Metabolic syndrome, type 2 diabetes and obesity are risk factors for the development of liver fibrosis and steatosis (liver fat accumulation) in people living with HIV, including those who do not have viral hepatitis co-infection, according to research presented at the 9th International AIDS Society Conference on HIV Science (IAS 2017) last month in Paris.
As effective antiretroviral therapy (ART) has reduced deaths from opportunistic infections, liver disease has become a major cause of morbidity and mortality among people living with HIV. Hepatitis B or C, heavy alcohol consumption and other causes of liver injury can lead to the development of fibrosis and steatosis, but these may also occur without such liver-specific risk factors.
Fibrosis occurs when scar tissue replaces normal hepatocytes, the cells that carry out the liver's viral functions. Cirrhosis is the most advanced stage of fibrosis (stage F4). Steatosis occurs when hepatocytes fill up with fat. Non-alcoholic fatty liver disease (NAFLD) develops in people who do not drink heavily; non-alcoholic steatohepatitis (NASH) is its more advanced stage. Over time, these progressive conditions can lead to liver function impairment, liver cancer and the need for a liver transplant.
A recently published systematic review found that at least one in five people living with HIV who do not have co-infection with hepatitis B or C had NASH. Metabolic syndrome, hypertension and high body mass index were found to be significant risk factors for NAFLD in people living with HIV.
Maud Lemoine of Imperial College London presented findings from a study of the association between metabolic syndrome and liver fibrosis in HIV-positive people without viral hepatitis (known as HIV monoinfection). Metabolic syndrome is a cluster of factors associated with elevated cardiovascular risk, including abdominal obesity, high blood pressure, abnormal blood lipid levels and high blood glucose, a sign of insulin resistance and type 2 diabetes.
The METAFIB study, conducted at a single centre in France, looked at nearly 500 HIV-positive people without hepatitis B or C virus (HBV or HCV) co-infection who said they did not drink heavily and did not have other causes of chronic liver disease.
Fibrosis was assessed using transient elastography (FibroScan), a non-invasive method of measuring liver 'stiffness' using sound waves; a stiffer liver indicates more extensive fibrosis.
Among participants with valid liver stiffness results, 203 people with metabolic syndrome were matched by age and sex with 202 people who did not. Nearly 90% were men and the average age was 53 years. Participants had been HIV-positive for around 17 years on average, most were on ART with undetectable viral load and the mean CD4 count was over 600 cells/mm3. People with metabolic syndrome had a higher body mass index, were more likely to be obese and more likely to have insulin resistance (49 vs 9%) or type 2 diabetes (15 vs 1%).
The researchers found that participants with metabolic syndrome were significantly more likely to have liver fibrosis compared to those without it. A quarter of people with metabolic syndrome had moderate fibrosis (stage F2), compared with about 7% of those without. Advanced fibrosis (stage F3) was seen in about 15% of those with and 3% of those without metabolic syndrome, and for cirrhosis the proportions were about 8% and 1%, respectively.
People with moderate or worse fibrosis had significantly higher levels of inflammatory markers than those with absent or mild fibrosis (stage F0 or F1), including C-reactive protein, interleukin 6, leptin and adiponectin (two hormones produced by adipose or fat tissue) and a marker linked to macrophage activation (a type of immune system white blood cell). This was also the case when comparing people with and without cirrhosis.
After adjusting for other factors, participants with metabolic syndrome were about twice as likely to have at least stage F2 fibrosis, about four times more likely to have at least stage F3 fibrosis and about eight times more likely to have cirrhosis. Those with obesity were about three times more likely to have stage F2 or F3 fibrosis and about four times more likely to have cirrhosis. Liver enzyme (ALT and AST) levels, HIV-related factors and type of ART did not predict fibrosis status.
"HIV-monoinfected patients with metabolic syndrome are at risk of liver fibrosis and should be systematically screened for liver fibrosis irrespective of transaminases levels or HIV parameters," the investigators concluded.
"Mass fat measured by [body mass index] and circulating level of leptin is strongly associated with liver fibrosis independently of HIV parameters and ART exposure," they added.
They suggested that adipose tissue, insulin resistance and macrophage activation "are probably key players" in the development of liver fibrosis in HIV-positive people without viral hepatitis.
Hugo Perazzo of Fundação Oswaldo Cruz in Rio de Janeiro, Brazil, and colleagues looked at factors associated with liver fibrosis and steatosis among HIV-positive people without hepatitis B or C who were on long-term ART.
The researchers hypothesised that a single 'hit' – such as type 2 diabetes, obesity or a genetic risk factor – could cause simple steatosis, but additional hits may be needed for progression cirrhosis or NASH. These factors might include chronic inflammation and immune activation associated with HIV or use of hepatotoxic antiretrovirals.
This study included 395 participants from the PROSPEC-HIV cohort. About 60% were women and the average age was 45 years. Eighty per cent had undetectable viral load and the median CD4 count was approximately 660 cells/mm3. They had been on ART for a median of seven years and many had used older antiretrovirals associated with metabolic or liver-related side-effects. About a third had metabolic syndrome, but more had at least one of its components including abdominal obesity (68%) and abnormal blood lipids (61%).
Perazzo reported that 9% of participants met the criteria for fibrosis and 35% met the criteria for steatosis according to FibroScan. Women and men were equally likely to have fibrosis, but men were significantly more likely to have steatosis. Older age was a risk factor for fibrosis, but not for steatosis.
In a multivariate analysis, having type 2 diabetes nearly tripled the risk for fibrosis and having a CD4 count below 200 cells/mm3 increased the risk by almost eightfold. For steatosis, metabolic syndrome was associated with fourfold higher risk, obesity alone with almost elevenfold higher risk and type 2 diabetes with almost tenfold higher risk.
Longer duration of ART use – especially older nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir) or stavudine (Zerit) – was associated with steatosis independently of metabolic factors, the researchers concluded.
They recommended that prevention and management of non-infectious conditions such as metabolic syndrome should be integrated into HIV care to decrease the burden of liver disease among people living with HIV.
Lemoine M et al. Metabolic syndrome and obesity are the cornerstones of liver fibrosis in HIV-monoinfected patients: results of the METAFIB study. 9th International AIDS Society Conference on HIV Science, Paris, abstract MOAB0304, July 2017.
Perazzo H et al. Predictor factors associated with liver fibrosis and steatosis by transient elastography in HIV-monoinfected patients under long-term combined antiretroviral therapy: the PROSPEC-HIV study. 9th International AIDS Society Conference on HIV Science, Paris, abstract MOAB0305, July 2017.