HBcrAg Levels Are Associated With Virological Response to Treatment With Interferon in Patients With Hepatitis Delta

Abstract

HIDIT-II Study GroupStandard treatment of hepatitis delta virus (HDV) infection remains pegylated-interferon alfa (peg-IFNα) in most centers, which is not only associated with rather low efficacy but several adverse events. Hepatitis B core-related antigen (HBcrAg) is linked to intrahepatic covalently closed circular DNA levels and has previously been suggested as response predictor in IFN-based treatment of hepatitis B virus (HBV) mono-infection. This study aimed to investigate the value of HBcrAg in the management of patients with HBV/HDV co-infection undergoing peg-IFNα treatment. The Hep-Net-International-Delta-Hepatitis-Intervention Trial-2 study included 120 patients co-infected with HBV/HDV. Patients were treated for 96 weeks with peg-IFNα and either tenofovir or placebo. Ninety-nine patients with HDV-RNA results 24 weeks after end of treatment (FU24) were included in this analysis, of whom 32 patients (32.3%) had undetectable HDV RNA at FU24. HBcrAg was measured at baseline, week 12, 24, 48, 96, and FU24. HBcrAg levels showed no significant correlation with HDV RNA but were significantly linked to treatment outcome. HBcrAg levels < 4.5 log IU/mL at baseline, week 24, and week 48 had high negative predictive value (NPV) for achieving undetectable HDV RNA at FU24 (81.8%, 87.1% and 95.0%, respectively). Similarly, HBcrAg levels at week 96 were significantly higher in patients with viral relapse until FU24 (3.0 vs. 3.63 log IU/mL; P = 0.0089). Baseline, week 24, and week 48 HBcrAg levels were also associated with the likelihood of achieving HBsAg level < 100 IU/mL at FU24 (HBcrAg < 3.0 log IU/mL: NPV 91.7%, 90.4% and 92.3%, respectively). Test statistics improved when combining HBcrAg with additional viral and clinical parameters. Conclusion: HBcrAg is linked to treatment response to peg-IFNα in patients with HBV/HDV co-infection and could be a promising marker to determine treatment futility. (Hepatology Communications 2022;6:480-495).C hronic hepatitis D virus (HDV) infection, also known as hepatitis delta, is the most severe form of chronic viral hepatitis and frequently leads to liver cirrhosis, hepatic decompensation, and the development of hepatocellular carcinoma. (1) HDV is a defective satellite virus, and the RNA genome

Kinetics and predictive value of HBcrAg, HBV RNA and anti‐HBc during bulevirtide treatment of chronic HDV‐infected patients

“…In contrast, HBV RNA levels were undetectable in the majority of patients and anti‐HBc levels only declined numerically. HBcrAg and HBV RNA levels both reflect HBV cccDNA transcriptional activity and were associated with response to antiviral treatment with PEG‐IFNa in HBV mono‐ and HBV/HDV coinfection 4,5 . For HBV infection, their decline during IFN‐based treatment has been linked to immune modulation effects of IFN lowering HBV transcript levels.…”

“…So far, markers identifying patients that benefit most from certain antiviral strategies for hepatitis D are not available. Novel virological markers reflecting HBV cccDNA transcriptional activity and host immune response activity were associated with response to interferon (IFN) treatment in hepatitis B virus (HBV) monoinfection and also HBV/HDV coinfection 4,5 . However, the kinetic profile and predictive value of these markers, HBV RNA, hepatitis B core related antigen (HBcrAg) and antibodies against the HBV nucleocapsid protein (anti‐HBc) during antiviral treatment with BLV have not been investigated, so far.…”

Bulevirtide in the Treatment of Hepatitis Delta: Drug Discovery, Clinical Development and Place in Therapy

“… 48 , 49 Likewise, late relapses were recognized in the HIDIT-II trial that tested tenofovir plus pegIFN. 50 In both studies, however, a few patients sustained undetectable serum HDV-RNA indefinitely, occasionally despite remaining positive for HBsAg.…”

Hepatitis delta virus: Disease assessment and stratification

“…Serum HBcrAg declined readily in treatment responders (pegylated interferon‐alpha) and maybe a useful predictive marker. Patients with baseline HBcrAg levels <4.5 log IU/ml were more likely to achieve undetectable HDV RNA at 24 weeks of post‐treatment follow‐up (negative predictive value 81.8%), and those who relapsed had higher end‐of‐treatment HBcrAg levels (3.63 vs. 3.0 < 3.0 log IU/ml) 35 . Taken together, HBcrAg is a surrogate marker of active HDV infection and is potentially useful to gauge treatment response.…”

“…HBcrAg levels (3.63 vs. 3.0 < 3.0 log IU/ml). 35 Taken together, HBcrAg is a surrogate marker of active HDV infection and is potentially useful to gauge treatment response.…”