Human Immunodeficiency Virus (HIV), Nonalcoholic Fatty Liver Disease (NAFLD), Nonalcoholic Steatohepatitis (NASH)
Conditions
Keywords
Human immunodeficiency virus (HIV), Nonalcoholic fatty liver disease (NAFLD), Nonalcoholic steatohepatitis (NASH), Growth hormone releasing hormone, tesamorelin
Brief summary
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.
Interventions
DRUGtesamorelin
DRUGPlacebo
inactive substance that looks like tesamorelin
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Liver Fat as Measured by 1-H Magnetic Resonance Spectroscopy | change between baseline and 12 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score | change between baseline and 12 months | 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: 1. steatosis, graded from 0 \[\<5% liver fat\] to grade 3 \[\>66% liver fat\] 2. lobular inflammation, graded from 0 \[no foci of inflammation\] to 3 \[\>4 foci per 200x field\] 3. 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 in Alanine Aminotransferase (ALT) | change from baseline to 12 months | change (value at 12 months minus value at baseline) |
| Change in Aspartate Aminotransferase (AST) | change from baseline to 12 months | change (value at 12 months minus value at baseline) |
Countries
United States
Participant flow
Pre-assignment details
1 subject was randomized to tesamorelin but self-discontinued during the baseline visit, prior to receiving any study drug. This individual is included in baseline characteristics but is not counted as starting tesamorelin (hence the discrepancy between 61 total enrolled and the 30 in tesamorelin and 30 in placebo group shown in participant flow).
Participants by arm
| Arm | Count |
|---|---|
| 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.
tesamorelin | 31 |
| 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.
Placebo: inactive substance that looks like tesamorelin | 30 |
| Total | 61 |
Baseline characteristics
| Characteristic | Tesamorelin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 52 years STANDARD_DEVIATION 8 | 54 years STANDARD_DEVIATION 7 | 53 years STANDARD_DEVIATION 7 |
| Hepatic Fibrosis Stage Data Not Available | 2 Participants | 1 Participants | 3 Participants |
| Hepatic Fibrosis Stage Stage 0 (No Fibrosis) | 15 Participants | 18 Participants | 33 Participants |
| Hepatic Fibrosis Stage Stage 1 Fibrosis | 4 Participants | 5 Participants | 9 Participants |
| Hepatic Fibrosis Stage Stage 2 Fibrosis | 6 Participants | 4 Participants | 10 Participants |
| Hepatic Fibrosis Stage Stage 3 Fibrosis | 4 Participants | 2 Participants | 6 Participants |
| Race/Ethnicity, Customized Race Black (all ethnicities) | 8 Participants | 10 Participants | 18 Participants |
| Race/Ethnicity, Customized Race Other (all ethnicities) | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Race White (all ethnicities) | 21 Participants | 19 Participants | 40 Participants |
| Sex: Female, Male Female | 24 Participants | 24 Participants | 48 Participants |
| Sex: Female, Male Male | 7 Participants | 6 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 30 | 1 / 43 |
| other Total, other adverse events | 29 / 31 | 29 / 30 | 35 / 43 |
| serious Total, serious adverse events | 4 / 31 | 2 / 30 | 3 / 43 |
Outcome results
Primary
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.
Time frame: change between baseline and 12 months
Population: These are participants who had magnetic resonance spectroscopy for hepatic fat fraction at 0 and 12 months. This is different from the primary analysis population reported in the manuscript.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tesamorelin | Change in Liver Fat as Measured by 1-H Magnetic Resonance Spectroscopy | -4.7 percent (hepatic fat fraction) | Standard Deviation 6.6 |
| Placebo | Change in Liver Fat as Measured by 1-H Magnetic Resonance Spectroscopy | 0.0 percent (hepatic fat fraction) | Standard Deviation 4.1 |
Secondary
Change in Alanine Aminotransferase (ALT)
change (value at 12 months minus value at baseline)
Time frame: change from baseline to 12 months
Population: all participants with available data at both baseline and 12 month visits
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tesamorelin | Change in Alanine Aminotransferase (ALT) | -2 units/liter (U/L) | Standard Deviation 11 |
| Placebo | Change in Alanine Aminotransferase (ALT) | 5 units/liter (U/L) | Standard Deviation 15 |
Secondary
Change in Aspartate Aminotransferase (AST)
change (value at 12 months minus value at baseline)
Time frame: change from baseline to 12 months
Population: all participants with available data at both baseline and 12 month visits
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tesamorelin | Change in Aspartate Aminotransferase (AST) | -2 units/liter (U/L) | Standard Deviation 11 |
| Placebo | Change in Aspartate Aminotransferase (AST) | -2 units/liter (U/L) | Standard Deviation 4 |
Secondary
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: 1. steatosis, graded from 0 \[\<5% liver fat\] to grade 3 \[\>66% liver fat\] 2. lobular inflammation, graded from 0 \[no foci of inflammation\] to 3 \[\>4 foci per 200x field\] 3. 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.
Time frame: change between baseline and 12 months
Population: all participants with available biopsy data from both baseline and 12 month visits
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tesamorelin | Change in Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score | -0.16 score on a scale, NAFLD activity score | Standard Deviation 1.34 |
| Placebo | Change in Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score | 0.13 score on a scale, NAFLD activity score | Standard Deviation 1.03 |