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Hepatitis B Virus Reactivation

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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 August 2019) | Viewed by 52104

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Dr. Valentina Svicher

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Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
Interests: SARS-CoV-2; drug resistance; immune escape; HBV chronic infection; HBV reactivation; hepatocellular carcinoma; HIV; HDV
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Prof. Dr. Loredana Sarmati

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Clinical Infectious Diseases, Department of System Medicine, Tor Vergata University, 00133 Rome, Italy
Interests: HIV infection; HBV infection; hospital-acquired infections; fungal infection

Dr. Romina Salpini

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Department of Experimental Medicine, Tor Vergata University, 00133 Rome, Italy
Interests: hepatitis B virus; vaccine-escape mutants; occult hepatitis B; HCC; HIV coinfection; HDV coinfection; ultrasensitive assays; viral variability
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The reactivation of hepatitis B virus (HBV), driven by immunosuppression, represents a virological and clinical challenge since, if not properly managed, it can lead to severe forms of hepatitis and result in death from acute liver failure. HBV reactivation is defined as an abrupt HBV reappearance in the serum of a person with a resolved infection, or a marked increase of serum HBV-DNA in a patient with chronic infection during immunosuppression. The risk of HBV reactivation is related to the persistence in the nuclei of hepatocytes of the circular covalently-closed DNA (cccDNA). This mini-chromosome acts as template to generate RNAs necessary for viral replication, and its transcriptional activity is modulated by the immune system. The equilibrium between viral replication and immune control can explain why immunosuppression can enhance HBV replication in chronically infected patients and reactivate “quiescent” HBV in individuals with a resolved infection. HBV reactivation is most commonly reported in patients receiving cancer chemotherapy for hematological malignancies and among those undergoing hematopoietic stem cell transplantation. Nevertheless, this event can occur in a wide variety of clinical settings requiring immunosuppressive therapy (solid tumors, solid organ transplantation, gastrointestinal, and rheumatologic or dermatological inflammatory or autoimmune diseases). Recent findings also highlight the risk of HBV reactivation in patients with chronic hepatitis B and C infection who pharmacologically eradicate hepatitis C virus.

In this light, this Special Issue is aimed at providing a comprehensive overview and new insights into virological and immunological mechanisms underlying HBV persistence and factors promoting viral reactivation. This Special Issue will also provide insights and future directions to optimize the management of patients who are at risk of HBV reactivation.

Assoc. Prof. Valentina Svicher
Prof. Dr. Loredana Sarmati
Dr. Romina Salpini
Guest Editors

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Keywords

HBV persistence
cccDNA
Immunology of HBV persistence
HBV reactivation
Immune-escape mutations

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Related Special Issue

Virological and Immunological Factors Underlying HBV Functional Cure and HBV Reactivation in Viruses

Published Papers (11 papers)

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Research

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13 pages, 1425 KiB

Open AccessArticle

A Hyper-Glycosylation of HBV Surface Antigen Correlates with HBsAg-Negativity at Immunosuppression-Driven HBV Reactivation in Vivo and Hinders HBsAg Recognition In Vitro

by Romina Salpini, Lorenzo Piermatteo, Arianna Battisti, Luna Colagrossi, Marianna Aragri, Katia Yu La Rosa, Ada Bertoli, Patrizia Saccomandi, Miriam Lichtner, Massimo Marignani, Sarah Maylin, Constance Delaugerre, Filomena Morisco, Nicola Coppola, Aldo Marrone, Nerio Iapadre, Carlotta Cerva, Stefano Aquaro, Mario Angelico, Loredana Sarmati, Massimo Andreoni, Jens Verheyen, Francesca Ceccherini-Silberstein, Massimo Levrero, Carlo Federico Perno, Laura Belloni and Valentina Svicher Show full author list Hide full author list

Viruses 2020, 12(2), 251; https://doi.org/10.3390/v12020251 - 23 Feb 2020

Cited by 9 | Viewed by 3694

Abstract

Immune-suppression driven Hepatitis B Virus (HBV)-reactivation poses serious concerns since it occurs in several clinical settings and can result in severe forms of hepatitis. Previous studies showed that HBV strains, circulating in patients with HBV-reactivation, are characterized by an enrichment of immune-escape mutations in HBV surface antigen (HBsAg). Here, we focused on specific immune-escape mutations associated with the acquisition of N-linked glycosylation sites in HBsAg (NLGSs). In particular, we investigated profiles of NLGSs in 47 patients with immunosuppression-driven HBV-reactivation and we evaluated their impact on HBsAg-antigenicity and HBV-replication in vitro. At HBV-reactivation, despite a median serum HBV-DNA of 6.7 [5.3–8.0] logIU/mL, 23.4% of patients remained HBsAg-negative. HBsAg-negativity at HBV-reactivation correlated with the presence of >1 additional NLGSs (p < 0.001). These NLGSs are located in the major hydrophilic region of HBsAg (known to be the target of antibodies) and resulted from the single mutation T115N, T117N, T123N, N114ins, and from the triple mutant S113N+T131N+M133T. In vitro, NLGSs strongly alter HBsAg antigenic properties and recognition by antibodies used in assays for HBsAg-quantification without affecting HBsAg-secretion and other parameters of HBV-replication. In conclusion, additional NLGSs correlate with HBsAg-negativity despite HBV-reactivation, and hamper HBsAg-antigenicity in vitro, supporting the role of NGSs in immune-escape and the importance of HBV-DNA for a proper diagnosis of HBV-reactivation. Full article

(This article belongs to the Special Issue Hepatitis B Virus Reactivation)

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17 pages, 2903 KiB

Open AccessArticle

ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection upon DNA Damage

by Anastasiya Kostyusheva, Sergey Brezgin, Ekaterina Bayurova, Ilya Gordeychuk, Maria Isaguliants, Irina Goptar, Felix Urusov, Anastasiya Nikiforova, Elena Volchkova, Dmitry Kostyushev and Vladimir Chulanov

Viruses 2019, 11(11), 997; https://doi.org/10.3390/v11110997 - 31 Oct 2019

Cited by 26 | Viewed by 4944

Abstract

Chronic hepatitis B virus infection (CHB) caused by the hepatitis B virus (HBV) is one of the most common viral infections in the world. Reactivation of HBV infection is a life-threatening condition observed in patients with CHB receiving chemotherapy or other medications. Although HBV reactivation is commonly attributed to immune suppression, other factors have long been suspected to play a role, including intracellular signaling activated in response to DNA damage. We investigated the effects of DNA-damaging factors (doxorubicin and hydrogen peroxide) on HBV reactivation/replication and the consequent DNA-damage response. Dose-dependent activation of HBV replication was observed in response to doxorubicin and hydrogen peroxide which was associated with a marked elevation in the mRNA levels of ataxia-telangiectasia mutated (ATM) and ATM- and RAD3-related (ATR) kinases. Downregulation of ATM or ATR expression by shRNAs substantially reduced the levels of HBV RNAs and DNA. In contrast, transcriptional activation of ATM or ATR using CRISPRa significantly increased HBV replication. We conclude that ATM and ATR are essential for HBV replication. Furthermore, DNA damage leading to the activation of ATM and ATR transcription, results in the reactivation of HBV replication. Full article

(This article belongs to the Special Issue Hepatitis B Virus Reactivation)

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14 pages, 1351 KiB

Open AccessArticle

Clinical and Virological Aspects of HBV Reactivation: A Focus on Acute Liver Failure

by Olympia E. Anastasiou, Martin Theissen, Jens Verheyen, Barbara Bleekmann, Heiner Wedemeyer, Marek Widera and Sandra Ciesek

Viruses 2019, 11(9), 863; https://doi.org/10.3390/v11090863 - 16 Sep 2019

Cited by 5 | Viewed by 4052

Abstract

Hepatitis B virus (HBV) reactivation in immunosuppressed patients can cause considerable morbidity and mortality. The aim of our study was to evaluate factors associated with acute liver failure (ALF) in HBV reactivation. Clinical, laboratory, and virological data of 87 patients with HBV reactivation were analyzed retrospectively. Teno torque virus (TTV) plasma loads were measured as a measure of immune competence. HBV genomes isolated from 47 patients were analyzed by next-generation sequencing. A functional analysis of identified HBsAg mutants was performed. In patients with ALF the diagnosis was significantly later confirmed than in the non-ALF group. Patients diagnosed during immunosuppression had a milder clinical course compared to later diagnosed patients (p = 0.018, OR = 4.17). TTV viral loads did not differ significantly between the two groups. The HBV genomes isolated from ALF patients had higher viral complexity. A mutation in C-region of HBsAg (L216*), was associated with reduced HBsAg production and secretion. Patients diagnosed with HBV reactivation during immunosuppression had a milder clinical course compared to patients diagnosed during immune reconstitution. ALF was associated with higher viral complexity. An HBsAg mutation (L216*) was found to be more frequent in ALF patients and was associated with reduced HBsAg production and secretion. Full article

(This article belongs to the Special Issue Hepatitis B Virus Reactivation)

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10 pages, 981 KiB

Open AccessArticle

Caucasian Ethnicity, but Not Treatment Cessation Is Associated with HBsAg Loss Following Nucleos(t)ide Analogue-Induced HBeAg Seroconversion

by Stijn Van Hees, Heng Chi, Bettina Hansen, Stefan Bourgeois, Hans Van Vlierberghe, Thomas Sersté, Sven Francque, David Wong, Dirk Sprengers, Christophe Moreno, Frederik Nevens, Harry Janssen and Thomas Vanwolleghem

Viruses 2019, 11(8), 687; https://doi.org/10.3390/v11080687 - 26 Jul 2019

Cited by 10 | Viewed by 3089

Abstract

It is well appreciated that ethnicity influences the natural history and immune responses during a chronic hepatitis B infection. In this study, we explore the effect of ethnicity and treatment cessation on Hepatitis B surface Antigen (HBsAg) seroclearance in patients with Nucleos(t)ide Analogue (NA)-induced Hepatitis B e Antigen (HBeAg) seroconversion. We performed a multi-ethnic, multicentric observational cohort study. The analyzed cohort consisted of 178 mono-infected, predominantly male (75.3%) chronic hepatitis B patients of mixed ethnicity (44.4% Asians, 48.9% Caucasians) with nucleos(t)ide analogue-induced HBeAg seroconversion. Treatment was withdrawn in 105 patients and continued in 73, leading to HBsAg loss in 14 patients off- and 16 patients on-treatment, respectively. Overall, HBsAg loss rates were not affected by treatment cessation (hazard ratio 1.45, p = 0.372), regardless of consolidation treatment duration. Caucasian ethnicity was associated with an increased chance of HBsAg loss (hazard ratio 6.70, p = 0.001), but hepatitis B virus genotype was not (p = 0.812). In conclusion, ethnicity is the most important determinant for HBsAg loss after NA-induced HBeAg seroconversion, with up to six-fold higher HBsAg loss rates in Caucasians compared to Asians, irrespective of treatment cessation and consolidation treatment duration. Full article

(This article belongs to the Special Issue Hepatitis B Virus Reactivation)

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Review

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10 pages, 231 KiB

Open AccessReview

HBV Infection in HIV-Driven Immune Suppression

by Loredana Sarmati and Vincenzo Malagnino

Viruses 2019, 11(11), 1077; https://doi.org/10.3390/v11111077 - 19 Nov 2019

Cited by 31 | Viewed by 5928

Abstract

Worldwide, approximately 10% of all human immunodeficiency virus (HIV)-infected people are also chronically coinfected with hepatitis B virus (HBV). HBV infection has a poor prognosis in HIV-positive people and has been documented by an increased risk of developing chronic HBV infection (CHB), progression to liver fibrosis and end-stage liver disease (ESLD) and evolution of hepatocellular carcinoma (HCC). Furthermore, in HIV patients, HBV-resolved infection is often associated with the appearance of HBV-DNA, which configures occult HBV infection (OBI) as a condition to be explored in coinfected patients. In this narrative review we summarize the main aspects of HBV infection in HIV-positive patients, emphasizing the importance of carefully considering the coinfected patient in the context of therapeutic strategies of antiretroviral therapy. Full article

(This article belongs to the Special Issue Hepatitis B Virus Reactivation)

17 pages, 343 KiB

Open AccessReview

HBV Reactivation in Patients Undergoing Hematopoietic Stem Cell Transplantation: A Narrative Review

by Giuseppe Gentile and Guido Antonelli

Viruses 2019, 11(11), 1049; https://doi.org/10.3390/v11111049 - 10 Nov 2019

Cited by 18 | Viewed by 4411

Abstract

HBV reactivation (HBVr) can occur due to the ability of HBV to remain latent in the liver as covalently closed circular DNA and by the capacity of HBV to alter the immune system of the infected individuals. HBVr can occur in patients undergoing hematopoietic stem cell transplantation (HSCT) with a clinical spectrum that ranges from asymptomatic infection to fulminant hepatic failure. The risk of HBVr is determined by a complex interplay between host immunity, virus factors, and immunosuppression related to HSCT. All individuals who undergo HSCT should be screened for HBV. HSCT patients positive for HBsAg and also those HBcAb-positive/HBsAg-negative are at high risk of HBV reactivation (HBVr) due to profound and prolonged immunosuppression. Antiviral prophylaxis prevents HBVr, decreases HBVr-related morbidity and mortality in patients with chronic or previous HBV. The optimal duration of antiviral prophylaxis remains to be elucidated. The vaccination of HBV-naïve recipients and their donors against HBV prior to HSCT has an important role in the prevention of acquired HBV infection. This narrative review provides a comprehensive update on the current concepts, risk factors, molecular mechanisms, prevention, and management of HBVr in HSCT. Full article

(This article belongs to the Special Issue Hepatitis B Virus Reactivation)

15 pages, 595 KiB

Open AccessReview

Hematological Malignancies and HBV Reactivation Risk: Suggestions for Clinical Management

by Alessandra Zannella, Massimo Marignani and Paola Begini

Viruses 2019, 11(9), 858; https://doi.org/10.3390/v11090858 - 14 Sep 2019

Cited by 6 | Viewed by 3976

Abstract

It is well known that hepatitis B virus reactivation (HBVr) can occur among patients undergoing treatment for hematological malignancies (HM). The evaluation of HBVr risk in patients undergoing immunosuppressive treatments is a multidimensional process, which includes conducting an accurate clinical history and physical examination, consideration of the virological categories, of the medication chosen to treat these hematological malignancies and the degree of immunosuppression induced. Once the risk of reactivation has been defined, it is crucial to adopt adequate management strategies (should reactivation occur). The purpose of treatment is to prevent dire clinical consequences of HBVr such as acute/fulminant hepatitis, and liver failure. Treatment will be instituted according to the indications and evidence provided by current international recommendations and to prevent interruption of lifesaving anti-neoplastic treatments. In this paper, we will present the available data regarding the risk of HBVr in this special population of immunosuppressed patients and explore the relevance of effective prevention and management of this potentially life-threatening event. A computerized literature search was performed using appropriate terms to discover relevant articles. Current evidence supports the policy of universal HBV testing of patients scheduled to undergo treatment for hematological malignancies, and clinicians should be aware of the inherent risk of viral reactivation among the different virological categories and classes of immunosuppressive drugs. Full article

(This article belongs to the Special Issue Hepatitis B Virus Reactivation)

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13 pages, 258 KiB

Open AccessReview

Hepatitis B Virus (HBV) Reactivation Following Pharmacological Eradication of Hepatitis C Virus (HCV)

by Mariantonietta Pisaturo, Margherita Macera, Loredana Alessio, Federica Calò and Nicola Coppola

Viruses 2019, 11(9), 850; https://doi.org/10.3390/v11090850 - 13 Sep 2019

Cited by 20 | Viewed by 5003

Abstract

The US Food and Drug Administration issued a black box warning related to the risk of reactivation of overt/occult hepatitis B virus (HBV) infection during direct acting-antivirals (DAA) treatment. This review evaluated the prevalence of HBV reactivation after hepatitis C virus (HCV) pharmacological suppression and hypothesized the management and prevention of this reactivation. During and after DAA-based treatment, reactivation of HBV infection is common in patients with detectable serum HBsAg (from 2% to 57%) and very low (less than 3%) in individuals with isolated anti-HBc antibodies. The severity of hepatic damage may range from HBV reactivation without hepatitis to fulminant hepatic failure requiring liver transplantation. Thus, HBsAg-positive patients should receive nucleo(s)tide analog (NA) treatment or prophylaxis at the same time as DAA therapy. For those patients with occult B infection, there are no sufficient recommendations to start prophylactic treatment. Reactivation of overt or occult HBV infection during or after eradication of HCV infection is an issue to consider, and additional studies would help to determine the best management of this virological and clinical event. Full article

(This article belongs to the Special Issue Hepatitis B Virus Reactivation)

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12 pages, 257 KiB

Open AccessReview

New Markers in Monitoring the Reactivation of Hepatitis B Virus Infection in Immunocompromised Hosts

by Valentina Svicher, Romina Salpini, Vincenzo Malagnino, Lorenzo Piermatteo, Mohammad Alkhatib, Carlotta Cerva and Loredana Sarmati

Viruses 2019, 11(9), 783; https://doi.org/10.3390/v11090783 - 25 Aug 2019

Cited by 13 | Viewed by 4348

Abstract

Hepatitis B virus (HBV) persistence is at the basis of HBV reactivation as a consequence of chemotherapy and immunosuppressive treatments. The identification of early viral replication indicators and markers of effective HBV immunological control would be useful in monitoring patients who are at risk of potential viral reactivation during the course of immunosuppressive treatment. Currently, international guidelines have shared some criteria to identify patients with a low, medium or high risk of HBV reactivation; however, permanently placing a patient in a definitive category is not always easy. More often, patients move from one category to another during the course of their immunosuppressive treatment; therefore, in many cases, there are no precise indicators or tools for monitoring possible reactivation and establishing the duration and suspension of antiviral prophylaxis. Historically, the sequence of HBV antigens and antibodies and HBV DNA levels has been used to evaluate the different stages of the acute and chronic phases of an HBV infection. In the last few years, new biomarkers, such as anti-HBs and anti-HBc titres, HBV core-related antigen (HBcrAg), ultra-sensitive HBsAg evaluation and HBV RNA, have been used in patients with an HBV infection to evaluate their diagnostic and prognostic potential. The aim of this review is to evaluate the published results on the use of new infection markers in the diagnosis and monitoring of HBV reactivation over the course of immunosuppressive treatments. Moreover, the importance of viral genotypic studies was emphasized, given the diagnostic and therapeutic implications of the mutational profiles of HBsAg during the HBV reactivation phase. Full article

(This article belongs to the Special Issue Hepatitis B Virus Reactivation)

17 pages, 1755 KiB

Open AccessReview

Immune-Escape Hepatitis B Virus Mutations Associated with Viral Reactivation upon Immunosuppression

by Ivana Lazarevic, Ana Banko, Danijela Miljanovic and Maja Cupic

Viruses 2019, 11(9), 778; https://doi.org/10.3390/v11090778 - 24 Aug 2019

Cited by 66 | Viewed by 7888

Abstract

Hepatitis B virus (HBV) reactivation occurs as a major complication of immunosuppressive therapy among persons who have recovered from acute hepatitis and those who have controlled chronic infection. Recent literature data emphasize the presence of a high degree of S gene variability in HBV isolates from patients who developed reactivation. In reactivated HBV, the most frequently detected mutations belong to the second loop of “a” determinant in HBsAg. These mutations were identified to be immune escape and responsible for vaccine- and diagnostic-escape phenomena. Their emergence clearly provides survival in the presence of a developed humoral immune response and is often associated with impaired serological diagnosis of HBV reactivation. The knowledge of their existence and roles can elucidate the process of reactivation and strongly highlights the importance of HBV DNA detection in monitoring all patients with a history of HBV infection who are undergoing immunosuppression. This review discusses the possible influence of the most frequently found immune-escape mutations on HBV reactivation. Full article

(This article belongs to the Special Issue Hepatitis B Virus Reactivation)

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8 pages, 193 KiB

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Roles of Hepatitis B Virus Mutations in the Viral Reactivation after Immunosuppression Therapies

by Jun Inoue, Takuya Nakamura and Atsushi Masamune

Viruses 2019, 11(5), 457; https://doi.org/10.3390/v11050457 - 19 May 2019

Cited by 18 | Viewed by 3648

Abstract

Reactivation of hepatitis B virus (HBV) is a major problem in patients receiving chemotherapy for malignant diseases or immunosuppression therapies. It has been thought that a reduction in the immune responses might result in the reactivation of HBV replication from covalently closed circular DNA (cccDNA) residing in hepatocytes. However, not only the host’s immune status, but also viral mutations have been reported to be associated with reactivation. Especially, several case reports about amino acid mutations in hepatitis B surface antigen (HBsAg) that escape from immune reactions have been reported, and recent reports showed that the frequencies of such mutations are higher than previously expected. In this review, we summarize the characteristics of viral mutations, including immune escape mutations in HBV-reactivated patients, and discuss their significance. Full article

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