People with HIV were more likely to develop fatty liver disease if they took antiretroviral treatment that contains an integrase inhibitor or tenofovir alafenamide (TAF), a German research group has found.
Non-alcoholic fatty liver disease (NAFLD) develops through accumulation of fat in the liver. People with diabetes and / or high body mass are more likely to develop fatty liver, or steatosis. One in four people in North America and Europe is estimated to have fatty liver disease but estimates of prevalence in people with HIV vary enormously.
A small proportion of people with fatty liver disease go on to develop non-alcoholic steatohepatitis (NASH), an inflammatory state that can lead to severe liver damage (cirrhosis). NASH increases the risk of developing liver cancer (hepatocellular carcinoma), but the risks of progression from non-alcoholic fatty liver disease to NASH, to cirrhosis and liver cancer in people with HIV are unclear.
Dr Jenny Bischoff and colleagues at University Hospital Bonn carried out a prospective cohort study to investigate the prevalence of fatty liver disease and risk factors for the development of fatty liver disease in people with HIV not coinfected with hepatitis C. Amongst other factors, they wanted to investigate whether weight gain associated with antiretroviral treatment raised the risk.
The study recruited people with HIV with alcohol intake under 30g a day for men and 20g a day for women, as high alcohol intake is also a risk factor for liver damage. Three hundred and nineteen people were recruited and followed for an average of three-and-a-half years. Participants had an average age of 45 years and 77% were male. Sixteen percent were of African origin and six percent of Asian origin.
Participants had been diagnosed with HIV an average of nine years prior to study entry and had been taking antiretroviral treatment for an average of eight years.
Researchers used Fibroscan ultrasound scanning to assess liver stiffness and steatosis in all participants on entry into the study and at annual visits. They also calculated liver fibrosis scores using liver stiffness and laboratory measurements and calculated FAST scores using liver stiffness and levels of the liver enzyme AST to identify patients at higher risk of NASH.
At baseline, 19% of participants were taking an integrase inhibitor, 40% a boosted protease inhibitor and 40% a non-nucleoside reverse transcriptase inhibitor as part of their antiretroviral treatment. Eighty-six percent had an undetectable viral load on study entry.
Six percent of study participants had type 2 diabetes at baseline, 20% had high blood pressure and 46% already had some degree of steatosis, including 17.5% who had severe steatosis and 13.8% who had advanced steatosis.
During the follow-up period, 20% of participants either developed steatosis or progressed to a more advanced stage of steatosis. Among those followed for five years, only 36% remained free of steatosis by the end of the study period, compared with 54% at study entry. The proportion with severe steatosis increased from 17.5% to 50% over the same period. Thirty percent of all participants with steatosis at baseline experienced a worsening of steatosis grade during the follow-up period.
Regression analysis showed that male sex and a body mass index above 23 kg/m2 were significantly associated with the development of steatosis, so that whereas 68% of men with a BMI above 23 developed steatosis, only 25% of women with BMI above 23 did so.
As almost all participants were taking TDF, TAF and/or an integrase inhibitor, the investigators carried out a multivariable analysis to identify other risk factors – including drug exposure – that were associated with the development of steatosis.
The risk of developing steatosis was more than seven times greater in people with type 2 diabetes (hazard ratio 7.6, 95% confidence interval 2.31-24.98, p<0.001) than those without. The risk was also elevated in people taking tenofovir alafenamide (HR 5.07, 95% CI 2.36-10.89, p<0.001), an integrase inhibitor (HR 2.35, 95% CI 1.37-4.04, p=0.002) and those with a lowest-ever CD4 count below 200 (HR 2.87, 95% CI 1.54-5.32, p<0.001).
Higher body mass index steatosis (HR 2.61, 95% CI 95% CI 1.38-4.93, p=0.003) and greater liver stiffness (HR 2.41, 95% CI 1.10-5.74, p=0.048) also raised the risk of developing steatosis.
As well as having a higher risk of developing steatosis, participants taking TAF or an integrase inhibitor developed steatosis more quickly or experienced more rapid progression than people taking other drugs. People taking TAF or integrase inhibitors also had a greater risk of progression to NASH, shown by changes in FAST score during follow-up. Furthermore, they had a higher risk of weight gain of at least 5% or 10% compared to people not taking those drugs.
"Weight gain associated with antiretroviral regimens and the development of steatosis are linked."
Participants taking tenofovir disoproxil fumarate (TDF) had a significantly lower risk of developing steatosis or experiencing progression of steatosis compared to people not taking the drug (HR 0.28, 95% CI 0.12-0.64), and a lower risk of progression to NASH. They also had a lower risk of weight gain of at least 5% or 10% compared to people not taking TDF.
The study investigators conclude that weight gain associated with antiretroviral regimens and the development of steatosis are linked and that TDF may play a role in protecting against both weight gain and steatosis.
They recommend that people with HIV with a body mass index above 23, and anyone taking TAF or an integrase inhibitor, should undergo Fibroscan screening and other testing to establish the extent of liver damage. They also recommend that the current European AIDS Clinical Society algorithm for NAFLD should be reviewed in the light of this evidence.
Bischoff J et al. Stratifying the risk of NAFLD in patients with HIV under combination antiretroviral therapy (cART). EClinical Medicine, 40: 101116, 2021.