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What will it take to cure hepatitis B? therapies in research
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Hepatology Communications 2023 April
Wen-Juei Jeng, Anna S. Lok
Download the PF here
Download the PF here
Abstract
The current treatment of chronic HBV infection, pegylated interferon-α (pegIFNα) and nucleos(t)ide analog (NA), can suppress HBV replication, reverse liver inflammation and fibrosis and reduce the risks of cirrhosis, HCC, and HBV-related deaths, but relapse is common when the treatment is stopped before HBsAg loss. There have been major efforts to develop a cure for HBV, defined as sustained HBsAg loss after a finite course of therapy. This requires the suppression of HBV replication and viral protein production and the restoration of immune response to HBV. Direct-acting antivirals targeting virus entry, capsid assembly, viral protein production and secretion are in clinical trials. Immune modulatory therapies to stimulate adaptive or innate immunity and/or to remove immune blockade are being tested. NAs are included in most and pegIFNα in some regimens. Despite the combination of 2 or more therapies, HBsAg loss remains rare in part because HbsAg can be derived not only from the covalently closed circular DNA but also from the integrated HBV DNA. Achievement of a functional HBV cure will require therapies to eliminate or silence covalently closed circular DNA and integrated HBV DNA. In addition, assays to differentiate the source of circulating HBsAg and to determine HBV immune recovery, as well as standardization and improvement of assays for HBV RNA and hepatitis B core-related antigen, surrogate markers for covalently closed circular DNA transcription, are needed to accurately assess response and to target treatments according to patient/disease characteristics. Platform trials will allow the comparison of multiple combinations and channel patients with different characteristics to the treatment that is most likely to succeed. Safety is paramount, given the excellent safety profile of NA therapy.
"The challenges to HBV cure relate to the reservoirs for HBV replication and antigen production covalently closed circular DNA (cccDNA) and integrated HBV DNA and the impaired innate and adaptive immune responses against HBV.
Whether it is possible to achieve partial cure with new therapies remains to be determined; however, caution must be exercised when treatment is stopped before HBsAg loss as severe flares, including hepatic decompensation, have been reported in clinical trials of new antiviral drugs. Combination therapies will be needed to achieve a functional cure.
At the 2016 American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) HBV Treatment Endpoints Conference,22 HBV cure was categorized as sterilizing, functional, and partial. Sterilizing cure….”
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