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Limitations of Existing HBV Therapy
Current treatment for CHB infection is limited to two classes of prescribed therapies: interferon alpha and its pegylated form (PEG-IFN), and nucleos(t)ides analogs (NAs).
Interferon alpha (IFN-α): Interferons are naturally occurring cytokines with immunomodulatory, anti-proliferative and antiviral activities. IFN-α and its pegylated form (PEG-IFN-α) are administered as injectables and are approved for treatment of CHB in most countries. PEG-IFN-α is the most prescribed IFN in CHB because it has longer half-life that requires once-weekly administration compared to daily injections with IFN-α. Durable response rates (functional cure) with PEG-IFNα are higher in patients with HBV genotypes A and C infections (up to 14% for genotype A) and lower with genotypes B and D infections (up to 2% for genotype D). Although IFN-α and PEG-IFNα provide higher sustained virological suppression (functional cure) rates than NAs, they are poorly tolerated by most patients and overall suppression efficacy is low. Recent evidence suggests that HBV infected cells are resistant to Interferon antiviral activity which may explain the poor viral suppression efficacy and low functional cure rates associated PEG-IFN-α in CHB.
Nucleos(t)ide analogs (NAs): NAs are antiviral agents that inhibit the activity of the viral polymerase and thus inhibit the formation of infectious virus progeny. Importantly, NAs do not inhibit the host gene expression machinery that is used in the production of virus proteins; consequently, NAs prescribed for CHB do not block expression of HBV genes from cccDNA or production of non-infectious sub-viral particles. The most potent prescribed NAs for CHB, including Entecavir and Tenofovir, can effectively suppress HBV replication in some patients. However, HBV replication is suppressed to below the limit of HBV DNA detection in only two-thirds of patients after 1 year of treatment. Furthermore, greater than 50% of patients having detectable HBV DNA levels after 1 year still have detectable HBV DNA after 3 years of treatment with Entecavir. Sustained Virological Response (SVR), or functional cure, is rare with use of NA monotherapy, ranging from 0-3% after 1 year of treatment and less than 10 % after longer term treatment. A simple hypothesis to explain the poor functional cure rates after long term NA treatment is that the infectious virus continues to be produced at levels that are sufficient for continuous intra-hepatic viral infection, thus enabling the maintenance of a stable pool of infected hepatocytes even in patients with HBV DNA levels below the limits of detection. This hypothesis is illustrated in Figure 2.
Click to enlarge.
Figure 2. Incomplete suppression of HBV replication can explain poor functional cure rates with current HBV drugs.
Poor functional cure rates after long-term NA treatment can be explained by incomplete suppression of HBV replication, whereby infectious virus is produced at levels sufficient for continual intra-hepatic infection even when HBV DNA levels are below the limit of detection. Figure 2 illustrates this hypothesis and compares HBV DNA and HBsAg levels in plasma (bar graph), and infected hepatocyte number (liver diagram) in CHB patients that are either untreated (left panel), treated with current standard of care (center panel) or treated with a drug combination that provides full suppression of HBV replication (right panel). In patients with CHB, HBV DNA levels are used as a surrogate quantitative measure of circulating virus (HBV replication) and HBsAg levels are used as a surrogate proportionate measure of copies of cccDNA and infected hepatocytes.
Untreated. CHB patients have a stable pool of infected hepatocytes that produce high levels of both infectious virus and sub-viral particles that can be quantified in plasma by measuring HBV DNA and HBsAg levels.
Current standard of care. Current prescribed HBV therapy does not fully suppress HBV replication, even in patients with HBV DNA levels below the limit of detection. The limit of HBV DNA detection is 20 IU/ml or 116 copies per mL; up to 600,000 copies of virus are still circulating in patients that have achieved undetectable HBV DNA status. This level of residual viremia is sufficient to maintain continual new infection of hepatocytes at a rate that is higher than the loss of infected hepatocytes. As such, the cccDNA mini-chromosomes present in this stable pool of infected hepatocytes will continue to produce new virions and sub-viral particles and explains why viral load relapse occurs in CHB patients when NA treatment is stopped.
Standard of care in combination with Core Inhibitor. A drug combination regimen of standard of care and a Core Inhibitor could provide complete suppression of HBV replication. A functional cure of CHB infection will be achieved when virus production is reduced to levels that are lower than those required for intra-hepatic infection and the loss of infected hepatocytes by natural hepatocyte turnover occurs at a rate that exceeds that of new infection of hepatocytes. Core Inhibitors such as NVR 3-778 alone or in combination with existing HBV therapies (NA or IFN) may elicit complete and sustained suppression of viral replication and thereby lead to improved functional cure rates in patients with CHB.
TECHNOLOGY
Chronic Hepatitis B
HBV Lifecycle
Limitations of Existing HBV Therapy
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