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Monitoring Novel HBV Markers Worthwhile in HBeAg-positive Patients Coinfected With HIV

Key findings

  • This study assessed associations of two newer biomarkers, hepatitis B core-related antigen (HBcrAg) and HBV RNA, with other HBV markers and liver histology in 56 patients with HBV–HIV coinfection (96% with complete or partial dual viral suppression)
  • Over 192 weeks, HBV RNA and HBcrAg remained detectable in all HBeAg-positive patients, suggesting ongoing viral transcription
  • HBV RNA and HBcrAg did not decline significantly in HBeAg-negative patients
  • Monitoring HBV RNA and HBcrAg during antiviral treatment may be informative in HBeAg-positive patients but seems to be of limited utility in those who are HBeAg-negative

Several familiar serum markers—hepatitis B e antigen (HBeAg), hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA levels—are important biomarkers of HBV activity.

In a previous analysis of adults coinfected with HBV and HIV, the HBV–HIV Cohort Study of the Hepatitis B Research Network demonstrated that two novel markers, HBV RNA and hepatitis B core-related antigen (HBcrAg), reflect HBV transcription and may better indicate HBV activity. Those results were presented at the 2020 meeting of the American Association for the Study of Liver Diseases.

Subsequently, Raymond Chung, MD, vice chief of the Division of Gastroenterology and director of the Hepatology and the Liver Center at Massachusetts General Hospital, and colleagues in the research network evaluated the longitudinal dynamics of HBV RNA and HBcrAg in the same HBV–HIV co-infected cohort.

In HBeAg-positive patients, the newer HBV markers indicated continued HBV infection control over time. However, as the researchers report in Clinical Gastroenterology and Hepatology, those markers did not further improve in HBeAg-negative patients.


The prospective study involved adults with HBV–HIV coinfection who were being treated at eight Hepatitis B Research Network clinical centers in the U.S. and Canada. Examinations including blood testing were performed at study entry and every 24 weeks thereafter for up to 192 weeks.

This analysis included 56 participants who had a liver biopsy upon both study entry and exit. 97% were on combination antiretroviral therapy (cART), 84% had complete dual viral suppression and 12% had partial dual suppression.


Changes in the new markers varied according to whether a participant was HBeAg-positive or -negative at study entry:


  • HBV RNA and HBcrAg stayed quantifiable in all patients, suggesting ongoing viral transcription, although levels declined significantly over time
  • The decreases in HBV RNA and HBcrAg corresponded with decreases in HBeAg, HBsAg and HBV DNA


  • HBV RNA and HBcrAg levels were generally lower and more variable than in HBeAg-positive participants and did not change meaningfully over the four years of follow-up, suggesting a plateau in the effect of antiviral therapy
  • HBsAg and HBV DNA declined significantly during the follow-up period

Clinical Relevance

These results have several applications to the care of HBV–HIV coinfected patients in whom HBV is suppressed:

  • Monitoring of HBV RNA and HBcrAg during antiviral treatment appears to have a role in managing HBeAg-positive patients but appears to have limited clinical utility in HBeAg-negative patients
  • HBV RNA levels can fluctuate from undetectable to detectable, so any treatment decisions influenced by this marker should be based on serial assessments
  • cART should be continued in the absence of HBeAg and HBsAg loss
  • With continued maintenance of cART in HBeAg-positive patients, there might be eventual loss of HBeAg and perhaps the development of antibodies against HBe

The data also highlight the need for innovative therapies directed at other HBV targets to accomplish a functional cure for HBV, since there appears to be residual transcription and translation of HBV, even with ostensible suppression of viral replication.

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