Finite nucleos(t)ide analogue therapy in hepatitis B e antigen‐negative chronic hepatitis B: From an “option” to an “active recommendation”

Abstract

Nucleos(t)ide analogue (Nuc) including entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide may suppress hepatitis B virus (HBV) DNA profoundly but have no direct action on covalently closed circular DNA, which is a very stable template for HBV production. Therefore, decades of long-term Nuc therapy are required to maintain HBV suppression and to achieve hepatitis B surface antigen (HBsAg) loss in hepatitis B e antigen (HBeAg)-negative patients. However, there are concerns including financial burden, adherence, and willingness for indefinite long-term Nuc therapy. Patients lost to follow-up and hence not monitored may risk severe relapse that may deteriorate to hepatic decompensation or even hepatic failure. Cessation of Nuc therapy in HBeAgnegative patients was initially considered in early 2000s. Earlier findings in Asian patients that finite Nuc therapy over 2-3 years is feasible and safe have founded Asian-Pacific Association for the Study of Liver stopping rule since 2008. Subsequent studies have confirmed the feasibility and safety of the strategy of finite Nuc therapy, which has finally been accepted as "an option" by American and European liver associations since 2016. More recent large studies since 2018 have further confirmed the pivotal findingof greatly increased HBsAg loss rate (~5-year 39%) after stopping Nuc therapy. With the high HBsAg loss rate as the main justification, the paradigm shift from indefinite longterm therapy to finite Nuc therapy in HBeAg-negative patients has been changing from an "option" to an "active recommendation" aiming to achieve HBsAg loss. More studies are needed to fine-tuning the strategy, including research for the optimal duration of consolidation therapy, timing to stop, and to start retreatment.

Current Perspectives on Nucleos(t)ide Analogue Therapy for the Long-Term Treatment of Hepatitis B Virus

“…Moreover, different biochemical criteria of retreatment have been applied in the previously published studies making difficult to compare and obtain solid conclusions. 79 , 90 , 92 , 100 However, our recommendation is in consonance with Liaw and Chien advice 86 , 101 that retreatment criteria should not be determined at one single time point and careful and close assessment is required to better define the type of hepatitis flare for optimal retreatment decision.…”

Severe hepatitis B flares with hepatic decompensation after withdrawal of nucleos(t)ide analogues: A population‐based cohort study

“…Without concrete data to directly assess the outcomes of such a practice, there is no basis for discussion and it might be argued that the policy is the new paradigm. 28,29 To enhance the generalizability…”

“…This population‐based study offers empirical evidence that challenges the restrictive policy on NUC reimbursement in Taiwan. Without concrete data to directly assess the outcomes of such a practice, there is no basis for discussion and it might be argued that the policy is the new paradigm 28,29 . To enhance the generalizability of our study, we not only excluded patients with cirrhosis or portal hypertension but also identified a sub‐cohort of “eligible” patients to stop NUCs.…”

Clinical trials reimagined

“…Effective nucleos(t)ide therapies to suppress hepatitis B DNA are available for patients with chronic viral hepatitis B; however, long-term therapy may be problematic in regions with limited resources. Identification of individuals who can safely discontinue nucleos(t)ide analog therapy is a significant unmet need until higher rates of functional cure are attained 67 . Interferon is administered for a limited time with a higher rate of HBsAg clearance, but it is difficult for some individuals to tolerate, and many populations have inadequate response rates.…”

“…Identification of individuals who can safely discontinue nucleos(t)ide analog therapy is a significant unmet need until higher rates of functional cure are attained. [67] Interferon is administered for a limited time with a higher rate of HBsAg clearance, but it is difficult for some individuals to tolerate, and many populations have inadequate response rates. Even with longer durations of therapy with nucleos(t)ide analogs, HBsAg loss or functional cure is uncommon, and the greatest unmet therapeutic need is to combine therapies that target replication and modulate immunity to achieve high rates of functional cure with finite durations of therapy.…”