Viruses

Editorial

5 pages, 204 KiB

Open AccessEditorial

Targeting Subviral Particles: A Critical Step in Achieving HBV Functional Cure but Where Are We with Current Agents in Clinical Development?

by Andrew Vaillant

Viruses 2022, 14(6), 1193; https://doi.org/10.3390/v14061193 - 31 May 2022

Cited by 5 | Viewed by 1684

Abstract

The recent review [...] Full article

(This article belongs to the Special Issue Recent Advances in Management of Hepatitis B and towards Achieving a HBV Cure)

Research

Jump to: Editorial, Review

16 pages, 593 KiB

Open AccessArticle

Molecular and Serological Characterization of Hepatitis B Virus (HBV)-Positive Samples with Very Low or Undetectable Levels of HBV Surface Antigen

by Mary C. Kuhns, Vera Holzmayer, Mark Anderson, Anne L. McNamara, Silvia Sauleda, Dora Mbanya, Pham T. Duong, Nguyen T. T. Dung and Gavin A. Cloherty

Viruses 2021, 13(10), 2053; https://doi.org/10.3390/v13102053 - 13 Oct 2021

Cited by 18 | Viewed by 2810

Abstract

Background: Gaps remain in the detection of nucleic acid test (NAT) yield and occult hepatitis B virus (HBV) infection (OBI) by current HBV surface antigen (HBsAg) assays. The lack of detection may be due to HBsAg levels below current assay detection limits, mutations [...] Read more.

Background: Gaps remain in the detection of nucleic acid test (NAT) yield and occult hepatitis B virus (HBV) infection (OBI) by current HBV surface antigen (HBsAg) assays. The lack of detection may be due to HBsAg levels below current assay detection limits, mutations affecting HBsAg assays or HBsAg levels, or the masking of HBsAg by antibody to HBsAg (anti-HBs). In this study, we evaluate the incremental detection of NAT yield and OBI from five diverse geographic areas by an improved sensitivity HBsAg assay and characterize the samples relative to the viral load, anti-HBs status, and PreS1–S2–S mutations. Included is a comparison population with HBV DNA levels comparable to OBI, but with readily detectable HBsAg (High Surface–Low DNA, HSLD). Methods: A total of 347 samples collected from the USA, South Africa, Spain, Cameroon, Vietnam, and Cote D’Ivoire representing NAT yield (HBsAg(−), antibody to HBV core antigen (anti-HBc)(−), HBV DNA(+), N = 131), OBI (HBsAg(−), anti-HBc(+), HBV DNA(+), N = 188), and HSLD (HBsAg(+), anti-HBc(+), HBV DNA(+), N = 28) were tested with ARCHITECT HBsAg NEXT (HBsAgNx) (sensitivity 0.005 IU/mL). The sequencing of the PreS1–S2–S genes from a subset of 177 samples was performed to determine the genotype and assess amino acid variability, particularly in anti-HBs(+) samples. Results: HBsAgNx detected 44/131 (33.6%) NAT yield and 42/188 (22.3%) OBI samples. Mean HBV DNA levels for NAT yield and OBI samples were lower in HBsAgNx(−) (50.3 and 25.9 IU/mL) than in HBsAgNx(+) samples (384.1 and 139.5 IU/mL). Anti-HBs ≥ 10 mIU/mL was present in 28.6% HBsAgNx(+) and 45.2% HBsAgNx(−) OBI, and in 3.6% HSLD samples. The genotypes were A1, A2, B, C, D, E, F, and H. There was no significant difference between HBsAgNx(−) and HBsAgNx(+) in the proportion of samples harboring substitutions or in the mean number of substitutions per sample in PreS1, PreS2, or S for the NAT yield or OBI (p range: 0.1231 to >0.9999). A total of 21/27 (77.8%) of HBsAgNx(+) OBI carried S escape mutations, insertions, or stop codons. HSLD had more PreS1 and fewer S substitutions compared to both HBsAgNx(−) and HBsAgNx(+) OBI. Mutations/deletions associated with impaired HBsAg secretion were observed in the OBI group. Conclusions: HBsAgNx provides the improved detection of NAT yield and OBI samples. Samples that remain undetected by HBsAgNx have exceptionally low HBsAg levels below the assay detection limit, likely due to low viremia or the suppression of HBsAg expression by host and viral factors. Full article

(This article belongs to the Special Issue Recent Advances in Management of Hepatitis B and towards Achieving a HBV Cure)

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14 pages, 1893 KiB

Open AccessArticle

Improved Specificity and Safety of Anti-Hepatitis B Virus TALENs Using Obligate Heterodimeric FokI Nuclease Domains

by Tiffany Smith, Prashika Singh, Kay Ole Chmielewski, Kristie Bloom, Toni Cathomen, Patrick Arbuthnot and Abdullah Ely

Viruses 2021, 13(7), 1344; https://doi.org/10.3390/v13071344 - 12 Jul 2021

Cited by 11 | Viewed by 2774

Abstract

Persistent hepatitis B virus (HBV) infection remains a serious medical problem worldwide, with an estimated global burden of 257 million carriers. Prophylactic and therapeutic interventions, in the form of a vaccine, immunomodulators, and nucleotide and nucleoside analogs, are available. Vaccination, however, offers no [...] Read more.

Persistent hepatitis B virus (HBV) infection remains a serious medical problem worldwide, with an estimated global burden of 257 million carriers. Prophylactic and therapeutic interventions, in the form of a vaccine, immunomodulators, and nucleotide and nucleoside analogs, are available. Vaccination, however, offers no therapeutic benefit to chronic sufferers and has had a limited impact on infection rates. Although immunomodulators and nucleotide and nucleoside analogs have been licensed for treatment of chronic HBV, cure rates remain low. Transcription activator-like effector nucleases (TALENs) designed to bind and cleave viral DNA offer a novel therapeutic approach. Importantly, TALENs can target covalently closed circular DNA (cccDNA) directly with the potential of permanently disabling this important viral replicative intermediate. Potential off-target cleavage by engineered nucleases leading to toxicity presents a limitation of this technology. To address this, in the context of HBV gene therapy, existing TALENs targeting the viral core and surface open reading frames were modified with second- and third-generation FokI nuclease domains. As obligate heterodimers these TALENs prevent target cleavage as a result of FokI homodimerization. Second-generation obligate heterodimeric TALENs were as effective at silencing viral gene expression as first-generation counterparts and demonstrated an improved specificity in a mouse model of HBV replication. Full article

(This article belongs to the Special Issue Recent Advances in Management of Hepatitis B and towards Achieving a HBV Cure)

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14 pages, 1343 KiB

Open AccessArticle

Detection of Q129H Immune Escape Mutation in Apparently Healthy Hepatitis B Virus Carriers in Southwestern Nigeria

by Olufisayo Adeyemi Adesina, Olusola Anuoluwapo Akanbi, Oluyinka Oladele Opaleye, Margaret Oluwatoyin Japhet, Bo Wang, Adekemi Olubukunola Oluyege, Patrycja Klink and C.-Thomas Bock

Viruses 2021, 13(7), 1273; https://doi.org/10.3390/v13071273 - 29 Jun 2021

Cited by 10 | Viewed by 2807

Abstract

As the global effort to eradicate hepatitis B continues, immune escape mutations (IEMs) and drug resistance mutations (DRMs) affecting its diagnosis, treatment, and prevention are compromising this goal. However, knowledge about the prevalence and circulation of these mutations in Nigeria is scarce. Serum [...] Read more.

As the global effort to eradicate hepatitis B continues, immune escape mutations (IEMs) and drug resistance mutations (DRMs) affecting its diagnosis, treatment, and prevention are compromising this goal. However, knowledge about the prevalence and circulation of these mutations in Nigeria is scarce. Serum samples (n = 199) from apparently healthy prospective blood donors, pregnant women, and individuals presenting with fever in southwestern Nigeria were analyzed for the presence of IEMs and DRMs by means of nested PCR in the HBV S (HBs) and HBV polymerase (Pol) genes, followed by phylogenetic and mutational analyses. In total, 25.1% (n = 50/199) of samples were positive for HBV, as measured by PCR. In 41 samples (20.6%), both fragments could be amplified, whereas the HBs gene and the Pol gene fragment alone were detected in 0.5% (n = 1/199) and 4% (n = 8/199) of samples, respectively. Sequences were successfully obtained for all 42 HBs gene fragments but for only 31/49 Pol gene fragments (totaling 73 sequences from 44 individuals). All sequences were identified as HBV genotype E. IEMs were present in 18.2% (n = 8/44) of the sequences of HBV-positive individuals with available sequences. IEM Q129H was detected in eight out of the 44 (18.2%) HBV isolates sequenced in this study; however, no DRMs were observed. This study confirms the circulation of HBV IEMs and reports the presence of Q129H IEM for the first time in Nigeria. Intensified research on the dynamics of IEM is necessary in order to enhance the elimination of HBV. Full article

(This article belongs to the Special Issue Recent Advances in Management of Hepatitis B and towards Achieving a HBV Cure)

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24 pages, 10048 KiB

Open AccessArticle

Treatment with the Immunomodulator AIC649 in Combination with Entecavir Produces Antiviral Efficacy in the Woodchuck Model of Chronic Hepatitis B

by Kyle E. Korolowicz, Manasa Suresh, Bin Li, Xu Huang, Changsuek Yon, Xuebing Leng, Bhaskar V. Kallakury, Robin D. Tucker and Stephan Menne

Viruses 2021, 13(4), 648; https://doi.org/10.3390/v13040648 - 9 Apr 2021

Cited by 8 | Viewed by 3092

Abstract

As current interventions for chronic hepatitis B (CHB) rarely induce cure, more effective drugs are needed. Short-term treatment of woodchucks with the novel immunomodulator AIC649, a parapoxvirus-based stimulator of toll-like receptor 9 dependent and independent pathways, has been shown to reduce viral DNA [...] Read more.

As current interventions for chronic hepatitis B (CHB) rarely induce cure, more effective drugs are needed. Short-term treatment of woodchucks with the novel immunomodulator AIC649, a parapoxvirus-based stimulator of toll-like receptor 9 dependent and independent pathways, has been shown to reduce viral DNA and surface antigen via a unique, biphasic response pattern. The present study evaluated long-term AIC649 treatment in combination with Entecavir for potency and safety in woodchucks. AIC649 monotreatment induced modest reductions in serum viral DNA and surface and e antigens that were associated with the same biphasic response pattern previously observed. Entecavir monotreatment reduced transiently viremia but not antigenemia, while AIC649/Entecavir combination treatment mediated superior viral control. Undetectability of viral antigens and elicitation of antibodies in AIC649/Entecavir-treated woodchucks correlated with the expression of interferons and suppression of viral replication in liver. Combination treatment was well tolerated, and liver enzyme elevations were minor and transient. It was concluded that the AIC649-mediated effects were most likely based on an improvement and/or reconstitution of antiviral immune responses that are typically deficient in CHB. As a combination partner to Entecavir, the antiviral efficacy of AIC649 was markedly enhanced. This preclinical study supports future evaluation of AIC649 for treatment of human CHB. Full article

(This article belongs to the Special Issue Recent Advances in Management of Hepatitis B and towards Achieving a HBV Cure)

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Review

Jump to: Editorial, Research

12 pages, 275 KiB

Open AccessReview

Early Treatment Consideration in Patients with Hepatitis B ‘e’ Antigen-Positive Chronic Infection: Is It Time for a Paradigm Shift?

by Apostolos Koffas, Lung-Yi Mak, Upkar S. Gill and Patrick T. F. Kennedy

Viruses 2022, 14(5), 900; https://doi.org/10.3390/v14050900 - 26 Apr 2022

Cited by 9 | Viewed by 2738

Abstract

Chronic hepatitis B (CHB) is associated with significant morbidity and mortality, due to the adverse sequelae of cirrhosis and hepatocellular carcinoma (HCC). To date, antiviral therapy has been reserved for patients with ostensibly active liver disease, fibrosis or cirrhosis, and/or increased risk of [...] Read more.

Chronic hepatitis B (CHB) is associated with significant morbidity and mortality, due to the adverse sequelae of cirrhosis and hepatocellular carcinoma (HCC). To date, antiviral therapy has been reserved for patients with ostensibly active liver disease, fibrosis or cirrhosis, and/or increased risk of HCC. Historically, patients with hepatitis B ‘e’ antigen (HBeAg)-positive chronic infection, were not offered antiviral therapy. Nevertheless, there has been compelling evidence emerging in recent years, demonstrating that this disease phase is in fact not characterized by immunological tolerance. HBV integration into the human genome is a frequent event found in these patients. Additionally, it may well be associated with active inflammation and fibrosis, even in the presence of persistently normal liver enzymes. Likewise, it appears that the mechanisms of hepatocarcinogenesis are already present during this early stage of the disease. This was reflected in the European Association for the Study of the Liver (EASL) guidelines, where treating patients above the age of 30 years with HBeAg-positive chronic infection was proposed. Lowering the treatment threshold to broaden treatment eligibility is likely to slow disease progression and reduce the risk of developing HCC. The current review discusses the reasons to consider early antiviral therapy in HBeAg-positive chronic infection. Full article

(This article belongs to the Special Issue Recent Advances in Management of Hepatitis B and towards Achieving a HBV Cure)

15 pages, 805 KiB

Open AccessReview

HBsAg Loss as a Treatment Endpoint for Chronic HBV Infection: HBV Cure

by Maryam Moini and Scott Fung

Viruses 2022, 14(4), 657; https://doi.org/10.3390/v14040657 - 22 Mar 2022

Cited by 36 | Viewed by 5843

Abstract

Despite the availability of effective vaccines and antiviral therapy over the past two to three decades, chronic hepatitis B virus (HBV) infection remains a major global health threat as a leading cause of cirrhosis and liver cancer. Functional HBV cure defined as hepatitis [...] Read more.

Despite the availability of effective vaccines and antiviral therapy over the past two to three decades, chronic hepatitis B virus (HBV) infection remains a major global health threat as a leading cause of cirrhosis and liver cancer. Functional HBV cure defined as hepatitis B surface antigen (HBsAg) loss and undetectable serum HBV DNA is associated with improved clinical outcomes in patients with chronic HBV infection. However, spontaneous loss of HBsAg is rare and occurs in only 1% of all HBsAg-positive individuals annually. Furthermore, the rate of functional cure with currently available antiviral therapy is even lower, <1% patients on treatment per year. Nonetheless, HBsAg loss has become the new target or therapeutic endpoint for antiviral treatment. Recently, there has been much excitement surrounding the development of novel antiviral agents such as small interfering RNA (siRNA), core assembly modulators (CAMs), nucleic acid polymers (NAPs) among others, which may be used in combination with nucleos(t)ide analogs and possibly immunomodulatory therapies to achieve functional cure in a significant proportion of patients with chronic hepatitis B. Novel assays with improved sensitivity for detection of very low levels of HBsAg and to determine the source of HBsAg production will also be required to measure efficacy of newer antiviral treatments for HBV cure. In this narrative review, we will define HBV cure, discuss various sources of HBsAg production, evaluate rates of HBsAg loss with current and future antiviral agents, review clinical factors associated with spontaneous HBsAg loss, and explore clinical implications of functional cure. Full article

(This article belongs to the Special Issue Recent Advances in Management of Hepatitis B and towards Achieving a HBV Cure)

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9 pages, 242 KiB

Open AccessReview

Global Disparities in Hepatitis B Elimination—A Focus on Africa

by Mark W. Sonderup and C. Wendy Spearman

Viruses 2022, 14(1), 82; https://doi.org/10.3390/v14010082 - 3 Jan 2022

Cited by 38 | Viewed by 5205

Abstract

In 2016, WHO member states at the World Health Assembly adopted a Global Health Sector Strategy that included a policy of eliminating viral hepatitis. Clear targets were established to assist in achieving this by 2030. The strategy, while achievable, has exposed existing global [...] Read more.

In 2016, WHO member states at the World Health Assembly adopted a Global Health Sector Strategy that included a policy of eliminating viral hepatitis. Clear targets were established to assist in achieving this by 2030. The strategy, while achievable, has exposed existing global disparities in healthcare systems and their ability to implement such policies. Compounding this, the regions with most disparity are also those where the hepatitis B prevalence and disease burden are the greatest. Foundational to hepatitis B elimination is the identification of both those with chronic infection and crucially pregnant women, and primary prevention through vaccination. Vaccination, including the birth dose and full three-dose coverage, is key, but complete mother-to-child transmission prevention includes reducing the maternal hepatitis B viral load in the third trimester where appropriate. Innovations and simplified tools exist in order to achieve elimination, but what is desperately required is the will to implement these strategies through the support of appropriate investment and funding. Without this, disparities will continue. Full article

(This article belongs to the Special Issue Recent Advances in Management of Hepatitis B and towards Achieving a HBV Cure)

12 pages, 256 KiB

Open AccessReview

Hepatitis D Review: Challenges for the Resource-Poor Setting

by Alice U. Lee and Caroline Lee

Viruses 2021, 13(10), 1912; https://doi.org/10.3390/v13101912 - 23 Sep 2021

Cited by 13 | Viewed by 3094

Abstract

Hepatitis D is the smallest virus known to infect humans, the most aggressive, causing the most severe disease. It is considered a satellite or defective virus requiring the hepatitis B surface antigen (HBsAg) for its replication with approximately 10–70 million persons infected. Elimination [...] Read more.

Hepatitis D is the smallest virus known to infect humans, the most aggressive, causing the most severe disease. It is considered a satellite or defective virus requiring the hepatitis B surface antigen (HBsAg) for its replication with approximately 10–70 million persons infected. Elimination of hepatitis D is, therefore, closely tied to hepatitis B elimination. There is a paucity of quality data in many resource-poor areas. Despite its aggressive natural history, treatment options for hepatitis D to date have been limited and, in many places, inaccessible. For decades, Pegylated interferon alpha (Peg IFN α) offered limited response rates (20%) where available. Developments in understanding viral replication pathways has meant that, for the first time in over three decades, specific therapy has been licensed for use in Europe. Bulevirtide (Hepcludex^®) is an entry inhibitor approved for use in patients with confirmed viraemia and compensated disease. It can be combined with Peg IFN α and/or nucleos(t)ide analogue for hepatitis B. Early reports suggest response rates of over 50% with good tolerability profile. Additional agents showing promise include the prenylation inhibitor lonafarnib, inhibitors of viral release (nucleic acid polymers) and better tolerated Peg IFN lambda (λ). These agents remain out of reach for most resource limited areas where access to new therapies are delayed by decades. strategies to facilitate access to care for the most vulnerable should be actively sought by all stakeholders. Full article

(This article belongs to the Special Issue Recent Advances in Management of Hepatitis B and towards Achieving a HBV Cure)

16 pages, 707 KiB

Open AccessReview

Functional Cure of Hepatitis B Virus Infection in Individuals With HIV-Coinfection: A Literature Review

by Anders Boyd, Lorenza N. C. Dezanet and Karine Lacombe

Viruses 2021, 13(7), 1341; https://doi.org/10.3390/v13071341 - 11 Jul 2021

Cited by 13 | Viewed by 3905

Abstract

In individuals infected with hepatitis B virus (HBV), the loss of hepatitis B surface antigen (HBsAg) is the ultimate therapeutic goal, which defines “functional cure.” For individuals living with human immunodeficiency virus (HIV), functional cure occurs roughly 2 per 100 person-years during potent [...] Read more.

In individuals infected with hepatitis B virus (HBV), the loss of hepatitis B surface antigen (HBsAg) is the ultimate therapeutic goal, which defines “functional cure.” For individuals living with human immunodeficiency virus (HIV), functional cure occurs roughly 2 per 100 person-years during potent anti-HBV containing antiretroviral therapy. Although this rate may be higher than expected in treated HBV mono-infected individuals, rates of functional cure widely vary between studies (0.6–10.5 per 100 person-years). Similar to HBV mono-infection, the phase of HBV infection, HBV (sub-)genotypes and hepatitis B “e” Ag-negative variants are associated with functional cure in treated HIV-HBV co-infection. In specifically HIV-HBV co-infected individuals, strong increases in CD4+ T cell counts after treatment initiation have also been linked to functional cure, yet this finding is inconsistent across studies. Several markers directly or indirectly reflecting HBV activity are being developed to predict functional cure, such as quantification of HBsAg, hepatitis B core-related antigen, HBsAg protein composition, anti-hepatitis B core antibodies and interferon-gamma-inducible protein 10. Few have been assessed during treatment in HIV-HBV co-infected individuals and none have been validated to predict functional cure. Novel therapeutics for HBV cure are essential for individuals with HIV-HBV co-infection and need to be separately evaluated in this population. Full article

(This article belongs to the Special Issue Recent Advances in Management of Hepatitis B and towards Achieving a HBV Cure)

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16 pages, 310 KiB

Open AccessReview

Screening for Hepatocellular Carcinoma in Chronic Hepatitis B: An Update

by James Lok and Kosh Agarwal

Viruses 2021, 13(7), 1333; https://doi.org/10.3390/v13071333 - 10 Jul 2021

Cited by 3 | Viewed by 2897

Abstract

(1) Background: Hepatocellular carcinoma (HCC) is an important cause of mortality in individuals with chronic hepatitis B infection, with screening of high-risk groups recommended in all major international guidelines. Our understanding of the risk factors involved has improved over time, encouraging researchers to [...] Read more.

(1) Background: Hepatocellular carcinoma (HCC) is an important cause of mortality in individuals with chronic hepatitis B infection, with screening of high-risk groups recommended in all major international guidelines. Our understanding of the risk factors involved has improved over time, encouraging researchers to develop models that predict future risk of HCC development. (2) Methods: A literature search of the PubMed database was carried out to identify studies that derive or validate models predicting HCC development in patients with chronic hepatitis B. Subsequently, a second literature search was carried out to explore the potential role of novel viral biomarkers in this field. (3) Results: To date, a total of 23 models have been developed predicting future HCC risk, of which 12 have been derived from cohorts of treatment-naïve individuals. Most models have been developed in Asian populations (n = 20), with a smaller number in Caucasian cohorts (n = 3). All of the models demonstrate satisfactory performance in their original derivation cohorts, but many lack external validation. In recent studies, novel viral biomarkers have demonstrated utility in predicting HCC risk in patients with chronic hepatitis B, amongst both treated and treatment-naïve patients. (4) Conclusion: Several models have been developed to predict the risk of HCC development in individuals with chronic hepatitis B infection, but many have not been externally validated outside of the Asian population. Further research is needed to refine these models and facilitate a more tailored HCC surveillance programme in the future. Full article

(This article belongs to the Special Issue Recent Advances in Management of Hepatitis B and towards Achieving a HBV Cure)

24 pages, 1285 KiB

Open AccessReview

Strategies to Inhibit Hepatitis B Virus at the Transcript Level

by Bingqian Qu and Richard J. P. Brown

Viruses 2021, 13(7), 1327; https://doi.org/10.3390/v13071327 - 9 Jul 2021

Cited by 11 | Viewed by 4534

Abstract

Approximately 240 million people are chronically infected with hepatitis B virus (HBV), despite four decades of effective HBV vaccination. During chronic infection, HBV forms two distinct templates responsible for viral transcription: (1) episomal covalently closed circular (ccc)DNA and (2) host genome-integrated viral templates. [...] Read more.

Approximately 240 million people are chronically infected with hepatitis B virus (HBV), despite four decades of effective HBV vaccination. During chronic infection, HBV forms two distinct templates responsible for viral transcription: (1) episomal covalently closed circular (ccc)DNA and (2) host genome-integrated viral templates. Multiple ubiquitous and liver-specific transcription factors are recruited onto these templates and modulate viral gene transcription. This review details the latest developments in antivirals that inhibit HBV gene transcription or destabilize viral transcripts. Notably, nuclear receptor agonists exhibit potent inhibition of viral gene transcription from cccDNA. Small molecule inhibitors repress HBV X protein-mediated transcription from cccDNA, while small interfering RNAs and single-stranded oligonucleotides result in transcript degradation from both cccDNA and integrated templates. These antivirals mediate their effects by reducing viral transcripts abundance, some leading to a loss of surface antigen expression, and they can potentially be added to the arsenal of drugs with demonstrable anti-HBV activity. Thus, these candidates deserve special attention for future repurposing or further development as anti-HBV therapeutics. Full article

(This article belongs to the Special Issue Recent Advances in Management of Hepatitis B and towards Achieving a HBV Cure)

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16 pages, 615 KiB

Open AccessReview

Screening for Hepatocellular Carcinoma in Patients with Hepatitis B

by Yashasavi Sachar, Mayur Brahmania, Renumathy Dhanasekaran and Stephen E. Congly

Viruses 2021, 13(7), 1318; https://doi.org/10.3390/v13071318 - 8 Jul 2021

Cited by 7 | Viewed by 4246

Abstract

Chronic hepatitis B (CHB) infection is a significant risk factor for developing hepatocellular carcinoma (HCC). As HCC is associated with significant morbidity and mortality, screening patients with CHB at a high risk for HCC is recommended in an attempt to improve these outcomes. [...] Read more.

Chronic hepatitis B (CHB) infection is a significant risk factor for developing hepatocellular carcinoma (HCC). As HCC is associated with significant morbidity and mortality, screening patients with CHB at a high risk for HCC is recommended in an attempt to improve these outcomes. However, the screening recommendations on who to screen and how often are not uniform. Identifying patients at the highest risk of HCC would allow for the best use of health resources. In this review, we evaluate the literature on screening patients with CHB for HCC, strategies for optimizing adherence to screening, and potential risk stratification tools to identify patients with CHB at a high risk of developing HCC. Full article

(This article belongs to the Special Issue Recent Advances in Management of Hepatitis B and towards Achieving a HBV Cure)

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16 pages, 769 KiB

Open AccessReview

Novel Antivirals in Clinical Development for Chronic Hepatitis B Infection

by Lung-Yi Mak, Wai-Kay Seto and Man-Fung Yuen

Viruses 2021, 13(6), 1169; https://doi.org/10.3390/v13061169 - 18 Jun 2021

Cited by 25 | Viewed by 4715

Abstract

Globally, chronic hepatitis B (CHB) infection is one of the leading causes of liver failure, decompensated cirrhosis, and hepatocellular carcinoma. Existing antiviral therapy can suppress viral replication but not fully eradicate the virus nor the risk of liver-related complications. Novel treatments targeting alternative [...] Read more.

Globally, chronic hepatitis B (CHB) infection is one of the leading causes of liver failure, decompensated cirrhosis, and hepatocellular carcinoma. Existing antiviral therapy can suppress viral replication but not fully eradicate the virus nor the risk of liver-related complications. Novel treatments targeting alternative steps of the viral cycle or to intensify/restore the host’s immunity are being developed. We discuss novel drugs that have already entered clinical phases of development. Agents that interfere with specific steps of HBV replication include RNA interference, core protein allosteric modulation, and inhibition of viral entry or viral protein excretion (NAPs and STOPS). Agents that target the host’s immunity include toll-like receptor agonists, therapeutic vaccines, immune checkpoint modulators, soluble T-cell receptors, and monoclonal antibodies. Most have demonstrated favorable results in suppression of viral proteins and genomic materials (i.e., HBV DNA and/or pre-genomic RNA), and/or evidence on host-immunity restoration including cytokine responses and T-cell activation. Given the abundant clinical experience and real-world safety data with the currently existing therapy, any novel agent for CHB should be accompanied by convincing safety data. Combination therapy of nucleos(t)ide analogue, a novel virus-directing agent, and/or an immunomodulatory agent will be the likely approach to optimize the chance of a functional cure in CHB. Full article

(This article belongs to the Special Issue Recent Advances in Management of Hepatitis B and towards Achieving a HBV Cure)

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15 pages, 907 KiB

Open AccessReview

Review of Lambda Interferons in Hepatitis B Virus Infection: Outcomes and Therapeutic Strategies

by Laura A. Novotny, John Grayson Evans, Lishan Su, Haitao Guo and Eric G. Meissner

Viruses 2021, 13(6), 1090; https://doi.org/10.3390/v13061090 - 9 Jun 2021

Cited by 9 | Viewed by 4135

Abstract

Hepatitis B virus (HBV) chronically infects over 250 million people worldwide and causes nearly 1 million deaths per year due to cirrhosis and liver cancer. Approved treatments for chronic infection include injectable type-I interferons and nucleos(t)ide reverse transcriptase inhibitors. A small minority of [...] Read more.

Hepatitis B virus (HBV) chronically infects over 250 million people worldwide and causes nearly 1 million deaths per year due to cirrhosis and liver cancer. Approved treatments for chronic infection include injectable type-I interferons and nucleos(t)ide reverse transcriptase inhibitors. A small minority of patients achieve seroclearance after treatment with type-I interferons, defined as sustained absence of detectable HBV DNA and surface antigen (HBsAg) antigenemia. However, type-I interferons cause significant side effects, are costly, must be administered for months, and most patients have viral rebound or non-response. Nucleos(t)ide reverse transcriptase inhibitors reduce HBV viral load and improve liver-related outcomes, but do not lower HBsAg levels or impart seroclearance. Thus, new therapeutics are urgently needed. Lambda interferons (IFNLs) have been tested as an alternative strategy to stimulate host antiviral pathways to treat HBV infection. IFNLs comprise an evolutionarily conserved innate immune pathway and have cell-type specific activity on hepatocytes, other epithelial cells found at mucosal surfaces, and some immune cells due to restricted cellular expression of the IFNL receptor. This article will review work that examined expression of IFNLs during acute and chronic HBV infection, the impact of IFNLs on HBV replication in vitro and in vivo, the association of polymorphisms in IFNL genes with clinical outcomes, and the therapeutic evaluation of IFNLs for the treatment of chronic HBV infection. Full article

(This article belongs to the Special Issue Recent Advances in Management of Hepatitis B and towards Achieving a HBV Cure)

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22 pages, 961 KiB

Open AccessReview

Novel Biomarkers of Hepatitis B Virus and Their Use in Chronic Hepatitis B Patient Management

by Alicia Vachon and Carla Osiowy

Viruses 2021, 13(6), 951; https://doi.org/10.3390/v13060951 - 21 May 2021

Cited by 34 | Viewed by 4998

Abstract

Even though an approved vaccine for hepatitis B virus (HBV) is available and widely used, over 257 million individuals worldwide are living with chronic hepatitis B (CHB) who require monitoring of treatment response, viral activity, and disease progression to reduce their risk of [...] Read more.

Even though an approved vaccine for hepatitis B virus (HBV) is available and widely used, over 257 million individuals worldwide are living with chronic hepatitis B (CHB) who require monitoring of treatment response, viral activity, and disease progression to reduce their risk of HBV-related liver disease. There is currently a lack of predictive markers to guide clinical management and to allow treatment cessation with reduced risk of viral reactivation. Novel HBV biomarkers are in development in an effort to improve the management of people living with CHB, to predict disease outcomes of CHB, and further understand the natural history of HBV. This review focuses on novel HBV biomarkers and their use in the clinical setting, including the description of and methodology for quantification of serum HBV RNA, hepatitis B core-related antigen (HBcrAg), quantitative hepatitis B surface antigen (qHBsAg), including ultrasensitive HBsAg detection, quantitative anti-hepatitis B core antigen (qAHBc), and detection of HBV nucleic acid-related antigen (HBV-NRAg). The utility of these biomarkers in treatment-naïve and treated CHB patients in several clinical situations is further discussed. Novel HBV biomarkers have been observed to provide critical clinical information and show promise for improving patient management and our understanding of the natural history of HBV. Full article

(This article belongs to the Special Issue Recent Advances in Management of Hepatitis B and towards Achieving a HBV Cure)

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17 pages, 4138 KiB

Open AccessReview

Transaminase Elevations during Treatment of Chronic Hepatitis B Infection: Safety Considerations and Role in Achieving Functional Cure

by Andrew Vaillant

Viruses 2021, 13(5), 745; https://doi.org/10.3390/v13050745 - 23 Apr 2021

Cited by 4 | Viewed by 5218

Abstract

While current therapies for chronic HBV infection work well to control viremia and stop the progression of liver disease, the preferred outcome of therapy is the restoration of immune control of HBV infection, allowing therapy to be removed while maintaining effective suppression of [...] Read more.

While current therapies for chronic HBV infection work well to control viremia and stop the progression of liver disease, the preferred outcome of therapy is the restoration of immune control of HBV infection, allowing therapy to be removed while maintaining effective suppression of infection and reversal of liver damage. This “functional cure” of chronic HBV infection is characterized by the absence of detectable viremia (HBV DNA) and antigenemia (HBsAg) and normal liver function and is the goal of new therapies in development. Functional cure requires removal of the ability of infected cells in the liver to produce the hepatitis B surface antigen. The increased observation of transaminase elevations with new therapies makes understanding the safety and therapeutic impact of these flares an increasingly important issue. This review examines the factors driving the appearance of transaminase elevations during therapy of chronic HBV infection and the interplay of these factors in assessing the safety and beneficial nature of these flares. Full article

(This article belongs to the Special Issue Recent Advances in Management of Hepatitis B and towards Achieving a HBV Cure)

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