Tesamorelin reduces liver fat and fibrosis progression in people with HIV and non-alcoholic fatty liver disease

Treatment with tesamorelin, a synthetic growth hormone-releasing hormone, reduced liver fat content and reduced the progression of liver fibrosis in people with HIV who had non-alcoholic fatty liver disease, researchers report in The Lancet HIV.

Non-alcoholic fatty liver disease (NAFLD) – the accumulation of fat in the liver – is a growing cause of liver disease in people living with HIV. Research presented earlier this year at The International Liver Congress showed that the prevalence of NAFLD more than doubled among people with HIV between 2006 and 2016 and accounted for 25% of cases of liver disease diagnosed in people living with HIV in the United States receiving Medicare insurance. A study presented at the same conference showed that almost a third of people living with HIV in cohorts in Italy and Canada had NAFLD, and a quarter of these were at risk of progressing to advanced liver disease.

The authors of the study published this week say that NAFLD will soon become the greatest cause of liver-related ill health and deaths in people living with HIV, as more people are cured of hepatitis C.

Glossary

non-alcoholic fatty liver disease (NAFLD)

Non-alcoholic fatty liver disease (NAFLD) is a very common disorder and refers to a group of conditions where there is accumulation of excess fat in the liver of people who drink little or no alcohol. The most common form of NAFLD is a non-serious condition called fatty liver, by which fat accumulates in the liver cells. A small group of people with NAFLD may have a more serious condition named non-alcoholic steatohepatitis (NASH).

placebo

A pill or liquid which looks and tastes exactly like a real drug, but contains no active substance.

fibrosis

Scarring of the liver – the development of hard, fibrous tissue. See also ‘cirrhosis’, which is more severe scarring.

hormone

A chemical messenger which stimulates or suppresses cell and tissue activity. Hormones control most bodily functions, from simple basic needs like hunger to complex systems like reproduction, and even the emotions and mood.

exclusion criteria

Defines who cannot take part in a research study. Eligibility criteria may include disease type and stage, other medical conditions, previous treatment history, age, and gender. For example, many trials exclude women who are pregnant, to avoid any possible danger to a baby, or people who are taking a drug that might interact with the treatment being studied.

The risk of developing NAFLD is higher in people who are obese, especially if they have central fat accumulation.

NAFLD may lead to liver inflammation (NASH), scarring and hardening of the liver (fibrosis) and to liver cancer. As people with HIV live longer, conditions such as NAFLD are emerging as new health problems which require monitoring and management.

Tesamorelin has been studied as a treatment for abdominal fat accumulation, or lipodystrophy, in people living with HIV and is approved for the reduction of visceral fat in people living with HIV in the United States. It stimulates production of growth hormone, which is suppressed in people living with HIV. The extent of growth hormone secretion inhibition corresponds to central fat accumulation and weight gain.

By stimulating the production of growth hormone, tesamorelin also promotes an increase in levels of insulin-line growth factor (IGF-1), which promotes lipolysis (the breakdown of fats).

A previous study showed that tesamorelin reduced liver fat content over six months of follow-up in people living with HIV.

To investigate the potential of tesamorelin as a treatment for NAFLD in people living with HIV, investigators at Massachusetts General Hospital and the US National Institutes of Health randomised 61 people living with HIV who had hepatic steatosis (liver fat content of 5% or greater) to receive either tesamorelin 2mg once daily or a placebo for 12 months, followed by open-label tesamorelin treatment for all participants for six months.

The study excluded people who drank large amounts of alcohol, people with poorly controlled diabetes, people with chronic hepatitis B or C infection, and people with a variety of other liver conditions, including advanced fibrosis or cirrhosis. The study also excluded people with active cancer (not in remission), men with a history of prostate cancer and anyone receiving treatment with systemic corticosteroids. The study also excluded anyone with a CD4 count below 100 or a detectable viral load.

Tesamorelin was administered as a subcutaneous daily injection and participants were trained in how to make up the powdered form of the drug into an injectable form. Participants in the placebo group followed an identical process.

The study population was predominantly male (77% in the tesamorelin group, 80% in the placebo group) and approximately two-thirds white.

The mean liver fat content was 12.9% in the tesamorelin group and 14.7% in the placebo group.

Approximately one-third of participants had NASH and 48% of the tesamorelin and 38% of the placebo group already has some degree of liver fibrosis. 13.8% of the tesamorelin group and 6.9% of the placebo group has stage 3 fibrosis.

The primary outcome of the study was the change in liver fat fraction after 12 months of treatment. Intent-to-treat analysis showed that hepatic fat fraction declined by 4.1% in the tesamorelin group but remained unchanged in the placebo group (p=0.018), a relative reduction of 37% (p=0.016).

Liver fat changes were not affected by race, antiretroviral use, statin use (32% of tesamorelin recipients and 46% of the placebo group were taking a statin).

Just over a third of people in the tesamorelin group (35%) experienced a reduction of hepatic fat below 5% by 12 months, so that they were no longer classified as having NAFLD, compared to 4% of the placebo group (p=0.0069).

Tesamorelin recipients were significantly less likely to experience progression of fibrosis (10% vs 37% in the placebo group, p= 0.044) and there was an association between a higher level of liver inflammation (measured by NAS score) and improvement in NAS score. Fibrosis was measured by biopsy at baseline and after 12 months on treatment.

The investigators note that fibrosis stage is the most important predictor of mortality in people with NAFLD and that preventing the progression of fibrosis is an important criterion for judging the value of treatments for NAFLD.

There were no significant differences in liver enzymes, fasting glucose, CD4 count, lipids or body weight between the two groups, except for visceral adipose tissue, which fell significantly in the tesamorelin group.

There was no difference in adverse events between the two groups, although two people in the tesamorelin group withdrew due to the development of raised blood sugar (hyperglycaemia), a known side effect of the drug. Tesamorelin was otherwise well tolerated and adherence to daily subcutaneous injections was high (80% of all scheduled injections carried out in the tesamorelin group and 87% in the placebo group), measured by returned vials of study medication.

The investigators say that further studies are needed to find out if the effects on liver fat and fibrosis persist after discontinuation of treatment, and when to initiate treatment with tesamorelin.

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