Individualizing Strategies for Chronic Hepatitis B—What Should We Do About Patients in the Gray Zone?

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Current guidelines recommend antiviral therapy for persons living with chronic HBV infection with active liver inflammation and/or liver fibrosis. The long-term goal is to reduce liver injury, progression to cirrhosis, and development of hepatocellular carcinoma (HCC). Although the approved oral antivirals—ie, nucleos(t)ide analogues (NAs)—are highly effective at suppressing viral replication, reversing liver fibrosis, and reducing risk of end-stage liver disease, NA treatment rarely leads to hepatitis B surface antigen (HBsAg) loss, which is considered a functional cure. Discontinuation of NA treatment can lead to clinical relapse, even after many decades. Furthermore, the risk of HCC is reduced with NA therapy—but not eliminated. 

Whom to Treat and Whom to Monitor
There is little debate regarding the need for treatment of certain groups (Table), specifically:

• Patients with cirrhosis
• Patients with HCC
• Patients with persistently elevated ALT and HBV DNA ≥2000 IU/
• Patients coinfected with hepatitis delta virus
• Patients coinfected with HIV
• Patients who are immunocompromised
• Pregnant patients with high-level viremia (>200,000 IU/mL) during late pregnancy (second/third trimester) to reduce risk of vertical transmission
• Patients with extrahepatic manifestations of HBV

Conversely, many experts agree that other patients are unlikely to need treatment, such as those with HBV DNA levels persistently <2000 IU/mL—especially with low HBsAg levels by quantitative assay, no liver fibrosis/inflammation, and persistently normal ALT.

Expanding Whom to Treat
Recent expert discussions have revolved around expanding HBV treatment criteria—in particular, considering treatment of younger individuals with high HBV DNA levels even if they have normal liver enzymes and no fibrosis, historically referred to as immune tolerant (high replicative/noninflammatory HBeAg-positive chronic HBV).

There is also controversy regarding treating those who fall outside the strict guideline-recommended indications for treatment, such as persons with minimally elevated ALT, especially if they have comorbid conditions such as metabolic-associated fatty liver disease. Expert guidelines recommend consideration of treatment if there is a family history of HCC, but specific family history details are often unknown. Further, HBV DNA can fluctuate from low to moderate levels that may not be captured even with serial monitoring. In some patients, a quantitative HBsAg level can help guide treatment decisions, but more data are needed in diverse patient cohorts (eg, with different genotypes), and there is a need for improved viral serum biomarkers. In my practice, I also discuss obtaining a liver biopsy to confirm absence of inflammation and fibrosis.

The rationales for expanding treatment include: (1) NAs are safe and well tolerated, and generic options are available at greatly reduced cost; (2) there is evidence suggesting that moderate to high levels of HBV DNA in young patients are linked to increased risk for cirrhosis and HCC in the long term due to HBV integration into the host genome; and (3) treatment reduces stigma, as well as infectivity to susceptible persons.

In summary, current HBV treatment paradigms are being challenged. The risks vs benefits of treatment need to be weighed and must account for patient preference, cost, and long-term adherence.

A cure for chronic hepatitis B may still be many years away, and to me, it is important that we use all of our available tools in the fight against HBV—including HBV vaccination for prevention, along with safe and effective treatments to reduce the risk of liver disease progression and liver cancer development. 

Your Thoughts?
How do you approach the care of patients with high HBV DNA levels and normal ALT with HBeAg-positive chronic hepatitis B? Do you tend to favor treatment in most cases, or do you have a higher threshold that requires the presence of other risk factors for disease progression? Please join the conversation and share your experiences in the comments box.

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