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 NAFLD to NASH, to cirrhosis and liver cancer in
people with HIV are unclear.
A non-invasive test, used instead of a biopsy, to measure the stiffness
or elasticity of the liver using an ultrasound probe.
Improvement in a tumour. Also, a mathematical model that allows us to measure the degree to which one of more factors influence an outcome.
Abnormal fat deposits in the liver.
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 co-infected with hepatitis C. Amongst other factors, they wanted to investigate whether weight gain associated with antiretroviral treatment raised the risk of fatty liver disease.
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 per cent were of
African origin and 6% 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
per cent had an undetectable viral load on study entry.
Six per cent 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
per cent 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 tenofovir disoproxil fumarate (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 TAF (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.
Participants taking 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 regimen 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.