A team of researchers at Massachusetts General Hospital (MGH) led by Steven Grinspoon, MD, has identified a novel therapeutic strategy to significantly improve a form of liver disease that affects many people living with human immunodeficiency virus (HIV), according to a study to be published online in TheLancet HIV on October 10. There is currently no treatment for non-alcoholic fatty liver disease (NAFLD) in HIV patients, but the results of this research could eventually lead to a first-in-class therapy for this serious condition. The research was supported by and conducted in part by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. Study drug was supplied by Theratechnologies, Inc.
The emergence of antiretroviral therapy (ART) has revolutionized the care and management of HIV. However, people with HIV who receive these life-saving treatments often develop deposits of visceral fat, which surrounds internal organs in the abdomen, as well as other deposits of “ectopic” fat, which is stored in organs or muscle instead of fatty tissue. Visceral fat increases the risk for cardiovascular disease, type 2 diabetes, and other conditions. Ectopic fat also accumulates in the liver, resulting in NAFLD. Estimates suggest that 15 to 40 percent of HIV patients may have NAFLD. Left untreated, NAFLD can progress to a condition called nonalcoholic steatohepatitis (NASH), resulting in inflammation and damaged liver cells. This harm can ultimately lead to cirrhosis (permanent tissue scarring) and liver failure.
People with HIV who develop significant deposits of visceral fat have disturbed production of growth hormone (GH), explains Grinspoon who is also chief of the MGH Metabolism Unit, who first identified this phenomenon. GH oxidizes, or “burns,” visceral fat. Grinspoon and his colleagues developed the drug tesamorelin (Egrifta), which triggers the physiologic production of GH and has been shown to reduce visceral fat by about 15 to 20 percent. It’s approved by the Food and Drug Administration (FDA) for treating excess abdominal fat and irregular fat distribution in people with HIV.
To find out if tesamorelin can reduce liver fat and improve other features of NAFLD, Grinspoon and colleagues studied 61 men and women with HIV and NAFLD. The study was performed in collaboration with Colleen Hadigan, MD, senior research physician in NIAID’s Laboratory of Immunoregulation and a senior author of the paper along with Grinspoon. The investigators compared subjects who injected the drug daily to a similar group of participants who received placebo injections. After one year, tesamorelin led to a relative reduction in liver fat levels of 37 percent; for more than one in three subjects given the drug (35 percent) liver fat was reduced to below the threshold for NAFLD, compared to four percent given the placebo.
The study also showed that tesamorelin slowed the progression of fibrosis, or formation of scar tissue, which impairs liver function and can lead to cirrhosis: After 12 months, just two treated subjects (10.5 percent) had advancing fibrosis compared to nine (37.5 percent) in the placebo group. Overall, tesamorelin was well tolerated.
Grinspoon and colleagues are looking forward to further the development of tesamorelin for treating NAFLD in HIV patients. They’re also studying whether the drug might reduce visceral fat and improve NAFLD in the general population of people without HIV. “For the first time, we have a potential therapeutic that can reduce fat and prevent progression of fibrosis in NAFLD,” says Grinspoon. “We have a chance to intervene early, when this condition is still relatively benign.”
The primary author of the Lancet HIV paper is Steven Grinspoon, MD, who is also professor of Medicine at Harvard Medical School (HMS). Senior co-authors are Takara Stanley, MD, an associate professor of Pediatrics at HMS and an assistant pediatrician at MGH; and Lindsay Fourman, MD, is an instructor in medicine at MGH. The study was conducted in collaboration with scientists at the National Institutes of Health, including the National Cancer Insitute and NIAID, which funded this research.
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