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State-of-the-Art Chronic Hepatitis Viruses Research in Asia

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 28645

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Dr. Rong-Nan Chien

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Guest Editor

Liver Research Unit, Chang-Gung Memorial Hospital and University College of Medicine, Taoyuan, Taiwan
Interests: hepatitis virus; HBV; HCV; HDV

Special Issue Information

Dear Colleagues,

Chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) is a major global health problem, and an important cause of morbidity and mortality such as hepatic decompensation, liver cirrhosis (LC) and/or hepatocellular carcinoma (HCC). Approximately 2 billion people have been infected by HBV worldwide, and about 1 million die annually, with most (64%) residing in the Asia Pacific region. In addition, approximately 70-80 million patients are infected by HCV globally, and 0.7 million die annually from complications. Hence, the World Health Organization (WHO) launched an ultimate goal during the 69^th World Health Assembly (WHA) in May 2016: to eliminate viral hepatitis as a public health threat by 2030. The plan of execution to achieve this goal can be divided into three strategies: reduction in new chronic hepatitis B/hepatitis C infection by 90%, reduction in deaths from hepatitis B/hepatitis C by 65%, and proper treatment for 80% of patients with chronic hepatitis B/hepatitis C.

The many basic and clinical studies focused on the virology, epidemiology, immunology, natural history, current drug treatment, new drug development and long-term outcomes of both HBV and HCV infection have provided a better understanding of hepatitis virus infection in recent decades. Such research provides the chance to eliminate or cure these chronic viral infections. Therefore, we welcome contributions to this Special Issue of Viruses, “State-of-the-Art Chronic Viral Hepatitis Research in Asia”. The aim is to provide comprehensive information on all aspects of chronic hepatitis viruses infection research in Asia. Contributions to this Special Issue will advance our knowledge on chronic hepatitis viruses, and strengthen our opportunity to eliminate both HBV and HCV infection in Asia.

Dr. Rong-Nan Chien
Guest Editor

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Keywords

hepatitis B virus
hepatitis C virus
chronic hepatitis
liver cirrhosis
hepatocellular carcinoma
hepatic decompensation
hepatitis viruses elimination

Published Papers (10 papers)

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Editorial

Jump to: Research, Review

2 pages, 174 KiB

Open AccessEditorial

State-of-the-Art Chronic Hepatitis Viruses Research in Asia

by Rong-Nan Chien

Viruses 2023, 15(5), 1172; https://doi.org/10.3390/v15051172 - 15 May 2023

Viewed by 924

Abstract

Approximately 400 million people worldwide are living with chronic viral hepatitis [...] Full article

(This article belongs to the Special Issue State-of-the-Art Chronic Hepatitis Viruses Research in Asia)

Research

Jump to: Editorial, Review

11 pages, 614 KiB

Open AccessArticle

Hepatitis C Virus Reactivation in Anti-HCV Antibody-Positive Patients with Chronic Hepatitis B Following Anti-HBV Therapies

by Yi-Tse Su, Ming-Ling Chang, Rong-Nan Chien and Yun-Fan Liaw

Viruses 2022, 14(9), 1858; https://doi.org/10.3390/v14091858 - 24 Aug 2022

Cited by 4 | Viewed by 3297

Abstract

Background and Aims: Whether hepatitis C virus (HCV) reactivation occurs and how the viral load evolves in anti-HCV antibody-positive chronic hepatitis B (CHB) patients who underwent nucleos(t)ide analogue (Nuc) therapies remain unsolved. Methods: A cohort of 66 such patients was studied. Results: At the start of Nuc treatment (baseline), all patients had detectable hepatitis B virus (HBV) DNA levels (6.05 ± 1.88 log IU/mL), while HCV RNA levels (3.79 ± 1.43 log IU/mL) were detected (i.e., chronic hepatitis C (CHC)) in only 13 patients (19.7%). Following Nuc therapies, HBV DNA levels reached the nadirs at end of therapy (EOT) (6.05 ± 1.88 vs. 0.25 ± 0.99 log IU/mL, p < 0.0001) and relapsed at 6 months after EOT (6mEOT) at a level of 3.45 ± 2.64 log IU/mL compared with EOT (p < 0.0001). Among the 13 CHC patients, a non-significant decrease in HCV RNA was noted at EOT (3.52 ± 1.71 vs. 2.77 ± 2.63 log IU/mL, p = 0.166) but tended to decrease further at 6mEOT (2.77 ± 2.63 vs. 1.89 ± 2.06 log IU/mL, p = 0.063). Two of the thirteen CHC patients showed an increase in HCV-RNA ≥ 1 log10 IU/mL at EOT, and one of the fifty-three patients with undetectable HCV RNA at baseline (i.e., resolved past HCV infection) showed detectable HCV RNA at year 1 (3200 IU/mL) and year 2 (1240 IU/mL) following entecavir therapy. Conclusions: HCV reactivation did occur during HBV suppression, and the rate was 4.5% (3/66), 15.4% (2/13), and 1.9% (1/53), for all patients, CHC patients, and patients with resolved past HCV infection, respectively. The reverse HBV and HCV viral evolutions at 6mEOT indicate that HBV relapse may suppress HCV replication again. Full article

(This article belongs to the Special Issue State-of-the-Art Chronic Hepatitis Viruses Research in Asia)

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10 pages, 853 KiB

Open AccessArticle

Hepatitis B Co-Infection Has Limited Impact on Liver Stiffness Regression in Chronic Hepatitis C Patients Treated with Direct-Acting Antivirals

by Cheng-Er Hsu, Yen-Chun Liu, Ya-Ting Cheng, Wen-Juei Jeng, Rong-Nan Chien, Chun-Yen Lin, Dar-In Tai and I-Shyan Sheen

Viruses 2022, 14(4), 786; https://doi.org/10.3390/v14040786 - 10 Apr 2022

Cited by 1 | Viewed by 1749

Abstract

Introduction: High sustained virological response (SVR) rate (>95%) and liver stiffness regression can be achieved with direct acting antivirals treatment (DAA) in patients with chronic hepatitis C virus (CHC) infection. Reactivation of hepatitis B virus (HBV) was reported during DAA treatment in patients co-infected with HBV, although its impact on liver stiffness remains unknown. This study aims to investigate whether the liver stiffness (LSM) regression is different between HBV/HCV co-infected and mono-HCV-infected patients. Materials and Methods: CHC patients with/without HBV co-infection who received DAA treatment and achieved SVR12 between March 2015 and December 2019 in Chang Gung Memorial Hospital, Linkou branch were prospectively enrolled. LSM was assessed by transient elastography (TE, Fibroscan) at baseline and after SVR. Propensity score matching (PSM) at 3:1 ratio, adjusted for age, gender, pre-DAA alanine aminotransferase (ALT), platelet count, and LSM, between CHC with and without HBV co-infection, was performed before further analysis. Results: Among 906 CHC patients enrolled, 52 (5.7%) patients had HBV/HCV co-infection. Patients with HBV/HCV co-infection were of younger age (61.8 vs. 63.2, p = 0.31), with a higher proportion of males (53.8% vs. 38.9%, p = 0.03), and lower pretreatment LSM level (8.15 vs. 10.2 kPa, p = 0.09), while other features were comparable. After PSM, patients with HBV/HCV co-infection had insignificantly lower LSM regression compared to mono-HCV-infected patients (−0.85 kPa vs. −1.65 kPa, p = 0.250). Conclusions: The co-infection of HBV among CHC patients has limited impact on liver stiffness regression after successful DAA treatment. Full article

(This article belongs to the Special Issue State-of-the-Art Chronic Hepatitis Viruses Research in Asia)

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14 pages, 3513 KiB

Open AccessArticle

Fungal Secondary Metabolite Exophillic Acid Selectively Inhibits the Entry of Hepatitis B and D Viruses

by Chisa Kobayashi, Yoshihiro Watanabe, Mizuki Oshima, Tomoyasu Hirose, Masako Yamasaki, Masashi Iwamoto, Masato Iwatsuki, Yukihiro Asami, Kouji Kuramochi, Kousho Wakae, Hideki Aizaki, Masamichi Muramatsu, Camille Sureau, Toshiaki Sunazuka and Koichi Watashi

Viruses 2022, 14(4), 764; https://doi.org/10.3390/v14040764 - 06 Apr 2022

Cited by 10 | Viewed by 2842

Abstract

Current anti-hepatitis B virus (HBV) drugs are suppressive but not curative for HBV infection, so there is considerable demand for the development of new anti-HBV agents. In this study, we found that fungus-derived exophillic acid inhibits HBV infection with a 50% maximal inhibitory concentration (IC₅₀) of 1.1 µM and a 50% cytotoxic concentration (CC₅₀) of >30 µM in primary human hepatocytes. Exophillic acid inhibited preS1-mediated viral attachment to cells but did not affect intracellular HBV replication. Exophillic acid appears to target the host cells to reduce their susceptibility to viral attachment rather than acting on the viral particles. We found that exophillic acid interacted with the HBV receptor, sodium taurocholate cotransporting polypeptide (NTCP). Exophillic acid impaired the uptake of bile acid, the original function of NTCP. Consistent with our hypothesis that it affects NTCP, exophillic acid inhibited infection with HBV and hepatitis D virus (HDV), but not that of hepatitis C virus. Moreover, exophillic acid showed a pan-genotypic anti-HBV effect. We thus identified the anti-HBV/HDV activity of exophillic acid and revealed its mode of action. Exophillic acid is expected to be a potential new lead compound for the development of antiviral agents. Full article

(This article belongs to the Special Issue State-of-the-Art Chronic Hepatitis Viruses Research in Asia)

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10 pages, 1041 KiB

Open AccessArticle

Community-Based Screening for Hepatitis B and C Infectivity Using Two Quantitative Antigens to Identify Endemic Townships

by Wei-Cheng Huang, Yu-Chen Lin, Po-Ju Chen, Nien-Tzu Hsu, Chia-Ling Tu, Te-Sheng Chang, Chao-Hung Hung, Kwong-Ming Kee, Wen-Hua Chao and Sheng-Nan Lu

Viruses 2022, 14(2), 304; https://doi.org/10.3390/v14020304 - 01 Feb 2022

Cited by 4 | Viewed by 1593

Abstract

Screening and linkage to care are essential to achieve viral hepatitis elimination before 2030. The accurate identification of endemic areas is important for controlling diseases with geographic aggregation. Viral activity drives prognosis of chronic hepatitis B and hepatitis C virus infection. This screening was conducted in Chiayi County from 2018–2019. All residents aged 30 years or older were invited to participate in quantitative HBsAg (qHBsAg) and HCV Ag screening. Among the 4010 participants (male:female = 1630:2380), the prevalence of qHBsAg and HCV Ag was 9.9% (396/4010) and 4.1% (163/4010), respectively. High-prevalence townships were identified, three for qHBsAg > 15% and two for HCV Ag > 10%. The age-specific prevalence of qHBsAg was distributed in an inverse U-shape with a peak (16.0%, 68/424) for subjects in their 40 s; for HCV, prevalence increased with age. Concentrations of qHBsAg < 200 IU/mL were found in 54% (214/396) of carriers. The rate of oral antiviral treatment for HCV was 75.5% (114/151), with subjects younger than 75 years tending to undergo treatment (85.6% vs. 57.4%, p < 0.001). QHBsAg and HCV Ag core antigens can reflect the concentration of the viral load, which serves as a feasible screening tool. Using quantitative antigen screening for hepatitis B and C in community-based screening, two hyperendemic townships were identified from an endemic county. Full article

(This article belongs to the Special Issue State-of-the-Art Chronic Hepatitis Viruses Research in Asia)

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Review

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16 pages, 1140 KiB

Open AccessReview

Innate Immunity, Inflammation, and Intervention in HBV Infection

by Ge Yang, Pin Wan, Yaru Zhang, Qiaoru Tan, Muhammad Suhaib Qudus, Zhaoyang Yue, Wei Luo, Wen Zhang, Jianhua Ouyang, Yongkui Li and Jianguo Wu

Viruses 2022, 14(10), 2275; https://doi.org/10.3390/v14102275 - 17 Oct 2022

Cited by 16 | Viewed by 2657

Abstract

Hepatitis B virus (HBV) infection is still one of the most dangerous viral illnesses. HBV infects around 257 million individuals worldwide. Hepatitis B in many individuals ultimately develops hepatocellular carcinoma (HCC), which is the sixth most common cancer and the third leading cause of cancer-related deaths worldwide. The innate immunity acts as the first line of defense against HBV infection through activating antiviral genes. Along with the immune responses, pro-inflammatory cytokines are triggered to enhance the antiviral responses, but this may result in acute or chronic liver inflammation, especially when the clearance of virus is unsuccessful. To a degree, the host innate immune and inflammatory responses dominate the HBV infection and liver pathogenesis. Thus, it is crucial to figure out the signaling pathways involved in the activation of antiviral factors and inflammatory cytokines. Here, we review the interplay between HBV and the signal pathways that mediates innate immune responses and inflammation. In addition, we summarize current therapeutic strategies for HBV infection via modulating innate immunity or inflammation. Characterizing the mechanisms that underlie these HBV-host interplays might provide new approaches for the cure of chronic HBV infection. Full article

(This article belongs to the Special Issue State-of-the-Art Chronic Hepatitis Viruses Research in Asia)

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16 pages, 1103 KiB

Open AccessReview

Drug Discovery Study Aimed at a Functional Cure for HBV

by Takehisa Watanabe, Sanae Hayashi and Yasuhito Tanaka

Viruses 2022, 14(7), 1393; https://doi.org/10.3390/v14071393 - 26 Jun 2022

Cited by 5 | Viewed by 3134

Abstract

Hepatitis B virus (HBV) causes acute and, most importantly, chronic hepatitis B worldwide. Antiviral treatments have been developed to reduce viral loads but few patients with chronic hepatitis B (CHB) achieve a functional cure. The development of new therapeutic agents is desirable. Recently, many novel agents have been developed, including drugs targeting HBV-DNA and HBV-RNA. This review provides an overview of the developmental status of these drugs, especially direct acting antiviral agents (DAAs). Serological biomarkers of HBV infection are essential for predicting the clinical course of CHB. It is also important to determine the amount and activity of covalently closed circular DNA (cccDNA) in the nuclei of infected hepatocytes. Hepatitis B core-associated antigen (HBcrAg) is a new HBV marker that has an important role in reflecting cccDNA in CHB, because it is associated with hepatic cccDNA, as well as serum HBV DNA. The highly sensitive HBcrAg (iTACT-HBcrAg) assay could be a very sensitive HBV activation marker and an alternative to HBV DNA testing for monitoring reactivation. Many of the drugs currently in clinical trials have shown efficacy in reducing hepatitis B surface antigen (HBsAg) levels. Combination therapies with DAAs and boost immune response are also under development; finding the best combinations will be important for therapeutic development. Full article

(This article belongs to the Special Issue State-of-the-Art Chronic Hepatitis Viruses Research in Asia)

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14 pages, 345 KiB

Open AccessReview

Novel Pegylated Interferon for the Treatment of Chronic Viral Hepatitis

by Yi-Wen Huang, Albert Qin, Chan-Yen Tsai and Pei-Jer Chen

Viruses 2022, 14(6), 1128; https://doi.org/10.3390/v14061128 - 25 May 2022

Cited by 11 | Viewed by 2204

Abstract

Ropeginterferon alfa-2b is a novel mono-pegylated and extra-long-acting interferon, being developed for the treatment of myeloproliferative neoplasm (MPN) and chronic viral hepatitis. It has a favorable pharmacokinetic profile and less frequent dosing schedule, i.e., once every two to four weeks, compared to conventional pegylated interferon products, which have multiple isomers and are administered weekly. It was approved for the long-term treatment of polycythemia vera, an MPN, and has been included in the NCCN clinical practice guidelines for this indication. Ropeginterferon alfa-2b has demonstrated efficacy and showed a favorable safety profile for the treatment of chronic viral hepatitis in several clinical studies. In this article, we review its pharmacokinetics and available clinical data and suggest that ropeginterferon alfa-2b administered once every two weeks can serve as a new treatment option for patients with chronic viral hepatitis, including chronic hepatitis B, C, and D. Full article

(This article belongs to the Special Issue State-of-the-Art Chronic Hepatitis Viruses Research in Asia)

12 pages, 1150 KiB

Open AccessReview

Current Trend in Antiviral Therapy for Chronic Hepatitis B

by Rong-Nan Chien and Yun-Fan Liaw

Viruses 2022, 14(2), 434; https://doi.org/10.3390/v14020434 - 21 Feb 2022

Cited by 52 | Viewed by 7025

Abstract

Since active hepatitis B virus (HBV) replication is the key driver of hepatic necroinflammation and disease progression, the treatment aim of chronic hepatitis B (CHB) is to suppress HBV replication permanently to prevent hepatic decompensation, liver cirrhosis and/or hepatocellular carcinoma and prolong survival. Currently, pegylated interferon (Peg-IFN), entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are the first-line drugs of choice. Peg-IFN therapy has been used rarely due to its subcutaneous injection and significant side effect profile. Once daily oral ETV, TDF and TAF can suppress HBV DNA profoundly but have no direct action on cccDNA of the HBV-infected hepatocytes, hence continuing long-term therapy is usually needed to maintain HBV suppression, but the ultimate goal of HBsAg loss was rarely achieved (10 year 2%). In addition, long-term NUC therapy comes with several concerns such as increasing cost, medication adherence and loss-to-follow-up. Studies, mainly from Taiwan, have shown that finite NUCs therapy of two to three years in HBeAg-negative patients is feasible, safe and has a great benefit of much increasing HBsAg loss rate up to 30%/5 year. These have led an emerging paradigm shift to finite NUC therapy in HBeAg-negative patients globally. However, off-NUC relapse with hepatitis B flares may occur and have a risk of decompensation or even life-threatening outcomes. Therefore, proper monitoring, assessment, and retreatment decisions are crucial to ensure safety. Ideally, retreatment should be not too late to ensure safety and also not too early to allow further immune response for further HBsAg decline toward HBsAg loss. Assessment using combined HBsAg/ALT kinetics during hepatitis flare is better than biochemical markers alone to make a right retreatment decision. The strategy of finite NUC therapy has set a benchmark of high HBsAg loss rate to be achieved by the new anti-HBV drugs which are under preclinical or early phase study. Full article

(This article belongs to the Special Issue State-of-the-Art Chronic Hepatitis Viruses Research in Asia)

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10 pages, 895 KiB

Open AccessReview

Approaches for Detection of Hepatitis B Virus Pre-S Gene Deletions and Pre-S Deleted Proteins and Their Application in Prediction of Higher Risk of Hepatocellular Carcinoma Development and Recurrence

by Yueh-Te Lin, Long-Bin Jeng, Ih-Jen Su and Chiao-Fang Teng

Viruses 2022, 14(2), 428; https://doi.org/10.3390/v14020428 - 18 Feb 2022

Cited by 5 | Viewed by 2399

Abstract

Hepatocellular carcinoma (HCC) is among the most common and lethal human cancers worldwide and is closely associated with chronic hepatitis B virus (HBV) infection. Pre-S deleted proteins are naturally occurring mutant forms of HBV large surface proteins that are expressed by HBV surface genes harboring deletion mutations over the pre-S gene segments. It has been well demonstrated that HBV pre-S deleted proteins function as important oncoproteins, which promote malignant phenotypes of hepatocytes through the activation of multiple oncogenic signaling pathways and result in HCC formation. The oncogenic signaling pathways activated by pre-S deleted proteins have been verified as potential therapeutic targets for the prevention of HCC development. Moreover, the presence of pre-S gene deletions and the expression of pre-S deleted proteins in the blood and liver tissues of HBV-infected patients have been evaluated as valuable biomarkers for predicting a higher risk of HCC development and recurrence after curative surgical resection. Therefore, the precise detection of pre-S gene deletions and pre-S deleted proteins holds great promise as regards identifying the patients at higher risk of HCC development and recurrence, thus aiding in more timely and better treatments to improve their survival. This review summarizes the major approaches used for the detection of pre-S gene deletions and pre-S deleted proteins, including the approaches based on Sanger DNA sequencing, pre-S gene chips, next-generation sequencing and immunohistochemistry staining, and it highlights their important applications in the prediction of higher risks of HCC development and recurrence. Full article

(This article belongs to the Special Issue State-of-the-Art Chronic Hepatitis Viruses Research in Asia)

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