Family Affair: How Family History Helps Navigate Clinical Decisions Around HBV Treatment and Monitoring

When managing patients with chronic hepatitis B, some clinical scenarios fall into the gray zones of current guidance. In this commentary, I discuss how I incorporate family history into treatment and monitoring decisions in certain clinical gray zones. In addition, I will walk through how to choose among recommended nucleos(t)ide analogues (NAs) once a decision has been made to initiate treatment.

Incorporation of Family History in the Management of Hepatitis B
Current hepatitis B management guidelines from the American Association for the Study of Liver Diseases (AASLD) recommend that in patients not meeting treatment thresholds for immune-active hepatitis B, either with alanine aminotransferase <2 x upper limit of normal or HBV DNA <2000 IU/mL for hepatitis B e antigen (HBeAg)–negative patients or <20,000 IU/mL for HBeAg-positive patients, a family history of hepatitis B virus (HBV)–related hepatocellular carcinoma (HCC) or cirrhosis should be considered in deciding whether to initiate treatment for hepatitis B. 

Multiple studies have corroborated the findings of increased risk of HCC in patients, including HBV carriers, with a family history of HBV-related HCC. Loomba and colleagues demonstrated that a family history of HCC multiplies the risk of HCC at each stage of HBV infection and reported a 40% increase in cumulative risk of HCC when both family history and HBeAg are present.

A family history of HBV-related HCC or cirrhosis should influence the decision not only to start treatment for hepatitis B, but also to initiate long-term screening for HCC. The AASLD recommends HCC screening in hepatitis B surface antigen (HBsAg)–positive patients with a first-degree family member with a history of HCC. The optimal age at which these patients start HCC screening is not yet established.

For patients in the gray zone or not meeting treatment criteria—including following the consideration of age, cirrhosis, degree of fibrosis and inflammation, extrahepatic manifestations, and quantitative HBsAg level—a family history of HBV-related HCC or cirrhosis would shift my decision toward starting treatment for hepatitis B and initiating HCC screening, based on AASLD guidelines and strong data associating family history and HCC risk.

Choosing Among NAs for Chronic Hepatitis B Treatment
Once you have decided to initiate treatment, how do you choose among the recommended NAs? Entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) are the recommended first-line NAs for patients with chronic hepatitis B, given their potent antiviral activity and high barrier to resistance. Older NAs such as lamivudine, telbivudine, and adefovir are not preferred due to their low barriers to resistance.

When selecting NA therapy, several factors should be considered:

• Presence of decompensated cirrhosis. TDF and ETV are preferred, as TAF has not been studied in these patients. The AASLD suggests that the “use of TAF would be reasonable in patients when TDF adverse effects are a concern and entecavir is not an option.”
• Prior HBV treatment. Tenofovir (TDF or TAF) is recommended over ETV for patients who have had prior antiviral exposure or resistance. ETV is not recommended for patients with lamivudine- or telbivudine-resistant HBV infection.  
• Patients with or at risk for osteopenia/osteoporosis or renal disease. ETV or TAF is preferred. TAF has lower rates of bone and renal abnormalities than TDF does. If a patient is on TDF, monitor renal function and switch to TAF or ETV if TDF-associated bone/renal dysfunction develops. The European Association for the Study of the Liver suggests the following indications in selecting ETV or TAF over TDF: age older than 60 years, bone disease (chronic steroid use, fragility fractures, osteoporosis), or renal alterations (glomerular filtration rate <60 mL/min, albuminuria, low phosphate, hemodialysis).
• Pregnancy. TDF is preferred due to the lack of sufficient data with ETV or TAF.
• Medication cost/insurance coverage. Not all NAs are covered by each patient’s insurance, and healthcare professionals should discuss the potential cost associated with the various treatments based on the patient’s insurance coverage.

Your Thoughts?
Do you consider family history of HBV-related HCC or cirrhosis in your decision to start HBV treatment or HCC surveillance? What factors do you consider in choosing among the recommended NAs? Answer the polling question and join the conversation by posting in the discussion section.