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
The Novira Therapeutics 作者: newchinabok 时间: 2015-11-7 07:52
图2。不完全抑制HBV复制功能可以解释of穷人经常错过与HBV药物治疗。
可怜的脾脏功能治疗后长期NA治疗can be explained by不完全抑制HBV复制的病毒,传染性is produced at whereby Levels sufficient for连续性肝内感染HBV DNA水平,即使是below the limit of检测。图2对HBV DNA例举这假说和HBsAg水平与血浆(图表),and感染肝细胞数(liver图)在慢性乙型肝炎患者that are either untreated(左面板),处理以及电流标准of Care(中心Panel)或处理与药物组合,提供完整的HBV复制的抑制(right of Panel)。慢性乙型肝炎患者HBV DNA水平,are used as a Surrogate Measure of circulating病毒定量(HBV复制)和HBsAg水平are used as a替代proportionate Measure of拷贝of cccdna and感染肝细胞。
untreated。CHB患者有稳定的感染肝细胞产生高池of that levels of both传染性病毒和亚病毒颗粒that can be量化血浆HBV DNA和乙肝表面抗原水平的测量。
目前的护理标准。目前的规定禁止乙肝HBV therapy does not fully复制,HBV DNA水平甚至患者below the limit of检测。the limit of HBV DNA检测是20 IU /毫升每毫升116份金;up to 600000份病毒are still of that have achieved装上引信的循环在患者HBV DNA的地位。This level of残余病毒血症足够to maintain持续不断的新感染的肝细胞在脾脏of that is higher than the loss of感染肝细胞。是这样的,cccdna迷你染色体present in this稳定池of感染肝细胞产生新的病毒将继续与亚病毒颗粒和病毒负荷形容词说明哪些为什么CHB患者发生在当Na treatment is stopped。
标准of Care in combination with core抑制剂。有药物组合制度标准of Care and核心能提供完整的抑制剂抑制HBV复制的。功能康复of CHB病毒感染will be achieved reduced to是当生产水平下than those that are required for肝内肝细胞感染and the loss of infected by自然发生在脾,肝细胞的营业额超过that of New感染的肝细胞。核心抑制剂如专用3 778单独或组合以及现有的疗法,在HBV(Na或IFN)可能持续抑制病毒和引出完整的复制和从而of lead to改进治疗CHB患者脾功能。
科技
慢性乙型肝炎
乙型肝炎病毒的生命周期
现有的乙肝治疗的局限性
the novira疗法作者: newchinabok 时间: 2015-11-7 07:59
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.作者: newchinabok 时间: 2015-11-7 08:09