Adipose-ing a solution

Visceral fat can predict liver fibrosis and fibrosis progression in people with HIV

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MONTREAL—Theratechnologies Inc., the makers of tesamorelin, recently declared that Dr. Lindsay Fourman from Harvard Medical School had proffered data in a presentation for the 2020 Conference on Retroviruses and Opportunistic Infection, or CROI (the event was held virtually this year because of the novel coronavirus), demonstrating that visceral fat is a clinical predictor of liver fibrosis and liver fibrosis progression in people infected with the human immunodeficiency virus (HIV).
The findings highlight the critical role played by excess visceral adiposity in the progression of fibrosis among HIV-infected patients with nonalcoholic fatty liver disease (NAFLD). This information may further the development of not just prediction tools, but also perhaps therapeutic strategies for hepatic fibrosis in this population.
The information comes from a sub-analysis of the recent study led by Dr. Steven Grinspoon, conducted at the Massachusetts General Hospital and the National Institute of Allergy and Infectious Diseases, and funded by the National Institutes of Health. The study assessed the effect of tesamorelin on NAFLD and non-alcoholic steatohepatitis (NASH) in patients living with HIV, and was published in The Lancet HIV.
“Visceral adiposity was found to be a novel clinical predictor of accelerated hepatic disease, which suggests that therapies to reduce visceral fat may be particularly effective in HIV-associated NAFLD,” said Grinspoon, who is a professor of medicine at Harvard Medical School, chief of the Metabolism Unit at the Massachusetts General Hospital and a scientific advisor to Theratechnologies.
“Although estimates of prevalence vary from 13 percent to 60 percent, NAFLD is likely to be present in 25 percent or more of people with HIV, with an increased prevalence in those with visceral or generalized obesity. NAFLD is expected to soon become the leading cause of liver-related morbidity and mortality in people with HIV,” the study notes.
Results from the sub-analysis presented during the CROI conference demonstrate a significant association between liver fibrosis and visceral fat. This sub-analysis from biopsied patients demonstrated that visceral fat at baseline was higher (284 ± 91 cm2) in the 25 patients with hepatic fibrosis (stage 1, 2 and 3), compared to the 33 patients who did not present with fibrosis (212 ± 95 cm2). Researchers noted that there was no difference in subcutaneous fat and body mass index between the groups.
“Findings of this new sub-analysis are particularly interesting as they support the clinical relevance of visceral adipose tissue as a potential noninvasive marker for the diagnosis of liver fibrosis and the importance of treating visceral adiposity,” added Dr. Christian Marsolais, senior vice president and chief medical officer of Theratechnologies.
The sub-analysis also demonstrated that 37.5 percent of the 24 patients with paired biopsies (at the beginning and at the end of the trial) in the placebo group had fibrosis progression. Higher visceral fat was the only clinical predictor of liver fibrosis progression. Baseline liver fibrosis and its progression was found to be associated to age, sex, race, duration of HIV infection or CD4 count.
The randomized, double-blind, multicenter trial from which the data were drawn assessed the effect of tesamorelin on liver fat and histology in people living with HIV with NAFLD. At baseline, liver biopsies revealed that 43 percent of patients had liver fibrosis and 33 percent had NASH. A total of 61 patients received 2 mg of tesamorelin daily or an identical placebo for a period of 12 months. The primary endpoint of the study was a change in hepatic fat fraction.
“Considering our results in the context of existing and emerging treatment strategies, tesamorelin is the only drug thus far to show efficacy in reducing liver fat and preventing fibrosis progression specifically in HIV. To our knowledge, the only other pharmacological strategy that has been specifically tested for NAFLD in people with HIV is the bile acid conjugate aramchol, which did not reduce liver fat in 50 people with HIV and lipodystrophy that were given the drug for 12 weeks,” explains the study. “Tesamorelin is FDA approved to reduce visceral fat in people with HIV with central adiposity. Our results now suggest that it might be beneficial among the larger group of people with HIV and NAFLD.”
After 12 months of treatment, liver fat in patients on tesamorelin had decreased by 32 percent, while it had increased by 5 percent in placebo patients from baseline, amounting to a 37-percent relative reduction in liver fat. And 35 percent of patients in the tesamorelin group returned to liver fat values below 5 percent, in comparison to only 4 percent of patients on placebo. The study concluded that only 10.5 percent of patients in the tesamorelin group experienced progression of liver fibrosis, compared to 37.5 percent in patients receiving a placebo.
“Our data demonstrate an effect of tesamorelin to prevent progression of fibrosis among people with HIV and NAFLD, with strong relationships between reductions in liver fat and fibrosis. Importantly, this suggests that the strategy of tesamorelin, aimed mechanistically at reducing liver fat, might be useful to prevent liver fibrosis in people with HIV,” states the study. “Studies of individuals achieving visceral fat reduction with tesamorelin show that visceral fat reaccumulates after discontinuation of treatment, and studies investigating the use of tesamorelin in NAFLD and NASH will need to investigate whether effects are durable beyond the treatment period.”

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