Viral and immune factors associated with successful treatment withdrawal in HBeAg-negative chronic hepatitis B patients

Mireia García-López,Sabela Lens,Laura J Pallett,Barbara Testoni,Sergio Rodríguez-Tajes,Zoe Mariño,Concepción Bartres,Ester García-Pras,Thais Leonel,Elena Perpiñán,Juan José Lozano,Francisco Rodríguez-Frías,George Koutsoudakis,Fabien Zoulim,Mala K Maini,Xavier Forns,Sofía Pérez-Del-Pulgar

doi:10.1016/j.jhep.2020.11.043

Abstract

Background & AimsFactors associated with a successful outcome upon nucleos(t)ide analogue (NA) treatment withdrawal in HBeAg-negative chronic hepatitis B (CHB) patients have yet to be clarified. The objective of this study was to analyse the HBV-specific T cell response, in parallel with peripheral and intrahepatic viral parameters, in patients undergoing NA discontinuation.MethodsTwenty-seven patients without cirrhosis with HBeAg-negative CHB with complete viral suppression (>3 years) were studied prospectively. Intrahepatic HBV-DNA (iHBV-DNA), intrahepatic HBV-RNA (iHBV-RNA), and covalently closed circular DNA (cccDNA) were quantified at baseline. Additionally, serum markers (HBV-DNA, HBsAg, HBV core-related antigen [HBcrAg] and HBV-RNA) and HBV-specific T cell responses were analysed at baseline and longitudinally throughout follow-up.ResultsAfter a median follow-up of 34 months, 22/27 patients (82%) remained off-therapy, of whom 8 patients (30% of the total cohort) lost HBsAg. Baseline HBsAg significantly correlated with iHBV-DNA and iHBV-RNA, and these parameters were lower in patients who lost HBsAg. All patients had similar levels of detectable cccDNA regardless of their clinical outcome. Patients achieving functional cure had baseline HBsAg levels ≤1,000 IU/ml. Similarly, an increased frequency of functional HBV-specific CD8+ T cells at baseline was associated with sustained viral control off treatment. These HBV-specific T cell responses persisted, but did not increase, after treatment withdrawal. A similar, but not statistically significant trend, was observed for HBV-specific CD4+ T cell responses.ConclusionsDecreased cccDNA transcription and low HBsAg levels are associated with HBsAg loss upon NA discontinuation in patients with HBeAg-negative CHB. The presence of functional HBV-specific T cells at baseline are associated with a successful outcome after treatment withdrawal.Lay summaryNucleos(t)ide analogue therapy can be discontinued in a high proportion of chronic hepatitis B patients without cirrhosis. The strength of HBV-specific immune T cell responses may contribute to successful viral control after antiviral treatment interruption. Our comprehensive study provides in-depth data on virological and immunological factors than can help guide individualised therapy in patients with chronic hepatitis B.

Highlights

Functional cure, defined as the loss of HBsAg, with or without the development of anti-HBs antibodies, is regarded as the optimal treatment endpoint in patients with HBeAg-negative chronic hepatitis B (CHB)
HBV-specific T cell responses at baseline are associated with virological control off-treatment To evaluate the impact of the HBV-specific T cell response on the clinical outcome after nucleos(t)ide analogue (NA) discontinuation, we investigated the effector capacity of HBV-specific CD4+ and CD8+ T cells after in vitro stimulation with overlapping peptides (OLP) spanning the core, envelope, or polymerase proteins
Several new direct-acting antivirals and immunomodulatory compounds are in clinical evaluation with the aim of achieving functional cure of CHB with finite treatment duration.[15]

Summary

Introduction

Functional cure, defined as the loss of HBsAg, with or without the development of anti-HBs antibodies, is regarded as the optimal treatment endpoint in patients with HBeAg-negative chronic hepatitis B (CHB). A high proportion of these patients achieved sustained virological remission (low HBV-DNA levels and normal alanine aminotransferase [ALT] levels). Despite this recommendation, some clinicians may be reluctant to offer NA withdrawal to their patients owing to the high probability of viral rebound after stopping antiviral therapy (serum HBV-DNA >2,000 IU/ml in about 55–70%).[5] viral relapses are not always associated with ALT flares and, when transitory, may lead to long-term virological remission. An increased frequency of functional HBV-specific CD8+ T cells at baseline was associated with sustained viral control off treatment. Conclusions: Decreased cccDNA transcription and low HBsAg levels are associated with HBsAg loss upon NA discontinuation in

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