Publications by authors named "Steven K Grinspoon"

167 Publications

Delineating tesamorelin response pathways in HIV-associated NAFLD using a targeted proteomic and transcriptomic approach.

Sci Rep 2021 May 18;11(1):10485. Epub 2021 May 18.

Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street 5LON207, Boston, MA, 02114, USA.

NAFLD is a leading comorbidity in HIV with an exaggerated course compared to the general population. Tesamorelin has been demonstrated to reduce liver fat and prevent fibrosis progression in HIV-associated NAFLD. We further showed that tesamorelin downregulated hepatic gene sets involved in inflammation, tissue repair, and cell division. Nonetheless, effects of tesamorelin on individual plasma proteins pertaining to these pathways are not known. Leveraging our prior randomized-controlled trial and transcriptomic approach, we performed a focused assessment of 9 plasma proteins corresponding to top leading edge genes within differentially modulated gene sets. Tesamorelin led to significant reductions in vascular endothelial growth factor A (VEGFA, log-fold change - 0.20 ± 0.35 vs. 0.05 ± 0.34, P = 0.02), transforming growth factor beta 1 (TGFB1, - 0.35 ± 0.56 vs. - 0.05 ± 0.43, P = 0.05), and macrophage colony stimulating factor 1 (CSF1, - 0.17 ± 0.21 vs. 0.02 ± 0.20, P = 0.004) versus placebo. Among tesamorelin-treated participants, reductions in plasma VEGFA (r = 0.62, P = 0.006) and CSF1 (r = 0.50, P = 0.04) correlated with a decline in NAFLD activity score. Decreases in TGFB1 (r = 0.61, P = 0.009) and CSF1 (r = 0.64, P = 0.006) were associated with reduced gene-level fibrosis score. Tesamorelin suppressed key angiogenic, fibrogenic, and pro-inflammatory mediators. CSF1, a regulator of monocyte recruitment and activation, may serve as an innovative therapeutic target for NAFLD in HIV. Clinical Trials Registry Number: NCT02196831.
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http://dx.doi.org/10.1038/s41598-021-89966-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131688PMC
May 2021

Growth Hormone Releasing Hormone Reduces Circulating Markers of Immune Activation in Parallel with Effects on Hepatic Immune Pathways in Individuals with HIV-Infection and Nonalcoholic Fatty Liver Disease.

Clin Infect Dis 2021 Apr 14. Epub 2021 Apr 14.

Metabolism Unit, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA.

Background: The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis modulates critical metabolic pathways; however, little is known regarding effects of augmenting pulsatile GH secretion on immune function in humans. This study used proteomics and gene set enrichment analysis to assess effects of a GH releasing hormone (GHRH) analog, tesamorelin, on circulating immune markers and liver tissue in people with HIV (PWH) and NAFLD.

Methods: 92 biomarkers associated with immunity, chemotaxis, and metabolism were measured in plasma samples from 61 PWH with NAFLD who participated in a double-blind, randomized trial of tesamorelin versus placebo for 12 months. Gene set enrichment analysis was performed on serial liver biopsies targeted to immune pathways.

Results: Tesamorelin, compared to placebo, decreased interconnected proteins related to cytotoxic T-cell and monocyte activation. Circulating concentrations of 13 proteins were significantly decreased, and no proteins increased, by tesamorelin. These included four chemokines (CCL3, CCL4, CCL13 [MCP4], IL8 [CXCL8]), two cytokines (IL-10 and CSF-1), and four T-cell associated molecules (CD8A, CRTAM, GZMA, ADGRG1), as well as ARG1, Gal-9, and HGF. Network analysis indicated close interaction among the gene pathways responsible for these proteins, with imputational analyses suggesting down regulation of a closely related cluster of immune pathways. Targeted transcriptomics using liver tissue confirmed a significant end-organ signal of down-regulated immune activation pathways.

Conclusions: Long-term treatment with a GHRH analog reduced markers of T-cell and monocyte/macrophage activity, suggesting that augmentation of the GH axis may ameliorate immune activation in an HIV population with metabolic dysregulation, systemic and end organ inflammation.
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http://dx.doi.org/10.1093/cid/ciab019DOI Listing
April 2021

Coronary Vasculature and Myocardial Structure in HIV: Physiologic Insights from the Renin-Angiotensin-Aldosterone System.

J Clin Endocrinol Metab 2021 Feb 24. Epub 2021 Feb 24.

Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

The landscape of HIV medicine dramatically changed with the advent of contemporary antiretroviral therapies (ART) which has allowed persons with HIV (PWH) to achieve good virologic control, essentially eliminating HIV-related complications and increasing life expectancy. As PWH are living longer, non-communicable diseases, such as cardiovascular disease (CVD), have become a leading cause of morbidity and mortality in PWH with rates that are 50-100% higher than in well-matched persons without HIV. In this review, we focus on disease of the coronary microvasculature and myocardium in HIV. We highlight a key hormonal system important to cardiovascular endocrinology, the renin-angiotensin-aldosterone system (RAAS), as a potential mediator of inflammatory driven-vascular and myocardial injury and consider RAAS blockade as a physiologically-targeted strategy to reduce CVD in HIV.
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http://dx.doi.org/10.1210/clinem/dgab112DOI Listing
February 2021

Increased CHIP Prevalence Amongst People Living with HIV.

medRxiv 2020 Nov 7. Epub 2020 Nov 7.

People living with human immunodeficiency virus (PLWH) have significantly increased risk for cardiovascular disease in part due to inflammation and immune dysregulation. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related acquisition and expansion of hematopoietic stem cells due to leukemogenic driver mutations, increases risk for both hematologic malignancy and coronary artery disease (CAD). Since increased inflammation is hypothesized to be both a cause and consequence of CHIP, we hypothesized that PLWH have a greater prevalence of CHIP. We searched for CHIP in multi-ethnic cases from the Swiss HIV Cohort Study (SHCS, n=600) and controls from the Atherosclerosis Risk in the Communities study (ARIC, n=8,111) from blood DNA-derived exome sequences. We observed that HIV is associated with increased CHIP prevalence, both in the whole study population and in a subset of 230 cases and 1002 matched controls selected by propensity matching to control for demographic imbalances (SHCS 7%, ARIC 3%, p=0.005). Additionally, unlike in ARIC, ASXL1 was the most commonly implicated mutated CHIP gene. We propose that CHIP may be one mechanism through which PLWH are at increased risk for CAD. Larger prospective studies should evaluate the hypothesis that CHIP contributes to the excess cardiovascular risk in PLWH.
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http://dx.doi.org/10.1101/2020.11.06.20225607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654930PMC
November 2020

Effects of Integrase Inhibitor-Based ART on the NLRP3 Inflammasome Among ART-Naïve People With HIV.

Open Forum Infect Dis 2020 Oct 29;7(10):ofaa459. Epub 2020 Sep 29.

Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

The NOD-like receptor protein family pyrin domain containing 3 (NLRP3) inflammasome, activated in the setting of HIV, contributes to pro-atherogenic inflammation. Among antriretroviral therapy-naïve people with HIV (vs controls), levels of caspase-1-a key component of the NLRP3 inflammasome-were significantly increased. Six months of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate significantly decreased caspase-1 levels in association with CD4+/CD8+ ratio recovery.

. ClinicalTrials.gov NCT01766726.
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http://dx.doi.org/10.1093/ofid/ofaa459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588107PMC
October 2020

Relationship of IGF-1 and IGF-Binding Proteins to Disease Severity and Glycemia in Nonalcoholic Fatty Liver Disease.

J Clin Endocrinol Metab 2021 Jan;106(2):e520-e533

Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Context: Growth hormone (GH) and IGF-1 help regulate hepatic glucose and lipid metabolism, and reductions in these hormones may contribute to development of nonalcoholic fatty liver disease (NAFLD).

Objective: To assess relationships between hepatic expression of IGF1 and IGF-binding proteins (IGFBPs) and measures of glycemia and liver disease in adults with NAFLD. Secondarily to assess effects of GH-releasing hormone (GHRH) on circulating IGFBPs.

Design: Analysis of data from a randomized clinical trial of GHRH.

Setting: Two US academic medical centers.

Participants: Participants were 61 men and women 18 to 70 years of age with HIV-infection, ≥5% hepatic fat fraction, including 39 with RNA-Seq data from liver biopsy.

Main Outcome Measures: Hepatic steatosis, inflammation, and fibrosis by histopathology and measures of glucose homeostasis.

Results: Hepatic IGF1 mRNA was significantly lower in individuals with higher steatosis and NAFLD Activity Score (NAS) and was inversely related to glucose parameters, independent of circulating IGF-1. Among the IGFBPs, IGFBP2 and IGFBP4 were lower and IGFBP6 and IGFBP7 (also known as IGFBP-related protein 1) were higher with increasing steatosis. Hepatic IGFBP6 and IGFBP7 mRNA levels were positively associated with NAS. IGFBP7 mRNA increased with increasing fibrosis. Hepatic IGFBP1 mRNA was inversely associated with glycemia and insulin resistance, with opposite relationships present for IGFBP3 and IGFBP7. GHRH increased circulating IGFBP-1 and IGFBP-3, but decreased IGFBP-2 and IGFBP-6.

Conclusions: These data demonstrate novel relationships of IGF-1 and IGFBPs with NAFLD severity and glucose control, with divergent roles seen for different IGFBPs. Moreover, the data provide new information on the complex effects of GHRH on IGFBPs.
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http://dx.doi.org/10.1210/clinem/dgaa792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823253PMC
January 2021

Effects of tesamorelin on hepatic transcriptomic signatures in HIV-associated NAFLD.

JCI Insight 2020 08 20;5(16). Epub 2020 Aug 20.

Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Nonalcoholic fatty liver disease (NAFLD) is a common comorbidity among people living with HIV that has a more aggressive course than NAFLD among the general population. In a recent randomized placebo-controlled trial, we demonstrated that the growth hormone-releasing hormone analog tesamorelin reduced liver fat and prevented fibrosis progression in HIV-associated NAFLD over 1 year. As such, tesamorelin is the first strategy that has shown to be effective against NAFLD among the population with HIV. The current study leveraged paired liver biopsy specimens from this trial to identify hepatic gene pathways that are differentially modulated by tesamorelin versus placebo. Using gene set enrichment analysis, we found that tesamorelin increased hepatic expression of hallmark gene sets involved in oxidative phosphorylation and decreased hepatic expression of gene sets contributing to inflammation, tissue repair, and cell division. Tesamorelin also reciprocally up- and downregulated curated gene sets associated with favorable and poor hepatocellular carcinoma prognosis, respectively. Notably, among tesamorelin-treated participants, these changes in hepatic expression correlated with improved fibrosis-related gene score. Our findings inform our knowledge of the biology of pulsatile growth hormone action and provide a mechanistic basis for the observed clinical effects of tesamorelin on the liver.
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http://dx.doi.org/10.1172/jci.insight.140134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455119PMC
August 2020

An Evaluation of Baseline Kidney Function in the REPRIEVE Trial of Pitavastatin in Human Immunodeficiency Virus.

J Infect Dis 2020 07;222(Suppl 1):S41-S51

Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, USA.

Background: Chronic kidney disease is a common comorbid condition among persons living with human immunodeficiency virus (PWH). We characterized baseline kidney function in the REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) trial cohort.

Methods: REPRIEVE enrolled PWH with low to moderate cardiovascular risk based on traditional risk factors to evaluate the effect of statin therapy on cardiovascular events. We determined baseline estimated glomerular filtration rate (eGFR) with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Modification of Diet in Renal Disease, and Cockcroft-Gault equations, and we evaluated baseline factors associated with eGFR <90 mL/min/1.73 m2 by logistic regression. We performed Bland-Altman plots and scatterplots to assess agreement between equations.

Results: Among 7770 participants enrolled, the median age was 50 years, 31% were female (natal sex), 43% black or African American and 15% Asian, the median body mass index (calculated as calculated as weight in kilograms divided by height in meters squared) was 25.8, and the median CD4 cell count 620/µL. The median CKD-EPI eGFR was 97 mL/min/1.73 m2, and 38% had an eGFR <90 mL/min/1.73 m2. In the adjusted model, factors associated with eGFR <90 mL/min/1.73 m2 included white race, older age, higher body mass index, high-income region of enrollment, hypertension, and tenofovir disoproxil fumarate. The CKD-EPI and Modification of Diet in Renal Disease equations demonstrated strong agreement, particularly at lower eGFR values. Overall, there was 56% concordance between the 3 equations (categories <60, 60 to <90, ≥90 mL/min), improving to 73% after accounting for individual body surface area.

Conclusions: REPRIEVE enrolled a diverse cohort including a substantial number of PWH with reduced kidney function. Factors associated with reduced eGFR included traditional risk factors and tenofovir disoproxil fumarate exposure. Three commonly used equations have only fair agreement, with potential implications for both clinical care and epidemiologic studies.

Clinical Trials Registration: NCT02344290.
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http://dx.doi.org/10.1093/infdis/jiaa222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347080PMC
July 2020

Physical Function Impairment and Frailty in Middle-Aged People Living With Human Immunodeficiency Virus in the REPRIEVE Trial Ancillary Study PREPARE.

J Infect Dis 2020 07;222(Suppl 1):S52-S62

University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.

Background: People with human immunodeficiency virus (PWH) are at risk for accelerated development of physical function impairment and frailty; both associated with increased risk of falls, hospitalizations, and death. Identifying factors associated with physical function impairment and frailty can help target interventions.

Methods: The REPRIEVE trial enrolled participants 40-75 years of age, receiving stable antiretroviral therapy with CD4+ T-cell count >100 cells/mm3, and with low to moderate cardiovascular disease risk. We conducted a cross-sectional analysis of those concurrently enrolled in the ancillary study PREPARE at enrollment.

Results: Among the 266 participants, the median age was 51 years; 81% were male, and 45% were black, and 28% had hypertension. Body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) was 25 to <30 in 38% and ≥30 in 30%, 33% had a high waist circumference, 89% were physically inactive, 37% (95% confidence interval, 31%, 43%) had physical function impairment (Short Physical Performance Battery score ≤10), and 6% (4%, 9%) were frail and 42% prefrail. In the adjusted analyses, older age, black race, greater BMI, and physical inactivity were associated with physical function impairment; depression and hypertension were associated with frailty or prefrailty.

Conclusions: Physical function impairment was common among middle-aged PWH; greater BMI and physical inactivity are important modifiable factors that may prevent further decline in physical function with aging.

Clinical Trials Registration: NCT02344290.
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http://dx.doi.org/10.1093/infdis/jiaa249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347078PMC
July 2020

Patterns of Antiretroviral Therapy Use and Immunologic Profiles at Enrollment in the REPRIEVE Trial.

J Infect Dis 2020 07;222(Suppl 1):S8-S19

Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Background: Patterns of antiretroviral therapy (ART) use and immunologic correlates vary globally, and contemporary trends are not well described.

Methods: The REPRIEVE trial (Randomized Trial to Prevent Vascular Events in HIV) enrolled persons with human immunodeficiency virus (HIV) who were aged 40-75 years, receiving ART, and had low-to-moderate cardiovascular disease risk. ART use was summarized within Global Burden of Disease (GBD) super-regions, with adjusted linear and logistic regression analyses examining associations with immune parameters and key demographics.

Results: A total of 7770 participants were enrolled, with a median age of 50 years (interquartile range, 45-55 years); 31% were female, 43% were black or African American, 15% were Asian, 56% had a body mass index >25 (calculated as weight in kilograms divided by height in meters squared), and 49% were current or former smokers. The median CD4 T-cell count was 620/µL (interquartile range, 447-826/ µ L), and the median duration of prior ART use, 9.5 years (5.3-14.8) years. The most common ART regimens were nucleoside/nucleotide reverse-transcriptase inhibitor (NRTI) plus nonnucleoside reverse-transcriptase inhibitor (43%), NRTI plus integrase strand transfer inhibitor (25%), and NRTI plus protease inhibitor (19%). Entry ART varied by GBD region, with shifts during the trial enrollment period. In adjusted analyses, entry CD4 cell count and CD4/CD8 ratio were associated with GBD region, sex, entry regimen, duration of ART, and nadir CD4 cell count; CD4 and CD8 cell counts were also associated with body mass index and smoking status.

Conclusions: There were substantial variations in ART use by geographic region and over time, likely reflecting the local availability of specific medications, changes in treatment guidelines and provider/patient preferences. The analyses of CD4 cell counts and CD4/CD8 ratios may provide valuable insights regarding immune correlates and outcomes in people living with HIV.

Clinical Trials Registration: NCT02344290.
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http://dx.doi.org/10.1093/infdis/jiaa259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347081PMC
July 2020

Leveraging a Landmark Trial of Primary Cardiovascular Disease Prevention in Human Immunodeficiency Virus: Introduction From the REPRIEVE Coprincipal Investigators.

J Infect Dis 2020 07;222(Suppl 1):S1-S7

Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) is the largest study of cardiovascular disease in human immunodeficiency virus. Enrolling 7770 participants from 2015 to 2019 with sites across 5 continents, REPRIEVE will assess the effects of a statin as a cardiovascular disease prevention strategy in people with HIV (PWH) receiving antiretroviral therapy (ART). Although the primary purpose of REPRIEVE, and its substudy assessing coronary plaque, is to assess cardiovascular outcomes, the trial is a rich source of data on population characteristics and critical comorbidities in PWH, particularly across Global Burden of Disease (GBD) regions, reflective of the ethnic, racial, and gender diversity in this global epidemic. The purpose of this Supplement is to leverage the rich phenotyping in REPRIEVE, to provide data on detailed patterns of baseline ART and immune function by GBD region, reproductive aging among cisgender women, and data on the participation and clinical characteristics of transgender participants. We also leveraged REPRIEVE to assess critical comorbidities, including renal dysfunction, muscle function and frailty, and myocardial steatosis. REPRIEVE is a remarkable collaboration between funders, trial networks, clinical research sites, clinical and data coordinating centers, and willing participants who devoted their time to make the trial possible.
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http://dx.doi.org/10.1093/infdis/jiaa098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347079PMC
July 2020

Characteristics of REPRIEVE Trial Participants Identifying Across the Transgender Spectrum.

J Infect Dis 2020 07;222(Suppl 1):S31-S40

National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

Because persons who identify across the transgender spectrum (PATS) are a key population in human immunodeficiency virus (HIV) yet are underreported in HIV and cardiovascular research, we aimed to characterize this population within the REPRIEVE global clinical trial (n = 7770). Acceptance of gathering gender identity was high (96%). Participation by PATS was 1.7% overall, 2.4% among natal males, 0.3% among natal females, and varied across geographic regions (from 0% in sub-Saharan Africa to 2.3% in High Income Region). Thirty percent of natal male PATS identified other than transgender. Some characteristics differed by gender. Most notably, 38% of natal male PATS receiving gender-affirming treatment had waist circumference >102 cm (compared with ≤25% in other groups). Given that PATS is a key population, HIV research should routinely report trial participation and outcomes by gender in addition to natal sex, to provide the results needed to optimize medical care to PATS.
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http://dx.doi.org/10.1093/infdis/jiaa213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347077PMC
July 2020

Correlates and Timing of Reproductive Aging Transitions in a Global Cohort of Midlife Women With Human Immunodeficiency Virus: Insights From the REPRIEVE Trial.

J Infect Dis 2020 07;222(Suppl 1):S20-S30

Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Background: Reproductive aging may contribute to cardiometabolic comorbid conditions. We integrated data on gynecologic history with levels of an ovarian reserve marker (anti-müllerian hormone [AMH)] to interrogate reproductive aging patterns and associated factors among a subset of cisgender women with human immunodeficiency virus (WWH) enrolled in the REPRIEVE trial.

Methods: A total of 1449 WWH were classified as premenopausal (n = 482) (menses within 12 months; AMH level ≥20 pg/mL; group 1), premenopausal with reduced ovarian reserve (n = 224) (menses within 12 months; AMH <20 pg/mL; group 2), or postmenopausal (n = 743) (no menses within12 months; AMH <20 pg/mL; group 3). Proportional odds models, adjusted for chronologic age, were used to investigate associations of cardiometabolic and demographic parameters with reproductive aging milestones (AMH <20 pg/mL or >12 months of amenorrhea). Excluding WWH with surgical menopause, age at final menstrual period was summarized for postmenopausal WWH (group 3) and estimated among all WWH (groups 1-3) using an accelerated failure-time model.

Results: Cardiometabolic and demographic parameters associated with advanced reproductive age (controlling for chronologic age) included waist circumference (>88 vs ≤88 cm) (odds ratio [OR], 1.38; 95% confidence interval, 1.06-1.80; P = .02), hemoglobin (≥12 vs <12 g/dL) (2.32; 1.71-3.14; P < .01), and region of residence (sub-Saharan Africa [1.50; 1.07-2.11; P = .02] and Latin America and the Caribbean [1.59; 1.08-2.33; P = .02], as compared with World Health Organization Global Burden of Disease high-income regions). The median age (Q1, Q3) at the final menstrual period was 48 (45, 51) years when described among postmenopausal WWH, and either 49 (46, 52) or 50 (47, 53) years when estimated among all WWH, depending on censoring strategy.

Conclusions: Among WWH in the REPRIEVE trial, more advanced reproductive age is associated with metabolic dysregulation and region of residence. Additional research on age at menopause among WWH is needed.

Clinical Trials Registration: NCT0234429.
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http://dx.doi.org/10.1093/infdis/jiaa214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347076PMC
July 2020

Myocardial Steatosis Among Antiretroviral Therapy-Treated People With Human Immunodeficiency Virus Participating in the REPRIEVE Trial.

J Infect Dis 2020 07;222(Suppl 1):S63-S69

Infectious Diseases Section, Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System and David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California, USA.

Background: People with human immunodeficiency virus (PWH) face increased risks for heart failure and adverse heart failure outcomes. Myocardial steatosis predisposes to diastolic dysfunction, a heart failure precursor. We aimed to characterize myocardial steatosis and associated potential risk factors among a subset of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) participants.

Methods: Eighty-two PWH without known heart failure successfully underwent cardiovascular magnetic resonance spectroscopy, yielding data on intramyocardial triglyceride (IMTG) content (a continuous marker for myocardial steatosis extent). Logistic regression models were applied to investigate associations between select clinical characteristics and odds of increased or markedly increased IMTG content.

Results: Median (Q1, Q3) IMTG content was 0.59% (0.28%, 1.15%). IMTG content was increased (> 0.5%) among 52% and markedly increased (> 1.5%) among 22% of participants. Parameters associated with increased IMTG content included age (P = .013), body mass index (BMI) ≥ 25 kg/m2 (P = .055), history of intravenous drug use (IVDU) (P = .033), and nadir CD4 count < 350 cells/mm³ (P = .055). Age and BMI ≥ 25 kg/m2 were additionally associated with increased odds of markedly increased IMTG content (P = .049 and P = .046, respectively).

Conclusions: A substantial proportion of antiretroviral therapy-treated PWH exhibited myocardial steatosis. Age, BMI ≥ 25 kg/m2, low nadir CD4 count, and history of IVDU emerged as possible risk factors for myocardial steatosis in this group.

Clinical Trials Registration: NCT02344290; NCT03238755.
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http://dx.doi.org/10.1093/infdis/jiaa245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347082PMC
July 2020

Reply to Maurice and Lemoine.

Clin Infect Dis 2021 03;72(5):909

Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1093/cid/ciaa796DOI Listing
March 2021

Differential Plasma Protein Regulation and Statin Effects in Human Immunodeficiency Virus (HIV)-Infected and Non-HIV-Infected Patients Utilizing a Proteomics Approach.

J Infect Dis 2020 08;222(6):929-939

Massachusetts General Hospital, Metabolism Unit and Harvard Medical School, Boston, Massachusetts, USA.

Background: People with human immunodeficiency virus (PWH) demonstrate increased atherosclerotic cardiovascular disease (ASCVD). Statins are being studied to prevent ASCVD in human immunodeficiency virus (HIV), but little is known regarding the effects of statins on a broad range of inflammatory and cardiovascular proteins in this population.

Methods: We used a highly specific discovery proteomic approach (Protein Extension Assay), to determine statin effects on over 350 plasma proteins in relevant ASCVD pathways among HIV and non-HIV groups. Responses to pitavastatin calcium were assessed in 89 PWH in the INTREPID trial and 46 non-HIV participants with features of central adiposity and insulin resistance. History of cardiovascular disease was exclusionary for both studies.

Results: Among participants with HIV, PCOLCE (enzymatic cleavage of type I procollagen) significantly increased after pitavastatin therapy and PLA2G7 (systemic marker of arterial inflammation) decreased. Among participants without HIV, integrin subunit alpha M (integrin adhesive function) and defensin alpha-1 (neutrophil function) increased after pitavastatin therapy and PLA2G7 decreased. At baseline, comparing participants with and without HIV, differentially expressed proteins included proteins involved in platelet and endothelial function and immune activation.

Conclusions: Pitavastatin affected proteins important to platelet and endothelial function and immune activation, and effects differed to a degree within PWH and participants without HIV.
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http://dx.doi.org/10.1093/infdis/jiaa196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430172PMC
August 2020

Clinical Predictors of Liver Fibrosis Presence and Progression in HIV-Associated NAFLD.

Clin Infect Dis 2020 Apr 9. Epub 2020 Apr 9.

Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Background: Nonalcoholic fatty disease (NAFLD) affects over one-third of people living with HIV. Nonetheless, the natural history of HIV-associated NAFLD is poorly understood, including which patients are most likely to have a progressive disease course.

Methods: We leveraged a randomized trial of the growth hormone-releasing hormone analogue tesamorelin to treat NAFLD in HIV. Sixty-one participants with HIV-associated NAFLD were randomized to tesamorelin or placebo for 12 months. Participants underwent liver biopsy at baseline and 12 months with histologic evaluation performed by an expert pathologist blinded to treatment.

Results: In all participants with baseline biopsies (n=58), 43% had hepatic fibrosis. Individuals with fibrosis had higher NAFLD Activity Score (NAS) (3.6±2.0 vs. 2.0±0.8, P<0.0001) and visceral fat content (284±91 cm2 vs. 212±95 cm2, P=0.005), but no difference in hepatic fat or BMI. Among placebo-treated participants with paired biopsies (n=24), 38% had hepatic fibrosis progression over 12 months. For each 25 cm2 higher visceral fat at baseline, the odds of fibrosis progression increased by 37% (OR 1.37, 95% CI 1.03, 2.07). There was no difference in baseline NAS score between fibrosis progressors and non-progressors, though NAS score rose over time in the progressor group (1.1±0.8 vs. -0.5±0.6, P<0.0001).

Conclusions: In this longitudinal study of HIV-associated NAFLD, high rates of hepatic fibrosis and progression were observed. Visceral adiposity was identified as a novel clinical predictor of worsening fibrosis. In contrast, baseline histologic characteristics were not found to relate to fibrosis changes over time. Further studies are needed to identify additional biomarkers of accelerated disease.
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http://dx.doi.org/10.1093/cid/ciaa382DOI Listing
April 2020

Successful recruitment of a multi-site international randomized placebo-controlled trial in people with HIV with attention to diversity of race and ethnicity: critical role of central coordination.

HIV Res Clin Pract 2020 02 11;21(1):11-23. Epub 2020 Mar 11.

Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) is a multicenter, randomized, placebo-controlled trial, designed to test whether a statin medication can prevent cardiovascular disease in people with HIV. REPRIEVE recently completed enrollment of 7557 participants at over 100 clinical sites globally. Participant groups of focus were women, and racial and ethnic minorities. To describe recruitment methods and strategies developed by the REPRIEVE Clinical Coordinating Center (CCC) and share best practices learned from the recruitment process. Enrollment targets were agreed upon with the primary funder, the National Heart, Lung, and Blood Institute (NHLBI) and were milestone driven. Milestones included number of sites activated, number of participants enrolled within specific time frames, and proportion of women and minorities enrolled. Strategies to achieve these milestones included structured interviews with site-designated REPRIEVE Recruitment Champions to develop best practices, development of a multimedia campaign, and site level recruitment support. Recruitment initiated March, 2015 and completed March, 2019. The final accrual target was 7500 participants over 48 months. The trial met this target within the time specified. Overall, 10,613 screens were completed, 48% of participants enrolled from sites outside of North America, 32% were female, 44% were Black or African American, and 25% were Hispanic or Latino. REPRIEVE met its overall projected recruitment goal by using multiple, simultaneous strategies to specifically target a diverse population including minority subgroups. REPRIEVE benefited from the development of recruitment strategies with clear targets and communication of accrual targets to study teams.
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http://dx.doi.org/10.1080/25787489.2020.1733794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664829PMC
February 2020

Measures of Adipose Tissue Redistribution and Atherosclerotic Coronary Plaque in HIV.

Obesity (Silver Spring) 2020 04 21;28(4):749-755. Epub 2020 Feb 21.

Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Objective: People with HIV (PWH) who are well treated on antiretroviral therapy remain at increased risk for body composition changes, including increased visceral adipose tissue (VAT) and reduced subcutaneous adipose tissue (SAT), as well as increased cardiovascular disease (CVD). The relationship between adipose compartments and coronary disease is not well understood among PWH.

Methods: A total of 148 PWH and 68 uninfected individuals without CVD were well phenotyped for VAT and SAT via single-section abdominal computed tomography (CT) at L4. Coronary artery calcium (CAC) score was assessed by noncontrast cardiac CT and coronary plaque composition by coronary CT angiography.

Results: Increased VAT was significantly related to increased presence of plaque (OR, 1.55 per 100 cm ; P = 0.008) and CAC > 0 (OR, 1.56 per 100 cm ; P = 0.006) in the HIV group. In contrast, increased SAT was related to reduced presence of plaque (OR, 0.79 per 100 cm ; P = 0.057) and reduced CAC > 0 (OR, 0.69 per 100 cm , P = 0.007) among PWH. The VAT to SAT ratio showed a strong relationship to overall presence of calcified plaque (OR, 3.30; P = 0.03) and CAC > 0 (OR, 3.57; P < 0.001) in the HIV group. VAT and waist to hip ratio, but not SAT, were strong predictors of plaque in the uninfected group. BMI did not relate in either group.

Conclusions: Fat redistribution phenotyping by simultaneous quantification of VAT and SAT as independent measures could help identify those PWH at higher risk for CVD.
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http://dx.doi.org/10.1002/oby.22742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093223PMC
April 2020

Association of In Utero HIV Exposure With Obesity and Reactive Airway Disease in HIV-Negative Adolescents and Young Adults.

J Acquir Immune Defic Syndr 2020 02;83(2):126-134

Metabolism Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA.

Background: HIV-negative individuals with in utero HIV exposure represent an emerging population, exceeding 18 million people worldwide. Long-term clinical outcomes among HIV-exposed uninfected (HEU) individuals into adolescence and young adulthood remain unknown.

Setting: US academic health system.

Methods: In this observational cohort study, we leveraged a patient data registry to identify 50 HEU adolescents and young adults. We also identified 141 HIV-unexposed controls that were matched to HEU subjects up to 3:1 on age of last encounter (±2 years), birthdate (±5 years), sex, race/ethnicity, and zip code. All subjects were born since January 1, 1990, with medical records available into adolescence and young adulthood. Primary outcomes were most recent body mass index (BMI) z-score and presence of reactive airway disease (RAD). Records were manually reviewed to extract health information.

Results: Fifty HEU adolescents and young adults (18 ± 3 years, 54% men) and 141 matched controls (19 ± 3 years, 54% men) were compared. HEU individuals had a higher BMI z-score (1.12 ± 1.08 vs. 0.73 ± 1.09, P = 0.03) and an increased prevalence of obesity (42% vs. 22%, P = 0.009) compared with controls. HEU subjects also had a higher prevalence of RAD vs. controls (40% vs. 23%, P = 0.03). These differences persisted on adjusting for demographic, socioeconomic, maternal, and birth-related factors. Maternal prenatal CD4 T-cell count was inversely associated with BMI z-score among HEU adolescents (r = -0.47, P = 0.01).

Conclusions: HEU adolescents and young adults exhibited a heightened prevalence of obesity and RAD compared with HIV-unexposed controls. Additional studies are needed to optimize care for the expanding population of HEU individuals transitioning to adulthood.
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http://dx.doi.org/10.1097/QAI.0000000000002235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237070PMC
February 2020

Brief Report: Adipogenic Expression of Brown Fat Genes in HIV and HIV-Related Parameters.

J Acquir Immune Defic Syndr 2019 12;82(5):491-495

Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

Context: Persons with HIV are at increased risk for adipose dysfunction, which could mediate metabolic complications such as cardiovascular disease, fatty liver disease, and diabetes. We have previously reported reduced browning and beiging capacity of the subcutaneous adipose depot in HIV.

Objective: We sought to evaluate how HIV-related parameters are related to the expression of brown and beige fat genes in the abdominal subcutaneous adipose tissue.

Design: Eighteen persons with HIV underwent punch biopsy of abdominal subcutaneous fat to determine mRNA expression of adipose-related genes using quantitative reverse transcriptase-polymerase chain reaction.

Results: Duration of antiretroviral therapy use, particularly related to protease inhibitor use, was significantly related to reduced expression of multiple brown and beige fat genes (including UCP1, PGC1α, PRDM16 and others, all P ≤ 0.04) in the abdominal subcutaneous fat. In addition, duration of HIV and CD4 T-cell count were significantly correlated with reduced expression of multiple brown and beige fat genes in the abdominal subcutaneous fat (PGC1α, P2XR5, TMEM26, CD137, all P ≤ 0.05 for duration of HIV; and PGC1α, ZIC1, PRDM16, PAT2, P2RX5, TMEM26, CD137, all P ≤ 0.04). In contrast, HIV viral load did not correlate with any brown or beige fat genes.

Conclusions: Key HIV-related parameters reflective of nonacute infection (increased duration of HIV and duration of antiretroviral therapy use) or relatively reduced immunologic function (lower CD4 count) were linked to reduced expression of brown and beige fat gene in the abdominal subcutaneous adipose depot.

Clinical Trial Registration: NCT01098045.
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http://dx.doi.org/10.1097/QAI.0000000000002180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857717PMC
December 2019

Effects of tesamorelin on non-alcoholic fatty liver disease in HIV: a randomised, double-blind, multicentre trial.

Lancet HIV 2019 12 11;6(12):e821-e830. Epub 2019 Oct 11.

Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address:

Background: Non-alcoholic fatty liver disease (NAFLD) is a substantial cause of comorbidity in people with HIV and there are no proven pharmacological treatments for the disease in this population. We assessed the effects of tesamorelin on liver fat and histology in people with HIV and NAFLD.

Methods: This randomised, double-blind, multicentre study with identical placebo as a comparator was done in a hospital and a medical research centre in the USA. People with HIV infection and a hepatic fat fraction (HFF) of 5% or more by proton magnetic resonance spectroscopy were eligible. Participants were randomly assigned (1:1) to receive either tesamorelin 2 mg once daily or placebo once daily for 12 months, followed by a 6-month open-label phase during which all participants received tesamorelin 2 mg daily. The randomisation list was prepared by the study statistician using a permuted block algorithm within each stratum with randomly varying block sizes. The primary endpoint was change in HFF between baseline and 12 months. The primary safety endpoint was glucose. Analysis was by intention to treat using all available data. This trial is registered with ClinicalTrials.gov, number NCT02196831.

Findings: 61 patients were enrolled between Aug 20, 2015, and Jan 16, 2019, of whom 30 received tesamorelin and 30 received placebo. Patients receiving tesamorelin had a greater reduction of HFF than did patients receiving placebo, with an absolute effect size of -4·1% (95% CI -7·6 to -0·7, p=0·018), corresponding to a -37% (95% CI -67 to -7, p=0·016) relative reduction from baseline. After 12 months, 35% of individuals receiving tesamorelin and 4% receiving placebo had a HFF of less than 5% (p=0·0069). Changes in fasting glucose and glycated haemoglobin were not different between groups at 12 months. Individuals in the tesamorelin group experienced more localised injection site complaints than those in the placebo group, though none were judged to be serious.

Interpretation: Tesamorelin might be beneficial in people with HIV and NAFLD. Further studies are needed to determine the long-term effects of tesamorelin on liver histology.

Funding: National Institutes of Health and National Institute of Allergy and Infectious Diseases.
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http://dx.doi.org/10.1016/S2352-3018(19)30338-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981288PMC
December 2019

Every Minute Counts-The Time Is Now to Understand Predictors of Stroke in HIV.

EClinicalMedicine 2019 Aug 16;13:8-9. Epub 2019 Aug 16.

Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States of America.

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http://dx.doi.org/10.1016/j.eclinm.2019.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734098PMC
August 2019

Individual coronary plaque changes on serial CT angiography: Within-patient heterogeneity, natural history, and statin effects in HIV.

J Cardiovasc Comput Tomogr 2020 Mar - Apr;14(2):144-148. Epub 2019 Aug 21.

Cardiovascular Imaging Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Background: It is not known how the volume and composition of individual coronary plaques change over time in HIV-infected people and whether statins influence these changes.

Methods: We included forty adults with HIV and subclinical coronary atherosclerosis who participated in a randomized controlled trial of placebo vs. atorvastatin. All participants underwent serial coronary computed tomography angiography at baseline and after one year. Individual coronary plaques were measured to assess the within-patient variability of plaque volume and composition changes. Left-main, proximal-right, proximal-left-anterior descending, and proximal-circumflex coronary segments were considered proximal. Plaque voxels with attenuation ≤130 Hounsfield Units (HU) were defined as noncalcified and further divided into fatty (<40HU) and fibrotic (40-130HU) components.

Results: In 37 patients who completed the trial, there were 92 coronary plaques. Individual plaque changes varied highly, with some plaques increasing while others decreased in the same patient. Overall, 77% vs. 51% of individual plaques progressed, while 24% vs. 49% regressed in placebo and statin, respectively (p = 0.016). Substantial increases in proximal plaques drove the progression in placebo. Statins suppressed these large increases, resulting in a 3-fold lower variance in plaque volume change compared to placebo (p = 0.025). Statins suppressed progression of fibrotic (p = 0.015) plaque, with a trend towards reducing fatty (p = 0.075) plaque and no significant effect on the calcified portion (p = 0.203).

Conclusion: In persons with HIV, a population with increased atherosclerosis burden and cardiovascular risk, individual coronary plaque changes vary within a given individual. Large increases in proximal plaques characterize progression, and statins act in part by stabilizing progressing plaques by reducing fatty and fibrotic plaque components, without influencing the calcified portion.
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http://dx.doi.org/10.1016/j.jcct.2019.08.011DOI Listing
September 2020

Caspase-1 Activation Is Related With HIV-Associated Atherosclerosis in an HIV Transgenic Mouse Model and HIV Patient Cohort.

Arterioscler Thromb Vasc Biol 2019 09 18;39(9):1762-1775. Epub 2019 Jul 18.

From the Department of Neuroscience, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (A.C.K., F.L., S.D., J.A.R., E.K., X.P., J.G., T.H.B., X.Q.).

Objective: Atherosclerotic cardiovascular disease (ASCVD) is an increasing cause of morbidity and mortality in people with HIV since the introduction of combination antiretroviral therapy. Despite recent advances in our understanding of HIV ASCVD, controversy still exists on whether this increased risk of ASCVD is due to chronic HIV infection or other risk factors. Mounting biomarker studies indicate a role of monocyte/macrophage activation in HIV ASCVD; however, little is known about the mechanisms through which HIV infection mediates monocyte/macrophage activation in such a way as to engender accelerated atherogenesis. Here, we experimentally investigated whether HIV expression is sufficient to accelerate atherosclerosis and evaluated the role of caspase-1 activation in monocytes/macrophages in HIV ASCVD. Approach and Results: We crossed a well-characterized HIV mouse model, Tg26 mice, which transgenically expresses HIV-1, with ApoE mice to promote atherogenic conditions (Tg26/ApoE). Tg26/ApoE have accelerated atherosclerosis with increased caspase-1 pathway activation in inflammatory monocytes and atherosclerotic vasculature compared with ApoE. Using a well-characterized cohort of people with HIV and tissue-banked aortic plaques, we documented that serum IL (interleukin)-18 was higher in people with HIV compared with non-HIV-infected controls, and in patients with plaques, IL-18 levels correlated with monocyte/macrophage activation markers and noncalcified inflammatory plaques. In autopsy-derived aortic plaques, caspase-1+ cells and CD (clusters of differentiation) 163+ macrophages correlated.

Conclusions: These data demonstrate that expression of HIV is sufficient to accelerate atherogenesis. Further, it highlights the importance of caspase-1 and monocyte/macrophage activation in HIV atherogenesis and the potential of Tg26/ApoE as a tool for mechanistic studies of HIV ASCVD.
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http://dx.doi.org/10.1161/ATVBAHA.119.312603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703939PMC
September 2019

Serum Lipocalin 2 (Neutrophil Gelatinase-Associated Lipocalin) in Relation to Biomarkers of Inflammation and Cardiac Stretch During Activation of the Renin-Angiotensin-Aldosterone System in Human Immunodeficiency Virus.

J Infect Dis 2019 09;220(9):1420-1424

Program in Nutritional Metabolism, Massachusetts General Hospital and Harvard Medical School, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, Pennsylvania.

Purpose: To evaluate the relationship of lipocalin 2 to inflammation and cardiac injury with increased aldosterone in human immunodeficiency virus (HIV).

Methods: A standardized 6-day low-sodium diet was used to stimulate renin-angiotensin-aldosterone system (RAAS) activation, and serum lipocalin 2 and biomarkers of inflammation and cardiac stretch were assessed among persons with or without HIV.

Results: Lipocalin 2 levels increased with RAAS activation compared with suppression in the HIV group (median level [interquartile range], 71.3 [59.2-99.7] vs 67.0 [51.8-86.3] ng/mL; P = .01). During RAAS activation, lipocalin 2 was related to biomarkers of inflammation (tumor necrosis factor α [P = .007]), monocyte/macrophage activation (soluble CD163 [P = .005] and chemokine [C-C motif] ligand 2 [P = .03]), and markers of cardiac stretch (brain natriuretic peptide [P < .001] and N-terminal fragment of the prohormone brain natriuretic peptide [P = .001]) in HIV.

Conclusion: Lipocalin 2 may be important in modulating aldosterone-induced inflammation, monocyte activation, and cardiac stretch during RAAS activation in HIV.

Clinical Trial Registration: NCT01407237.
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http://dx.doi.org/10.1093/infdis/jiz346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761935PMC
September 2019

Characteristics, Prevention, and Management of Cardiovascular Disease in People Living With HIV: A Scientific Statement From the American Heart Association.

Circulation 2019 07 3;140(2):e98-e124. Epub 2019 Jun 3.

As early and effective antiretroviral therapy has become more widespread, HIV has transitioned from a progressive, fatal disease to a chronic, manageable disease marked by elevated risk of chronic comorbid diseases, including cardiovascular diseases (CVDs). Rates of myocardial infarction, heart failure, stroke, and other CVD manifestations, including pulmonary hypertension and sudden cardiac death, are significantly higher for people living with HIV than for uninfected control subjects, even in the setting of HIV viral suppression with effective antiretroviral therapy. These elevated risks generally persist after demographic and clinical risk factors are accounted for and may be partly attributed to chronic inflammation and immune dysregulation. Data on long-term CVD outcomes in HIV are limited by the relatively recent epidemiological transition of HIV to a chronic disease. Therefore, our understanding of CVD pathogenesis, prevention, and treatment in HIV relies on large observational studies, randomized controlled trials of HIV therapies that are underpowered to detect CVD end points, and small interventional studies examining surrogate CVD end points. The purpose of this document is to provide a thorough review of the existing evidence on HIV-associated CVD, in particular atherosclerotic CVD (including myocardial infarction and stroke) and heart failure, as well as pragmatic recommendations on how to approach CVD prevention and treatment in HIV in the absence of large-scale randomized controlled trial data. This statement is intended for clinicians caring for people with HIV, individuals living with HIV, and clinical and translational researchers interested in HIV-associated CVD.
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http://dx.doi.org/10.1161/CIR.0000000000000695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993364PMC
July 2019

Rationale and design of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE).

Am Heart J 2019 06 4;212:23-35. Epub 2019 Mar 4.

Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC.

Background: Cardiovascular disease (CVD) is more frequent among people with HIV (PWH) and may relate to traditional and nontraditional factors, including inflammation and immune activation. A critical need exists to develop effective strategies to prevent CVD in this population.

Methods: The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) (A5332) is a prospective, randomized, placebo-controlled trial of a statin strategy for the primary prevention of major adverse cardiovascular events (MACE) in PWH with low to moderate traditional risk. At least 7,500 PWH, 40-75 years of age, on stable antiretroviral therapy, will be randomized to pitavastatin calcium (4 mg/d) or identical placebo and followed for up to 8 years. Participants are enrolled based on the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) atherosclerotic cardiovascular disease (ASCVD) risk score and low-density lipoprotein cholesterol (LDL-C) level with a goal to identify a low- to moderate-risk population who might benefit from a pharmacologic CVD prevention strategy. Potential participants with a risk score ≤ 15% were eligible based on decreasing LDL-C thresholds for increasing risk score >7.5% (LDL-C <190 mg/dL for risk score <7.5%, LDL-C <160 mg/dL for risk score 7.6%-10%, and LDL-C<130 mg/dL for risk score 10.1%-15%). The primary objective is to determine effects on a composite end point of MACE. Formal and independent adjudication of clinical events will occur using standardized criteria. Key secondary end points include effects on MACE components, all-cause mortality, specified non-CVD events, AIDS and non-AIDS events, and safety.

Results: To date, REPRIEVE has enrolled >7,500 participants at approximately 120 sites across 11 countries, generating a diverse and representative population of PWH to investigate the primary objective of the trial.

Conclusions: REPRIEVE is the first trial investigating a primary CVD prevention strategy in PWH. REPRIEVE will inform the field of the efficacy and safety of a statin strategy among HIV-infected participants on antiretroviral therapy and provide critical information on CVD mechanisms and non-CVD events in PWH.
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http://dx.doi.org/10.1016/j.ahj.2018.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535121PMC
June 2019

Rationale and design of the Mechanistic Substudy of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE): Effects of pitavastatin on coronary artery disease and inflammatory biomarkers.

Am Heart J 2019 06 4;212:1-12. Epub 2019 Mar 4.

MGH Program in Nutritional Metabolism and Harvard Medical School, Boston, MA.

Background: People with HIV (PWH) have increased cardiovascular events, inflammation, and high-risk coronary atherosclerosis. Statin therapy has been shown to lower the risk of cardiovascular disease (CVD) in the general population, but whether this results from reductions in coronary atherosclerosis and is mediated by decreased inflammation remains unknown.

Methods: REPRIEVE is a randomized, placebo-controlled trial of pitavastatin calcium (4 mg/day) vs. placebo enrolling at least 7500 PWH between 40-75 years, on antiretroviral therapy (ART), with low to moderate traditional CVD risk. The Mechanistic Substudy of REPRIEVE (A5333s) is co-enrolling 800 participants from 31 US sites. These participants undergo serial contrast enhanced coronary computed tomography angiography (CCTA) and measurements of biomarkers of inflammation and immune activation at baseline and after 2 years of follow-up. The primary objectives are to determine the effects of pitavastatin on noncalcified coronary atherosclerotic plaque (NCP) volume, low attenuation plaque, and positive remodeling and on changes in immune activation and inflammation and to assess relationships between the two. Changes in CAD will be assessed in a standardized fashion by a core lab with expert readers blinded to time points and participant information; immune activation and inflammation assessment is also performed centrally.

Results: To date the Mechanistic Substudy has completed planned enrollment, with 805 participants.

Conclusion: This study represents the first large, randomized, CCTA-based assessment of the effects of a primary prevention strategy for CVD on high-risk CAD, immune activation and inflammation among PWH. The study will assess pitavastatin's effects on coronary plaque, and the interrelationship of these changes with biomarkers of immune activation and inflammation in PWH to determine mechanisms of CVD prevention and improved outcomes in this population.
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http://dx.doi.org/10.1016/j.ahj.2019.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596304PMC
June 2019