Pathophysiology

“As HBV is not directly cytopathic, host responses to the virus-infected hepatocytes are believed to mediate liver cell injury and, with long-term chronic liver inflammation and ineffective immune-mediated viral clearance, contribute to the development of cirrhosis and liver cancer (92), (93).” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“Whereas HBV appears to induce little or no innate immune activation, the adaptive immune response mediates both viral clearance as well as liver disease.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“The host DNA repair machinery9 converts the incoming DNA to covalently closed circular DNA (cccDNA) molecules that are packaged into chromatin-like minichromosomes by histone and non-histone proteins,10,11 whereupon it acts as the HBV transcriptional template and long-lived reservoir in the hepatocyte nucleus.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“A major hurdle to HBV “cure” is the presence of cccDNA in the hepatocyte nucleus in a non-integrated form or episome. cccDNA serves as the template for transcription of all viral RNAs including pregenomic RNA and thus plays a key role in the viral lifecycle.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“The half-life of cccDNA is long thus explaining why it is difficult to cure HBV infection and why HBV can reactivate either spontaneously or following immune suppression, many years after clearance of HBsAg.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“Current therapies (pegylated interferon alfa [pegIFNa] and nucleos(t)ide analogues [NAs]) are not curative due to persistence of covalently closed circular DNA (cccDNA), a stable, non-integrated form of viral DNA located in the hepatocyte nucleus, as well as HBV DNA that is directly integrated into the host genome.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“Integrated HBV DNA is derived from linear genomic DNA present in viral particles or produced from aberrantly processed relaxed circular genomic DNA following an infection, and can drive expression of hepatitis B surface antigen (HBsAg) and HBx. DNA integration events accumulate over the course of viral infection, ranging from a few percent during early phases to nearly 100 percent of infected cells after prolonged chronic infections.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“Because integrated DNA is responsible for persistence of HBsAg in the absence of viral replication it impacts established criteria for the resolution of HBV infection, which rely on HBsAg as a diagnostic marker.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“Hindering the goal of functional cure as a treatment endpoint is the fact that HBsAg in serum originates from two sources, cccDNA and integrated HBV DNA. Although novel treatments in development may potentially eliminate or silence cccDNA, they may not abolish ongoing RNA transcription from integrated viral genomes, and HBsAg would remain detectable in serum.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“Although qHBsAg reflects covalently closed circular DNA and intrahepatic DNA levels, it also measures HBsAg that arises from integrated DNA, thereby reducing its specificity as a biomarker for viral replication.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“Since NAs do not directly affect the HBV cccDNA transcriptional template, a modest decrease in cccDNA is observed after long-term NA therapy, most likely due to the indirect impact of NAs on de novo infections and intracellular replenishment coupled with the gradual dilution of the cccDNA pool through cell division.253,254 Low rates of HBsAg loss on NA treatment are ascribed to the limited effect of NAs on the cccDNA template and to the significant contribution of HBV integration to HBsAg production, especially in HBeAg-negative individuals.” (opens the source at this quote in a new tab)CopyFlag

“By contrast, nucleos(t)ide analogues only inhibit HBV genome replication; they have minimal effects on the immune response or the cccDNA minichromosome reservoir, and are not curative.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“Continued transcription from cccDNA and integrated viral genomes may explain the relatively minor decrease in serum HBsAg levels during NA therapy despite undetectable serum HBV DNA levels.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“HBV-specific T cells necessary for HBV control (and may also play a role in hepatic inflammation) are dysfunctional and may be depleted or deleted in chronic HBV.53,54 Their exhausted phenotype has been attributed to persistent antigen exposure and increased expression of T cell inhibitory responses,3,52,55 providing the basis for the focus on reducing HBsAg production.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“Chronic exposure to high levels of HBV antigens, especially HBsAg, results in host immune dysfunction. Multiple immune signaling pathways are influenced by HBV antigens, which ultimately result in virus-specific and global T-cell dysfunction [43, 44].” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“For example, we now trust that HBV integration into the host genome often serves as a relevant source of hepatitis B surface antigen (HBsAg) expression during chronic infection, possibly triggering dysfunctional T cell responses and favouring detrimental immunopathology.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“More recent evidence suggests that HBsAg expression from integrated DNA might contribute to HBV pathogenesis by attenuating the immune response.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“During acute infection, cccDNA can be silenced and/or degraded through immune mechanisms, however in chronic infection the immune responses are dysfunctional and not easily restored by current treatments.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“HBV DNA integration events have primarily been investigated in the context of hepatocellular carcinoma development as they can activate known oncogenes and other growth promoting genes, cause chromosomal instability and, presumably, induce epigenetic alterations, promoting tumour growth.” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“Antiviral therapy may decrease HCC risk by suppressing viral replication, thereby decreasing clonal expansion and integration of HBV DNA into the host genome.” (opens the source at this quote in a new tab)CopyFlag

“Of all these surrogate endpoints, HBsAg loss is considered to be the most relevant because HBsAg seroclearance is associated with sustained off-treatment improvement in clinical outcomes.(1, 2) Additionally, HBsAg loss has been shown to have an additional clinical benefit (lower rates of HCC and hepatic decompensation) over HBV DNA suppression alone, particularly in patients with cirrhosis.(3, 4) Moreover, HBsAg seroclearance is easy to measure with standardized and widely available assays.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“Nonetheless, a sustained seroclearance of HBsAg, (i.e., rendering HBsAg to levels below the currently accepted detection enzyme immune assays, <0.05 IU/ml), plausibly implies profound suppression of replication of HBV, and suggests reduced overall expression from cccDNA and integrated viral genomes.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quoteCopyFlag

“Increasingly, there is emphasis on the achievement of HBsAg loss as the desired endpoint for treatment (functional cure), because of its association with reduction in clinical outcomes and long-term durability, though it is recognized that functional cure is infrequent with current approved therapies, albeit higher with peginterferon than for NAs.” (opens the source at this quote in a new tab)CopyFlag

“Loss of HBsAg (post therapy) is the ultimate goal of treatment, is the defining feature of functional cure of HBV infection,55 and is associated with an improved prognosis.” (opens the source at this quote in a new tab)CopyFlag