enrolled; muscle measures were available from 46 participants. The mean age was 50 (standard deviation [SD] 11) years and BMI 35.5 (5.6) kg/m2, 43% were women, 33% Black, and 39% Hispanic/Latino. Psoas muscle volume decreased by 9.3% (95% confidence interval [CI]: -13.4, -5.2; p<0.001) over 24 weeks but psoas muscle fat did not significantly change (-0.42%, CI: -1.00, 0.17; p=0.16). Chair rise and gait speed had non-significant improvements of 1.27 seconds (CI: -2.7, 0.10) and 0.05 m/sec (CI: -0.01, 0.10), respectively (both p>0.07). The prevalence of slow gait speed (< 1 m/sec) decreased from 63% to 46% (p=0.029). CONCLUSIONS: In PWH receiving low-dose semaglutide for MASLD, despite decreased psoas muscle volume, there was no significant change in physical function. This suggests that function was maintained despite significant loss of muscle concomitant with weight loss.

Pre-pandemic Metabolic Correlates of COVID-19 Severity and Long COVID Incidence in People Living with HIV.

Host metabolic dysregulation, especially in tryptophan metabolism, is intricately linked to COVID-19 severity and its post-acute sequelae (Long COVID). People living with HIV (PLWH) experience similar metabolic dysregulation and face an increased risk of developing Long COVID. However, whether pre-existing HIV-associated metabolic dysregulations contribute in predisposing PLWH to severe COVID-19 outcomes remains underexplored. Analyzing pre-pandemic samples from PLWH with documented post-infection outcomes, we found specific metabolic alterations, including increased tryptophan catabolism, predicting an elevated risk of severe COVID-19 and the incidence of Long COVID. These alterations warrant further investigation for their potential prognostic and mechanistic significance in determining COVID-19 complications.

Information and resources VA health system leaders need to manage enrollment and retention for Post-9/11 veterans.

OBJECTIVE: To understand Veterans Health Administration (VA) leaders' information and resource needs for managing post-9/11 Veterans' VA enrollment and retention. DATA SOURCES AND STUDY SETTING: Interviews conducted from March-May 2022 of VA Medical Center (VAMC) leaders (N = 27) across 15 sites, using stratified sampling based on VAMC characteristics: enrollment rates, number of recently separated Veterans in catchment area, and state Medicaid expansion status. STUDY DESIGN: Interview questions were developed using Petersen et al.'s Factors Influencing Choice of Healthcare System framework as a guide. Interviews were transcribed verbatim, and two coders analyzed the interviews using Atlas.ti, a qualitative software program. Coders followed the qualitative coding philosophy developed by Crabtree and Miller, a process of developing codes for salient concepts as they are identified during the analysis process. DATA COLLECTION/EXTRACTION METHODS: Two coders analyzed 22% (N = 6) of the interviews and discussed and adjudicated any discrepancies. One coder independently coded the remainder of the interviews. PRINCIPAL FINDINGS: Several key themes were identified regarding facilitators and barriers for VA enrollment including reputation for high-quality VA care, convenience of VA services, awareness of VA services and benefits, and VA mental health services. Nearly every VA leader actively used tools and data to understand enrollment and retention rates and sought to enroll and retain more Veterans. To improve the management of enrollment and retention, VA leaders would like data shared in an easily understandable format and the capability to share data between the VA and community healthcare systems. CONCLUSIONS: Enrollment and retention information is important for healthcare leaders to guide their health system decisions. Various tools are currently being used to try to understand the data. However, a multifunctional tool is needed to better aggregate the data to provide VA leadership with key information on Veterans' enrollment and retention.

SHBG, Free Testosterone, and Type 2 Diabetes Risk in Middle-aged African Men: A Longitudinal Study.

Objectives: To investigate longitudinal changes in SHBG and free testosterone (free T) levels among Black middle-aged African men, with and without coexistent HIV, and explore associations with incident dysglycaemia and measures of glucose metabolism. Design: This longitudinal study enrolled 407 Black South African middle-aged men, comprising primarily 322 men living without HIV (MLWOH) and 85 men living with HIV (MLWH), with normal fasting glucose at enrollment. Follow-up assessments were conducted after 3.1 ± 1.5 years. Methods: At baseline and follow-up, SHBG, albumin, and total testosterone were measured and free T was calculated. An oral glucose tolerance test at follow-up determined dysglycaemia (impaired fasting glucose, impaired glucose tolerance, type 2 diabetes) and glucose metabolism parameters including insulin sensitivity (Matsuda index), insulin resistance (homeostasis model assessment of insulin resistance), and beta(ß)-cell function (disposition index). The primary analysis focussed on MLWOH, with a subanalysis on MLWH to explore whether associations in MLWOH differed from MLWH. Results: The prevalence of dysglycaemia at follow-up was 17% (n = 55) in MLWOH. Higher baseline SHBG was associated with a lower risk of incident dysglycaemia (odds ratio 0.966; 95% confidence interval 0.945-0.987) and positively associated with insulin sensitivity (ß = 0.124, P < .001) and ß-cell function (ß = 0.194, P = .001) at follow-up. Free T did not predict dysglycaemia. In MLWH, dysglycaemia prevalence at follow-up was 12% (n = 10). Neither baseline SHBG nor free T were associated with incident dysglycaemia and glucose metabolism parameters in MLWH. Conclusion: SHBG levels predict the development of dysglycaemia in middle-aged African men but do not exhibit the same predictive value in MLWH.

Transgender Women With Suppressed Testosterone Display Lower Burden of Coronary Disease Than Matched Cisgender Men.

Context: Cardiovascular disease (CVD) in transgender women (TW) may be affected by gender-affirming hormone therapy (GAHT) and HIV, but few data compare TW on contemporary GAHT to well-matched controls. Objective: We compared CVD burden and biomarker profiles between TW and matched cisgender men (CM). Methods: Adult TW on GAHT (n = 29) were recruited for a cross-sectional study (2018-2020). CM (n = 48) from the former Multicenter AIDS Cohort Study were matched 2:1 to TW on HIV serostatus, age ±5 years, race/ethnicity, BMI category and antiretroviral therapy (ART) type. Cardiac parameters were measured by CT and coronary atherosclerosis by coronary CT angiography; sex hormone and biomarker concentrations were measured centrally from stored samples. Results: Overall, median age was 53 years and BMI 29 kg/m2; 69% were non-white. All participants with HIV (71%) had viral suppression on ART. Only 31% of TW had testosterone suppression (<50 ng/dL, TW-S). Traditional CVD risk factors were similar between groups, except that TW-S had higher BMI than TW with non-suppressed testosterone (TW-T). TW-S had no evidence of non-calcified coronary plaque or advanced coronary stenosis, whereas TW-T and CM had similar burden. TW had lower prevalence of any coronary plaque, calcified plaque and mixed plaque than CM, regardless of testosterone concentrations and HIV serostatus. Estradiol but not testosterone concentrations moderately and negatively correlated with the presence of coronary plaque and stenosis. Small sample size limited statistical power. Conclusion: Older TW with suppressed total testosterone on GAHT had no CT evidence of non-calcified coronary plaque or advanced coronary stenosis. Longitudinal studies to understand relationships between GAHT and CVD risk in TW are needed.

Association between switching to integrase strand transfer inhibitors and incident diabetes in people with HIV.

OBJECTIVE: Integrase strand transfer inhibitors (INSTI) are associated with weight gain in people with HIV (PWH), but their impact on diabetes is unclear. We evaluated the association between switching from nonnucleoside reverse-transcriptase inhibitors (NNRTI) or protease inhibitors (PI) to INSTI and incident diabetes. DESIGN: Longitudinal cohort study. METHODS: We included PWH aged ≥18 years from the Johns Hopkins HIV Clinical Cohort (2007-2023) without history of diabetes who had used NNRTI or PI for ≥180 days. We followed participants up to 10 years from HIV primary care visits where they switched to INSTI or continued NNRTI or PI. We estimated the hazard of incident diabetes associated with switching to INSTI using weighted Cox regression with robust variance estimator. RESULTS: We included 2075 PWH who attended 22 116 visits where they continued NNRTI or PI and 631 visits where they switched to INSTI. Switching to INSTI was associated with a weighted hazard ratio (wHR) of 1.11 [95% confidence interval (CI), 0.77-1.59] for incident diabetes. The association if no weight gain occurred during the first two years was not qualitatively different (wHR 1.22; 95% CI, 0.82-1.80). In a posthoc analysis, switching to INSTI conferred a significant wHR of 1.79 (95% CI, 1.13-2.84) for diabetes within the first two years but not after. CONCLUSIONS: Switching from NNRTI or PI to INSTI did not significantly increase overall diabetes incidence in PWH, although there may be elevated risk in the first two years. These findings can inform considerations when switching to INSTI-based regimens.

Risk factors for progression from prediabetes to diabetes among older people with HIV.

OBJECTIVE: Risk factors for progression from prediabetes mellitus (pre-DM) to diabetes mellitus (DM) among people with HIV (PWH) receiving modern antiretroviral therapy (ART) require better characterization. DESIGN: AIDS Clinical Trials Group (ACTG) A5322 (HAILO) was an observational cohort study of PWH ≥40 years old. Participants initiated ART through ACTG randomized clinical trials. METHODS: We used Cox proportional hazards regression models to identify risk factors for development of DM among HAILO participants with pre-DM. RESULTS: Among 1035 HAILO participants, 74 (7%) had pre-DM at entry and another 679 (66%) developed pre-DM during follow-up. Of 753 PWH with pre-DM, 167 (22%) developed DM. In multivariable models, the risk of developing DM was greater with higher BMI, lower CD4 count (≤200 cells/mm 3 ), hypertriglyceridemia, or higher waist circumference at pre-DM diagnosis ( P  < 0.01). CONCLUSION: Rates of pre-DM and progression to DM remain high among virally suppressed PWH receiving modern ART regimens. Traditional risks for DM, such as higher BMI or waist circumference, are associated with increased risk of incident DM among PWH with pre-DM. The association between lower CD4 + and progression to DM suggests a role for advanced immunodeficiency and inflammation. Further investigation of interventions aimed at preventing DM among PWH with pre-DM is needed. Optimizing prevention and treatment for DM may be an intervenable opportunity to improve long-term outcomes for PWH.

Associations between epicardial, visceral, and subcutaneous adipose tissue with diastolic function in men with and without HIV.

BACKGROUND: People with HIV (PWH) are at greater risk for diastolic dysfunction compared with persons without HIV (PWOH). An increase in visceral adipose tissue is common among PWH and greater visceral adipose tissue is associated with diastolic dysfunction among PWOH. We investigated associations of visceral adipose tissue, subcutaneous adipose tissue, and other fat depots with subclinical diastolic dysfunction among men with and without HIV (MWH and MWOH). DESIGN: Cross-sectional analysis of MWH and MWOH in the Multicenter AIDS Cohort Study (MACS). METHODS: Participants underwent echocardiography for diastolic dysfunction assessment and CT scanning including subcutaneous, visceral, epicardial, and liver adiposity measurements. Diastolic dysfunction was defined by characterizing heart function on antiretroviral therapy0 criteria. Odds for diastolic dysfunction with each measure of adiposity were estimated using multivariable logistic regression. RESULTS: Among 403 participants (median age 57, 55% white, median BMI 26 kg/m 2 ), 25% met criteria for diastolic dysfunction and 59% MWH (82% undetectable plasma HIV RNA). Greater epicardial adipose tissue area was associated with higher odds of diastolic dysfunction [odds ratio:1.54 per SD; 95%confidence interval (CI) 1.15-2.05] when adjusted for demographics, HIV serostatus, and cardiovascular risk factors. This association did not differ by HIV serostatus and persisted when excluding MWH who were not virally suppressed. Less subcutaneous adipose tissue was associated with higher odds of diastolic dysfunction. Other adipose depots were not associated with diastolic dysfunction. CONCLUSION: Greater epicardial adipose tissue and less subcutaneous adipose tissue were associated with diastolic dysfunction, regardless of HIV serostatus and viral suppression. Greater epicardial adipose tissue and less subcutaneous adipose tissue observed among PWH may contribute to risk for heart failure with preserved ejection fraction in this population.

Improving perioperative acetaminophen administration for safer and cost-effective multimodal analgesia in pediatric surgery: A QI initiative.

BACKGROUND: The use of acetaminophen in the perioperative period has emerged as an attractive option for providing safer and cost-effective analgesia in children. AIMS: The primary aim of our project was to increase the use of acetaminophen (both oral and intravenous) in the perioperative period from a baseline of 39.5% to 50% for all surgical patients within 24 months. The secondary aim was to increase the use of enteral acetaminophen from 10% to 52.5% during the same period. METHODS: A multidisciplinary team was formed, and model for improvement was chosen as the QI methodology. The primary measure was the total percentage of surgical patients receiving any form of perioperative acetaminophen, while our secondary measure was the percentage use of oral acetaminophen administration. We also tracked the average maximum PACU (Post Anesthesia Care Unit) pain scores and the percentage of patients receiving IV opioids. Multiple interventions were conducted, including education, increasing the availability of acetaminophen, and optimizing the electronic medical record (EMR). Monthly data was collected using an automated report in the EMR. RESULTS: We successfully achieved our goal, increasing the use of acetaminophen from 39.5% to 70% within four months. Despite some fluctuations, by the end of 24 months, we not only met but surpassed our goal, with 63% of patients receiving perioperative acetaminophen. Similarly, the usage of oral acetaminophen increased from a baseline of 10% to 78%. Our average maximum PACU pain scores improved from 5.4 to 5.2, and the percentage of patients receiving rescue opioids decreased from 15.4 to 13.1. CONCLUSION: We successfully achieved and sustained our goals of improving acetaminophen use for our surgical patients without worsening pain scores or worsening use of intravenous opioids. Future directions include further refining our strategies and exploring additional opportunities to optimize pain management in pediatric perioperative settings.

Metabolic and inflammatory perturbation of diabetes associated gut dysbiosis in people living with and without HIV infection.

BACKGROUND: Gut dysbiosis has been linked with both HIV infection and diabetes, but its interplay with metabolic and inflammatory responses in diabetes, particularly in the context of HIV infection, remains unclear. METHODS: We first conducted a cross-sectional association analysis to characterize the gut microbial, circulating metabolite, and immune/inflammatory protein features associated with diabetes in up to 493 women (~ 146 with prevalent diabetes with 69.9% HIV +) of the Women's Interagency HIV Study. Prospective analyses were then conducted to determine associations of identified metabolites with incident diabetes over 12 years of follow-up in 694 participants (391 women from WIHS and 303 men from the Multicenter AIDS Cohort Study; 166 incident cases were recorded) with and without HIV infection. Mediation analyses were conducted to explore whether gut bacteria-diabetes associations are explained by altered metabolites and proteins. RESULTS: Seven gut bacterial genera were identified to be associated with diabetes (FDR-q < 0.1), with positive associations for Shigella, Escherichia, Megasphaera, and Lactobacillus, and inverse associations for Adlercreutzia, Ruminococcus, and Intestinibacter. Importantly, the associations of most species, especially Adlercreutzia and Ruminococcus, were largely independent of antidiabetic medications use. Meanwhile, 18 proteins and 76 metabolites, including 3 microbially derived metabolites (trimethylamine N-oxide, phenylacetylglutamine (PAGln), imidazolepropionic acid (IMP)), 50 lipids (e.g., diradylglycerols (DGs) and triradylglycerols (TGs)) and 23 non-lipid metabolites, were associated with diabetes (FDR-q < 0.1), with the majority showing positive associations and more than half of them (59/76) associated with incident diabetes. In mediation analyses, several proteins, especially interleukin-18 receptor 1 and osteoprotegerin, IMP and PAGln partially mediate the observed bacterial genera-diabetes associations, particularly for those of Adlercreutzia and Escherichia. Many diabetes-associated metabolites and proteins were altered in HIV, but no effect modification on their associations with diabetes was observed by HIV. CONCLUSION: Among individuals with and without HIV, multiple gut bacterial genera, blood metabolites, and proinflammatory proteins were associated with diabetes. The observed mediated effects by metabolites and proteins in genera-diabetes associations highlighted the potential involvement of inflammatory and metabolic perturbations in the link between gut dysbiosis and diabetes in the context of HIV infection.

Immunoglobulin G N-glycan markers of accelerated biological aging during chronic HIV infection.

People living with HIV (PLWH) experience increased vulnerability to premature aging and inflammation-associated comorbidities, even when HIV replication is suppressed by antiretroviral therapy (ART). However, the factors associated with this vulnerability remain uncertain. In the general population, alterations in the N-glycans on IgGs trigger inflammation and precede the onset of aging-associated diseases. Here, we investigate the IgG N-glycans in cross-sectional and longitudinal samples from 1214 women and men, living with and without HIV. PLWH exhibit an accelerated accumulation of pro-aging-associated glycan alterations and heightened expression of senescence-associated glycan-degrading enzymes compared to controls. These alterations correlate with elevated markers of inflammation and the severity of comorbidities, potentially preceding the development of such comorbidities. Mechanistically, HIV-specific antibodies glycoengineered with these alterations exhibit a reduced ability to elicit anti-HIV Fc-mediated immune activities. These findings hold potential for the development of biomarkers and tools to identify and prevent premature aging and comorbidities in PLWH.

Population-average mediation analysis for zero-inflated count outcomes.

Mediation analysis is an increasingly popular statistical method for explaining causal pathways to inform intervention. While methods have increased, there is still a dearth of robust mediation methods for count outcomes with excess zeroes. Current mediation methods addressing this issue are computationally intensive, biased, or challenging to interpret. To overcome these limitations, we propose a new mediation methodology for zero-inflated count outcomes using the marginalized zero-inflated Poisson (MZIP) model and the counterfactual approach to mediation. This novel work gives population-average mediation effects whose variance can be estimated rapidly via delta method. This methodology is extended to cases with exposure-mediator interactions. We apply this novel methodology to explore if diabetes diagnosis can explain BMI differences in healthcare utilization and test model performance via simulations comparing the proposed MZIP method to existing zero-inflated and Poisson methods. We find that our proposed method minimizes bias and computation time compared to alternative approaches while allowing for straight-forward interpretations.