In this video, Steven Grinspoon, MD, speaks about effective treatments of steatosis in patients with HIV, including whether tesamorelin could decrease liver fat in men and women living with HIV and nonalcoholic fatty liver disease (DAFLD), and the challenges of finding these treatments.
Additional Resource:
- Grinspoon, SK. Mechanisms and treatments of steatosis in HIV. Presented at: Conference on Retroviruses and Opportunistic Infections 2021; March 7-10, 2021. https://ww2.aievolution.com/cro2101/index.cfm?do=abs.viewAbs&abs=1032
- Stanley TL, Fourman LT, Feldpausch MN, et al. Effects of tesamorelin on non-alcoholic fatty liver disease in HIV: a randomised, double-blind, multicentre trial [published online October 29, 2019]. Lancet HIV. https://doi.org/10.1016/S2352-3018(19)30338-8
Steven K. Grinspoon, MD, is a professor of medicine and director of the Nutrition Obesity Research Center at Harvard Medical School in Boston, Massachusetts. He is also the chief of the Metabolism Unit and the MGH Endowed Chair in Neuroendocrinology and Metabolism at Massachusetts General Hospital in Boston, Massachusetts.
TRANSCRIPT:
Dr Steven Grinspoon: I'm Dr. Steven Grinspoon. I'm a professor of medicine at Harvard Medical School. I'm chief of the Metabolism Unit at MGH. I've had a long‑standing interest in the metabolic complications of HIV, including fatty liver disease.
Whenever you encounter something that is a public health issue, you want to try and find treatment for it. I would begin by saying, in the general population, many people are trying to develop therapies for NAFLD, nonalcoholic fatty liver disease. There haven't been any that have been FDA approved to date, although there are some that are getting close.
Unfortunately, not a lot of HIV patients have been in those trials in the general population. Luckily, in the HIV space there are some interesting developments. One is tesamorelin, as you mentioned, which may be the most advanced of them because it was studied in a randomized placebo‑controlled trial that had liver biopsy data. Our group has been involved in that.
Patients with HIV have low growth hormone levels. The secretion of growth hormone is reduced in association with excess fat and obesity and visceral adiposity. They have low growth hormone levels to begin with. Growth hormone is an important hormone that oxidizes or burns fat.
When you have a low level of growth hormone, you may accumulate excess fat in many places, including the liver. There have been studies to suggest that that's a very important pathway to maintain homeostasis in the liver to reduce fat and reduce the inflammation.
We had the idea that if you could augment the natural levels of growth hormone through increases in growth hormone pulsatility through a drug called tesamorelin, you might be able to burn some of that fat and reduce some of that fat in the liver.
We've completed one study so far in patients specifically with NAFLD, although we've done many studies. Tesamorelin is approved for the HIV population as a drug to reduce visceral fat and lipodystrophy. It's already approved, but it's not approved for the use of NAFLD yet.
We did an experimental study in which we looked at its effects on NAFLD and showed that it reduced liver fat significantly, on the order of 35 percent, relative to placebo. This was also associated with the prevention of fibrosis progression, which was rapid in the HIV group in general but prevented by tesamorelin significantly.
There was no increase in blood sugar levels, which was important for that strategy. There were also decreases in inflammatory markers such as CRP. Even the liver enzymes, like ALT, were reduced with tesamorelin. When you take it together, you have an agent, thus far in preliminary studies, which reduces visceral fat, reduces liver fat, reduces liver inflammation, and prevents fibrosis.
Of course, this set of studies will need to be further confirmed. It's promising, I'd say. It basically addresses a set of physiological problems in the HIV population that exist, the low growth hormone and the increased liver fat in that population.
It's not the only agent. Whenever you consider fatty liver disease, you also want to talk about lifestyle changes, which are important and probably should be the first‑line therapy, to be honest with you. I mentioned that in my symposium.
If you lose about 10 percent of your weight, you get significant reductions of liver fat and fibrosis. That's always a good idea, but we all know that that can be hard to achieve. It's a good goal. It should be tried, but you might need pharmacological therapy.
On top of tesamorelin, there are other things that have been tried. Pioglitazone, which is a diabetic agent, has had some efficacy. Semaglutide, which is another diabetic agent, which is associated with weight loss and was proven to reduce liver inflammation in the non‑HIV population and reduce weight, is being tried, I think, in the HIV population. That's promising.
Vitamin E has had some mild effects. There have been some failures. Aramchol was a failure in HIV, did not reduce liver fat. I would say that there are a number of potential strategies out there. Another one is cenicriviroc, which is a CCR2/CCR5 antagonist, which may reduce inflammation, although it's had some setbacks in the general population.
Tesamorelin may be the most advanced of the agents that are being tried and may be studied further in that population. The important thing is it's a natural hypothalamic peptide which augments our own growth hormone pulsatility. It's a gentle drug. It's working to correct a problem that's existing physiologically in those patients.
I'd like to thank the audience who are watching this and for the people who participated in the symposium. Thank you so much.