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CROI 2014: Tesamorelin Growth-Hormone Releaser Reduces Liver Fat in People with HIV

Tesamorelin, a synthetic form of growth-hormone-releasing hormone (GHRH), which the FDA has approved to reduce excess visceral abdominal fat in people living with HIV, also reduced associated liver fat in an HIV positive cohort chosen for abdominal adiposity, according to the results from a randomized, placebo-controlled trial presented at the 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014) this week in Boston.

"This represents the first successful medical strategy shown to reduce liver fat in HIV-infected patients," said Steven Grinspoon of Massachusetts General Hospital, who presented the findings.

However, Grinspoon noted that a potential downside to the treatment is that tesamorelin could worsen glucose homeostasis, though he said that this effect resolved over the 6 months of the trial -- probably because negative effects of tesamolerin were offset by the drug's beneficial effects on visceral fat (which improved insulin sensitivity).

Hepatic or liver fat is strongly associated with the visceral abdominal fat accumulation that is often increased in people with HIV compared to uninfected individuals. 30%-40% of people with HIV have non-alcoholic fatty liver disease (NAFLD), which is defined as having 5% or more liver fat. People with chronic hepatitis B or C can also develop fatty liver, known as steatosis.

Hepatic fat can contribute to metabolic abnormalities and other serious complications. For instance, non-alcoholic steatohepatitis (NASH) is seen in approximately 20%-40% of HIV positive people with NAFLD, and is associated with inflammation, liver damage, fibrosis, and cirrhosis. NAFLD and NASH can progress to end-stage liver disease or hepatocellular carcinoma. They are also associated with insulin resistance, dyslipidemia (abnormal blood fat levels), and increased risk of cardiovascular disease.

Currently, there are no treatment strategies to reduce liver fat and manage NAFLD in people with HIV.

Tesamorelin is a synthetic analog of growth hormone releasing hormone, which induces the pituitary gland to produce growth hormone. It has previously been shown to reduce visceral fat in people HIV. However, those studies did not evaluate its effects on liver fat, and its effects on detailed measures of insulin sensitivity and other metabolic parameters remained unknown.

Grinspoon and colleagues designed this study to investigate the effects of tesamorelin on hepatic fat. In addition, they also investigated the effects of tesamorelin on other fat depots, insulin sensitivity, and cardiovascular risk markers, including carotid intima-media thickness (cIMT).

Participants and Method

This study included 50 men and women with HIV on antiretroviral therapy (ART) who had abdominal fat accumulation (waist >95 cm and waist:hip ratio >0.94 for men; waist >94 cm and waist:hip ratio >0.88 for women). They could not have used any anti-diabetic agents, growth hormone, growth-hormone-releasing hormone, or glucocorticoid during the past 6 months or lipid-lowering drugs within 3 months of screening.

Participants were randomized to receive either 2 mg tesamorelin or placebo by subcutaneous injection daily for 6 months.

At baseline, the groups were well matched. Participants were mostly in their late 40s and early 50s, had been HIV infected for 16 to 21 years, and had similar treatment histories. The percentage of patients with hepatitis C coinfection was carefully matched (23% in each arm).

The trial’s primary endpoints were changes in liver fat as measured by magnetic resonance spectroscopy and changes in visceral adipose tissue (VAT) as measured by computed tomography. Secondary endpoints involved changes in intramyocellular lipids, liver function tests (ALT and AST liver enzymes), and carotid intima-media thickness, glucose, and insulin resistance.

The investigators hypothesized that tesamorelin might initially perturb glucose metabolism, so they took detailed measures of glucose levels and insulin sensitivity, monitoring oral glucose tolerance and adiponectin (a protein involved in regulating glucose levels as well as fatty acid breakdown), and performing euglycemic hyperinsulemic clamp testing on a subset of patients to definitively determine the drug’s effects on insulin resistance and sensitivity.

Results

• 7 participants discontinued treatment, 3 of them due to adverse events, leaving 20 patients on placebo and 23 on tesamorelin at month 6.
• After 6 months on treatment, tesamorelin-treated participants had significantly reduced visceral fat compared with placebo recipients (reduction of 34+9 cm² vs a gain of 8+11 cm²).
• This amounted to a 16.5% net change in visceral fat, consistent with prior studies.
• Tesamorelin had no effect on subcutaneous fat, also consistent with earlier studies, and body mass index did not change.
• There was a significant net decrease in overall fat, however, and fat in the trunk was reduced on tesamorelin compared with placebo (-0.4 vs 0.6 kg, respectively).
• There was a significant 40% reduction in liver fat in the tesamorelin group vs a 27% gain in the placebo group, which was highly statistically significant.
• There were significant correlations between the change in hepatic fat and visceral adipose tissue, insulin resistance according to HOMA-IR, AST level, and triglycerides.
• In terms of clinical differences in AST, there was a 4-point drop in AST on tesamorelin compared to a similar rise on placebo, but this difference was not significant; however, tesamorelin did significantly reduce AST in participants with high baseline levels.
• Looking at glucose changes, there was an early increase after 2 weeks on tesamorelin.
• Fasting glucose increased more in the tesamorelin group compared with the placebo group at 2 weeks (increases of 9 vs 2 mg/dL, respectively.
• At 3 and 6 months, however, changes in fasting and 2-hour glucose and fasting insulin were not significantly different between the 2 groups.
• The subgroup who underwent euglycemic hyperinsulinemic clamp testing showed clear worsening in insulin-stimulated glucose disposal, a measure of insulin sensitivity, at 3 months, but it returned to baseline levels after 6 months. Insulin-like growth factor-1 (IGF-1) levels increased as expected in the tesamorelin group.
• As far as other cardiovascular measures, cIMT decreased by 4% over 6 months within the tesamorelin group (-0.03) and decreased, though not significantly, in the placebo group.
• There was a near-significant change in adiponectin, which might have reached significance in a larger patient cohort.
• Tesamorelin was generally well tolerated.
• There were no significant differences in adverse events leading to treatment discontinuation between the groups, nor in minor adverse events.

"There were clear relationships in both the placebo and tesamorelin groups such that the more the visceral fat improved, the more the insulin sensitivity improved," said Grinspoon, but the effects of tesamorelin were complex.

"The visceral fat went down enough so that the net effect on insulin sensitivity was neutral on tesamorelin, so you’re okay, it didn’t negatively affect you," he continued. "So tesamorelin is a complicated drug -- it’s extremely effective to reduce visceral fat, and that reduction in visceral fat improved insulin sensitivity, but it also has direct insulin antagonistic affects, at least initially. So if you give it long enough and perhaps let the initial perturbations wear off, you will win.”

In conclusion, "tesamorelin reduced liver fat in association with decreased VAT in a cohort chosen for abdominal adiposity," said Grinspoon. Further study is needed to determine the effects of tesamorelin on liver fat and steatohepatitis in an HIV-infected cohort chosen specifically for increased liver fat, i.e., people with NAFLD or NASH.

There are a number of limitations to the study, including the sample size. "It’s a relatively small sample size due to the detailed nature of the physiologic endpoints, and therefore it may have been underpowered to detect changes in the secondary endpoints, though it was obviously robustly powered enough to detect the change in liver fat," said Dr Grinspoon. In addition, the participants were mostly male.

Grinspoon noted that previous studies have shown a return of visceral fat with discontinuation of tesamorelin treatment, so a similar pattern might be seen in liver fat after treatment discontinuation. 

This issue was of great concern to some clinicians in the audience. "I am a little troubled, when we stopped the drug the effects seemed to reverse. So if I have a 20 year old I’m starting on treatment today, I’m looking at potentially keeping him on treatment for 50 or 60 years, and the long-term side effects and toxicities of boosting growth hormone are a little troubling to me," said one.

"It’s equally troubling to me," Grinspoon responded. "Most drugs work when you give them and don’t work when you don’t give them. The issue, though, is whether you could jump-start someone with [tesamorelin] and then have another drug -- or maybe lifestyle change come in afterwards."

"That’s really the study that needs to be done," he continued. "I don’t think this drug should be given life-long to people. It’s too expensive and it’s too cumbersome to use. But it really gives a jolt. It really reduces visceral fat, and liver fat now. So the question is, can we design a study that would have a follow up -- lifestyle or some kind of maintenance? That really is a study that needs to be done."

3/7/14

Reference

T Stanley, M Feldpausch, J Oh, S Grinspoon, et al. Effects of Tesamorelin On Hepatic Fat in HIV Patients: A Randomized, Placebo-Controlled Trial. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6. Abstract 135.