HIV Lipodystrophy and Fatty Liver: Causes, Tests, Care

HIV-associated lipodystrophy is a condition that changes the way the body makes, uses and stores fat, and it may affect some people with HIV. Fat can build up around the organs in the belly and be lost from the face, arms and legs. The exact cause is unknown, but the HIVinfo fact sheet of the National Institutes of Health (NIH) links it to HIV infection and some HIV medicines. The same fact sheet tells readers to talk to a health care provider about treatment options, including potential changes to HIV medicine, and says the effects of lipodystrophy could be reduced through dietary changes and regular exercise.

Where does fat build up or thin out, and what causes it?

The fact sheet also calls lipodystrophy fat redistribution, in which the body abnormally takes fat from one region and relocates it to another part of the body (HIVinfo, HIV and Lipodystrophy). The way it affects each person can vary based on numerous factors, including sex. Women tend to have fat buildup, also called lipohypertrophy, around the organs in the belly, on the back of the neck between the shoulders and in the breasts. Men tend to have fat loss, also called lipoatrophy, in the arms and legs, around the hips and on the face.

HIVinfo states that people with lipodystrophy often have other metabolic problems, including high cholesterol and insulin resistance, which can lead to diabetes. If untreated, the fact sheet adds, metabolic problems caused by lipodystrophy can also lead to other conditions, such as heart disease.

On causes, the fact sheet, last reviewed on October 18, 2024, says the exact cause remains unknown and that lipodystrophy may be attributed to HIV. It adds that some HIV-related medicines could cause lipodystrophy, particularly after long-term use, and it names five that have been linked to it: atazanavir, darunavir, fosamprenavir, ritonavir and tipranavir. For a person taking one of these who believes lipodystrophy is present, the fact sheet says to consult a health care provider about adjusting the treatment regimen, and it adds: "Do not stop taking your current HIV medicine unless your doctor advises you to do so."

Why do abdominal fat and liver fat matter?

Abdominal fat is measured in two compartments, subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). An analysis from the Framingham Heart Study measured both by multidetector computed tomography in 3,001 participants who were free of clinical cardiovascular disease (Fox et al. 2007, PubMed 17576866). Among both women and men, SAT and VAT were significantly associated with blood pressure, fasting plasma glucose, triglycerides and high-density lipoprotein cholesterol, and with increased odds of hypertension, impaired fasting glucose, diabetes mellitus and metabolic syndrome. VAT was more strongly correlated with most metabolic risk factors than SAT was.

For people with HIV, the abstract of the 26-week trial described in the tesamorelin section states that visceral adipose tissue accumulates during antiretroviral therapy in many patients who are infected with HIV, and that this process is associated with an increased cardiovascular risk. The table sets the Framingham odds ratios beside the fat changes HIVinfo names and a liver-fat estimate.

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) defines nonalcoholic fatty liver disease, or NAFLD, also referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), as a condition in which excess fat builds up in the liver, a buildup that is not caused by heavy alcohol use (NIDDK, Definition and Facts of NAFLD and NASH). One form of this fatty liver disease, nonalcoholic steatohepatitis (NASH), has inflammation of the liver and liver damage in addition to fat, and NIDDK says it may lead to cirrhosis of the liver, in which the liver is scarred and permanently damaged.

NIDDK calls cardiovascular disease the most common cause of death in people who have NAFLD. The abstract of the liver-fat trial described in the tesamorelin section calls NAFLD a substantial cause of comorbidity in people with HIV.

How are body-fat changes and liver fat assessed?

Waist measurement was an entry test in the two trials summarized in the FDA prescribing information for tesamorelin (FDA prescribing information, revised 02/2024). Their main inclusion criteria were age 18 to 65 years, a waist circumference threshold of 95 cm (37.4 inches) with a waist-to-hip ratio threshold of 0.94 for men, and 94 cm (37.0 inches) with 0.88 for women. The same trials assessed visceral adipose tissue by computed tomography (CT) scan at the L4-L5 vertebral level. In the Framingham analysis, VAT but not SAT contributed significantly to risk factor variation after adjustment for body mass index and waist circumference.

Blood tests in the label trials covered glucose and lipids. Fasting blood glucose below 150 mg/dL was an inclusion criterion, and triglycerides and the ratio of total cholesterol to HDL cholesterol were secondary endpoints. Mean baseline hemoglobin A1c (HbA1c) was 5.3% among patients in both the treated and the placebo groups.

For the liver, NIDDK says doctors use medical history, a physical exam and tests to diagnose NAFLD (NIDDK, Diagnosis of NAFLD and NASH). A doctor may suspect NAFLD if a blood test shows increased levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The imaging tests NIDDK lists are ultrasound, CT scan and magnetic resonance imaging (MRI), and it says routine imaging tests can show fat in the liver.

What treatment options do the sources describe?

HIVinfo tells a person who has HIV and thinks lipodystrophy is also present to talk to a health care provider about treatment options, including potential changes to HIV medicine. The fact sheet also states: "Never stop taking your HIV medicines without consulting your doctor."

Aside from changing medicines, HIVinfo says the effects of lipodystrophy could be reduced through dietary changes and regular exercise. It adds that liposuction (surgical fat removal) and injectable facial fillers are sometimes used to treat lipodystrophy. The fact sheet also says a health care provider could prescribe non-HIV medicines to help treat lipodystrophy; one with an FDA indication for excess abdominal fat is described next.

Where does tesamorelin fit among these options?

Tesamorelin, sold under the brand name Egrifta, is a growth hormone-releasing factor analog and an injectable prescription medicine. Its prescribing information states that it is indicated for the reduction of excess abdominal fat in HIV-infected adult patients with lipodystrophy.

What does the label say is not established?

The label's limitations of use state that long-term cardiovascular safety has not been established. They state that the medicine is not indicated for weight loss management, as it has a weight neutral effect, and that there are no data to support improved compliance with antiretroviral therapies. Prescribers are told to consider the risk and benefit of continuing treatment in patients who have not had a reduction in visceral adipose tissue. The label's four contraindications are disruption of the hypothalamic-pituitary axis, for example from pituitary gland tumor or surgery, active malignancy, known hypersensitivity to tesamorelin or the excipients, and pregnancy.

What did the 26-week trials find?

A trial published in 2007 randomly assigned 412 patients with HIV (86% of whom were men) who had an accumulation of abdominal fat to subcutaneous injections of tesamorelin or placebo for 26 weeks (Falutz et al. 2007, PubMed 18057338). Visceral adipose tissue, the primary end point as shown on computed tomography, decreased by 15.2% in the tesamorelin group and increased by 5.0% in the placebo group. Adverse events did not differ significantly between the groups, but more patients in the tesamorelin group withdrew because of an adverse event.

The abstract and the label's Study 1 print the same registration number, NCT00123253, and the same count of 412 randomized patients, but their figures differ. The label derives its percentages from a statistical model in the intent-to-treat population with last observation carried forward, and reports mean treatment differences of -20% in Study 1 and -12% in Study 2. Study 1 and Study 2 are separate trials; their figures are shown side by side and are not ranked or pooled here.

What did the liver-fat trial find?

A randomised, double-blind trial enrolled 61 people with HIV and a hepatic fat fraction of 5% or more by proton magnetic resonance spectroscopy; 30 received tesamorelin and 30 received placebo for 12 months (Stanley et al. 2019, PubMed 31611038). Patients receiving tesamorelin had a greater reduction of hepatic fat fraction than patients receiving placebo, with an absolute effect size of -4.1% (95% CI -7.6 to -0.7), corresponding to a -37% relative reduction from baseline.

After 12 months, 35% of individuals receiving tesamorelin and 4% receiving placebo had a hepatic fat fraction of less than 5%, and changes in fasting glucose and glycated haemoglobin were not different between groups. The authors' interpretation is that tesamorelin might be beneficial in people with HIV and NAFLD, and that further studies are needed to determine the long-term effects on liver histology.

What side effects and monitoring does the label list?

The most commonly reported adverse reactions in the label are hypersensitivity reactions such as rash and urticaria, edema-related reactions such as arthralgia and peripheral edema, hyperglycemia, and injection site reactions. Injection site reactions occurred in 25% of treated patients and 14% of placebo-treated patients during the first 26 weeks of treatment in clinical trials.

On blood sugar, the label says treatment can result in glucose intolerance, and the percentages of patients with elevated HbA1c from baseline to week 26 were 5% in the treated group and 1% in the placebo group. It directs prescribers to evaluate glucose status before treatment begins and to monitor all treated patients periodically. It also says to monitor levels of IGF-1, a growth factor, during therapy, and that the effects of prolonged elevations in IGF-1 levels are unknown.

Hypersensitivity reactions occurred in 4% of treated patients in clinical trials. The label's instruction for a suspected reaction is to "seek prompt medical attention and immediately discontinue treatment".