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      Treatment of chronic hepatitis B naïve patients with a therapeutic vaccine containing HBs and HBc antigens (a randomized, open and treatment controlled phase III clinical trial)

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          Abstract

          Context

          Current drugs for chronic hepatitis B therapy have a poor efficacy in terms of post-treatment sustained viral suppression and generate important side effects during and after therapy. Therapeutic vaccination with HBV antigens is an attractive alternative to test.

          Objective

          Evaluating the efficacy of a therapeutic vaccine candidate (designated NASVAC) containing both hepatitis B surface antigen (HBsAg) and core antigen (HBcAg) versus pegylated interferon (Peg-IFN) in naïve chronic hepatitis B patients.

          Design, setting, participants

          An open phase III, randomised and treatment controlled clinical trial was conducted in a total of 160 CHB patients, allocated into two groups of 80 patients each to receive NASVAC or Peg-IFN. The vaccine formulation comprised 100 μg of each HBsAg and HBcAg, and was administered in 2 cycles of 5 doses. The control group received 48 subcutaneous injections of Peg-IFN alfa 2b, 180 μg per dose, every week, for 48 consecutive weeks.

          Main outcome measure

          The primary outcome measure was in relation with the proportion of patients showing reduction of the viral load under the limit of detection (250 copies/mL) after 24 weeks of treatment completion.

          Results

          Sustained control of HBV DNA was significantly more common in NASVAC group (p<0.05) at 24 weeks of follow up. NASVAC-induced increases of alanine aminotransferases (ALT) were detected in 85% patients after 5 nasal vaccinations, although seen in only 30% of patients receiving Peg-IFN. At the end of treatment (EOT) antiviral effect was comparable in both NASVAC and Peg-IFN groups. Clearance of Hepatitis B e antigen (HBeAg) was also more frequent in NASVAC group compared to Peg-IFN recipients. A lower progression to cirrhosis was found in NASVAC group compared to Peg-IFN group.

          Conclusion

          Nasvac induced a superior reduction of the viral load under the limit of detection compared to Peg-IFN treatment. It is a safe and efficacious finite alternative of antiviral treatment for CHB patients.

          Trial registration

          ClinicalTrials.gov NCT 01374308.

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          Most cited references20

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          Therapeutic vaccination of chronic hepatitis B patients with virus suppression by antiviral therapy: a randomized, controlled study of co-administration of HBsAg/AS02 candidate vaccine and lamivudine.

          Induction of curative immune responses by therapeutic vaccination in chronic viral infections such as chronic hepatitis B (CHB) is expected to be facilitated by reduction of viral load by antiviral treatment. In this open label, controlled, randomized study, 195 patients with HBeAg positive CHB were randomized to receive 12 doses of HBsAg with AS02B adjuvant candidate vaccine plus lamivudine daily for 52 weeks or lamivudine daily alone. The combined administration of vaccine and lamivudine was safe and well tolerated, but did not improve the HBe seroconversion rate (18.8%) when compared to treatment with lamivudine alone (16.1%) (p=0.6824). Despite induction of a vigorous HBsAg-specific lymphoproliferative response, cytokine production and anti-HBs antibodies, therapeutic vaccination with an adjuvanted HBsAg vaccine administered concomitantly with lamivudine did not demonstrate superior clinical efficacy in HBeAg positive CHB patients as compared to lamivudine therapy alone.
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            Natural history of chronic hepatitis B: phases in a complex relationship.

            Chronic hepatitis B (CHB) is a condition of global prevalence and its sequelae include cirrhosis and hepatocellular carcinoma. The natural history of CHB is a complex interplay of virological, environmental and host factors. The dynamic relationship between the virus and host evolves over the duration of the infection and different phases of the disease have been observed and described. These have been conceptualized in terms of the state of balance between the host immune system and the hepatitis B virus and have been given the labels immune tolerant, immune clearance, immune control and immune escape although other nomenclature is also used. Host factors, such as age at infection, determine progression to chronicity. Virological factors including hepatitis B viral load, mutations and genotype also have an impact on the adverse outcomes of the infection, as do hepatotoxic cofactors such as alcohol. Our understanding of the natural history of CHB has evolved significantly over the past few decades and characterizing the phase of disease of CHB remains an integral part of managing this virus in the clinic.
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              Clearance of hepatitis B surface antigen after bone marrow transplantation: role of adoptive immunity transfer.

              Adoptive immunity transfer has been reported to be effective in clearing chronic hepatitis B virus (HBV) infection. Two hundred twenty-six patients who received allogeneic bone marrow transplantation (BMT) between May 1990 and September 1995 were screened for hepatitis B markers. Twenty-one patients were hepatitis B surface antigen (HBsAg) positive before BMT. The median follow-up period was 20 months (range, 2-59 months). Two of these patients had sustained clearance of HBV infection after transplantation. Both patients were hepatitis B e antigen (HBeAg)-negative, hepatitis B e antibody (anti-HBe)-positive, and serum HBV DNA-negative (by dot-blot hybridization) before BMT. Both had a flare in the serum alanine transaminase (ALT) level around the time of HBsAg clearance. Sustained clearance of HBsAg was observed in 2 of the 5 patients who received hepatitis B surface antibody (anti-HBs)-positive marrow but in none of the 16 patients who received anti-HBs-negative marrow (P < .05). One additional patient who received anti-HBs-positive marrow had transient HBsAg seroconversion. Among the 18 patients who remained persistently HBsAg-positive after BMT, 3 had HBeAg seroconversion and 3 had reversion to HBeAg positivity. In this study, we found a significant association between clearance of HBV infection and anti-HBs-positive bone marrow donors. Adoptive immunity transfer is effective in clearing HBV from patients with chronic HBV infection.
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                Author and article information

                Contributors
                Role: Data curationRole: InvestigationRole: Methodology
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: Writing – original draftRole: Writing – review & editing
                Role: Formal analysisRole: MethodologyRole: Supervision
                Role: ConceptualizationRole: SupervisionRole: Validation
                Role: Formal analysisRole: Supervision
                Role: Formal analysisRole: Software
                Role: Formal analysisRole: Investigation
                Role: Formal analysisRole: Supervision
                Role: Supervision
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                22 August 2018
                2018
                : 13
                : 8
                : e0201236
                Affiliations
                [1 ] Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
                [2 ] Department of Medical Sciences, Toshiba General Hospital, Tokyo, Japan
                [3 ] Department of Biomedical Research, Center for Genetic Engineering and Biotechnology, Havana, Cuba
                [4 ] Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
                [5 ] Department of Medicine, Sai Sei Kai Imabari Hospital, Imabari, Japan
                The Chinese University of Hong Kong, HONG KONG
                Author notes

                Competing Interests: This study was partly funded by the Clinical Research Organization Bangladesh. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

                [¤]

                Current address: Department of Pathology, Ehime University Proteo-Science Center, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime

                Author information
                http://orcid.org/0000-0002-8139-2645
                Article
                PONE-D-17-44746
                10.1371/journal.pone.0201236
                6104936
                30133478
                861f4686-36aa-487f-9621-529604b6ac61
                © 2018 Al Mahtab et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 19 January 2018
                : 11 July 2018
                Page count
                Figures: 3, Tables: 3, Pages: 14
                Funding
                The trial was partially funded by the Center for Genetic Engineering and Biotechnology (CIGB) (Project name: Hepatitis B Therapeutic Vaccine). CIGB reimbursed Clinical Research Organization Ltd. (CRO Ltd.) for their efforts. The CIGB provided support in form of salaries for their authors EP, JCA, GG, and AT. The statistical analysis plan was written by AT (CIGB). CIGB did not have any additional role in the data collection and analysis, decision to publish or preparation of the manuscript. The URL of CIGB is as follows: http://www.cigb.edu.cu/es/.
                Categories
                Research Article
                Medicine and Health Sciences
                Infectious Diseases
                Infectious Disease Control
                Vaccines
                Research and Analysis Methods
                Research Design
                Clinical Research Design
                Adverse Events
                Biology and Life Sciences
                Immunology
                Vaccination and Immunization
                Medicine and Health Sciences
                Immunology
                Vaccination and Immunization
                Medicine and Health Sciences
                Public and Occupational Health
                Preventive Medicine
                Vaccination and Immunization
                Medicine and health sciences
                Clinical medicine
                Clinical trials
                Phase III clinical investigation
                Medicine and health sciences
                Pharmacology
                Drug research and development
                Clinical trials
                Phase III clinical investigation
                Research and analysis methods
                Clinical trials
                Phase III clinical investigation
                Medicine and health sciences
                Infectious diseases
                Viral diseases
                Hepatitis
                Hepatitis B
                Medicine and health sciences
                Gastroenterology and hepatology
                Liver diseases
                Infectious hepatitis
                Hepatitis B
                Biology and Life Sciences
                Microbiology
                Virology
                Viral Transmission and Infection
                Viral Load
                Medicine and Health Sciences
                Pharmacology
                Routes of Administration
                Medicine and Health Sciences
                Pharmaceutics
                Drug Therapy
                Custom metadata
                All relevant data are within the paper, its Supporting Information files, and at: Aguilar, Julio, 2018, "Replication Data for: Anonymized data set", https://doi.org/10.7910/DVN/IT467W, Harvard Dataverse, V1.

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