Visceral Fat Reduction Is Associated with Improved Liver Transaminases in HIV-Infected Patients Treated with the GHRH Analogue Tesamorelin

Presentation Number: OR09-6
Date of Presentation: April 4th, 2017

Lindsay T. Fourman*1, Natalia Czerwonka1, Meghan N. Feldpausch1, Jean-Claude Mamputu2, Julian Falutz3, Josée Morin4, Christian Marsolais2, Takara L. Stanley1 and Steven K. Grinspoon1
1Massachusetts General Hospital and Harvard Medical School, Boston, MA, 2Theratechnologies Inc., Montreal, QC, Canada, 3Montreal General Hospital and McGill University Health Centre, Montreal, QC, Canada, 4Excelsus Statistics Inc., Montreal, QC, Canada

Abstract

Background: Changes in body composition, characterized by visceral adipose tissue (VAT) accumulation and subcutaneous adipose tissue (SAT) loss, are common among HIV-infected individuals receiving antiretroviral therapy. Nonalcoholic fatty liver disease is increased in prevalence among this population with estimates as high as 40%, and is correlated with excess VAT.(1) Tesamorelin, a synthetic GHRH analogue, is an approved therapy for HIV lipodystrophy that has been shown to reduce VAT by 15-20% over 6-12 months, and to decrease liver fat.(2) Hypothesis: We hypothesized that VAT reduction in response to tesamorelin is associated with improved serum transaminases in HIV-infected individuals with transaminase elevations. Methods: This analysis combined data from two randomized, placebo-controlled phase III studies of tesamorelin in individuals with HIV and central fat distribution. Both studies consisted of a 6-month primary phase in which subjects were randomized 2:1 to receive tesamorelin (2 mg subcutaneously daily) or placebo, followed by a 6-month safety extension in which those assigned to tesamorelin were re-randomized to continue tesamorelin (T-T) or to start placebo (T-P). Tesamorelin responders were defined a priori by the FDA as individuals with ≥ 8% reduction in VAT. In an observed case analysis, we assessed relationships between transaminases and other baseline variables among all randomized patients. We then compared changes in transaminases by VAT responder status among tesamorelin-treated patients. Results: Of 816 randomized subjects, 343 receiving tesamorelin and 173 receiving placebo had ALT or AST > 30 U/L at baseline. ALT or AST > 30 U/L was associated with male gender (92% vs. 72%, p < 0.0001), race (p = 0.0003), Hepatitis B/C (25% vs. 17%, p = 0.006), testosterone use (24% vs. 13%, p < 0.0001), and lipid-lowering therapy (48% vs. 40%, p = 0.03). Elevated transaminases were also associated with increased VAT (191 ± 83 vs. 167 ± 83 cm2, p < 0.0001), decreased SAT (214 ± 112 vs. 263 ± 136 cm2, p < 0.0001), and reduced limb fat (6.6 ± 3.9 vs. 8.7 ± 5.1 kg, p < 0.0001). Among patients assigned to tesamorelin with baseline ALT or AST > 30 U/L, 177 (69%) were VAT responders and 80 (31%) were VAT non-responders at 26 weeks. Compared to non-responders, responders experienced greater reductions in ALT (-8.9 ± 22.6 vs. 1.4 ± 34.7 U/L, p = 0.001) and AST (-3.8 ± 12.9 vs. 0.4 ± 22.4 U/L, p = 0.04). The change in transaminases was sustained in initial responders at 52 weeks compared to baseline in both T-T and T-P groups. Conclusions: Elevated transaminases correlated with higher VAT and lower SAT in HIV-infected individuals. Among subjects treated with tesamorelin with elevated baseline transaminases, a clinically significant reduction in VAT was associated with significant decreases in ALT and AST by 26 weeks that persisted at 52 weeks.

 

Disclosure: JCM: Employee, Theratechnologies Inc.. JF: Consultant, Theratechnologies Inc.. CM: Employee, Theratechnologies. TLS: Advisory Group Member, Theratechnologies, Inc. SKG: Consultant, Theratechnologies. Nothing to Disclose: LTF, NC, MNF, JM