Publications

Most Recent Papers

Tesamorelin Improves Fat Quality Independent of Changes in Fat Quantity

Lake JE, LA K, Erlandson KM, Adrian S, Yenokyan G, Scherzinger A, Dubé MP, Stanley TGrinspoon S, Falutz J, Mamputu JC, Marsolais C, Mccomsey GA, Brown TT. Tesamorelin Improves Fat Quality Independent of Changes in Fat Quantity. AIDS. 2021 Mar 22. doi: 10.1097/QAD.0000000000002897. Epub ahead of print. PMID: 33756511.

Abstract

Objectives: Fat quality and quantity may affect health similarly or differently. Fat quality can be assessed by measuring fat density on CT scan (greater density=smaller, higher quality adipocytes). We assessed the effects of tesamorelin, a growth hormone-releasing hormone analogue that reduces visceral fat (VAT) quantity in some people living with HIV (PLWH), on fat density.

Design: Participants from two completed, placebo-controlled, randomized trials of tesamorelin for central adiposity treatment in PLWH were included if they had either a clinical response to tesamorelin (VAT decrease ≥8%, ≈70% of participants) or were placebo-treated.

Methods: CT VAT and subcutaneous fat (SAT) density (Hounsfield Units, HU) were measured by a central blinded reader.Results: Participants (193 responders, 148 placebo) were 87% male and 83% Caucasian. Baseline characteristics were similar across arms, including VAT (-91 HU both arms, p = 0.80) and SAT density (-94 HU tesamorelin, -95 HU placebo, p = 0.29). Over 26 weeks, mean (SD) VAT and SAT density increased in tesamorelin-treated participants only (VAT: + 6.2 (8.7) HU tesamorelin, + 0.3 (4.2) HU placebo, p < 0.0001; SAT: + 4.0 (8.7) HU tesamorelin, + 0.3 (4.8) HU placebo, p < 0.0001). The tesamorelin effects persisted after controlling for baseline VAT or SAT HU and area, and VAT (+2.3 HU, 95% CI [4.5, 7.3], p = 0.001) or SAT (+3.5 HU, 95% CI [2.3, 4.7], p < 0.001) area change.

Conclusions: In PLWH with central adiposity who experienced VAT quantity reductions on tesamorelin, VAT and SAT density increased independent of changes in fat quantity, suggesting that tesamorelin also improves VAT and SAT quality in this group.

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

Srinivasa S, Thomas TS, Feldpausch MN, Adler GK, Grinspoon SK. Coronary Vasculature and Myocardial Structure in HIV: Physiologic Insights from the Renin-Angiotensin-Aldosterone System. J Clin Endocrinol Metab. 2021 Feb 24:dgab112. doi: 10.1210/clinem/dgab112. Epub ahead of print. PMID: 33624807.

Abstract

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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Hot Flashes and Cardiovascular Disease Risk Indices Among Women with HIV

Toribio MFulda ESChu SM, Drobni ZD, Awadalla M, Cetlin MStanley TL, North CM, Nelson MD, Jerosch-Herold M, Szczepaniak LS, Burdo TH, Looby SE, Neilan TG, Zanni MV. Hot Flashes and Cardiovascular Disease Risk Indices Among Women With HIV. Open Forum Infect Dis. 2021 Jan 12;8(2):ofab011. doi: 10.1093/ofid/ofab011. PMID: 33575428; PMCID: PMC7863866.

Abstract

Women with HIV (WWH) transitioning through menopause have heightened cardiovascular disease (CVD) risk. In the general population, hot flash burden relates to CVD risk indices. We found higher hot flash burden among women with vs without HIV. Further, among WWH, hot flash burden related to select CVD risk indices.

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Relationship of Telomere Length to Fat Redistribution in HIV

Iyengar S, Cȏté HCF, Fitch KV, Torriani M, Feldpausch MSrinivasa S. Relationship of Telomere Length to Fat Redistribution in HIV. Open Forum Infect Dis. 2020 Oct 27;7(12):ofaa523. doi: 10.1093/ofid/ofaa523. PMID: 33335933; PMCID: PMC7733235.

Abstract

Persons with HIV demonstrate increased risk for aging-associated complications and have reduced telomere length (TL) compared with age-matched persons without HIV. Our data show that greater visceral fat is related to reduced TL in HIV, independent of age and smoking. Fat redistribution may be a relevant mediator of TL attrition in HIV.

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Pro-Inflammatory Interleukin-18 is Associated with Hepatic Steatosis and Elevated Liver Enzymes in People with HIV Monoinfection

Sim JH, Sherman JB, Stanley TL, Corey KE, Fitch KVLooby SE, Robinson JA, Lu MT, Burdo TH, Lo J. Pro-Inflammatory Interleukin-18 is Associated with Hepatic Steatosis and Elevated Liver Enzymes in People with HIV Monoinfection. AIDS Res Hum Retroviruses. 2021 Jan 25. doi: 10.1089/AID.2020.0177. Epub ahead of print. PMID: 33323025.

Abstract

People with HIV (PWH) are at an increased risk of developing nonalcoholic fatty liver disease (NAFLD). Interleukin (IL)-18 is regulated by inflammasomes in response to pathogens and danger signals and has been implicated in both the pathogenesis of NAFLD and HIV disease progression. We hypothesized that increased IL-18 may be associated with NAFLD and liver injury in PWH. This was an observational study of 125 PWH and 59 individuals without HIV in the Boston area. Participants with known hepatitis B, hepatitis C, and excessive alcohol use were excluded. IL-18 was measured in serum by enzyme-linked immunosorbent assay. Liver lipid content was assessed by liver-to-spleen computed tomography (CT) attenuation ratio. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and IL-18 levels were higher in PWH than in controls. In PWH, log10 IL-18 was associated with log10AST (r = 0.34, p = .0001), log10ALT (r = 0.33, p = .0002), log10HIV RNA (r = 0.29, p = .002), and inversely associated with liver-to-spleen ratio (r = -0.24, p = .02). In addition, log10 IL-18 was associated with log10 triglycerides (r = 0.26, p = .003), log10 MCP-1 (monocyte chemoattractant protein-1; r = 0.33, p = .0004), log10caspase-1 (r = 0.35, p < .0001), log10LPS (r = 0.28, p = .004), and inversely associated with high-density lipoprotein (r = -0.28, p = .002), and CD4+/CD8+ T cell ratio (r = -0.24, p = .007). In controls without HIV, log10 IL-18 was also associated with log10ALT (r = 0.44, p = .0005). After adjusting for potential confounders, the relationships between IL-18 and AST (p = .004) and ALT (p = .003) remained significant, and the relationship between IL-18 and liver-to-spleen ratio (p = .02). Increased inflammasome activation and subsequent monocyte recruitment in PWH may contribute to the development and progression of NAFLD. Clinical Trials Registration. NCT00455793.

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Most Cited Publications

Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease 

Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab. 2007 Jul;92(7):2506-12. doi: 10.1210/jc.2006-2190. Epub 2007 Apr 24. PMID: 17456578; PMCID: PMC2763385.

Abstract

Context: Metabolic changes and smoking are common among HIV patients and may confer increased cardiovascular risk.

Objective: The aim of the study was to determine acute myocardial infarction (AMI) rates and cardiovascular risk factors in HIV compared with non-HIV patients in two tertiary care hospitals.

Design, setting, and participants: We conducted a health care system-based cohort study using a large data registry with 3,851 HIV and 1,044,589 non-HIV patients. AMI rates were determined among patients receiving longitudinal care between October 1, 1996, and June 30, 2004.

Main outcome measures: The primary outcome was myocardial infarction, identified by International Classification of Diseases coding criteria.

Results: AMI was identified in 189 HIV and 26,142 non-HIV patients. AMI rates per 1000 person-years were increased in HIV vs. non-HIV patients [11.13 (95% confidence interval [CI] 9.58-12.68) vs. 6.98 (95% CI 6.89-7.06)]. The HIV cohort had significantly higher proportions of hypertension (21.2 vs. 15.9%), diabetes (11.5 vs. 6.6%), and dyslipidemia (23.3 vs. 17.6%) than the non-HIV cohort (P < 0.0001 for each comparison). The difference in AMI rates between HIV and non-HIV patients was significant, with a relative risk (RR) of 1.75 (95% CI 1.51-2.02; P < 0.0001), adjusting for age, gender, race, hypertension, diabetes, and dyslipidemia. In gender-stratified models, the unadjusted AMI rates per 1000 person-years were higher for HIV patients among women (12.71 vs. 4.88 for HIV compared with non-HIV women), but not among men (10.48 vs. 11.44 for HIV compared with non-HIV men). The RRs (for HIV vs. non-HIV) were 2.98 (95% CI 2.33-3.75; P < 0.0001) for women and 1.40 (95% CI 1.16-1.67; P = 0.0003) for men, adjusting for age, gender, race, hypertension, diabetes, and dyslipidemia. A limitation of this database is that it contains incomplete data on smoking. Smoking could not be included in the overall regression model, and some of the increased risk may be accounted for by differences in smoking rates.

Conclusions: AMI rates and cardiovascular risk factors were increased in HIV compared with non-HIV patients, particularly among women. Cardiac risk modification strategies are important for the long-term care of HIV patients.

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Adipose-derived circulating miRNAs regulate gene expression in other tissues 

Thomou T, Mori MA, Dreyfuss JM, Konishi M, Sakaguchi M, Wolfrum C, Rao TN, Winnay JN, Garcia-Martin R, Grinspoon SK, Gorden P, Kahn CR. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature. 2017 Feb 23;542(7642):450-455. doi: 10.1038/nature21365. Epub 2017 Feb 15. Erratum in: Nature. 2017 May 10;545(7653):252. PMID: 28199304; PMCID: PMC5330251.

Abstract

Adipose tissue is a major site of energy storage and has a role in the regulation of metabolism through the release of adipokines. Here we show that mice with an adipose-tissue-specific knockout of the microRNA (miRNA)-processing enzyme Dicer (ADicerKO), as well as humans with lipodystrophy, exhibit a substantial decrease in levels of circulating exosomal miRNAs. Transplantation of both white and brown adipose tissue-brown especially-into ADicerKO mice restores the level of numerous circulating miRNAs that are associated with an improvement in glucose tolerance and a reduction in hepatic Fgf21 mRNA and circulating FGF21. This gene regulation can be mimicked by the administration of normal, but not ADicerKO, serum exosomes. Expression of a human-specific miRNA in the brown adipose tissue of one mouse in vivo can also regulate its 3' UTR reporter in the liver of another mouse through serum exosomal transfer. Thus, adipose tissue constitutes an important source of circulating exosomal miRNAs, which can regulate gene expression in distant tissues and thereby serve as a previously undescribed form of adipokine.

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Soluble CD163, a novel marker of activated macrophages, is elevated and associated with noncalcified coronary plaque in HIV-infected patients 

Burdo TH, Lo J, Abbara S, Wei J, DeLelys ME, Preffer F, Rosenberg ES, Williams KC, Grinspoon S. Soluble CD163, a novel marker of activated macrophages, is elevated and associated with noncalcified coronary plaque in HIV-infected patients. J Infect Dis. 2011 Oct 15;204(8):1227-36. doi: 10.1093/infdis/jir520. PMID: 21917896; PMCID: PMC3203384.

Abstract

Background: Pro-inflammatory monocytes/macrophages may contribute to increased atherosclerosis in human immunodeficiency virus (HIV)-infected patients. We investigate--to our knowledge, for the first time--sCD163 and other markers of monocyte activation in relationship to atherosclerotic plaque in HIV-infected patients.

Methods: One hundred two HIV-infected and 41 HIV-seronegative men with equivalent cardiovascular risk factors and without history of coronary artery disease were prospectively recruited and underwent computed tomography coronary angiography.

Results: sCD163 levels and presence of plaque were significantly higher among antiretroviral-treated subjects with undetectable HIV RNA levels, compared with seronegative controls (1172 ± 646 vs. 883 ± 561 ng/mL [P = .02] for sCD163 and 61% vs. 39% [P = .03] for presence of plaque). After adjusting for age, race, lipids, blood pressure, glucose, smoking, sCD14, and HIV infection, sCD163 remained independently associated with noncalcified plaque (P = .008). Among HIV-infected patients, sCD163 was associated with coronary segments with noncalcified plaque (r = 0.21; P = .04), but not with calcium score. In contrast, markers of generalized inflammation, including C-reactive protein level, and D-dimer were not associated with sCD163 or plaque among HIV-infected patients.

Conclusions: sCD163, a monocyte/macrophage activation marker, is increased in association with noncalcified coronary plaque in men with chronic HIV infection and low or undetectable viremia. These data suggest a potentially important role of chronic monocyte/macrophage activation in the development of noncalcified vulnerable plaque.

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Arterial inflammation in patients with HIV 

Subramanian S, Tawakol A, Burdo TH, Abbara S, Wei J, Vijayakumar J, Corsini E, Abdelbaky A, Zanni MV, Hoffmann U, Williams KC, Lo JGrinspoon SK. Arterial inflammation in patients with HIV. JAMA. 2012 Jul 25;308(4):379-86. doi: 10.1001/jama.2012.6698. PMID: 22820791; PMCID: PMC3724172.

Abstract

Context: Cardiovascular disease is increased in patients with human immunodeficiency virus (HIV), but the specific mechanisms are unknown.

Objective: To assess arterial wall inflammation in HIV, using 18fluorine-2-deoxy-D-glucose positron emission tomography (18F-FDG-PET), in relationship to traditional and nontraditional risk markers, including soluble CD163 (sCD163), a marker of monocyte and macrophage activation.

Design, setting, and participants: A cross-sectional study of 81 participants investigated between November 2009 and July 2011 at the Massachusetts General Hospital. Twenty-seven participants with HIV without known cardiac disease underwent cardiac 18F-FDG-PET for assessment of arterial wall inflammation and coronary computed tomography scanning for coronary artery calcium. The HIV group was compared with 2 separate non-HIV control groups. One control group (n = 27) was matched to the HIV group for age, sex, and Framingham risk score (FRS) and had no known atherosclerotic disease (non-HIV FRS-matched controls). The second control group (n = 27) was matched on sex and selected based on the presence of known atherosclerotic disease (non-HIV atherosclerotic controls).

Main outcome measure: Arterial inflammation was prospectively determined as the ratio of FDG uptake in the arterial wall of the ascending aorta to venous background as the target-to-background ratio (TBR).

Results: Participants with HIV demonstrated well-controlled HIV disease (mean [SD] CD4 cell count, 641 [288] cells/μL; median [interquartile range] HIV-RNA level, <48 [<48 to <48] copies/mL). All were receiving antiretroviral therapy (mean [SD] duration, 12.3 [4.3] years). The mean FRS was low in both HIV and non-HIV FRS-matched control participants (6.4; 95% CI, 4.8-8.0 vs 6.6; 95% CI, 4.9-8.2; P = .87). Arterial inflammation in the aorta (aortic TBR) was higher in the HIV group vs the non-HIV FRS-matched control group (2.23; 95% CI, 2.07-2.40 vs 1.89; 95% CI, 1.80-1.97; P < .001), but was similar compared with the non-HIV atherosclerotic control group (2.23; 95% CI, 2.07-2.40 vs 2.13; 95% CI, 2.03-2.23; P = .29). Aortic TBR remained significantly higher in the HIV group vs the non-HIV FRS-matched control group after adjusting for traditional cardiovascular risk factors (P = .002) and in stratified analyses among participants with undetectable viral load, zero calcium, FRS of less than 10, a low-density lipoprotein cholesterol level of less than 100 mg/dL (<2.59 mmol/L), no statin use, and no smoking (all P ≤ .01). Aortic TBR was associated with sCD163 level (P = .04) but not with C-reactive protein (P = .65) or D-dimer (P = .08) among patients with HIV.

Conclusion: Participants infected with HIV vs noninfected control participants with similar cardiac risk factors had signs of increased arterial inflammation, which was associated with a circulating marker of monocyte and macrophage activation.

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Fracture prevalence among human immunodeficiency virus (HIV)-infected versus non-HIV-infected patients in a large U.S. healthcare system 

Triant VA, Brown TT, Lee H, Grinspoon SK. Fracture prevalence among human immunodeficiency virus (HIV)-infected versus non-HIV-infected patients in a large U.S. healthcare system. J Clin Endocrinol Metab. 2008 Sep;93(9):3499-504. doi: 10.1210/jc.2008-0828. Epub 2008 Jul 1. PMID: 18593764; PMCID: PMC2567857.

Abstract

Context: Reduced bone mineral density has been demonstrated among HIV-infected patients, but fracture prevalence is unknown.

Objective: The objective of the study was to compare fracture prevalence in HIV-infected and non-HIV-infected patients.

Design: This was a population-based study.

Setting: The study was conducted at a large U.S. health care system.

Patients: A total of 8525 HIV-infected and 2,208,792 non-HIV-infected patients with at least one inpatient or outpatient encounter between October 1, 1996, and March 21, 2008, was compared.

Main outcome measure: Fracture prevalence using specific International Classification of Diseases, Ninth Revision, Clinical Modification fracture codes was measured.

Results: The overall fracture prevalence was 2.87 vs. 1.77 patients with fractures per 100 persons in HIV-infected, compared with non-HIV-infected patients (P < 0.0001). Among females, the overall fracture prevalence was 2.49 vs. 1.72 per 100 persons in HIV-infected vs. non-HIV-infected patients (P = 0.002). HIV-infected females had a higher prevalence of vertebral (0.81 vs. 0.45; P = 0.01) and wrist (1.31 vs. 0.83; P = 0.01) fractures per 100 persons, compared with non-HIV-infected females but had a similar prevalence of hip fractures (0.47 vs. 0.56; P = 0.53). Among males, the fracture prevalence per 100 persons was higher in HIV-infected vs. non-HIV-infected patients for any fracture (3.08 vs. 1.83; P < 0.0001), vertebral fractures (1.03 vs. 0.49; P < 0.0001), hip fractures (0.79 vs. 0.45; P = 0.001), and wrist fractures (1.46 vs. 0.99; P = 0.001). Fracture prevalence was higher relative to non-HIV-infected patients among African-American and Caucasian females and Caucasian males.

Conclusions: Fracture prevalence is increased in HIV-infected compared with non-HIV-infected patients.

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Patents

GHRH or analogues thereof for use in treatment of hepatic disease

Patent Number: 10,799,562

Abstract

The present application relates to novel methods for preventing, slowing the progression of, or treating nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), and/or liver fibrosis, and/or reducing the risks of liver cancer in subjects, such as HIV-infected subjects, using a GHRH molecule, e.g., trans-3-hexenoyl-GHRH.sub.(1-44)-NH.sub.2, or a pharmaceutically acceptable salt thereof. The subjects may have particular pathological features such as liver fibrosis, a hepatic fat fraction (HFF) of at least about 10%, serum alanine aminotransferase (ALT) levels of at least about 30 U/L, and/or a NAFLD Activity Score (NAS) of at least 4 or 5.

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