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Natural History and Clinical Consequences of Hepatitis B Virus (HBV) Infection

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Infectious Diseases".

Deadline for manuscript submissions: closed (1 January 2022) | Viewed by 37899

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Special Issue Editor

Dr. Cristina Stasi

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Guest Editor

1. Interdepartmental Hepatology Center MASVE, Department of Experimental and Clinical Medicine, Careggi University Hospital, Florence, Italy
2. Epidemiology Unit, Regional Health Agency of Tuscany, Florence, Italy
Interests: chronic viral hepatitis; liver fibrosis assessment; liver diseases; clinical epidemiology

Special Issue Information

Dear Colleagues,

The World Health Organization has estimated that 257 million people are living with chronic hepatitis B virus (HBV) infection, with an estimated 887,000 deaths per year, mainly caused by cirrhosis and hepatocellular carcinoma. The highest HBV prevalence has been found in the Western Pacific (6.2%) and African (6.1%) regions. In industrialized countries, an effective vaccine has prevented HBV for over 15 years, significantly reducing its prevalence, complications (including liver cancer, cirrhosis and liver failure resulting in death) and, finally, economic impact. However, further efforts are needed to improve HBV vaccination coverage and ensure national immunization programs, especially for those people most exposed to the risk of HBV infection. The natural history of chronic HBV infection—considering the presence of the hepatitis B-e antigen (HBeAg), HBV DNA levels, alanine transaminase values and the presence or absence of liver inflammation—has been classified into these five following phases: HBeAg-positive chronic infection, HBeAg-positive chronic hepatitis, HBeAg-negative chronic infection, HBeAg-negative chronic hepatitis and HBsAg-negative. The current potent antiviral agents present a minimal risk of resistance and a very high rate of tolerability, resulting in a reduced risk of developing HBV long-term complications. The disadvantages include the unlimited duration of treatment, the low rate of the loss of Hepatitis B Surface Antigen (HBsAg) and low seroconversion to anti-HBs. Currently, several studies investigate drugs inducing the persistent suppression of HBV-DNA, HBsAg loss, seroconversion to anti-HBsAg and the clearance of covalently closed circular DNA (cccDNA). Most of therapeutic approaches for curing HBV target the cccDNA in order to inhibit its formation and transcription or degrade it. Other therapeutic approaches inhibit the translocation of the virus in the cytoplasm, the assembly of the nucleocapsid to DNA, or the release of HBsAg. Moreover, several trials evaluate the effects of HBV-specific immunomodulators, such as the anti-programmed cell death protein 1, and therapeutic vaccines, which boost the immune response.

The main goals of this Special Issue are those of publishing original studies and review articles exploring all of the aspects of HBV’s natural history, such as clinical diagnosis, treatments and prevention. Pre-clinical findings and results of clinical trials in the above-mentioned therapeutic area will be appreciated.

Potential topics include (but are not limited to) the following thematic areas:

The epidemiology of HBV infection
Vaccination against HBV
Occult HBV infection
The role of biomarkers in HBV
The invasive and non-invasive assessment of liver fibrosis in HBV patients
Hepatitis D virus coinfection and superinfection
HBV/HCV coinfection
HBV/HIV coinfection
Factors associated with the disease progression of a chronic HBV infection
HBV-related hepatocellular carcinoma
Progress in HBV research
New antiviral treatments
Public health approaches for the elimination of HBV infection.

Dr. Cristina Stasi
Guest Editor

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Keywords

HBV
Diagnosis
Fibrosis
Antiviral treatment
Hepatocellular carcinoma
Biomarkers
Prevention

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Published Papers (9 papers)

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Research

Jump to: Review

13 pages, 1269 KiB

Open AccessArticle

Different Kinetics of HBV-DNA and HBsAg in HCV Coinfected Patients during DAAs Therapy

by Piero Colombatto, Elena Palmisano, Gabriele Ricco, Daniela Cavallone, Filippo Oliveri, Barbara Coco, Antonio Salvati, Veronica Romagnoli, Lidia Surace, Marialinda Vatteroni, Mauro Pistello, Agostino Virdis, Ferruccio Bonino and Maurizia Rossana Brunetto

J. Clin. Med. 2022, 11(5), 1406; https://doi.org/10.3390/jcm11051406 - 4 Mar 2022

Cited by 1 | Viewed by 2105

Abstract

Direct-acting antivirals (DAAs) for hepatitis C virus (HCV) may induce hepatitis B virus (HBV) reactivations in co-infected patients, whose dynamics and outcomes could depend on the phase of HBV infection. We investigated HBsAg and HBV-DNA kinetics in fifteen untreated HBeAg Negative Infection (ENI) (4F-11M, 62.1y) and eight Nucleos(t)ide Analogs (NAs) treated Chronic Hepatitis B (CHB) (3F-6M, 54.8y) with HCV co-infection, receiving DAAs-regimens including Sofosbuvir (13) or not (10). All achieved a sustained virologic response (SVR) and normalized alanine-aminotransferase (ALT). At the direct acting antivirals’ (DAAs) baseline (BL), the HBV-DNA was undetectable (<6 IU/mL) in eight ENI and all CHB, the mean Log-HBsAg was lower in ENI than CHB (0.88 vs. 2.42, p = 0.035). During DAAs, HBV-DNA increased in untreated ENI by >1 Log in five and became detectable in two. Accordingly, mean BL Log-HBV-DNA (0.89) increased at week-4 (1.78; p = 0.100) and at the end of therapy (1.57; p = 0.104). Mean Log-HBsAg decreased at week-4 in ENI (from 0.88 to 0.55; p = 0.020) and CHB (from 2.42 to 2.15; p = 0.015). After DAAs, the HBsAg returned to pre-treatment levels in CHB, but not in ENI (six cleared HBsAg). Female gender and SOF were associated with a greater HBsAg decline. In conclusion, HBV reactivations during DAAs in HCV co-infected ENI caused moderate increases of HBV-DNA without ALT elevations. The concomitant HBsAg decline, although significant, did not modify individual pre-treatment profiles. Full article

(This article belongs to the Special Issue Natural History and Clinical Consequences of Hepatitis B Virus (HBV) Infection)

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18 pages, 992 KiB

Open AccessArticle

Quantitative HBsAg versus HBV DNA in Predicting Significant Hepatitis Activity of HBeAg-Positive Chronic HBV Infection

by Zhanqing Zhang, Wei Lu, Dong Zeng, Dan Huang, Weijia Lin, Li Yan and Yanling Feng

J. Clin. Med. 2021, 10(23), 5617; https://doi.org/10.3390/jcm10235617 - 29 Nov 2021

Cited by 3 | Viewed by 2446

Abstract

(1) Background: As specialparameters in predicting significant hepatitis activity of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B virus (HBV) infection, the quantitative standard of HBV DNA has not been agreed and that of hepatitis B surface antigen(HBsAg) has not been formed. Our objective is to evaluate the validity of HBsAg and HBV DNA in predicting the significant hepatitis activity of HBeAg-positive patients. (2) Methods: A population of 516 patients with HBeAg-positive chronic HBV infection was enrolled. Serum ALT was measured using an Abbott Architect c16000 autoanalyzer; diagnoses of liver pathological grade and stage referred to the Scheuer standard. Three levels of significant hepatitis activity were preset, which were successively “ALT ≥ 20 IU/L or Grade > G1 or Stage > S1”, “ALT ≥ 30 IU/L or Grade > G1 or Stage > S1” and “ALT ≥ 40 IU/L or Grade > G1 or Stage > S1”. (3) Results: A subpopulation of 288 patients with possible high HBV replication was selected based on locally weighted scatterplot smoothing regression curves between ALT and HBsAg, HBeAg and HBV DNA. In the subpopulation with possible high HBV replication, areas under receiver operating characteristic curves of HBsAg for predicting the three levels of significant hepatitis activity were successively 0.868, 0.839 and 0.789, which were all significantly greater than those of HBV DNA, as those were successively 0.553, 0.550 and 0.574 (p = 0.0002, p < 0.0001 and p < 0.0001). With the standard of HBsAg ≤ 4.699 log₁₀ IU/mL, the sensitivity and specificity of HBsAg for predicting the three levels of significant hepatitis activity were successively 75.81% and 81.82%, 79.23% and 78.57% and 80.82% and 67.44%. (4) Conclusion: Quantitative HBsAg instead of HBV DNA is valuable in predicting significant hepatitis activity of HBeAg-positive chronic HBV infection. Full article

(This article belongs to the Special Issue Natural History and Clinical Consequences of Hepatitis B Virus (HBV) Infection)

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16 pages, 1708 KiB

Open AccessArticle

Association of Low Serum Albumin Level with Higher Hepatocellular Carcinoma Recurrence in Patients with Hepatitis B Virus Pre-S2 Mutant after Curative Surgical Resection

by Long-Bin Jeng, Tsai-Chung Li, Shih-Chao Hsu, Wen-Ling Chan and Chiao-Fang Teng

J. Clin. Med. 2021, 10(18), 4187; https://doi.org/10.3390/jcm10184187 - 16 Sep 2021

Cited by 4 | Viewed by 2492

Abstract

Hepatocellular carcinoma (HCC) is, globally, one of the most prevalent and deadly human cancers; despite curative surgical resection, its high recurrence rate after surgery remains a large threat, resulting in poor patient survival. The hepatitis B virus (HBV) pre-S2 mutant that harbors deletions spanning the pre-S2 gene segment has emerged as an important oncoprotein for HCC development and a valuable prognostic biomarker for HCC recurrence; however, its relationship with clinicopathological factors is largely unexplored. In this study, the correlation of the deletion spanning the pre-S2 gene segment with clinicopathological factors and the association of such correlation with HCC recurrence after curative surgical resection were examined in HBV-related HCC patients. Inverse correlation between serum albumin level and the deletion spanning the pre-S2 gene segment was identified. HCC patients with the presence of the deletion spanning the pre-S2 gene segment and a low serum albumin level were associated with higher HCC recurrence than patients with either factor alone or neither factor were. Moreover, a combination of the serum albumin level and the deletion spanning the pre-S2 gene segment exhibited better performance than that of either factor alone in predicting HCC recurrence. Collectively, this study shows an association of low serum albumin level with pre-S2 mutant-positive HCC patients, and validates the prognostic value of this association in identifying patients with higher HCC recurrence after curative surgical resection. Full article

(This article belongs to the Special Issue Natural History and Clinical Consequences of Hepatitis B Virus (HBV) Infection)

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Review

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6 pages, 486 KiB

Open AccessReview

Management of Delta Hepatitis 45 Years after the Discovery of HDV

by Stefano Brillanti

J. Clin. Med. 2022, 11(6), 1587; https://doi.org/10.3390/jcm11061587 - 13 Mar 2022

Cited by 7 | Viewed by 2760

Abstract

In 1977 the viral Delta agent was discovered and subsequently characterized as the hepatitis Delta virus (HDV). HDV infection is associated with HBV infection since the defective HDV needs HBV to infect and replicate in the liver. Even if not a frequent cause of chronic liver disease, HDV infection is responsible for an aggressive progression of hepatitis towards advanced liver disease. At present, no FDA approved treatment exists for this specific form of hepatitis. Interferon alfa has been recommended as off-label therapy by major scientific societies (AASLD, EASL and APASL) and has proved effective in about one quarter of patients. In recent years, new therapeutic approaches have been studied, and EMA has approved a new drug (bulevirtide) for Delta hepatitis. In this review, we encompass the 45-year journey of managing Delta hepatitis and address the most recent developments in treating this severe and aggressive liver disease. Full article

(This article belongs to the Special Issue Natural History and Clinical Consequences of Hepatitis B Virus (HBV) Infection)

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12 pages, 1192 KiB

Open AccessReview

Capsid Assembly Modulators as Antiviral Agents against HBV: Molecular Mechanisms and Clinical Perspectives

by Valerio Taverniti, Gaëtan Ligat, Yannick Debing, Dieudonne Buh Kum, Thomas F. Baumert and Eloi R. Verrier

J. Clin. Med. 2022, 11(5), 1349; https://doi.org/10.3390/jcm11051349 - 1 Mar 2022

Cited by 35 | Viewed by 7046

Abstract

Despite a preventive vaccine being available, more than 250 million people suffer from chronic hepatitis B virus (HBV) infection, a major cause of liver disease and HCC. HBV infects human hepatocytes where it establishes its genome, the cccDNA with chromosomal features. Therapies controlling HBV replication exist; however, they are not sufficient to eradicate HBV cccDNA, the main cause for HBV persistence in patients. Core protein is the building block of HBV nucleocapsid. This viral protein modulates almost every step of the HBV life cycle; hence, it represents an attractive target for the development of new antiviral therapies. Capsid assembly modulators (CAM) bind to core dimers and perturb the proper nucleocapsid assembly. The potent antiviral activity of CAM has been demonstrated in cell-based and in vivo models. Moreover, several CAMs have entered clinical development. The aim of this review is to summarize the mechanism of action (MoA) and the advancements in the clinical development of CAMs and in the characterization of their mod of action. Full article

(This article belongs to the Special Issue Natural History and Clinical Consequences of Hepatitis B Virus (HBV) Infection)

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13 pages, 278 KiB

Open AccessReview

Hepatitis B Virus Infection in Pregnancy: Immunological Response, Natural Course and Pregnancy Outcomes

by Sirinart Sirilert and Theera Tongsong

J. Clin. Med. 2021, 10(13), 2926; https://doi.org/10.3390/jcm10132926 - 29 Jun 2021

Cited by 29 | Viewed by 4438

Abstract

This review aimed to provide an update on the impact of pregnancy on the natural course of hepatitis B virus (HBV) infection and also on the impact of HBV infection on adverse pregnancy outcomes, including mother-to-child transmission (MTCT). For the literature review, original research articles, review articles, and guidelines were narratively reviewed and comprehensively validated. The databases of PubMed, EMBASE, and CINAHL were carefully searched for articles in English on topics related to HBV infection, pregnancy, and vertical transmission from 1960 to May 2021. Immunological changes during pregnancy such as suppression of Th1 response and induction of Th2 immunity lead to an impaired immune reaction to HBV and stimulate viral activity along with the reduction of CD8 T cells to escape immune detection. The impact of pregnancy on the natural course of chronic HBV infection seems to be minimal, while pregnancy can increase morbidity and mortality in the case of advanced HBV hepatitis or cirrhosis. Importantly, hepatitis flare or alanine aminotransferase (ALT) flare can occur during pregnancy and is more common during the postpartum period due to the interaction between HBV and the immune response. Interestingly, the impact of HBV infection on adverse pregnancy outcomes is more serious than ever thought. Updated evidence indicates that pregnancies with chronic HBV infection increase the risk of preterm birth and gestational diabetes, especially in cases of positive hepatitis e antigen (HBeAg). Full article

(This article belongs to the Special Issue Natural History and Clinical Consequences of Hepatitis B Virus (HBV) Infection)

12 pages, 282 KiB

Open AccessReview

Fecal Microbiota Transplantation in Patients with HBV Infection or Other Chronic Liver Diseases: Update on Current Knowledge and Future Perspectives

by Mattia Paratore, Francesco Santopaolo, Giovanni Cammarota, Maurizio Pompili, Antonio Gasbarrini and Francesca Romana Ponziani

J. Clin. Med. 2021, 10(12), 2605; https://doi.org/10.3390/jcm10122605 - 12 Jun 2021

Cited by 14 | Viewed by 2686

Abstract

Liver disease and gut dysbiosis are strictly associated, and the pathophysiology of this bidirectional relationship has recently been the subject of several investigations. Growing evidence highlights the link between gut microbiota composition, impairment of the gut-liver axis, and the development or progression of liver disease. Therefore, the modulation of gut microbiota to maintain homeostasis of the gut-liver axis could represent a potential instrument to halt liver damage, modify the course of liver disease, and improve clinical outcomes. Among all the methods available to achieve this purpose, fecal microbiota transplantation (FMT) is one of the most promising, being able to directly reshape the recipient’s gut microbial communities. In this review, we report the main characteristics of gut dysbiosis and its pathogenetic consequences in cirrhotic patients, discussing the emerging data on the application of FMT for liver disease in different clinical settings. Full article

(This article belongs to the Special Issue Natural History and Clinical Consequences of Hepatitis B Virus (HBV) Infection)

11 pages, 625 KiB

Open AccessReview

Treatment or Prophylaxis against Hepatitis B Virus Infection in Patients with Rheumatic Disease Undergoing Immunosuppressive Therapy: An Update

by Cristina Stasi, Giacomo Tiengo, Sinan Sadalla and Anna Linda Zignego

J. Clin. Med. 2021, 10(12), 2564; https://doi.org/10.3390/jcm10122564 - 10 Jun 2021

Cited by 7 | Viewed by 3644

Abstract

Chronic hepatitis B virus (HBV) flares or reactivations are serious causes of morbidity or mortality in rheumatologic patients undergoing immunosuppressive therapy. The recent insights in the pathogenesis of rheumatic diseases led to the use of new immunosuppressive therapies indicated in case of failure, partial response, or intolerance of conventional synthetic disease-modifying anti-rheumatic drugs. Based on these premises, this review examines and discusses the main rheumatologic treatments that could require the initiation of prophylactic treatment or close monitoring of occult HBV infection in patients beginning antiviral therapy at the first signs of HBV reactivation, or antiviral treatment in chronic HBV-infected patients. We searched for relevant studies published in the last five years. Studies suggested that the presence of HBV infection is common in rheumatic patients and HBV reactivation during these immunosuppressant treatments is quite frequent in these kinds of patients. Therefore, before starting an immunosuppressive therapy, patients should be screened for HBsAg, anti-HBs, and anti-HBc and, on the basis of markers positivity, they should be carefully characterized for HBV infection phases. In conclusion, screening of HBV infection in patients undergoing immunosuppressive therapy with subsequent HBV monitoring, prophylaxis or treatment consistently reduces the risk of clinical consequences. Full article

(This article belongs to the Special Issue Natural History and Clinical Consequences of Hepatitis B Virus (HBV) Infection)

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23 pages, 1048 KiB

Open AccessReview

New Approaches to the Treatment of Chronic Hepatitis B

by Alexandra Alexopoulou, Larisa Vasilieva and Peter Karayiannis

J. Clin. Med. 2020, 9(10), 3187; https://doi.org/10.3390/jcm9103187 - 1 Oct 2020

Cited by 50 | Viewed by 7982

Abstract

The currently recommended treatment for chronic hepatitis B virus (HBV) infection achieves only viral suppression whilst on therapy, but rarely hepatitis B surface antigen (HBsAg) loss. The ultimate therapeutic endpoint is the combination of HBsAg loss, inhibition of new hepatocyte infection, elimination of the covalently closed circular DNA (cccDNA) pool, and restoration of immune function in order to achieve virus control. This review concentrates on new antiviral drugs that target different stages of the HBV life cycle (direct acting antivirals) and others that enhance both innate and adaptive immunity against HBV (immunotherapy). Drugs that block HBV hepatocyte entry, compounds that silence or deplete the cccDNA pool, others that affect core assembly, agents that degrade RNase-H, interfering RNA molecules, and nucleic acid polymers are likely interventions in the viral life cycle. In the immunotherapy category, molecules that activate the innate immune response such as Toll-like-receptors, Retinoic acid Inducible Gene-1 (RIG-1) and stimulator of interferon genes (STING) agonists or checkpoint inhibitors, and modulation of the adaptive immunity by therapeutic vaccines, vector-based vaccines, or adoptive transfer of genetically-engineered T cells aim towards the restoration of T cell function. Future therapeutic trends would likely be a combination of one or more of the aforementioned drugs that target the viral life cycle and at least one immunomodulator. Full article

(This article belongs to the Special Issue Natural History and Clinical Consequences of Hepatitis B Virus (HBV) Infection)

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