Impact of peginterferon alpha‐2b and entecavir hydrate combination therapy on persistent viral suppression in patients with chronic hepatitis B

Hagiwara, Satoru; Kudo, Masatoshi; Osaki, Yukio; Matsuo, Hiroo; Inuzuka, Tadashi; Matsumoto, Akihiro; Tanaka, Eiji; Sakurai, Toshiharu; Ueshima, Kazuomi; Inoue, Takamitsu; Yada, Norihisa; Nishida, Naoshi

doi:10.1002/jmv.23564

Cited by 20 publications

(18 citation statements)

References 36 publications

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“…Consistent with previous clinical reports ( [15][16][17][18][19][20], combination treatment with both entecavir and PEG-IFN reduced serum HBV DNA, intrahepatic HBV DNA, and cccDNA levels (Fig. 1C).…”

Section: Persistent Loss Of Serum Hbv Markers In Micesupporting

confidence: 92%

“…3B). The level of intrahepatic cccDNA is correlated with HBV activity (24), and it was reported that the levels at the end of treatment with entecavir plus PEG-IFN correlated with viral relapse after cessation of the treatment in chronic hepatitis B patients (20). Taken together, these results suggest that a high dose of entecavir plus PEG-IFN could inhibit HBV replication without an immune response through the extreme reduction of intrahepatic cccDNA levels in some mice.…”

Section: Persistent Loss Of Serum Hbv Markers In Micementioning

confidence: 85%

“…PEG-IFN monotherapy has been reported to result in hepatitis B e antigen (HBeAg) seroconversion in 29 to 32% of patients and in hepatitis B surface antigen (HBsAg) loss in 3 to 7% of patients at 24 weeks after completion of treatment (11,14). Combination therapy with both an NA and PEG-IFN-␣-2a has been shown to result in greater viral decline and HBeAg loss than NA therapy alone (15)(16)(17)(18) and resulted in reduced HBV cccDNA in chronic hepatitis B patients (19,20). Therefore, we hypothesized that combination therapy with high doses of NA and PEG-IFN could eliminate HBV infection in an immunodeficient animal model.…”

Section: H Epatitis B Virus (Hbv) Infection Is the Most Common Chronimentioning

confidence: 99%

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Persistent Loss of Hepatitis B Virus Markers in Serum without Cellular Immunity by Combination of Peginterferon and Entecavir Therapy in Humanized Mice

Uchida

Imamura

Hayes

et al. 2017

Antimicrob Agents Chemother

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Nucleot(s)ide analogues and peginterferon (PEG-IFN) treatment are the only approved therapies for chronic hepatitis B virus (HBV) infection. However, complete eradication of the virus, as indicated by persistent loss of hepatitis B surface antigen (HBsAg), is rare among treated patients. This is due to long-term persistence of the HBV genome in infected hepatocytes in the form of covalently closed circular DNA (cccDNA). In this study, we investigated whether administration of a large dose of a nucleoside analogue in combination with PEG-IFN can achieve long-term loss of HBsAg in human hepatocyte chimeric mice. Mice were treated with a high dose of entecavir and/or PEG-IFN for 6 weeks. High-dose combination therapy with both drugs resulted in persistently negative HBV DNA in serum. Although small amounts of HBV DNA and cccDNA (0.1 and 0.01 copy/cell, respectively) remained in the mouse livers, some of the mice remained persistently negative for serum HBV DNA at 13 weeks after cessation of the therapy. Serum HBsAg and hepatitis B corerelated antigen (HBcrAg) continued to decrease and eventually became negative at 12 weeks after cessation of the therapy. Analysis of the HBV genome in treated mice showed accumulation of G-to-A hypermutation and CpG III island methylation. Persistent loss of serum HBV DNA and loss of HBV markers by high-dose entecavir and PEG-IFN combination treatment in chimeric mice suggests that control of HBV can be achieved even in the absence of a cellular immune response.

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Section: Persistent Loss Of Serum Hbv Markers In Micesupporting

confidence: 92%

Section: Persistent Loss Of Serum Hbv Markers In Micementioning

confidence: 85%

Section: H Epatitis B Virus (Hbv) Infection Is the Most Common Chronimentioning

confidence: 99%

See 1 more Smart Citation

Persistent Loss of Hepatitis B Virus Markers in Serum without Cellular Immunity by Combination of Peginterferon and Entecavir Therapy in Humanized Mice

Uchida

Imamura

Hayes

et al. 2017

Antimicrob Agents Chemother

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show abstract

“…Incomplete clearance of Intrahepatic HBV cccDNA is the major obstacle for the current anti-viral therapy and also the cause of relapse after sustained anti-viral therapy 4, 13 . Earlier studies demonstrate that cccDNA quantification from liver biopsies of infected patients is a useful marker for assessment of treatment efficacy 7, 8 .…”

Section: Discussionmentioning

confidence: 99%

Baseline value of intrahepatic HBV DNA over cccDNA predicts patient’s response to interferon therapy

Yuan

Chen

et al. 2017

Sci Rep

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Methodology for accurate quantification of intra-hepatic cccDNA has long been a technical challenge, yet it is highly desired in the clinic. Here, we developed a sensitive method for quantification of intrahepatic cccDNA in liver biopsies from patients, which allowed to predict patient’s response to interferon therapy at baseline. Twenty-five patients with HBeAg+ CHB were recruited and liver biopsies were obtained at baseline and 1-year after interferon treatment, respectively. Both intrahepatic cccDNA and HBV DNA were absolutely quantified by a droplet digital PCR amplification system. Patients were categorized as either responder or non-responder group based on their HBeAg status 1-year after interferon therapy. Levels of both intrahepatic HBV DNA and HBV cccDNA were significantly reduced after interferon treatment among the responders, but not the non-responders, in comparison with their levels at baseline. Baseline values of intrahepatic HBV DNA over cccDNA significantly correlated with patient’s response to PEG-IFN therapy (P = 0.000). In addition, HBeAg seroconversion also correlates with a significant reduction in intrahepatic pgRNA production among the responders after interferon therapy (P = 0.030). In conclusion, our results suggest that baseline value of intrahepatic HBV DNA over cccDNA may be a preferable indicator for selecting appropriate patients for IFN-based therapy in the clinic.

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“…As previously mentioned, HBeAg seroconversion using PEG‐IFN‐α is 33%, with only 25% of HBeAg‐positive patients achieving undetectable HBV DNA . Although IFN and PEG‐IFN‐α may reduce intrahepatic cccDNA , neither therapy eradicates HBV cccDNA, and both are associated with adverse effects such as influenza‐like symptoms, fatigue, anorexia, depression, anxiety, irritability, and autoimmune disorders.…”

Section: Currently Approved Anti‐hbv Drugsmentioning

confidence: 99%

Antihepatitis B therapy: a review of current medications and novel small molecule inhibitors

Qiu

Chen

2013

Fundamemntal Clinical Pharma

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There are approximately 350 million hepatitis B virus (HBV) carriers worldwide. Chronic HBV infection increases the risk of liver cirrhosis and hepatocellular carcinoma. To date, two classes of antiviral drugs have been approved by the Food and Drug Administration for the treatment of hepatitis B, immunomodulators (interferon [IFN]-α and pegylated-interferon [PEG-IFN]-α) and nucleos(t)ide analogs (lamivudine, telbivudine, adefovir, tenofovir [TDF], and entecavir [ETV]). Of these, ETV, TDF, and PEG-IFN-α are the most effective and are currently recommended for anti-HBV therapy. However, these therapies are less than optimal because of their low rate of viral DNA and surface antigen clearance; thus, there exists a significant unmet medical need for safe and efficacious new anti-HBV drugs. Covering diverse chemical structures and mechanisms of action, non-nucleos(t)ide compounds offer great promise in the search for new anti-HBV drugs. This review summarizes the currently approved anti-HBV drugs and highlights advances in the identification and characterization of novel small molecule HBV inhibitors. We discuss the sources, structures, anti-HBV effects, mechanisms of action, and potential toxicities of these novel inhibitors.

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Impact of peginterferon alpha‐2b and entecavir hydrate combination therapy on persistent viral suppression in patients with chronic hepatitis B

Cited by 20 publications

References 36 publications

Persistent Loss of Hepatitis B Virus Markers in Serum without Cellular Immunity by Combination of Peginterferon and Entecavir Therapy in Humanized Mice

Persistent Loss of Hepatitis B Virus Markers in Serum without Cellular Immunity by Combination of Peginterferon and Entecavir Therapy in Humanized Mice

Baseline value of intrahepatic HBV DNA over cccDNA predicts patient’s response to interferon therapy

Antihepatitis B therapy: a review of current medications and novel small molecule inhibitors

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