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Tesamorelin Lowers Hepatic Fat in HIV+ With Excess Visceral Fat
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CROI 2014, March 3-6, 2014, Boston
Mark Mascolini
Tesamorelin, the subcutaneous agent licensed to treat excess visceral adipose tissue (VAT) in people with HIV infection, lowered hepatic fat in a 50-person placebo-controlled trial [1]. If this strategy is confirmed in larger groups--and proves practical--it would be the first strategy to reduce visceral fat in HIV-positive people.
High hepatic fat often accompanies excess VAT in people with HIV and may be a factor in the metabolic abnormalities that afflict them. Tesamorelin is a growth hormone-releasing hormone analog licensed to reduce visceral fat in people with HIV. To assess its impact on hepatic fat, Massachusetts General Hospital (MGH) researchers conducted a randomized trial.
They enrolled 18- to 65-year-old men and women with visceral adiposity and taking a stable antiretroviral regimen. Men had a waist circumference of at least 95 cm and a waist-to-hip ratio of at least 0.94; women had a waist circumference of at least 94 cm and a waist-to-hip ratio of at least 0.88. Study participants could not have taken antidiabetic agents, growth hormone, growth hormone-releasing hormone, or glucocorticoids in the past 6 months. Fasting blood sugar had to be below 126 mg/dL, creatinine below 1.4 mg/dL, and CD4 count above 200.
The MGH team randomized 28 people to tesamorelin and 22 to placebo. After 6 months 23 people remained in the tesamorelin arm and 20 in the placebo arm. Baseline variables did not differ in the tesamorelin and placebo groups: median age 49 and 53, 86% and 82% men, 71% and 64% white, 18% and 14% current smokers, average HIV duration 17 and 20 years, hepatitis C prevalence 23% and 23%.
After 6 months of treatment, VAT declined an average 34 cm(2) in the tesamorelin group while rising 8 cm(2) in the placebo group, a significant difference (P = 0.005). DXA-measured fat mass fell 0.2 kg with tesamorelin while rising 1.2 kg with placebo (P = 0.04), and trunk fat fell 0.4 kg with tesamorelin while rising 0.6 kg with placebo (P = 0.01). Subcutaneous adipose tissue rose marginally in both study arms, as did body mass index.
Liver fat dropped 40% with tesamorelin while rising 27% with placebo, a significant difference (P = 0.004). Lower VAT was significantly associated with lower liver fat (rho 0.31, P = 0.047). Aspartate aminotransferase (AST) dropped more with tesamorelin than with placebo, although the difference was not statistically significant. When the investigators limited the analysis to people with baseline AST above the group median, the AST decline in the tesamorelin group was statistically significant when compared with the placebo group (P = 0.005).
Carotid artery intima-media thickness, a predictor of atherosclerotic disease, declined more with tesamorelin than with placebo, but the difference lacked statistical significance (P = 0.15). Levels of adiponectin, a glucose regulator, rose with tesamorelin and fell with placebo, and the difference approached statistical significance (P = 0.06). Changes in fasting glucose, insulin resistance (HOMA-IR), and 2-hour glucose did not differ significantly between study arms.
Three people in the tesamorelin group and 1 in the placebo group stopped treatment because of an adverse event. The investigators recorded three serious adverse events in each arm--congestive heart failure exacerbation, pneumonia, and basal cell carcinoma in the tesamorelin arm.
Principal investigator Steven Grinspoon concluded that tesamorelin "represents the first successful medical strategy shown to reduce liver fat in HIV-infected patients." He called for further work "to determine the effects of tesamorelin on liver fat and steatohepatitis in an HIV-infected cohort chosen specifically for increased liver fat," since participants in this study were chosen for abdominal adiposity.
One attendee questioned the practicality of tesamorelin therapy for liver fat, given the high cost, need for subcutaneous injection, and reversion of gains once the drug stops. Grinspoon agreed that clinicians may not want to start lifelong tesamorelin therapy in a 20-year-old with liver fat. But he suggested the drug might be used to secure an initial large improvement that could be sustained by lifestyle interventions or newer therapies.
Reference
1. Stanley T, Feldpausch M, Oh J, Branch K, Torriani M, Grinspoon S. Effects of tesamorelin on hepatic fat in HIV patients: a randomized, placebo-controlled trial. CROI 2014. Conference on Retroviruses and Opportunistic Infections. March 3-6, 2014. Boston. Abstract 135.
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