The research was directed by Sofia Pérez del Pulgar and Xavier Forns, of Hospital Clínic/IDIBAPS, in collaboration with Mala Maini, of the Infections and Immunology Division of University College of London and Fabien Zoulim of the Cancer Research Center of Lyon. The study also involved the participation of HIBEREHD researchers from Hospital Vall d'Hebron, Barcelona and the CIBEREHD bioinformatics platform. The lead authors of the article are Mireia García-López, i-PFIS predoctoral researcher, and Sabela Lens, senior specialist at the Hospital Clínic Hepatology Department, both of whom are part of the IDIBAPS Viral, toxic, and metabolic liver diseases research group and are attached to CIBEREHD.
Current therapy against infection with the hepatitis B virus (HVB) is based on the use of nucleoside/nucleotide analogs (NUCs), which are able to control viral replication but cannot eliminate the virus from the liver. For this reason, most patients require lifelong treatment. This is due to the presence of cccDNA (covalently closed circular DNA), an intermediary of HVB replication that is refractory to NUC therapy. The cccDNA therefore persists in the nuclei of the liver cells, thus perpetuating virion production. To date, no efficacious and safe drugs have been developed that can interfere with the formation or activity of cccDNA.
In order to increase the functional cure rate (loss of surface antigen or HBsAg), the latest clinical guidelines of the European Association for the Study of the Liver (EASL) propose interrupting treatment with NUCs in noncirrhotic patients with HBeAg-negative chronic hepatitis B and viral suppression for more than 3 years. Despite these recommendations, the viral markers and immunologic factors associated with a good prognosis after withdrawal of the NUCs are yet to be defined. Thus, the objective of the study was to investigate the responses of HVB-specific T cells in parallel with peripheral and intrahepatic virologic markers, in a well-characterized cohort of patients with HBeAg-negative chronic hepatitis B who underwent suspension of NUC therapy.
The results of the study show that interrupting treatment is feasible in a high proportion (82%) of patients with HBeAg-negative chronic hepatitis B, of whom 30% lost HBsAg. Furthermore, patients who achieved a functional cure had low levels of HBsAg (≤1000 UI/mL) and reduced activity of transcriptional cccDNA at the time of suspending treatment with NUCs. In terms of the response of HVB-specific T cells, patients who remain without NUCs present a higher frequency of functional CD8 T cells and, therefore, a lower exhaustion profile, which may contribute to controlling HVB infection. It should be noted that these HVB-specific T-cell responses persisted but did not increase after suspension of treatment.
The study’s authors concluded that the low levels of HBsAg may be useful for identifying patients in whom interruption of treatment with NUCs, together with close monitoring, may be a valid therapeutic strategy for achieving a functional cure. Moreover, although the activity of the cccDNA is reduced in these patients, intrahepatic viral markers do not improve the predictive capacity of HBsAg. Nevertheless, for patients with a less favorable virologic profile, the functionality of HVB-specific T cells may contribute to virologic control after interruption of NUC therapy.
Viral and immune factors associated with successful treatment withdrawal in HBeAg-negative chronic hepatitis B patients.
García-López M, Lens S, Pallett LJ, Testoni B, Rodríguez-Tajes S, Mariño Z, Bartres C, García-Pras E, Leonel T, Perpiñán E, Lozano JJ, Rodríguez-Frías F, Koutsoudakis G, Zoulim F, Maini MK, Forns X, Pérez-Del-Pulgar S. J Hepatol. 2020 Dec 2:S0168-8278(20)33830-7. doi: 10.1016/j.jhep.2020.11.043. Online ahead of print. PMID: 33278456.