Liver function and ageing in people with HIV infection

Liver disease has emerged as a major cause (up to 20%) of morbidity and mortality in ageing people with HIV infection on effective ART. [28, 61-63] Age-related declines in liver volume (20-40%) and blood flow (35-50%) and reduced cytochrome P450 content result in impaired drug elimination and increased drug exposure in the older general population. [28, 64] This becomes important for people with HIV infection as clearance of several antiretroviral drugs is via hepatic metabolism, necessitating close monitoring and awareness of potential adverse effects of ART and other medications. In general, dose modification of antiretroviral drugs is only required when end stage liver disease is present. A detailed table outlining dose adjustment of antiretroviral drugs for impaired hepatic function is provided elsewhere  People with HIV infection are also vulnerable to liver injury through persistent HIV replication (chronic immune activation and inflammation), diabetes mellitus, substance use (particularly alcohol) and untreated HCV or hepatitis B virus (HBV) infection. [65, 66]. Hepatitis C virus infection is curable and reduces the long-term complications of liver fibrosis, cirrhosis and hepatocellular carcinoma. The direct-acting antivirals (DAAs) have proven to be well tolerated and highly efficacious in the context of co-infection with HIV, and every effort should be made to cure HCV infection in people with HIV infection, regardless of age.[66]  Suppression of HBV replication with appropriate ART will also reduce hepatic complications. Specific ASHM guidelines for HCV and HBV management can be found here and HBV: Treatment and Monitoring of Persons with HCV/HIV Co-infection and Treatment and Monitoring of Persons with HBV/HIV Co-infection. [42]

Older people with HIV infection found to have raised serum levels of hepatic transaminases need to have the following considered; (1) recent introduction of hepatotoxic medication, hepatotoxic herbal products or recreational drugs; (2) recent change in ART regimen or a potential drug-drug interaction (to determine attribution to the ART regimen, return to the original regimen if virologically suppressed, and observe change in ALT/AST in the next 4-8 weeks); (3) HBV reactivation, which may occur when ART regimens are changed leading to failure to control HBV replication; new HCV or hepatitis A virus (HAV) infection; (4) alcohol induced liver disease; (5) severe right heart failure and (6) non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD) - the most common cause of liver function test derangement.

Almost half of all people with HIV infection investigated for deranged liver function tests are found to have NAFLD, and the prevalence of NAFLD (25-35% worldwide) is now higher than in the general population. [42, 67, 68] Both ageing and metabolic dysregulation have been proposed as underlying mechanisms.[69] In population studies of people with HIV infection, NAFLD was found to be associated with high BMI, visceral adiposity, insulin resistance, dyslipidaemia and a high alanine aminotransferase/aspartate aminotransferase ratio. [68, 70-73] HIV infection may itself be associated with a fatty liver, as a result of multiple viral and host factors [69] and is associated with increased morbidity and mortality. [72]

NAFLD is defined as having hepatic steatosis involving >5% of hepatocytes; with the exclusion of secondary causes including alcoholic fatty liver disease (≥30 g alcohol for men and ≥ 20g for women of daily alcohol consumption). [42] NAFLD is often associated with other components of the metabolic syndrome (central obesity, dyslipidemia, hypertension, insulin resistance +/- glucose intolerance, proinflammatory state, prothrombotic state). [74] Hepatocellular carcinoma (HCC) is also a well-recognised complication of NAFLD and can occur in the absence of cirrhosis and histological evidence of NASH. [42]

Hepatic ultrasound is the preferred diagnostic measure for imaging of NAFLD, whereas liver biopsy is gold standard – demonstrating steatosis, hepatocyte ballooning and lobular inflammation.  Once NAFLD is suggested by ultrasound, risk of advanced fibrosis can be estimated by calculating the FIB-4 or Non-alcoholic fatty liver disease Fibrosis Score. [42] Lifestyle modification and weight loss are currently the main therapeutic interventions, [42] and entails caloric restriction, aiming for a target of 7-10% weight loss in persons with central obesity and exercise of at least moderate intensity at 150-200 min/week. [42] An antiretroviral drug regimen that does not increased serum lipids is also recommended for those with confirmed NAFLD.

Transient elastography, a non-invasive approach to a ‘liver stiffness measurement’, can be used to assess the degree of liver fibrosis and presence of cirrhosis. The severity of the chronic liver disease will determine ongoing management and surveillance, including need for liver biopsy, and screening for HCC and oeseophageal varices if severe fibrosis is detected (F4).  All people with HIV infection who have cirrhosis, including those with HBV infection that is medically suppressed or cured HCV infection, require screening for HCC by assay of serum alpha-fetoprotein levels and/or liver ultrasound every 6-12 months. Screening for oesophageal varices by upper gastro-intestinal tract endoscopy is recommended in any person with HIV infection who has liver cirrhosis and a liver stiffness measurement ≥ 20 or a platelet count ≤150,000/mL.

Key recommendations

  1. Liver disease has emerged as a major cause of morbidity and mortality in people with HIV infection. Therefore, screen for liver disease regularly, with liver function tests performed at least 6 monthly.
  2. Expected age-related decline in hepatic metabolism may lead to inadvertent increased drug exposure, and subsequent hepatotoxicity. Close monitoring and awareness of potential adverse effects in this population is recommended.
  3. Older people with HIV infection who develop derangement of liver function tests should undergo a full review of medications, including over the counter medications and supplements, alcohol use, and recreational drug use. New drug-drug interactions should be considered. Viral hepatitis serology should be performed and updated and depending on risk, repeated at regular intervals (i.e. 3-6 monthly if high risk). Immunisation with HAV and HBV vaccines is strongly recommended for those who are susceptible to HAV and HBV infection.
  4. Treatments for HCV infection are highly successful and well-tolerated and should be offered, if indicated.
  5. People with HIV infection have a high prevalence of NAFLD, the liver manifestation of metabolic syndrome. Ultrasound is the preferred diagnostic measure for imaging of NAFLD. Lifestyle modification and weight loss are currently the mainstay therapeutic interventions.
  6. The severity of the chronic liver disease as measured by APRI, FIB-4 or transient elastography will determine ongoing management and the need for surveillance and screening for HCC and oesophageal varices. HCC screening every 6 months and screening for oesophageal varices by upper gastrointestinal endoscopy, as required, are recommended.