Tesamorelin Effects on Liver Fat and Histology in HIV

Tesamorelin Effects on Liver Fat and Histology in HIV: A Collaborative UO1 Grant

Liver disease is one of the leading co-morbidities of human immunodeficiency virus (HIV) infection, and nonalcoholic fatty liver disease (NAFLD) is present in approximately 30-40% of patients with HIV infection. Nonalcoholic steatohepatitis (NASH) is a more severe form of NAFLD in which increased liver fat is also accompanied by inflammation, cellular damage, and fibrosis.

NAFLD is most prevalent in patients who also have increased visceral adiposity, and our group has previously shown that HIV-infected individuals with increased visceral adiposity generally have decreased growth hormone secretion. Tesamorelin is a growth hormone releasing hormone (GHRH) analogue that increases endogenous growth hormone secretion. Tesamorelin is FDA-approved for the reduction of visceral fat in HIV-infected individuals. In a previous study, treatment with tesamorelin in HIV-infected individuals selected for abdominal adiposity reduced liver fat. The current study is designed to test the effect of tesamorelin on liver fat and steatohepatitis in HIV-infected individuals who have NAFLD. The investigators hypothesize that tesamorelin will reduce liver fat and will also ameliorate the inflammation, fibrosis, and hepatocellular damage seen in conjunction with NASH.

Study Overview

• Status: Completed
• Conditions: Nonalcoholic Steatohepatitis (NASH); Human Immunodeficiency Virus (HIV); Nonalcoholic Fatty Liver Disease (NAFLD)
• Intervention / Treatment: Drug: tesamorelin; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• Men and women 18-70yo
• HIV-infection and treatment with a stable antiretroviral regimen for ≥ 6 months
• Hepatic steatosis as demonstrated by liver fat fraction ≥5% on 1H-MRS
• Hepatitis C antibody negative, or, if Hepatitis C antibody positive, either: a) known clinical disease, successful therapy ≥1 year prior to baseline and undetectable HCV RNA, or b) HCV resolved spontaneously and undetectable HCV RNA. Hepatitis B surface antigen negative at screen visit
• For females ≥50yo, negative mammogram within 1 year of baseline visit
• If use of Vitamin E ≥400 IU daily (in any formulation), stable dose for ≥6 months prior to study.

Exclusion criteria:

• Heavy alcohol use defined as consumption of more than 20g daily for women or more than 30g daily for men for at least 3 consecutive months over the past 5 years
• Use of insulin or thiazoledinediones (TZDs), or HbA1c ≥7%. Individuals with mild diabetes that is well-controlled with diet and/or oral anti-diabetic agents besides TZDs will be included. Use of oral anti-diabetics must have been stable for ≥6 months prior to study entry.
• Known diabetic retinopathy.
• Known cirrhosis, or Child-Pugh score ≥7, stage 4 fibrosis on biopsy, or clinical evidence of cirrhosis or portal hypertension on imaging or exam.
• Chronic corticosteroid use except intermittent use of topical steroid creams and/or prior short-term physiologic corticosteroid use in the ≤ 6 months prior to baseline visit
• Chronic use of methotrexate, amiodarone, or tamoxifen
• Known diagnosis of Alpha-1 antitrypsin deficiency, Wilson's disease, hemochromatosis, or autoimmune hepatitis
• Use of GH or GHRH within the past 1 year
• Change in lipid lowering or anti-hypertensive regimen within 3 months of screening
• HgB < 11.0 g/dL, CD4 < 100 th/mm3, or HIV viral load > 400 copies/mL
• Active malignancy
• For men, history of prostate cancer or evidence of prostate malignancy by PSA > 5 ng/mL
• Severe chronic illness judged by the investigator to present a contraindication to participation
• History of hypopituitarism, head irradiation or any other condition known to affect the GH axis
• Use of physiologic testosterone (men) or estrogen or progesterone (women) unless stable use for a year or more prior to study entry
• Routine MRI exclusion criteria such as the presence of a pacemaker or cerebral aneurysm clip
• Previous weight loss surgery
• For women, positive pregnancy test performed in a CLIA certified laboratory using a test with a sensitivity of at least 25mIU/mL, or breastfeeding.
• Known hypersensitivity to tesamorelin or mannitol
• Unwillingness to abstain from the conception process during the study (i.e., must agree not to participate in an active attempt to become pregnant or impregnate, donate sperm, or participate in in vitro fertilization)
• Unwillingness to use one (for males) or two (for females) reliable methods of contraception while engaging in heterosexual intercourse during the study. Acceptable methods for women include hormonal contraception (estrogen/progesterone or progesterone-only formulations) if stable for a year or more prior to study entry, intrauterine device, or barrier methods (condom, or diaphragm with spermicide). Acceptable methods for males include condom use. This requirement does not apply to women who have been post-menopausal for at least 24 consecutive months or have undergone surgical sterilization, or to men who have undergone surgical sterilization or have documented azoospermia.
• Not willing or able to adhere to dose schedules and required procedures per protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tesamorelin; tesamorelin 2mg subcutaneously daily x 12 months double-blind phase. At the end of 12 months, subjects enter open-label tesamorelin treatment phase for 6 months.	Drug: tesamorelin; Other Names: Egrifta
Placebo Comparator: Placebo; placebo subcutaneously daily x 12 months double-blind phase. At the end of 12 months, subjects enter open-label tesamorelin treatment phase for 6 months.	Drug: Placebo; inactive substance that looks like tesamorelin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Liver Fat as Measured by 1-H Magnetic Resonance Spectroscopy	change (value at 12 months minus value at baseline). Hepatic fat fraction is a standardized measure used to describe the percent fat in the liver. As it is determined by spectroscopy, it is quantified by the area under the lipid peak, standardized to the total area under the (lipid peak + water peak). Using 1-H Magnetic resonance spectroscopy to quantify liver fat in this manner was first described by Longo R et al., Invest Radiol, 1993, 28(4):297-302.	change between baseline and 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score	change (value at 12 months minus value at baseline). The nonalcoholic fatty liver disease (NAFLD) activity score is a standardized histological quantification of NAFLD severity designed and validated by the Nonalcoholic Steatohepatitis Clinical Research Network (Kleiner DE et al., Hepatology, 2005, 41(6):1313-1321). The score is the sum of three semi-quantitative histological grades: steatosis, graded from 0 [<5% liver fat] to grade 3 [>66% liver fat]; lobular inflammation, graded from 0 [no foci of inflammation] to 3 [>4 foci per 200x field]; hepatocellular ballooning, graded from 0 [no ballooning] to 2 [many cells/prominent ballooning] The "total" NAFLD activity score, a sum of the three components below, ranges from 0 to 8, with a higher score generally representing greater severity of NAFLD/nonalcoholic steatohepatitis.	change between baseline and 12 months
Change in Alanine Aminotransferase (ALT)	change (value at 12 months minus value at baseline)	change from baseline to 12 months
Change in Aspartate Aminotransferase (AST)	change (value at 12 months minus value at baseline)	change from baseline to 12 months

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Principal Investigator: Steven K Grinspoon, MD, MGH

Publications and helpful links

General Publications

• Stanley TL, Fourman LT, Feldpausch MN, Purdy J, Zheng I, Pan CS, Aepfelbacher J, Buckless C, Tsao A, Kellogg A, Branch K, Lee H, Liu CY, Corey KE, Chung RT, Torriani M, Kleiner DE, Hadigan CM, Grinspoon SK. Effects of tesamorelin on non-alcoholic fatty liver disease in HIV: a randomised, double-blind, multicentre trial. Lancet HIV. 2019 Dec;6(12):e821-e830. doi: 10.1016/S2352-3018(19)30338-8. Epub 2019 Oct 11.
• Fourman LT, Stanley TL, Billingsley JM, Sui SJH, Feldpausch MN, Boutin A, Zheng I, McClure CM, Corey KE, Torriani M, Kleiner DE, Hadigan CM, Chung RT, Grinspoon SK. Delineating tesamorelin response pathways in HIV-associated NAFLD using a targeted proteomic and transcriptomic approach. Sci Rep. 2021 May 18;11(1):10485. doi: 10.1038/s41598-021-89966-y.
• Stanley TL, Fourman LT, Wong LP, Sadreyev R, Billingsley JM, Feldpausch MN, Zheng I, Pan CS, Boutin A, Lee H, Corey KE, Torriani M, Kleiner DE, Chung RT, Hadigan CM, Grinspoon SK. 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 Aug 16;73(4):621-630. doi: 10.1093/cid/ciab019.
• Stanley TL, Fourman LT, Zheng I, McClure CM, Feldpausch MN, Torriani M, Corey KE, Chung RT, Lee H, Kleiner DE, Hadigan CM, Grinspoon SK. Relationship of IGF-1 and IGF-Binding Proteins to Disease Severity and Glycemia in Nonalcoholic Fatty Liver Disease. J Clin Endocrinol Metab. 2021 Jan 23;106(2):e520-e533. doi: 10.1210/clinem/dgaa792.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2015
• Primary Completion (Actual): January 16, 2019
• Study Completion (Actual): July 24, 2019

Study Registration Dates

• First Submitted: July 18, 2014
• First Submitted That Met QC Criteria: July 21, 2014
• First Posted (Estimate): July 22, 2014

Study Record Updates

• Last Update Posted (Actual): January 27, 2020
• Last Update Submitted That Met QC Criteria: January 13, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: Nonalcoholic fatty liver disease (NAFLD); Human immunodeficiency virus (HIV); tesamorelin; Nonalcoholic steatohepatitis (NASH); Growth hormone releasing hormone
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immune System Diseases; Slow Virus Diseases; Liver Diseases; HIV Infections; Fatty Liver; Non-alcoholic Fatty Liver Disease; Acquired Immunodeficiency Syndrome; Immunologic Deficiency Syndromes; Physiological Effects of Drugs; Growth Substances; Tesamorelin
• Other Study ID Numbers: 1U01AI115711 (U.S. NIH Grant/Contract); U01AI115711 (U.S. NIH Grant/Contract)