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HBV Monitoring: Gray Zone
Navigating the Gray Zone: Importance of Monitoring Patients With Indeterminate-Phase CHB

Released: December 21, 2023

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Key Takeaways
  • Because patients with CHB in the gray zone are at risk for disease progression and hepatocellular carcinoma, ongoing assessment of ALT and HBV DNA levels is crucial. 

Last week, I saw a Chinese couple with chronic hepatitis B (CHB). They were both hepatitis B e antigen (HBeAg) positive, but the woman was 26 years old with elevated alanine aminotransferase (ALT) and hepatitis B virus (HBV) DNA 10,000,000 IU/mL, whereas her husband was 36 years old with an almost normal ALT and HBV DNA 6000 IU/mL.

Based on these results, I recommended that she start antiviral therapy, but I recommended that he be monitored without antiviral therapy. 

Understandably, they had a difficult time grasping why I gave them different recommendations. I explained to them that the natural history of CHB is complex and dynamic, and it is determined by the interaction between the virus and the individual patient. Although the wife fell into the category of chronic hepatitis, it was difficult to define for the husband; he could fall into the category of chronic infection or an indeterminate phase known as the “gray zone.”

Here is the reasoning behind my differing recommendations.

HBV Phases
According to 2017 European Association for the Study of the Liver clinical guidelines, CHB can be classified into 2 categories—chronic infection and chronic hepatitis—and further differentiated into phases based on HBeAg and hepatitis B surface antigen (HBsAg) status. The 5 phases  are: (1) HBeAg-positive chronic infection, (2) HBeAg-positive chronic hepatitis, (3) HBeAg-negative chronic infection, (4) HBeAg-negative chronic hepatitis, and (5) HBsAg-negative phase (resolved CHB).

Chronic infection  is defined by persistently normal ALT levels and variable HBV DNA levels, with minimal or no liver damage. Individuals with HbeAg-positive chronic infection (immune-tolerant CHB) have high HBV DNA levels. By contrast, those with HbeAg-negative chronic infection (inactive carriers) have undetectable or low levels of HBV DNA (<2000 IU/mL). Periodic monitoring is recommended for those with chronic infection.

Chronic hepatitis  (or immune-active CHB)—regardless of HBeAg status—is defined by high levels of HBV DNA and elevated ALT; both parameters are regarded as risk factors  for disease progression in patients with CHB. Antiviral therapy is recommended  in patients with HbeAg-positive or HbeAg-negative chronic hepatitis (immune-active CHB) to reduce the incidence of liver cirrhosis and hepatocellular carcinoma (HCC). 

The Gray Zone 
The indeterminate phase, or gray zone, represents situations when HBV DNA and ALT levels do not fit into these well-described phases. In this phase, there is ambiguity about whether to treat or monitor the patient.

The proportion of patients who fall into the gray zone is variable depending on the ALT and HBV DNA criteria and the duration of follow-up used. The course of CHB is dynamic, and patients often revert from one phase to another. In one study, 36%  of individuals considered to be in the gray zone transformed into usual phases after a median follow-up of 14 weeks. However, in another study, only 6.3% of HbeAg-negative patients in the gray zone converted into an immune-active state and met criteria for antiviral therapy. 

Importance of Monitoring 
Because patients can revert to different HBV phases throughout their disease course, it is important to routinely test ALT and HBV DNA levels every 6 months and consider assessment of liver histology to clarify disease severity and evaluate the potential need to treat.

In patients with CHB in the gray zone, Yao  and colleagues found that independent risk factors for advanced disease were older age, HBeAg-positive status, and elevated ALT levels.

  • Age is an important factor affecting the natural course and long-term outcomes of patients with CHB. Of note, the incidence of adverse events to antiviral therapy increases with age and may affect treatment decisions. 
  • The HBeAg-positive CHB phase is usually associated with viral replication and hepatitis activity, and the persistent presence of HBeAg has been associated with a higher risk  of fibrosis progression and cirrhosis development.
  • Serum ALT always has been regarded as the most common biomarker of hepatitis activity. 

Based on an analysis by Kim  and colleagues, noncirrhotic, HBeAg-positive, immune-tolerant patients with CHB (normal ALT with HBV DNA ≥20,000 IU/mL) who were untreated had a higher 10-year HCC incidence compared with HBeAg  -positive, immune-active patients with CHB (ALT ≥80 IU/mL with HBV DNA ≥20,000 IU/mL) who received antiviral therapy (12.7% vs 6.1%, respectively; P <.001), suggesting that earlier antiviral therapy could decrease the risk of HCC in patients who are immune tolerant. 

These findings bring up 2 limitations with current treatment criteria, particularly among those who are immune tolerant with normal ALT and elevated HBV DNA levels: (1) the lack of precise evaluation of liver fibrosis and inflammation and (2) how strict clinical criteria are used to define “genuine immune tolerant.” Aside from moderate HBV DNA (<107 IU/mL) or borderline ALT levels, several other factors have been found to be related to the development of advanced fibrosis and associated with the development of HCC, such as older   age (older than 30-40 years), male sex, a family history of HCC, and a high FIB-4 value.

Decision to Treat 
At present, the decision of whether to initiate antiviral therapy for patients in the gray zone is a clinically challenging matter that often requires additional information, such as results of a liver biopsy or evaluation of liver fibrosis by noninvasive biomarkers.

The presence of advanced liver fibrosis or liver cirrhosis that sometimes occurs in these patients is an indication for urgent treatment and monitoring for HCC. Therefore, more attention should be paid to the patients in the gray zone, especially to those who are HBeAg positive. 

Back to the Case
For the husband described above—for whom it was difficult to determine if he fell into the category of chronic infection or gray zone and for whom I recommended monitoring instead of treatment—I repeated his labs and performed a FibroScan at his 6-month follow-up appointment. As expected, he remained HBeAg positive. Previously, his ALT was almost normal, and now it was more elevated, and his viral load was just above 3000 IU/mL, proving the dynamic nature of HBV disease. 

Some might define him as being immune tolerant, but to me, he fell into the gray zone based on his now-elevated ALT and slightly elevated HBV DNA. His FibroScan result was 8.2 kPa, which was abnormal in the context of viral replication. 

Based on these updated results, I recommended antiviral therapy. He was interested in starting treatment and has been suppressed ever since.

Your Thoughts?
How do you define patients with HBV in the gray zone? How does the gray zone affect your treatment and monitoring decisions? Join the discussion by posting a comment.