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Farag MS, van Campenhout MJH, Sonneveld MJ, Fung S, van Erpecum KJ, Wong DK, Verhey E, de Man R, De Knegt RJ, Brouwer JT, Baak HC, Feld JJ, Liem KS, Boonstra A, Hansen BE, Janssen HLA. Addition of PEG-interferon to long-term nucleos(t)ide analogue therapy enhances HBsAg decline and clearance in HBeAg-negative chronic hepatitis B: Multicentre Randomized Trial (PAS Study). J Viral Hepat 2024; 31:197-207. [PMID: 38243144 DOI: 10.1111/jvh.13918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 12/28/2023] [Accepted: 01/02/2024] [Indexed: 01/21/2024]
Abstract
We studied whether 48 weeks of PEG-IFN alfa-2a add-on increases HBsAg-decline and clearance in HBeAg-negative patients on long-term nucleo(s)tide analogue (NA) therapy. In this investigator-initiated, randomized, controlled trial conducted in Europe and Canada, HBeAg-negative patients treated with NA > 12 months, with HBVDNA < 200 IU/mL, were enrolled. Patients were randomized 2:1 to 48 weeks of PEG-IFN alfa-2a add-on (180 μg per week) or continued NA-monotherapy with subsequent follow-up to Week 72. Endpoints were HBsAg decline (≥1 log10 IU/mL) and HBsAg clearance at Week 48. Of the 86 patients in the modified-intention-to-treat analysis, 58 patients received PEG-IFN add-on, and 28 continued NA monotherapy. At Week 48, 16(28%) patients achieved HBsAg decline ≥1 log10 in the add-on arm versus none on NA-monotherapy (p < .001), and HBsAg clearance was observed in 6 (10%) PEG-IFN add-on patients versus 0% NA-monotherapy (p = .01). HBVRNA was only detected in 2% after PEG-IFN treatment versus 19% in NA-monotherapy (p = .002) at Week 48. PEG-IFN add-on therapy was well tolerated in majority of patients. Low baseline HBsAg levels (<10 IU/mL) identified patients most likely to achieve HBsAg loss with PEG-IFN add-on, whereas an HBsAg level > 200 IU/mL at on-treatment Week 12 was highly predictive of non-response (NPV = 100%). Addition of PEG-IFN to long-term NA enhanced HBsAg decline and increased the chance of HBsAg clearance in HBeAg-negative patients on long-term NA. On-treatment HBsAg levels >200 IU/mL identify patients unlikely to benefit from PEG-IFN add-on and could be used as a potential stopping-rule for PEG-IFN therapy. Our findings support further exploration of immune modulation add-on to antiviral therapy, preferably using response-guided strategies, to increase functional cure rates in patients with CHB.
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Affiliation(s)
- Mina S Farag
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Margo J H van Campenhout
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - M J Sonneveld
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Scott Fung
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Karel J van Erpecum
- Department of Gastroenterology, University Medical Center, Utrecht, The Netherlands
| | - David K Wong
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Elke Verhey
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Robert de Man
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Robert J De Knegt
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Johannes T Brouwer
- Department of Gastroenterology and Hepatology, Reinier de Graaf Groep, Delft, The Netherlands
| | - Hubertus C Baak
- Department of Gastroenterology and Hepatology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
| | - Jordan J Feld
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Kin Seng Liem
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - André Boonstra
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Bettina E Hansen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
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Olenginski LT, Attionu SK, Henninger EN, LeBlanc RM, Longhini AP, Dayie TK. Hepatitis B Virus Epsilon (ε) RNA Element: Dynamic Regulator of Viral Replication and Attractive Therapeutic Target. Viruses 2023; 15:1913. [PMID: 37766319 PMCID: PMC10534774 DOI: 10.3390/v15091913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 09/01/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023] Open
Abstract
Hepatitis B virus (HBV) chronically infects millions of people worldwide, which underscores the importance of discovering and designing novel anti-HBV therapeutics to complement current treatment strategies. An underexploited but attractive therapeutic target is ε, a cis-acting regulatory stem-loop RNA situated within the HBV pregenomic RNA (pgRNA). The binding of ε to the viral polymerase protein (P) is pivotal, as it triggers the packaging of pgRNA and P, as well as the reverse transcription of the viral genome. Consequently, small molecules capable of disrupting this interaction hold the potential to inhibit the early stages of HBV replication. The rational design of such ligands necessitates high-resolution structural information for the ε-P complex or its individual components. While these data are currently unavailable for P, our recent structural elucidation of ε through solution nuclear magnetic resonance spectroscopy marks a significant advancement in this area. In this review, we provide a brief overview of HBV replication and some of the therapeutic strategies to combat chronic HBV infection. These descriptions are intended to contextualize our recent experimental efforts to characterize ε and identify ε-targeting ligands, with the ultimate goal of developing novel anti-HBV therapeutics.
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Affiliation(s)
- Lukasz T. Olenginski
- Center for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA (R.M.L.)
- Department of Biochemistry, University of Colorado, Boulder, CO 80309, USA
| | - Solomon K. Attionu
- Center for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA (R.M.L.)
| | - Erica N. Henninger
- Center for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA (R.M.L.)
| | - Regan M. LeBlanc
- Center for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA (R.M.L.)
| | - Andrew P. Longhini
- Center for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA (R.M.L.)
- Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
- Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
| | - Theodore K. Dayie
- Center for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA (R.M.L.)
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Umemura M, Ogawa K, Morikawa K, Kubo A, Tokuchi Y, Yamada R, Kitagataya T, Shigesawa T, Shimazaki T, Kimura M, Suzuki K, Nakamura A, Ohara M, Kawagishi N, Izumi T, Nakai M, Sho T, Suda G, Natsuizaka M, Ono K, Murata K, Sugiyama M, Mizokami M, Sakamoto N. Effects of nucleos(t)ide analogs on hepatitis B surface antigen reduction with interferon-lambda 3 induction in chronic hepatitis B patients. Hepatol Res 2022; 52:586-596. [PMID: 35352445 DOI: 10.1111/hepr.13768] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 03/22/2022] [Accepted: 03/26/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Benefits of nucleos(t)ide analogs (NAs) on hepatitis B surface antigen (HBsAg) reduction and interferon-lambda3 (IFN-λ3) induction are still not known. This study aimed to investigate the effects of NAs on HBsAg reduction and association with serum IFN-λ3 levels in chronic hepatitis B (CHB) patients. METHODS A total of 91 patients [51 treated with nucleoside analog entecavir hydrate (ETV) and 40 treated with nucleotide analog adefovir dipivoxil (ADV) or tenofovir disoproxil fumarate (TDF)] with clinically evident CHB (chronic hepatitis, 57; liver cirrhosis, 34) were enrolled in this study. Serum IFN-λ3 levels among patients receiving ETV and ADV/TDF were measured before the initiation of therapy and 1, 3, and 5 years post-therapy. RESULTS The change (mean ± standard deviation) in serum HBsAg levels from baseline to year five was -0.38 ± 0.46 and -0.84 ± 0.64 log10 IU/ml in ETV and ADV/TDF groups, respectively (p = 0.0004). Higher serum IFN-λ3 levels were observed in ADV/TDF group compared with ETV group during treatment (p < 0.001). Serum IFN-λ3 levels showed negative correlation with HBsAg reduction in ADV/TDF group (r = -0.386, p = 0.038) at week 48. Nucleotide analogs (ADV/TDF) treatment has associated factors with -0.3 log HBsAg decline at 1 year, -0.5 log HBsAg decline at 3 years, and -0.8 log HBsAg decline at 5 years after NAs treatment on multivariate analysis. CONCLUSIONS Nucleotide analog (ADV/TDF) treatment reduced HBsAg levels greater compared with nucleoside analog (ETV) in parallel with IFN-λ3 induction.
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Affiliation(s)
- Machiko Umemura
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Kenichi Morikawa
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Akinori Kubo
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Yoshimasa Tokuchi
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Ren Yamada
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Takashi Kitagataya
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Taku Shigesawa
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Tomoe Shimazaki
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Megumi Kimura
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Kazuharu Suzuki
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Akihisa Nakamura
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Masatsugu Ohara
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Naoki Kawagishi
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Takaaki Izumi
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Masato Nakai
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Takuya Sho
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Mitsuteru Natsuizaka
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Kota Ono
- Clinical Research and Medical Innovation Center, Hokkaido University Hospital, Sapporo, Japan
| | - Kazumoto Murata
- Division of Virology, Department of Infection and Immunity, Jichi Medical University, Shimotsuke, Japan
| | - Masaya Sugiyama
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Masashi Mizokami
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
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Nagra N, Kozarek RA, Burman BE. Therapeutic Advances in Viral Hepatitis A-E. Adv Ther 2022; 39:1524-1552. [PMID: 35220557 DOI: 10.1007/s12325-022-02070-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 01/31/2022] [Indexed: 11/25/2022]
Abstract
Viral hepatitis remains a significant global health problem. All forms of viral hepatitis A through E (A-E) can lead to acute symptomatic infection, while hepatitis B and C can lead to chronic infection associated with significant morbidity and mortality related to progression to cirrhosis, end-stage-liver disease, and liver cancer. Viral hepatitis occurs worldwide, though certain regions are disproportionately affected. We now, remarkably, have highly effective curative regimens for hepatitis C, and safe and tolerable medications to suppress hepatitis B activity, and to prevent liver damage and slow disease progression. We have effective vaccines for hepatitis A and B which provide long-lasting immunity, while improved sanitation and awareness can curb outbreaks of hepatitis A and E. However, more effective and available preventive and curative strategies are needed to achieve global eradication of viral hepatitis. This review provides an overview of the epidemiology, transmission, diagnosis, and clinical features of each viral hepatitis with a primary focus on current and future therapeutic and curative options.
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Affiliation(s)
- Navroop Nagra
- Department of Gastroenterology, University of Louisville, Louisville, KY, 40202, USA
| | - Richard A Kozarek
- Center for Digestive Health, Virginia Mason Franciscan Health, 1100 9th Ave., Seattle, WA, 98101, USA
| | - Blaire E Burman
- Center for Digestive Health, Virginia Mason Franciscan Health, 1100 9th Ave., Seattle, WA, 98101, USA.
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Charatcharoenwitthaya P, Kaewdech A, Piratvisuth T. Controversies in Treating Chronic HBV: The Role of PEG-interferon-alfa. Clin Liver Dis 2021; 25:741-762. [PMID: 34593151 DOI: 10.1016/j.cld.2021.06.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Pegylated interferon-alpha therapy is one of the first-line chronic hepatitis B treatment. Finite treatment duration, absence of drug resistance, delayed response, and higher hepatitis B surface antigen loss than nucleos(t)ides analog therapy are the advantages of pegylated interferon-alpha treatment. Common side effects and subcutaneous injections requirement limit its use. Identifying patients likely to respond to pegylated interferon-alpha and optimizing treatment is reasonable. Motivating patients to complete the 48-week treatment is necessary. Treatment is stopped or switched to other treatment strategies in patients with stopping rule criteria. Combination therapy with nucleos(t)ides analog may improve response, but remains controversial.
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Affiliation(s)
- Phunchai Charatcharoenwitthaya
- Gastroenterology Division, Department of Internal Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Wang-Lang Road, Bangkok 10700, Thailand
| | - Apichat Kaewdech
- Gastroenterology and Hepatology Unit, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Kanchanawanich Road, Songkhla 90110, Thailand
| | - Teerha Piratvisuth
- Gastroenterology and Hepatology Unit, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Kanchanawanich Road, Songkhla 90110, Thailand; NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Prince of Songkla University, Kanchanawanich Road, Songkhla 90110, Thailand.
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6
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Sbarigia U, Vincken T, Wigfield P, Hashim M, Heeg B, Postma M. A comparative network meta-analysis of standard of care treatments in treatment-naïve chronic hepatitis B patients. J Comp Eff Res 2020; 9:1051-1065. [PMID: 32945178 DOI: 10.2217/cer-2020-0068] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Objective: Published network meta-analyses of chronic hepatitis B (CHB) treatments are either out-of-date or excluded key treatments. Therefore, we aimed to comprehensively update the efficacy evidence for the following end points: Hepatitis B surface antigen (HBsAg) loss, hepatitis B early antigen (HBeAg) seroconversion and hepatitis B virus DNA (HBV DNA) suppression. Materials & methods: Approved treatments in CHB and their combinations were evaluated. A systematic literature review was conducted to identify all randomized controlled trials in treatment-naïve CHB patients. Included studies reported at least one of the end points of interest. A frequentist probability network meta-analysis was performed for each end point. The choice of fixed effect or random-effect model was based on the I-square statistic, a measure of variation in study outcomes between studies. The analyses were performed separately for HBeAg-positive and HBeAg-negative patients. For the primary analyses, end points measured 48 ± 4 weeks after treatment initiation were considered. Results: A total of 47 randomized controlled trials (13,826 patients), covering 23 unique treatment regimens, were included: a total of 29 reported HBsAg loss, 36 reported HBeAg seroconversion and 37 reported HBV DNA suppression. For both HBsAg loss and HBeAg seroconversion, pegylated interferon-based regimens were the most effective strategy in both HBeAg-positive and HBeAg-negative patients. On the other hand, for HBV DNA suppression, nucleosides-based regimens were the most effective strategy in both HBeAg-positive and HBeAg-negative patients. Conclusion: Our findings confirm available evidence around the comparative efficacy of available CHB treatments. Therefore, they can be used to update relevant cost-effectiveness analyses and clinical guidelines.
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Affiliation(s)
| | - Talitha Vincken
- Ingress-Health, Weena 316 Rotterdam, 3012NJ, The Netherlands
| | - Peter Wigfield
- Ingress-Health, Weena 316 Rotterdam, 3012NJ, The Netherlands
| | - Mahmoud Hashim
- Ingress-Health, Weena 316 Rotterdam, 3012NJ, The Netherlands
| | - Bart Heeg
- Ingress-Health, Weena 316 Rotterdam, 3012NJ, The Netherlands
| | - Maarten Postma
- Unit of PharmacoEpidemiology & PharmacoEconomics, Rijksuniversiteit Groningen - Pharmacy, Groningen, The Netherlands.,Institute of Science in Healthy Aging & healthcaRE (SHARE), Universitair Medisch Centrum Groningen, Groningen, The Netherlands.,Epidemiology, Universitair Medisch Centrum Groningen, Groningen, The Netherlands
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7
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Brouwer WP, Chan HLY, Lampertico P, Hou J, Tangkijvanich P, Reesink HW, Zhang W, Mangia A, Tanwandee T, Montalto G, Simon K, Ormeci N, Chen L, Tabak F, Gunsar F, Flisiak R, Ferenci P, Akdogan M, Akyuz F, Hirankarn N, Jansen L, Wong VWS, Soffredini R, Liang X, Chen S, Groothuismink ZMA, Santoro R, Jaroszewicz J, Ozaras R, Kozbial K, Brahmania M, Xie Q, Chotiyaputta W, Xun Q, Pazgan-Simon M, Oztas E, Verhey E, Montanari NR, Sun J, Hansen BE, Boonstra A, Janssen HLA. Genome-wide Association Study Identifies Genetic Variants Associated With Early and Sustained Response to (Pegylated) Interferon in Chronic Hepatitis B Patients: The GIANT-B Study. Clin Infect Dis 2020; 69:1969-1979. [PMID: 30715261 PMCID: PMC6853659 DOI: 10.1093/cid/ciz084] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 03/11/2019] [Indexed: 02/07/2023] Open
Abstract
Background (Pegylated) Interferon ([Peg]IFN) therapy leads to response in a minority of chronic hepatitis B (CHB) patients. Host genetic determinants of response are therefore in demand. Methods In this genome-wide association study (GWAS), CHB patients, treated with (Peg)IFN for at least 12 weeks ± nucleos(t)ide analogues within randomized trials or as standard of care, were recruited at 21 centers from Europe, Asia, and North America. Response at 24 weeks after (Peg)IFN treatment was defined as combined hepatitis B e antigen (HBeAg) loss with hepatitis B virus (HBV) DNA <2000 IU/mL, or an HBV DNA <2000 IU/mL for HBeAg-negative patients. Results Of 1144 patients, 1058 (92%) patients were included in the GWAS analysis. In total, 282 (31%) patients achieved the response and 4% hepatitis B surface antigen (HBsAg) loss. GWAS analysis stratified by HBeAg status, adjusted for age, sex, and the 4 ancestry components identified PRELID2 rs371991 (B= −0.74, standard error [SE] = 0.16, P = 3.44 ×10–6) for HBeAg-positive patients. Importantly, PRELID2 was cross-validated for long-term response in HBeAg-negative patients. G3BP2 rs3821977 (B = 1.13, SE = 0.24, P = 2.46 × 10–6) was associated with response in HBeAg-negative patients. G3BP2 has a role in the interferon pathway and was further examined in peripheral blood mononuclear cells of healthy controls stimulated with IFNα and TLR8. After stimulation, less production of IP-10 and interleukin (IL)-10 proteins and more production of IL-8 were observed with the G3BP2 G-allele. Conclusions Although no genome-wide significant hits were found, the current GWAS identified genetic variants associated with (Peg)IFN response in CHB. The current findings could pave the way for gene polymorphism-guided clinical counseling, both in the setting of (Peg)IFN and the natural history, and possibly for new immune-modulating therapies. Clinical Trials Registation NCT01401400.
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Affiliation(s)
- Willem P Brouwer
- Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, The Netherlands
| | - Henry L Y Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Italy
| | - Pietro Lampertico
- Centro di riferimento per la diagnosi e lo studio delle malattie del fegato e delle vie biliari "Angela Maria ed Antonio Migliavacca" Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico di natura pubblica Cà Granda Ospedale Maggiore Policlinico, University of Milan, Italy
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Hepatology Unit and Dept of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | | | | | - Wenhong Zhang
- Clinical Center Hepatitis, Institute of Biomedical Science, Huashan hospital "Fu Dan University," Shanghai, China
| | - Alessandra Mangia
- Istituto di Ricovero e Cura a Carattere Scientifico di natura pubblica Casa Sollievo della Sofferenza, Foggia, Italy
| | - Tawesak Tanwandee
- Division of Gastroenterology, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Giuseppe Montalto
- Biomedical Department of Internal Medicine and Specialties, University of Palermo, Italy
| | - Kris Simon
- Wroclaw University of Medicine Department of Infectious Diseases and Hepatology, Poland
| | | | - Liang Chen
- Shanghai Public Health Center "Fu Dan University," China
| | - Fehmi Tabak
- Cerrahpasa Medical Faculty, Department of Infectious Diseases, Istanbul
| | | | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Poland
| | | | | | - Filiz Akyuz
- Istanbul Üniversitesi Istanbul Tip Fakültesi Hastanesi, Istanbul, Turkey
| | | | - Louis Jansen
- Academic Medical Centre, Amsterdam, The Netherlands
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Italy
| | - Roberta Soffredini
- Centro di riferimento per la diagnosi e lo studio delle malattie del fegato e delle vie biliari "Angela Maria ed Antonio Migliavacca" Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico di natura pubblica Cà Granda Ospedale Maggiore Policlinico, University of Milan, Italy
| | - Xieer Liang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Hepatology Unit and Dept of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shalom Chen
- Clinical Center Hepatitis, Institute of Biomedical Science, Huashan hospital "Fu Dan University," Shanghai, China
| | | | - Rosanna Santoro
- Istituto di Ricovero e Cura a Carattere Scientifico di natura pubblica Casa Sollievo della Sofferenza, Foggia, Italy
| | - Jerzy Jaroszewicz
- Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Poland.,Department of Infectious Diseases and Hepatology, Medical University of Silesia, Katowice, Poland
| | - Resat Ozaras
- Cerrahpasa Medical Faculty, Department of Infectious Diseases, Istanbul
| | | | - Mayur Brahmania
- Liver Clinic, Toronto General Hospital, University Health Network, Toronto, Canada
| | - Qing Xie
- Shanghai Ruijin Hospital, Jiao Tong University School of Medicine, Shanghai, China
| | - Watcharasak Chotiyaputta
- Division of Gastroenterology, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Qi Xun
- Shanghai Public Health Center "Fu Dan University," China
| | - Monika Pazgan-Simon
- Wroclaw University of Medicine Department of Infectious Diseases and Hepatology, Poland
| | | | - Elke Verhey
- Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, The Netherlands
| | - Noé R Montanari
- Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, The Netherlands
| | - Jian Sun
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Hepatology Unit and Dept of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Bettina E Hansen
- Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, The Netherlands
| | - Andre Boonstra
- Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, The Netherlands
| | - Harry L A Janssen
- Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, The Netherlands.,Liver Clinic, Toronto General Hospital, University Health Network, Toronto, Canada
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Wigfield P, Sbarigia U, Hashim M, Vincken T, Heeg B. Are Published Health Economic Models for Chronic Hepatitis B Appropriately Capturing the Benefits of HBsAg Loss? A Systematic Literature Review. PHARMACOECONOMICS - OPEN 2020; 4:403-418. [PMID: 31428938 PMCID: PMC7426349 DOI: 10.1007/s41669-019-00175-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
OBJECTIVES Sustained hepatitis B surface antigen (HBsAg) loss or 'functional cure' (FC) is considered an optimal treatment endpoint by international clinical guidelines for chronic hepatitis B (CHB), yet rarely is this achieved with current standard of care (SoC). This leads to an under-reporting of FC in clinical trials, observational studies and health economic (HE) models. This paper systematically identifies and assesses how FC is incorporated in published HE models of CHB. METHODS A systematic literature review was conducted in PubMed and Embase (conducted February 2019) to review how HBsAg loss is captured in HE models. The following items were extracted: rate of (and transition probabilities to) HBsAg loss, HBsAg loss health state costs, and HBsAg loss health state utilities. RESULTS Sixty-five economics evaluations were identified, and < 50% of these (27/65) incorporated HBsAg loss in their models. Only 15/27 stated HBsAg loss health state costs, 15/27 stated HBsAg loss health state utilities, and 11/27 mentioned treatment-specific transition probabilities to HBsAg loss. The majority of sources these inputs were derived from are not transparent. CONCLUSIONS The benefits of FC in current HE models are not well captured, as FC is often not reported or not directly related to modelled treatments. This has the potential for novel agents with higher efficacy compared with SoC to be overlooked and undervalued if their worth is not appropriately communicated. In order to ensure optimal access for patients to new and effective therapies, it is important that the benefits of FC are better assessed and captured within HE models.
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Affiliation(s)
- Peter Wigfield
- Ingress-health Nederland, Hofplein 20, 3032 AC Rotterdam, The Netherlands
| | - Urbano Sbarigia
- Janssen Pharmaceutica, Turnhoutseweg 30, 2340 Beerse, Belgium
| | - Mahmoud Hashim
- Ingress-health Nederland, Hofplein 20, 3032 AC Rotterdam, The Netherlands
| | - Talitha Vincken
- Ingress-health Nederland, Hofplein 20, 3032 AC Rotterdam, The Netherlands
| | - Bart Heeg
- Ingress-health Nederland, Hofplein 20, 3032 AC Rotterdam, The Netherlands
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9
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Fonseca MA, Ling JZJ, Al-Siyabi O, Co-Tanko V, Chan E, Lim SG. The efficacy of hepatitis B treatments in achieving HBsAg seroclearance: A systematic review and meta-analysis. J Viral Hepat 2020; 27:650-662. [PMID: 32170983 DOI: 10.1111/jvh.13283] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 11/20/2019] [Accepted: 01/13/2020] [Indexed: 02/06/2023]
Abstract
Current therapies for chronic hepatitis B (CHB) include nucleos(t)ide analogues (NAs) and interferon (IFN), but their relative efficacy as monotherapy or in combination has not been examined systematically for HBsAg loss (functional cure). Hence, we systematically reviewed the evidence for HBsAg loss in CHB patients treated with IFN, NA or the combination. We searched PubMed, EMBASE and abstracts from EASL, Asia Pacific Association for study of the Liver and American Association for the Study of Liver Disease for randomized controlled trials of CHB patients, comparing NA, IFN or the combination. The Cochrane Risk of Bias tool v2.0 and GRADE method were used. Analyses were stratified by NA genetic barrier, cirrhosis, type of combination therapy, HBeAg, treatment naivety, IFN dosage/duration and outcome duration. Sensitivity analysis was performed for selected strata, and HBsAg loss was measured at the end-of-study (EOS), end-of-treatment (EOT) or end-of-follow-up (EOF). Effects were reported as risk differences (RD) with 95% confidence intervals (CI) using a random-effects model. Forty-five studies were included, all with low risk of bias. For HBsAg loss at EOS, when comparing combination vs IFN, RD = 1%, 95%CI-1%, 2%; combination vs NA, RD = 5%, 95%CI 3%,7%; IFN vs NA, RD = 3%, 95%CI 2%,5%. Subgroup analysis showed a significant effect of standard IFN dose vs nonstandard; IFN duration ≥48 weeks vs <48 weeks, and loss of efficacy >2 years of follow-up. Similar findings were seen in HBsAg seroconversion, but only three studies reported HBsAg seroreversion. In conclusion, IFN monotherapy/combination had a small but significant increase in HBsAg loss over NA, associated with standard dose of IFN and ≥48 weeks of therapy, although this effect faded over time.
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Affiliation(s)
- Mariana Alves Fonseca
- Hospital DivinaProvidência, Porto Alegre, Brazil.,Hospital Moinhos de Vento, Porto Alegre, Brazil
| | - Joanna Zhi Jie Ling
- Royal Melbourne Institute of Technology, Melbourne, Vic., Australia.,Singapore Clinical Research Institute, Singapore City, Singapore
| | - Omar Al-Siyabi
- Division of Gastroenterology and Hepatology, Department of Medicine, Royal Hospital, Oman Muscat, Oman
| | - Vanessa Co-Tanko
- Division of Gastroenterology and Hepatology, Department of Medicine, UP-Philippine General Hospital, Manila, Philippines
| | - Edwin Chan
- Singapore Clinical Research Institute, Singapore City, Singapore.,Duke-NUS Medical School, Singapore City, Singapore
| | - Seng Gee Lim
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore City, Singapore.,Yong Loo Lin School of Medicine, National University of Singapore, Singapore City, Singapore
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10
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Ezzikouri S, Hoque Kayesh ME, Benjelloun S, Kohara M, Tsukiyama-Kohara K. Targeting Host Innate and Adaptive Immunity to Achieve the Functional Cure of Chronic Hepatitis B. Vaccines (Basel) 2020; 8:vaccines8020216. [PMID: 32403281 PMCID: PMC7349973 DOI: 10.3390/vaccines8020216] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 04/15/2020] [Accepted: 04/16/2020] [Indexed: 02/06/2023] Open
Abstract
Despite the availability of an effective preventive vaccine for hepatitis B virus (HBV) for over 38 years, chronic HBV (CHB) infection remains a global health burden with around 257 million patients. The ideal treatment goal for CHB infection would be to achieve complete cure; however, current therapies such as peg-interferon and nucleos(t)ide analogs are unable to achieve the functional cure, the newly set target for HBV chronic infection. Considering the fact functional cure has been accepted as an endpoint in the treatment of chronic hepatitis B by scientific committee, the development of alternative therapeutic strategies is urgently needed to functionally cure CHB infection. A promising target for future therapeutic strategies is immune modulation to restore dysfunctional HBV-specific immunity. In this review, we provide an overview of the progress in alternative therapeutic strategies, including immune-based therapeutic approaches that enhance host innate and adaptive immunity to achieve and increase the functional cure from CHB infection.
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Affiliation(s)
- Sayeh Ezzikouri
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca 20250, Morocco;
- Transboundary Animal Diseases Centre, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-0065, Japan;
- Correspondence: (S.E.); (K.T.-K.); Tel.: +212-5-2243-4470 (S.E.); Tel./Fax: +81-99-285-3589 (K.T.-K.)
| | - Mohammad Enamul Hoque Kayesh
- Transboundary Animal Diseases Centre, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-0065, Japan;
- Department of Microbiology and Public Health, Faculty of Animal Science and Veterinary Medicine, Patuakhali Science and Technology University, Barishal 8210, Bangladesh
| | - Soumaya Benjelloun
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca 20250, Morocco;
| | - Michinori Kohara
- Department of Microbiology and Cell Biology, The Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan;
| | - Kyoko Tsukiyama-Kohara
- Transboundary Animal Diseases Centre, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-0065, Japan;
- Correspondence: (S.E.); (K.T.-K.); Tel.: +212-5-2243-4470 (S.E.); Tel./Fax: +81-99-285-3589 (K.T.-K.)
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11
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Adverse events of nucleos(t)ide analogues for chronic hepatitis B: a systematic review. J Gastroenterol 2020; 55:496-514. [PMID: 32185517 PMCID: PMC7188775 DOI: 10.1007/s00535-020-01680-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 02/26/2020] [Indexed: 02/04/2023]
Abstract
Nucleos(t)ide analogues (NAs) are the main drug category used in chronic hepatitis B (CHB) treatment. Despite the fact that NAs have a favourable safety profile, undesired adverse events (AEs) may occur during the treatment of CHB. Given the eminent number of patients currently receiving NAs, even a small risk of any of these toxicities can represent a major medical issue. The main objective of this review was to analyse information available on AEs associated with the use of NAs in published studies. We choose the following MesH terms for this systematic review: chronic hepatitis B, side effects and treatment. All articles published from 1 January 1990 up to 19 February 2018 in MEDLINE of PubMed, EMBASE, the Cochrane Library and LILACS databases were searched. A total of 120 articles were selected for analysis, comprising 6419 patients treated with lamivudine (LAM), 5947 with entecavir (ETV), 3566 with tenofovir disoproxil fumarate (TDF), 3096 with telbivudine (LdT), 1178 with adefovir dipivoxil (ADV) and 876 with tenofovir alafenamide (TAF). The most common AEs in all NAs assessed were abdominal pain/discomfort, nasopharyngitis/upper respiratory tract infections, fatigue, and headache. TAF displays the highest density of AEs per patient treated among NAs (1.14 AE/treated patient). In conclusion, treatment of CHB with NAs is safe, with a low incidence of AEs. Despite the general understanding TAF being safer than TDF, the number of patients treated with TAF still is too small in comparison to other NAs to consolidate an accurate safety profile. PROSPERO Registration No. CRD42018086471.
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12
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Shen S, Wong GLH, Kuang Z, van Campenhout MJH, Fan R, Wong VWS, Yip TCF, Chi H, Liang X, Hu X, Lin W, Wu Y, Liu X, Boonstra A, Hou J, Sun J, Chan HLY. Development and validation of a model for hepatitis B e antigen seroconversion in entecavir-treated patients with chronic hepatitis B. J Med Virol 2019; 92:1206-1213. [PMID: 31724212 DOI: 10.1002/jmv.25628] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Accepted: 11/13/2019] [Indexed: 12/15/2022]
Abstract
Achieving hepatitis B e antigen (HBeAg) seroconversion is a satisfactory endpoint during antiviral treatment for chronic hepatitis B (CHB). This study aimed to develop and validate a novel scoring system to predict HBeAg seroconversion during entecavir (ETV) treatment. A total of 526 patients with HBeAg-positive CHB treated with ETV for at least 1 year were randomly assigned to the training and validation cohorts. Baseline parameters including hepatitis B virus DNA, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), and alanine aminotransferase level were quantified. Patients who achieved HBeAg seroconversion were compared with those without HBeAg seroconversion. A prediction model was established to predict HBeAg seroconversion during ETV treatment. After a median follow up of 2.67 years, 93 (36.0%) and 87 (32.5%) patients in the training and validation cohorts developed HBeAg seroconversion. A prediction score composed of age, HBsAg and HBcAb quantification was derived. Areas under receiver operating characteristic curve at 5 years of this prediction score were 0.70 and 0.72 in the training and validation cohorts. By using the dual cutoff values of 0.28 and 0.58, the model was endowed with high sensitivity and specificity to exclude or identify patients developing HBeAg seroconversion (90.3% sensitivity and 90.2% specificity in the training cohort as well as 92.8% sensitivity and 84.4% specificity in the validation cohort, respectively). A novel prediction score that uses baseline clinical variables was developed and validated. The score accurately estimates the probabilities of developing HBeAg seroconversion at 5-years ETV therapy in patients with CHB.
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Affiliation(s)
- Sheng Shen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Grace L-H Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.,State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Zhe Kuang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Margo J H van Campenhout
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Rong Fan
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Vincent W-S Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.,State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Terry C-F Yip
- Institute of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Heng Chi
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Xieer Liang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoyun Hu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Weiyin Lin
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yaobo Wu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoju Liu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - André Boonstra
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jian Sun
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Henry L-Y Chan
- Institute of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.,State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
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13
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Yeh ML, Huang JF, Dai CY, Yu ML, Chuang WL. Pharmacokinetics and pharmacodynamics of pegylated interferon for the treatment of hepatitis B. Expert Opin Drug Metab Toxicol 2019; 15:779-785. [PMID: 31593639 DOI: 10.1080/17425255.2019.1678584] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Introduction: Interferon (IFN) had both antiviral and immunomodulatory effects, and was one of the approved treatments for hepatitis B virus (HBV). Herein, we reviewed the pharmacokinetics and pharmacodynamics of pegylated IFN-α (PegIFN-α) for the treatment of HBV. Areas covered: The steady-state serum levels of PegIFN-α were reached within 5 to 8 weeks, and the week 48 mean trough concentrations were approximately 2-fold higher than week 1. There was also no difference of the pharmacokinetics in male or female, healthy volunteers or patients with hepatitis B or C infection. PegIFN-α did not affect the metabolism of the cytochrome P450 (CYP) isozymes, except inhibition of CYP1A2. There was also no pharmacokinetic interaction between PegIFN-α and HBV nucleot(s)ide analogues (NUCs). Forty-eight weeks of PegIFN-α achieved 32% of HBeAg seroconversion, 32-43% of HBV DNA suppression, 41-59% of ALT normalization, and 3% of HBsAg seroconversion rate with a post-treatment durable response up to 80% in the initial responders. Expert opinion: On-treatment HBsAg titer guided the treatment of HBV with PegIFN-α. The recommendation of PegIFN-α and NUC combination or switch remained controversial. New immunotherapeutic agents are now in development. Although, PegIFN-α should continue to play a role in the treatment of HBV.
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Affiliation(s)
- Ming-Lun Yeh
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital , Kaohsiung , Taiwan.,School of Medicine and Hepatitis Research Center, College of Medicine, Kaohsiung Medical University , Kaohsiung , Taiwan
| | - Jee-Fu Huang
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital , Kaohsiung , Taiwan.,School of Medicine and Hepatitis Research Center, College of Medicine, Kaohsiung Medical University , Kaohsiung , Taiwan.,Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University , Kaohsiung , Taiwan
| | - Chia-Yen Dai
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital , Kaohsiung , Taiwan.,School of Medicine and Hepatitis Research Center, College of Medicine, Kaohsiung Medical University , Kaohsiung , Taiwan.,Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University , Kaohsiung , Taiwan
| | - Ming-Lung Yu
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital , Kaohsiung , Taiwan.,School of Medicine and Hepatitis Research Center, College of Medicine, Kaohsiung Medical University , Kaohsiung , Taiwan.,Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University , Kaohsiung , Taiwan.,Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B) and Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University , Hsin-Chu , Taiwan.,Institute of Biomedical Sciences, National Sun Yat-Sen University , Kaohsiung , Taiwan
| | - Wan-Long Chuang
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital , Kaohsiung , Taiwan.,School of Medicine and Hepatitis Research Center, College of Medicine, Kaohsiung Medical University , Kaohsiung , Taiwan.,Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University , Kaohsiung , Taiwan
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14
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Hagiwara S, Nishida N, Watanabe T, Ida H, Sakurai T, Ueshima K, Takita M, Komeda Y, Nishijima N, Osaki Y, Kudo M. Sustained antiviral effects and clearance of hepatitis surface antigen after combination therapy with entecavir and pegylated interferon in chronic hepatitis B. Antivir Ther 2019; 23:513-521. [PMID: 29438098 DOI: 10.3851/imp3225] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/16/2018] [Indexed: 01/12/2023]
Abstract
BACKGROUND Although the efficacy of combination therapy with lamivudine or tenofovir and pegylated interferon (PEG-IFN) has been reported in patients with chronic hepatitis B (CHB), the long-term effect of the combination based on the observation of clinical course remains to be clarified. We previously reported the efficacy of combination therapy with entecavir (ETV) and PEG-IFN. Here, we investigated the long-term effect of this combination in patients with CHB. METHODS We administered both ETV and PEG-IFN-α2a or -2b simultaneously to 26 patients with HBV genotype C infection. Treatment was continued for 48 weeks followed by 24 weeks of observation period; we examined the virological and biochemical responses. We also analysed characteristics related to the post-treatment relapse. Finally, we investigated the long-term therapeutic effects. RESULTS Average reduction of intra-hepatic cccDNA level was 1.2 log copies/μg at the completion of administration. Pretreatment hepatitis B surface antigen (HBsAg) level with more than 3.5 log U/ml was identified as a predictive factor for relapse. Furthermore, the cumulative rates of HBsAg-negative patients at 1, 3 and 5 years after the completion of administration were 3.8, 8.4 and 15%, respectively (mean follow-up period: 4.8 years). CONCLUSIONS Baseline HBsAg level with more than 3.5 log U/ml is a useful predictor for relapse 24 weeks after the completion of administration in patients treated with combination therapy. Combination with ETV and PEG-IFN could be an option for treatment of CHB patients especially in those with baseline HBsAg levels of less than 3.5 log U/ml.
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Affiliation(s)
- Satoru Hagiwara
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Naoshi Nishida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Tomohiro Watanabe
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Hiroshi Ida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Toshiharu Sakurai
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Kazuomi Ueshima
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Masahiro Takita
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Yoriaki Komeda
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Norihiro Nishijima
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Yukio Osaki
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
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15
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Zhang Y, Li W, Liu Z, Ye J, Zou G, Zhang Z, Li J. Combination therapy based on pegylated interferon alfa improves the therapeutic response of patients with chronic hepatitis B who exhibit high levels of hepatitis B e-antigen at 24 weeks: A retrospective observational study. Medicine (Baltimore) 2019; 98:e17022. [PMID: 31490387 PMCID: PMC6738969 DOI: 10.1097/md.0000000000017022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Pegylated interferon alpha (PEG-IFN-α) is a first-line treatment for patients with chronic hepatitis B (CHB), but its efficacy varies from individual to individual. Early discrimination between responder and non-responder patients is important for optimal clinical management. In addition, low therapeutic efficacy is still a major issue; thus, treatment timing should be optimized.We reviewed our experience with hepatitis B e-antigen (HBeAg)-positive patients treated with PEG-IFN-α, alone or in combination with nucleoside analogues (NAs), from 2009 through 2014. Collected data included both general characteristics of 113 patients and laboratory data at baseline and at treatment weeks 12, 24, 52, and 76. The endpoint was HBeAg seroconversion at week 76.A total of 113 patients with changed to or start of NAs therapy were included in this study. At the end of treatment, 44 (38.9%) patients exhibited HBeAg seroconversion. Patients with HBeAg seroconversion had lower baseline HBeAg (475.5 vs 751.7; P = .007). The incidence of HBeAg seroconversion was significantly higher among patients with HBeAg ≤ 500 signal-to-cutoff ratio (S/CO) (OR = 2.60, 95% CI: 1.16-5.83, P = .02) at baseline, HBeAg S/CO ≤ 20 (OR = 3.37, 95% CI: 1.47-7.73, P = .003), or a higher than 10-fold HBeAg drop (OR = 3.55, 95% CI: 1.50-8.37, P = .003) at week 12 or HBeAg ≤ 15 S/CO (OR = 10.35, 95% CI: 4.09-26.20, P < .001) at week 24. Subgroup analyses demonstrated that in patients with HBeAg >20 S/CO at 24 weeks, the addition of NAs treatment may increase HBeAg seroconversion (23.3% vs 0%, P = .03).HBeAg levels had an impact on the rate of serological conversion in CHB patients receiving PEG-IFN-based treatment. Combination therapy with NAs should be considered in CHB patients maintaining a high HBeAg level after 24 weeks of PEG-IFN monotherapy.
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Affiliation(s)
- Yafei Zhang
- Department of Infectious Diseases, The First Affiliated Hospital, Anhui Medical University
- Department of Infectious Diseases, The Second Affiliated Hospital, Anhui Medical University, Hefei
| | - Wei Li
- Department of Liver Diseases, Fuyang Second People's Hospital, Fuyang, China
| | - Zhongping Liu
- Department of Infectious Diseases, The Second Affiliated Hospital, Anhui Medical University, Hefei
| | - Jun Ye
- Department of Infectious Diseases, The Second Affiliated Hospital, Anhui Medical University, Hefei
| | - Guizhou Zou
- Department of Infectious Diseases, The Second Affiliated Hospital, Anhui Medical University, Hefei
| | - Zhenhua Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital, Anhui Medical University, Hefei
| | - Jiabin Li
- Department of Infectious Diseases, The First Affiliated Hospital, Anhui Medical University
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16
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Zhao Z, Qin Z, Zhou L, Xiang L, You J, Cao R, Wang H, Wang B, Li M. The impact of IFNL3 genotype on interferon treatment outcome in patients chronically infected with hepatitis B virus: A meta-analysis. Microb Pathog 2019; 134:103598. [PMID: 31201901 DOI: 10.1016/j.micpath.2019.103598] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 06/11/2019] [Accepted: 06/11/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Polymorphisms near the interferon lambda 3 (IFNL3, also known as IL28B) have been proposed to be associated with interferon (IFN)-induced hepatitis C virus (HCV) clearance, but the impact of IFNL3 variations on the result of IFN-based therapy in chronic hepatitis B (CHB) infection is still poor understood. METHODS The purpose of this study was to evaluate the relationship between the IFNL3 polymorphisms and the effectiveness of IFN therapy in patients infected with CHB by means of meta-analysis. PubMed and Embase were utilized to identify relevant studies. Odds ratio (OR) and 95% confidence interval (CI) were analysed together to assess the strength of the association. Subgroup analysis was mainly performed according to HBeAg. RESULTS Twelve studies of 1645 CHB patients met the inclusion criteria and were selected in our meta-analysis. One polymorphism, rs12979860, near to the IFNL3 gene had significant association with the response of CHB patients to IFN-based therapy (OR = 2.35, 95% CI: 1.61-3.42 in allelic model). Another polymorphism, rs8099917, had a similar result (OR = 1.57, 95% CI: 1.03-2.40 in dominant model; and OR = 1.88, 95% CI: 1.21-2.90 in allelic model). When stratified by HBeAg, the antiviral outcome was markedly influenced by both two SNPs in HBeAg positive group (for rs12979860, OR = 1.90, 95% CI: 1.31-2.76 and OR = 2.07, 95% CI: 1.26-3.41 in dominant and allelic models respectively; for rs8099917, OR = 1.67, 95% CI: 1.04-2.67 in dominant model and OR = 1.77, 95% CI: 1.10-2.85 in allelic model). CONCLUSION We concluded that two polymorphisms (rs12979860 and rs8099917) of IFNL3 may play a crucial role in the IFN-based treatment of CHB, especially in HBeAg positive group.
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Affiliation(s)
- Zhongyi Zhao
- Department of Microbiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No.17 People's South Road, Chengdu, Sichuan, 610041, China.
| | - Zhen Qin
- Department of Microbiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No.17 People's South Road, Chengdu, Sichuan, 610041, China
| | - Linlin Zhou
- Department of Microbiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No.17 People's South Road, Chengdu, Sichuan, 610041, China
| | - Li Xiang
- Department of Microbiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No.17 People's South Road, Chengdu, Sichuan, 610041, China
| | - Jiangzhou You
- Department of Microbiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No.17 People's South Road, Chengdu, Sichuan, 610041, China
| | - Ranran Cao
- Department of Microbiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No.17 People's South Road, Chengdu, Sichuan, 610041, China
| | - Hongren Wang
- Department of Microbiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No.17 People's South Road, Chengdu, Sichuan, 610041, China
| | - Baoning Wang
- Department of Microbiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No.17 People's South Road, Chengdu, Sichuan, 610041, China.
| | - Mingyuan Li
- Department of Microbiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No.17 People's South Road, Chengdu, Sichuan, 610041, China; State Key Laboratory of Oral Diseases (Sichuan University), Chengdu, Sichuan, 610041, China.
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17
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Luo A, Jiang X, Ren H. Lamivudine therapy for chronic hepatitis B in children: a meta-analysis. Virol J 2019; 16:88. [PMID: 31272463 PMCID: PMC6610965 DOI: 10.1186/s12985-019-1193-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 06/24/2019] [Indexed: 02/08/2023] Open
Abstract
Background Currently, there is no consensus on the effects and safety of lamivudine therapy for chronic hepatitis B (CHB) in children. Method Both English and Chinese databases were searched comprehensively. An odds ratio (OR) and a standard mean difference (SMD) were used to assess the effects and safety of lamivudine therapy for CHB in children. Results Thirteen eligible studies were included in our analysis. The rates of Hepatitis B virus (HBV) response, biochemical response, hepatitis B e antigen (HBeAg) loss, HBeAg seroconversion, and hepatitis B surface antigen (HBsAg) loss were significantly higher in the lamivudine (LAM) therapy group than in the control group. The changes in children’s weight and height were similar between the two groups. Conclusions LAM therapy was efficacious for CHB in children. Additionally, it had no side effect on children’s height and weight. Electronic supplementary material The online version of this article (10.1186/s12985-019-1193-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Aoran Luo
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, 1 Yixueyuan Road, Chongqing, 400010, People's Republic of China
| | - Xiaoyan Jiang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, 1 Yixueyuan Road, Chongqing, 400010, People's Republic of China
| | - Hong Ren
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, 1 Yixueyuan Road, Chongqing, 400010, People's Republic of China.
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18
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Li G, Zhang Q, Yu Y, Qiu C, Zhang H, Zhang M, Song Z, Yang Y, Hong J, Lu J, Li N, Tang Q, Xu L, Wang X, Zhang W, Chen Z. Histological responses of peginterferon alpha add-on therapy in patients with chronic hepatitis B with advanced liver fibrosis after long-term nucleos(t)ide analog treatment. J Viral Hepat 2019; 26 Suppl 1:50-58. [PMID: 31380590 DOI: 10.1111/jvh.13152] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Accepted: 05/15/2019] [Indexed: 01/05/2023]
Abstract
Although long-term antiviral treatment with nucleos(t)ide analogs (NAs) can lead to histological improvement in patients with chronic hepatitis B (CHB), a substantial proportion of patients still fail to achieve regression of fibrosis. Here, we investigated whether peginterferon alpha (Peg-IFNα） add-on therapy had benefits on fibrosis regression in patients with sustained severe fibrosis even after long-term NA treatment. We conducted a retrospective analysis of data from 50 patients with CHB receiving 48 weeks of Peg-IFNα add-on therapy. All enrolled patients had advanced fibrosis or cirrhosis (S score ≥ 3) at baseline and underwent NA treatment for at least 1 year before Peg-IFNα addition. Paired liver biopsies before and after Peg-IFNα add-on treatment and laboratory tests at baseline, 24 weeks of treatment, 48 weeks of treatment and long-term follow-up were analysed. Of the 50 patients enrolled in this study, 34 patients (68.0%) had significant regression of fibrosis, and 42 (84.0%) showed significant remission of inflammation after Peg-IFNα add-on treatment. Compared with nonresponders, patients with significant histological improvement showed faster hepatitis B surface antigen (HBsAg) decline and tended to have higher cumulative hepatitis B e antigen (HBeAg) and HBsAg loss rates during long-term follow-up. Peg-IFNα add-on therapy led to significant regression of fibrosis and resolution of inflammation in patients with advanced fibrosis after long-term NA treatment.
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Affiliation(s)
- Guojun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Qiran Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Yiqi Yu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Chao Qiu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Biomedical Sciences and Key Laboratory of Medical Molecular Virology of Ministry of Education and Health, Fudan University, Shanghai, China
| | - Hanyue Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Miaoqu Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhangzhang Song
- Department of Hepatology, The Second Hospital of Yinzhou of Ningbo, Ningbo, China
| | - Yusheng Yang
- Department of Hepatology, The Second Hospital of Yinzhou of Ningbo, Ningbo, China
| | - Jiemin Hong
- Department of Infectious Diseases, Shenzhen University General Hospital, Guangdong Sheng, China
| | - Jian Lu
- Department of Infectious Diseases, Shenzhen University General Hospital, Guangdong Sheng, China
| | - Niuniu Li
- Department of Infectious Diseases, Shenzhen University General Hospital, Guangdong Sheng, China
| | - Quanzhen Tang
- Department of Infectious Diseases, Shenzhen University General Hospital, Guangdong Sheng, China
| | - Long Xu
- Department of Infectious Diseases, Shenzhen University General Hospital, Guangdong Sheng, China
| | - Xuanyi Wang
- Institutes of Biomedical Sciences and Key Laboratory of Medical Molecular Virology of Ministry of Education and Health, Fudan University, Shanghai, China
| | - Wenhong Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Biomedical Sciences and Key Laboratory of Medical Molecular Virology of Ministry of Education and Health, Fudan University, Shanghai, China
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
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19
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Zhang Q, Li G, Yu Y, Qiu C, Zheng J, Zhang H, Zhang M, Song Z, Yang Y, Du X, Hong J, Lu J, Li N, Tang Q, Xu L, Wang X, Huang Y, Zhang J, Chen Z, Zhang W. Histological response to combination therapy with nucleos(t)ide analogs and peginterferon alpha in treatment-naïve chronic hepatitis B patients. J Viral Hepat 2019; 26 Suppl 1:59-68. [PMID: 31380588 DOI: 10.1111/jvh.13153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Accepted: 05/15/2019] [Indexed: 12/09/2022]
Abstract
Although nucleos(t)ide analog (NA) monotherapy is effective in hepatitis B virus suppression and fibrosis regression, serological response rates are not satisfactory. Studies assessing the benefits of combination therapy with NAs and peginterferon alpha (PegIFNα) in patients with chronic hepatitis B (CHB) have produced conflicting results and mainly focused on serological outcomes. Histological changes in response to combination therapy have not been evaluated in real-world practice. This study aimed to evaluate the histological changes in response to NA-PegIFNα combination therapy in CHB patients and to comprehensively compare the efficacy of NA-PegIFNα combination therapy and NA monotherapy. We conducted a retrospective analysis of data from 40 CHB patients who underwent either NA-PegIFNα combination therapy or NA monotherapy. Changes in histology at 48 weeks after treatment initiation were evaluated. Serological characteristics were also analysed and compared between the NA-PegIFNα combination therapy and NA monotherapy groups and between histological responders and nonresponders. Compared to baseline biopsies, both fibrosis staging and necroinflammatory grading scores were significantly lower in the second biopsies examined post-treatment in both groups. Nearly all patients experienced a reduction in inflammation (87.5% in both groups), but there was a subgroup of patients who exhibited either no significant improvement or fibrosis progression (33.3% and 31.2% in the NA monotherapy and NA-PegIFNα combination therapy groups, respectively). Nearly, all patients achieved ALT normalization and sustained virological response (SVR) after 48 weeks of antiviral treatment. Approximately one-third of individuals (36.8% and 30% in the two groups, respectively) achieved HBeAg loss at 48 weeks after treatment initiation. Although there were no significant differences in overall rates of histological, biochemical, virological and serological responses between the two groups, an earlier virological response and a higher cumulative SVR rate over time were observed during long-term follow-up in patients treated with NA-PegIFNα combination therapy (P = 0.0129). Trends of more rapid HBeAg loss and a higher cumulative HBeAg loss rate throughout long-term follow-up were also observed but were not statistically significant. The ALT normalization rates at 24 and 48 weeks after treatment initiation were associated with the histological response. Significant regression of fibrosis and resolution of necroinflammation were induced with either NA-PegIFNα combination therapy or NA monotherapy. Significant biochemical, virological and serological responses were observed in both groups, and the response rates at 48 weeks were similar in the two groups. Over time during long-term follow-up, the virological and serological responses were faster and superior following the combination regimen.
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Affiliation(s)
- Qiran Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Guojun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Infectious Diseases, Shenzhen University General Hospital, Shenzhen, China
| | - Yiqi Yu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Chao Qiu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Biomedical Sciences and Key Laboratory of Medical Molecular Virology, Fudan University, Shanghai, China
| | - Jianming Zheng
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Hanyue Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Miaoqu Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhangzhang Song
- Department of Hepatology, The Second Hospital of Yinzhou of Ningbo, Ningbo, China
| | - Yusheng Yang
- Department of Hepatology, The Second Hospital of Yinzhou of Ningbo, Ningbo, China
| | - Xinfang Du
- Department of Hepatology, Beilun People's Hospital, Ningbo, China
| | - Jiemin Hong
- Department of Infectious Diseases, Shenzhen University General Hospital, Shenzhen, China
| | - Jian Lu
- Department of Infectious Diseases, Shenzhen University General Hospital, Shenzhen, China
| | - Niuniu Li
- Department of Infectious Diseases, Shenzhen University General Hospital, Shenzhen, China
| | - Quanzhen Tang
- Department of Infectious Diseases, Shenzhen University General Hospital, Shenzhen, China
| | - Long Xu
- Department of Infectious Diseases, Shenzhen University General Hospital, Shenzhen, China
| | - Xuanyi Wang
- Institutes of Biomedical Sciences and Key Laboratory of Medical Molecular Virology, Fudan University, Shanghai, China
| | - Yuxian Huang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Jiming Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.,Department of Hepatology, The Second Hospital of Yinzhou of Ningbo, Ningbo, China
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Wenhong Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Biomedical Sciences and Key Laboratory of Medical Molecular Virology, Fudan University, Shanghai, China
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20
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KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol 2019; 25:93-159. [PMID: 31185710 PMCID: PMC6589848 DOI: 10.3350/cmh.2019.1002] [Citation(s) in RCA: 161] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 03/25/2019] [Indexed: 02/06/2023] Open
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21
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van Campenhout MJH, Brouwer WP, Xie Q, Guo S, Chi H, Qi X, Tabak F, Streinu-Cercel A, Wang JY, Zhang NP, Idilman R, Reesink HW, Diculescu M, Simon K, Akdogan M, Mazur W, de Knegt RJ, Verhey E, Hansen BE, Janssen HLA. Long-term follow-up of patients treated with entecavir and peginterferon add-on therapy for HBeAg-positive chronic hepatitis B infection: ARES long-term follow-up. J Viral Hepat 2019; 26:109-117. [PMID: 30187612 DOI: 10.1111/jvh.12997] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 07/12/2018] [Accepted: 08/08/2018] [Indexed: 12/23/2022]
Abstract
Addition of peginterferon alpha (PEG-IFN add-on) to entecavir (ETV) treatment after a short lead-in phase results in more response than ETV monotherapy in HBeAg-positive chronic hepatitis B infection (CHB). This study is the first to assess long-term efficacy of this treatment strategy. Patients who received ETV ± 24 weeks of PEG-IFN add-on in a global trial (ARES study) and completed follow-up were eligible to participate in this observational LTFU study if they had at least one combined HBeAg and HBV DNA measurement beyond week 96 of the ARES study. The primary endpoint was combined response (HBeAg loss and HBV DNA <200 IU/mL) at LTFU. In total, 48 patients treated with PEG-IFN add-on and 48 patients treated with ETV monotherapy were included. The median follow-up duration was 226 (IQR 51) weeks, and 86/96 (90%) patients were initial non-responders. At LTFU, combined response was present in 13 (27%) vs 11 (23%) patients (P = 0.81), and 1 log10 HBsAg decline in 59% vs 28% (P = 0.02) for PEG-IFN add-on and ETV monotherapy, respectively. In 41 initial non-responders who continued ETV therapy, combined response at LTFU was present in 9 patients (PEG-IFN add-on: 5/22 [23%]; ETV monotherapy: 4/19 [21%]). Beyond week 96 of follow-up, rates of serological response became comparable between PEG-IFN add-on and ETV monotherapy. Although in this LTFU study initial non-responders were overrepresented in the add-on arm, PEG-IFN add-on possibly leads rather to accelerated HBeAg loss than to increased long-term HBeAg loss rates.
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Affiliation(s)
- Margo J H van Campenhout
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Willem Pieter Brouwer
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Qing Xie
- Infectious Diseases, Ruijin Hospital, Jiaotong University, Shanghai, China
| | - S Guo
- Infectious Diseases, Ruijin Hospital, Jiaotong University, Shanghai, China
| | - Heng Chi
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Xun Qi
- Gastroenterology and Hepatology, Shanghai Public Health Center, Fu Dan University, Shanghai, China
| | - Fehmi Tabak
- Cerrahpasa Medical Faculty, Istanbul, Turkey
| | - Adrian Streinu-Cercel
- Carol Davila University of Medicine and Pharmacy, National Institute for Infectious Diseases "Prof. Dr. Matei Balș", Bucharest, Romania
| | - Ji-Yao Wang
- Gastroenterology and Hepatology, Zhong Shan Hospital, Fu Dan University, Shanghai, China
| | - Ning-Ping Zhang
- Gastroenterology and Hepatology, Zhong Shan Hospital, Fu Dan University, Shanghai, China
| | | | - Hendrik W Reesink
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - Mircea Diculescu
- Department of Gastroenterology, Fundeni Clinical Institute, Bucharest, Romania
| | - Krzysztof Simon
- Division of Infectious Diseases and Hepatology, Wroclaw Medical University, Wroclaw, Poland
| | - Meral Akdogan
- Department of Gastroenterology, Yuksek Ihtisas Hospital, Ankara, Turkey.,Department of Infectious Diseases, Silesian Medical University, Katowice, Poland
| | - Włodzimierz Mazur
- Department of Infectious Diseases, Silesian Medical University, Katowice, Poland
| | - Rob J de Knegt
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Elke Verhey
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Bettina E Hansen
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.,Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada.,Toronto Center for Liver Disease, Toronto Western and General Hospital, University Health Network, Toronto, Canada
| | - Harry L A Janssen
- Toronto Center for Liver Disease, Toronto Western and General Hospital, University Health Network, Toronto, Canada
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22
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Jun DW, Ahn SB, Kim TY, Sohn JH, Kim SG, Lee SW, Kim BH, Kim DJ, Kim JK, Kim HS, Hwang SG, Choi WC, Tak WY, Lee HJ, Yoon KT, Yun BC, Lee SW, Baik SK, Park SH, Park JW, Park SJ, Lee JS. Efficacy of Pegylated Interferon Monotherapy versus Sequential Therapy of Entecavir and Pegylated Interferon in Hepatitis B e Antigen-Positive Hepatitis B Patients: A Randomized, Multicenter, Phase IIIb Open-Label Study (POTENT Study). Chin Med J (Engl) 2018; 131:1645-1651. [PMID: 29998882 PMCID: PMC6048918 DOI: 10.4103/0366-6999.235880] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Background: Until now, various types of combined therapy with nucleotide analogs and pegylated interferon (Peg-INF) in patients with hepatitis B patients have been tried. However, studies regarding the benefits of de novo combination, late-add on, and sequential treatment are very limited. The objective of the current study was to identify the efficacy of sequential treatment of Peg-INF after short-term antiviral treatment. Methods: Between June 2010 and June 2015, hepatitis B e antigen (HBeAg)-positive patients (n = 162) received Peg-IFN for 48 weeks (mono-treatment group, n = 81) and entecavir (ETV) for 12 weeks with a 48-week course of Peg-IFN starting at week 5 of ETV therapy (sequential treatment group, n = 81). The primary endpoint was HBeAg seroconversion at the end of follow-up period after the 24-week treatment. The primary endpoint was analyzed using Chi-square test, Fisher's exact test, and regression analysis. Results: HBeAg seroconversion rate (18.2% vs. 18.2%, t = 0.03, P = 1.000) and seroclearance rate (19.7% vs. 19.7%, t = 0.03, P = 1.000) were same in both mono-treatment and sequential treatment groups. The rate of alanine aminotransferase (ALT) normalization (45.5% vs. 54.5%, t = 1.12, P = 0.296) and serum hepatitis B virus (HBV)-DNA <2000 U/L (28.8% vs. 28.8%, t = 0.10, P = 1.000) was not different in sequential and mono-treatment groups at 24 weeks of Peg-INF. Viral response rate (HBeAg seroconversion and serum HBV-DNA <2000 U/L) was not different in the two groups (12.1% vs. 16.7%, t = 1.83, P = 0.457). Baseline HBV-DNA level (7 log10U/ml vs. 7.5 log10U/ml, t = 1.70, P = 0.019) and hepatitis B surface antigen titer (3.6 log10U/ml vs. 4.0 log10U/ml, t = 2.19, P = 0.020) were lower and predictors of responder in mono-treatment and sequential treatment groups, respectively. Conclusions: The current study shows no differences in HBeAg seroconversion rate, ALT normalization, and HBV-DNA levels between mono-therapy and sequential therapy regimens. Trial Registration: ClinicalTrials.gov, NCT01220596; https://clinicaltrials.gov/ct2/show/NCT01220596?term=NCT01220596&rank=1.
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Affiliation(s)
- Dae Won Jun
- Department of Internal Medicine, Hanyang University Seoul Hospital, Hanyang University, Seoul 04763, Korea
| | - Sang Bong Ahn
- Department of Internal Medicine, Nowon Eulji Hospital, Eulji University, Seoul 01830, Korea
| | - Tae Yeob Kim
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University, Guri 11923, Korea
| | - Joo Hyun Sohn
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University, Guri 11923, Korea
| | - Sang Gyune Kim
- Department of Internal Medicine, SoonChunHyang University Bucheon Hospital, SoonChunHyang University, Bucheon 14584, Korea
| | - Se Whan Lee
- Department of Internal Medicine, SoonChunHyang University Cheonan Hospital, SoonChunHyang University, Cheonan 31151, Korea
| | - Byung Ho Kim
- Department of Internal Medicine, Kyung Hee University Hospital, Kyung Hee University, Seoul 02453, Korea
| | - Dong Joon Kim
- Department of Internal Medicine, Chuncheon Sacred Heart Hospital, Hallym University, Chuncheon 24252, Korea
| | - Ja Kyung Kim
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University, Seoul 05355, Korea
| | - Hyoung Su Kim
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University, Seoul 06273, Korea
| | - Seong Gyu Hwang
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, Korea
| | - Won Choong Choi
- Department of Internal Medicine, Sanggye Paik Hospital, Inje University, Seoul 01757, Korea
| | - Won Young Tak
- Department of Internal Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Korea
| | - Heon Ju Lee
- Department of Internal Medicine, Yeungnam University Medical Center, Yeungnam University, Daegu 42415, Korea
| | - Ki Tae Yoon
- Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University, Yangsan 50612, Korea
| | - Byung Cheol Yun
- Department of Internal Medicine, Kosin University Gospel Hospital, Kosin University, Pusan 49267, Korea
| | - Sung Wook Lee
- Department of Internal Medicine, Dong A University Medical Center, Dong A University, Pusan 49201, Korea
| | - Soon Koo Baik
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University, Wonju 26426, Korea
| | - Seung Ha Park
- Department of Internal Medicine, Haeundae Paik Hospital, Inje University, Pusan 48108, Korea
| | - Ji Won Park
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University, Anyang 14068, Korea
| | - Sol Ji Park
- Department of Clinical Pharmacy, Graduate School of Clinical Pharmacy, Sungkyunkwan University, Suwon 16419, Korea
| | - Ji Sung Lee
- Clinical Research Center, Asan Medical Center, Seoul 05505, Korea
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23
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Chien RN, Kao JH, Peng CY, Chen CH, Liu CJ, Huang YH, Hu TH, Yang HI, Lu SN, Ni YH, Chuang WL, Lee CM, Wu JC, Chen PJ, Liaw YF. Taiwan consensus statement on the management of chronic hepatitis B. J Formos Med Assoc 2018; 118:7-38. [PMID: 30527436 DOI: 10.1016/j.jfma.2018.11.008] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Revised: 11/06/2018] [Accepted: 11/15/2018] [Indexed: 01/10/2023] Open
Abstract
The experts of Taiwan Association for the Study of Liver (TASL) have actively participated and led the guidelines on hepatitis B virus (HBV) management by Asian Pacific Association for the Study of Liver (APASL) which is the first international association for the study of liver to publish the statement on HBV management before. However, there are more and more new data on the natural history and treatment of HBV infection in the past decade. These include new application of an old biomarker (quantitative HBsAg), clinical significance of HBV genotype and naturally occurring mutations, the role of non-invasive examination in evaluating severity of hepatic fibrosis, clinical significance of outcome calculators, new drug or new combination strategies towards more effective therapy and organ transplantation including liver and non-liver transplantation. It is time to publish the guidelines on HBV management of Taiwan. Hence, TASL have conducted an expert meeting to review, to discuss and to debate the relevant literatures, followed by draft the manuscript of HBV management guidelines and recommendations. The guidelines include general management, indications for fibrosis assessment, time to start or stop drug therapy, choice of drug to initiate therapy, when and how to monitor the patients during and after stopping drug therapy. Recommendations on the therapy of patients in special circumstances, including women in childbearing age, patients with antiviral drug resistance, concurrent viral infection, hepatic decompensation, patient receiving immune suppression or chemotherapy and patients in the setting of liver transplantation and hepatocellular carcinoma, are also included.
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Affiliation(s)
- Rong-Nan Chien
- Liver Research Unit, Linkou Chang Gung Memorial Hospital and University College of Medicine, Taoyuan, Taiwan.
| | - Jia-Horng Kao
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Cheng-Yuan Peng
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chun-Jen Liu
- Graduate Institute of Clinical Medicine, Department of Internal Medicine and Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Hwa-I Yang
- Department of Genomic Research Center, Sinica Academia, Taipei, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan
| | - Won-Long Chuang
- Division of Hepatobiliary and Pancreas, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Chuan-Mo Lee
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jaw-Chin Wu
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Yun-Fan Liaw
- Liver Research Unit, Linkou Chang Gung Memorial Hospital and University College of Medicine, Taoyuan, Taiwan
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Hao Z, Biqing Z, Ling Y, Wenting Z. The Effectiveness of Antiviral Treatments for Patients with HBeAg-Positive Chronic Hepatitis B: A Bayesian Network Analysis. Can J Gastroenterol Hepatol 2018; 2018:3576265. [PMID: 30276197 PMCID: PMC6157142 DOI: 10.1155/2018/3576265] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Accepted: 08/30/2018] [Indexed: 12/12/2022] Open
Abstract
This network analysis is to determine the most effective treatment in HBeAg-positive patients. PubMed databases were searched for randomized controlled trials. Bayesian network meta-analysis was used to calculate the pairwise hazard ratios, 95% credible intervals, and ranking of surrogate outcomes. 9 studies were identified. The results show that NA add-on PEG IFN might be a better antiviral approach for HBeAg-positive patients in end point of treatment, with a comparable results of nucleoside/nucleotide analogs (NA), PEG IFN, PEG IFN add-on NA, PEG IFN combined NA, and PEG IFN combined placebo in alanine aminotransferase (ALT) normalization and HBV DNA undetectable. Cumulative probabilities of being the most efficacious treatment were NA add-on PEG IFN (30%) for HBeAg loss. The second efficacious (23%) is HBeAg seroconversion. This network analysis shows that NA add-on PEG IFN might be a better antiviral approach for HBeAg-positive patients in end point of treatment. But the long-term efficiency should be further determined.
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Affiliation(s)
- Zhang Hao
- Department of Infectious Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Yanjiang Road 151, Guangzhou 510120, China
| | - Zhu Biqing
- Guangzhou Kingmed Center for Clinical Laboratory Co., Ltd., Guangzhou International Biological Island, Spiral Three Road 10, Guangzhou 510330, China
| | - Yang Ling
- Department of Infectious Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Yanjiang Road 151, Guangzhou 510120, China
| | - Zeng Wenting
- Department of Infectious Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Yanjiang Road 151, Guangzhou 510120, China
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Su TH, Liu CJ. Combination Therapy for Chronic Hepatitis B: Current Updates and Perspectives. Gut Liver 2018; 11:590-603. [PMID: 28494575 PMCID: PMC5593320 DOI: 10.5009/gnl16215] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 06/30/2016] [Accepted: 07/02/2016] [Indexed: 12/25/2022] Open
Abstract
Nucleos(t)ide analogues (NUCs) and interferon have been used for several decades to treat chronic hepatitis B; however, the therapeutic response remains unsatisfactory. Although NUC therapy exhibits potent on-treatment viral suppression, frequent off-therapy virological relapses suggest an indefinite treatment course. Interferon modulates the innate and adaptive antiviral immune responses and thus increases the chance of viral eradication. Interferon therapy has the advantage of a finite duration, absence of drug resistance, and durable posttreatment responses. Therefore, the combination of NUCs and interferon can theoretically facilitate a synergistic therapeutic effect. This paper summarizes the current strategies of various combination therapies into three categories: the simultaneous “dual” strategy, sequential combination “add-on” strategy, and “switch” strategy. Generally, dual therapy exhibits greater on-treatment and off-therapy viral suppression and lower drug resistance compared with NUC monotherapy. Compared with interferon monotherapy, dual therapy has greater on-treatment viral suppression but shows no difference in off-therapy sustained virological responses. Specific add-on or switch strategies provide promising on-treatment efficacy in select patients. Pretreatment or on-treatment quantitative hepatitis B surface antigen and e antigen are predictive for the treatment efficacy of combination therapy. The optimal schedule of combination regimens and individualized therapy remain to be comprehensively evaluated.
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Affiliation(s)
- Tung-Hung Su
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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Noël N, Jacquelin B, Huot N, Goujard C, Lambotte O, Müller-Trutwin M. Interferon-associated therapies toward HIV control: The back and forth. Cytokine Growth Factor Rev 2018; 40:99-112. [PMID: 29555233 DOI: 10.1016/j.cytogfr.2018.03.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 03/08/2018] [Indexed: 02/07/2023]
Abstract
Human immunodeficiency virus (HIV) induces a persistent and incurable infection. However, the combined antiretroviral treatment (cART) has markedly changed the evolution of the infection and transformed a deadly disease into a manageable chronic infection. Withdrawal of cART generally leads though to resumption of the viral replication. The eradication of the virus from its cellular and anatomical reservoirs remains a goal-to-achieve for a cure. In this context, developing novel therapies contributing to this aim are an important field of research. Type I IFN has antiviral activity, which, before the presence of efficient anti-HIV drugs, has led to the testing of IFN-based therapeutic strategies during the early years of the pandemic. A historical overview of the results and its limitations that were put into light are reviewed here. In addition, several lessons could be drawn. For instance, the efficacy of the IFN-I depends on the timing of its administration and the context. Thus, the persistence of an endogenous IFN-signature, such as that generally observed in viremic patients, seems to be associated with a lower efficacy of IFN. Based on the lessons from previous trials, and in the context of cART and research for a cure, type I Interferon has regained interest and novel therapeutic approaches are currently tested in combination with cART, some with disappointing, other with encouraging results with regard to a reduction in the size of the HIV reservoir and/or delays in viral rebound after cessation of cART. Additional strategies are currently developed in addition to improve the antiviral function of the IFN-I, by using for instance other IFN subtypes than IFN-Iα2. In parallel, the development of innovative strategies aimed at counteracting the excessive activation of the IFN-pathways have been continued and their results are reviewed here as well. Altogether, the use of IFN-I in anti-HIV therapies has gone through distinct phases and many lessons could be drawn. Novel combinations are currently be tested that might provide interesting results.
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Affiliation(s)
- Nicolas Noël
- Institut Pasteur, Unité HIV, Inflammation & Persistence, Paris, France; Assistance Publique - Hopitaux de Paris, Service de Médecine Interne et Immunologie Clinique, Hopitaux Universitaires Paris Sud, Le Kremlin-Bicêtre, France; INSERM/CEA U1184, Immunologie des Maladies Virales et Autoimmunes, Le Kremlin Bicêtre, France; Faculté de Médecine Paris Sud, Le Kremlin-Bicêtre, France.
| | | | - Nicolas Huot
- Institut Pasteur, Unité HIV, Inflammation & Persistence, Paris, France
| | - Cécile Goujard
- Assistance Publique - Hopitaux de Paris, Service de Médecine Interne et Immunologie Clinique, Hopitaux Universitaires Paris Sud, Le Kremlin-Bicêtre, France; Faculté de Médecine Paris Sud, Le Kremlin-Bicêtre, France; CESP, INSERM U1018, Le Kremlin Bicêtre, France
| | - Olivier Lambotte
- Assistance Publique - Hopitaux de Paris, Service de Médecine Interne et Immunologie Clinique, Hopitaux Universitaires Paris Sud, Le Kremlin-Bicêtre, France; INSERM/CEA U1184, Immunologie des Maladies Virales et Autoimmunes, Le Kremlin Bicêtre, France; Faculté de Médecine Paris Sud, Le Kremlin-Bicêtre, France
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Straus SE. Unanticipated Risk in Clinical Research ∗ ∗The editors have included Dr. Stephen Straus'original unedited contribution, penned for the book's 2002 edition and published with minor modification in the second edition in 2007, to honor his memory. This is a classic and compelling chapter with a story that remains relevant today. References to regulation and guidelines may not be current. The editors have added current references as of the time of publication to the end of the chapter. PRINCIPLES AND PRACTICE OF CLINICAL RESEARCH 2018:141-159. [DOI: 10.1016/b978-0-12-849905-4.00011-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Wi CI, Kim WR, Gross JB, Stadheim LM, Poterucha JJ. Potential Efficacy of Pegylated Interferon-α and a Nucleos(t)ide Analogue as Combination Therapy for HBeAg-Positive Chronic Hepatitis B. Gut Liver 2017; 10:611-6. [PMID: 26190580 PMCID: PMC4933423 DOI: 10.5009/gnl14256] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Revised: 09/27/2014] [Accepted: 10/09/2014] [Indexed: 12/26/2022] Open
Abstract
Background/Aims Despite the potent suppression of the hepatitis B virus with modern antiviral agents, only a minority of HBeAg-positive patients achieve hepatitis B e antigen seroconversion. We aimed to explore the potential efficacy of combination therapy consisting of pegylated interferon (p-IFN) and an oral antiviral agent in patients with HBeAg-positive chronic hepatitis B. Methods The treatment protocol consisted of p-IFN-α-2a at 180 μg/wk for 48 weeks, with either entecavir or tenofovir added 8 weeks after the initiation of p-IFN and continued for at least 6 months after HBe seroconversion was achieved. Results To date, 10 patients have been treated under the protocol (eight adults, mean age 36±8 years; two adolescents, aged 12 and 16 years). All eight adult patients experienced loss of HBeAg at a mean of 72.3±66.9 weeks, including six patients who also developed anti-HBe and one patient who had HBs seroconversion. Although both adolescents remain on therapy, one adolescent had HBs seroconversion without HBe seroconversion. A total of nine of our 10 patients experienced a favorable serological transition. Conclusions The combination of p-IFN and a modern oral antiviral agent may be more effective than monotherapy with either class of agent in the treatment of HBeAg-positive chronic hepatitis B patients.
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Affiliation(s)
- Chung-Il Wi
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - W Ray Kim
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA.,Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - John B Gross
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Linda M Stadheim
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - John J Poterucha
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
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Woo ASJ, Kwok R, Ahmed T. Alpha-interferon treatment in hepatitis B. ANNALS OF TRANSLATIONAL MEDICINE 2017; 5:159. [PMID: 28480195 PMCID: PMC5401664 DOI: 10.21037/atm.2017.03.69] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2016] [Accepted: 02/28/2017] [Indexed: 12/15/2022]
Abstract
Pegylated interferon-α (PEG-IFN-α) is a first line option in the treatment of chronic hepatitis B. Compared with nucleos(t)ide analogues (NAs), therapy with PEG-IFN-α has the advantages of finite treatment duration and higher rates of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) seroconversion, but the disadvantage of greater adverse effects. Choosing PEG-IFN-α requires careful evaluation of the likelihood of achieving a sustained off-treatment response. Sustained off-treatment response with PEG-IFN-α can be predicted by baseline factors in HBeAg positive disease. These include genotype A or B, low viral load, high alanine aminotransferase (ALT), older age and female gender. On the other hand, no pre-treatment factors have been identified that can reliably predict response in HBeAg negative disease. Using on-treatment quantitative HBsAg levels, failure of a long term response can be identified with high negative predictive value (NPV). However, no combination of on treatment parameters have been identified so far that can precisely forecast successful treatment. Up until recently, there was little evidence supporting the use of combining PEG-IFN with NAs. The addition of PEG-IFN in patients who already have viral suppression with NAs therapy appears superior to continuing NAs alone in achieving a sustained response. Also, tenofovir disoproxil fumarate (TDF) in combination with PEG-IFN has been reported to enable significantly higher HBsAg loss than with either monotherapy alone. This occurred in both HBeAg positive and negative patients across all genotypes. In spite of recent developments, rates of HBsAg loss are still only in the order of 10% and so cure remains elusive. Further research is required to identify the optimal combination or sequential therapy regimen, and the subgroups with the highest rates of response so that they can be targeted.
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Affiliation(s)
- Aaron Shu Jeng Woo
- Division of Gastroenterology and Hepatology, Alexandra Health Khoo Teck Puat Hospital, Singapore
| | - Raymond Kwok
- Division of Gastroenterology and Hepatology, Alexandra Health Khoo Teck Puat Hospital, Singapore
| | - Taufique Ahmed
- Division of Gastroenterology and Hepatology, Alexandra Health Khoo Teck Puat Hospital, Singapore
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Cornberg M, Wong VWS, Locarnini S, Brunetto M, Janssen HLA, Chan HLY. The role of quantitative hepatitis B surface antigen revisited. J Hepatol 2017; 66:398-411. [PMID: 27575311 DOI: 10.1016/j.jhep.2016.08.009] [Citation(s) in RCA: 253] [Impact Index Per Article: 31.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 08/09/2016] [Accepted: 08/16/2016] [Indexed: 02/06/2023]
Abstract
In the past 10years, there has been a lot of enthusiasm surrounding the use of serum hepatitis B surface antigen (HBsAg) quantification to predict disease activity and monitor treatment response in chronic hepatitis B. The measurement of HBsAg levels have been standardized in IU/ml, and nowadays it is almost a mandatory measurement due to the development of new antiviral treatments aiming at HBsAg seroclearance, i.e., functional cure of hepatitis B. Recently, there has been an improved understanding of the molecular virology of HBsAg, and particularly the relative roles of covalently closed circular DNA and integrated hepatitis B virus (HBV) DNA. This has shed new light on the interpretation of HBsAg levels in different phases of chronic hepatitis B. HBsAg level can assist the differentiation of immune tolerance and immune clearance in hepatitis B e antigen (HBeAg)-positive patients, and it can predict inactive disease and spontaneous HBsAg seroclearance in HBeAg-negative patients. The determination of HBsAg level is pivotal to individualize pegylated interferon (PegIFN) treatment; it is the key investigation to decide early termination of PegIFN among non-responders. Among patients treated by nucleos(t)ide analogues, responders tend to have dramatic reduction of HBsAg to low levels, which may be followed by HBsAg seroclearance. With newer data on combination treatment of PegIFN and nucleos(t)ide analogues as well as emerging new antiviral agents, HBsAg quantification is expected to become increasingly important to monitor and guide antiviral therapy for chronic hepatitis B.
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Affiliation(s)
- Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Stephen Locarnini
- Victorian Infectious Diseases Reference Laboratory (VIDRL), Doherty Institute for Infection and Immunity, Melbourne, Australia
| | - Maurizia Brunetto
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Center of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Italy
| | - Harry L A Janssen
- Toronto Center for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada
| | - Henry Lik-Yuen Chan
- Department of Medicine and Therapeutics, Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.
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Al Ashgar H, Peedikayil MC, Al Quaiz M, Al Sohaibani F, Al Fadda A, Khan MQ, Thoralsson E, Al Thawadi S, Al Jedai A, Al Kahtani K. HBsAg clearance in chronic hepatitis B patients with add-on pegylated interferon alfa-2a to ongoing tenofovir treatment: A randomized controlled study. Saudi J Gastroenterol 2017; 23:190-198. [PMID: 28611343 PMCID: PMC5470379 DOI: 10.4103/sjg.sjg_541_16] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND/AIMS The ideal end point of treatment for chronic hepatitis B virus (HBV) infection is sustained off-therapy hepatitis B surface antigen (HBsAg) loss with or even without seroconversion to anti-HBs. We investigated the role of adding PEGylated interferon (PEG IFN) to ongoing tenofovir treatment in chronic HBV patients for achieving HBsAg clearance. PATIENTS AND METHODS In this randomized controlled trial, chronic HBV patients who have been receiving tenofovir for >6 months with HBV viral load <2000 IU/ml were randomized into two groups. One group (add-on therapy) was given subcutaneous PEG IFN 180 mcg weekly for 12 months in addition to tenofovir. Patients in the other group received only tenofovir 300 mg orally on a daily basis. Patients in both groups were followed up for a total of two years, and patients in both groups were given tenofovir 300 mg daily indefinitely until they developed HBsAg clearance. RESULTS Twenty-three patients were allocated to the PEG IFN and tenofovir (add-on therapy) group, and another 25 patients were recruited to the tenofovir monotherapy group. Before randomization, patients had received tenofovir for 1135 mean days (range203 to 1542 days). One patient (4.3%) in add-on therapy lost HBsAg and seroconverted. Within two years, mean HBsAg decreased significantly with add-on therapy (from 4753 IU/ml to 2402; P= 0.03); and it decreased from 5957 IU/ml to 4198; P= 0.09 in tenofovir monotherapy group. More patients in the add-on group developed serious side effects, with treatment discontinuation, and dose reductions (P = 0.3). CONCLUSION PEG IFN and tenofovir add-on therapy was successful in achieving HBsAg clearance and seroconversion in 4.3% of the patients. Add-on therapy patients had a significant decrease in HBsAg levels in two years; and no significant decrease in HBsAg levels with the tenofovir monotherapy. With no significant HBsAg clearance, the utility of this combination regimen is questionable.
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Affiliation(s)
- Hamad Al Ashgar
- Department of Medicine, Section of Gastroenterology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Musthafa C. Peedikayil
- Department of Medicine, Section of Gastroenterology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia,Address for correspondence: Dr. Musthafa C. Peedikayil, Department of Medicine, MBC 46, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. E-mail:
| | - Mohammed Al Quaiz
- Department of Medicine, Section of Gastroenterology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Fahad Al Sohaibani
- Department of Medicine, Section of Gastroenterology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Abdulrahman Al Fadda
- Department of Medicine, Section of Gastroenterology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Mohammed Q. Khan
- Department of Medicine, Section of Gastroenterology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Einar Thoralsson
- Department of Medicine, Section of Gastroenterology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Sahar Al Thawadi
- Department of Microbiology Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Ahmed Al Jedai
- Department of Pharmaceutical Care Services, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Khalid Al Kahtani
- Department of Medicine, Section of Gastroenterology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
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Drugs to Treat Viral Hepatitis. Infect Dis (Lond) 2017. [DOI: 10.1016/b978-0-7020-6285-8.00155-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
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Abstract
Chronic hepatitis B virus (HBV) infection has a significant public health impact. There are currently 7 approved therapies for chronic HBV, including standard and pegylated interferon (IFN)-α, and 5 nucleos(t)ide analogs (NUCs). IFN offers benefits over NUCs, including a finite duration of therapy and a higher rate of clearance of hepatitis Be antigen and surface antigen. These benefits need to be weighed against the potential adverse effects of IFN therapy. Some patients should not receive IFN because of advanced liver disease or comorbidities. This article reviews the mechanisms of action, efficacy, and clinical use of IFN therapy for HBV infection.
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Affiliation(s)
- Monica A Konerman
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA
| | - Anna S Lok
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
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Charatcharoenwitthaya P, Sukeepaisarnjaroen W, Piratvisuth T, Thongsawat S, Sanpajit T, Chonprasertsuk S, Jeamsripong W, Sripariwuth E, Komolmit P, Patcharatrakul T, Boonsirichan R, Bunchorntavakul C, Tuntipanichteerakul S, Tanwandee T. Treatment outcomes and validation of the stopping rule for response to peginterferon in chronic hepatitis B: A Thai nationwide cohort study. J Gastroenterol Hepatol 2016; 31:1874-1881. [PMID: 26997582 DOI: 10.1111/jgh.13378] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Revised: 02/26/2016] [Accepted: 03/13/2016] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS Peginterferon has demonstrated effectiveness in clinical trials in patients with chronic hepatitis B (CHB). However, its efficacy in real-life settings remains unclear. We investigated the efficacy of peginterferon for CHB and validated the performance of previously identified response predictors in clinical practice. METHODS We analyzed prospectively collected data from a Thai nationwide cohort of CHB patients treated with peginterferon alfa-2a (180 µg/week, 48 weeks). RESULTS Among a total of 233 patients, mostly with genotype B or C, sustained response was observed in 23% of 135 hepatitis B e antigen (HBeAg)-positive patients (HBeAg seroconversion with hepatitis B virus [HBV] DNA < 2000 IU/mL) and 42% of 98 HBeAg-negative patients (HBV DNA < 2000 IU/mL with aminotransferase normalization) at 24 weeks after treatment. Age, sex, presence of cirrhosis, genotype, and pretreatment levels of aminotransferase, HBV DNA, and hepatitis B surface antigen (HBsAg) were not identified as significant predictors of sustained response. In HBeAg-positive patients, HBsAg > 20 000 IU/mL at week 12 provided a good stopping rule, with a negative predictive value of 96%. In HBeAg-negative patients, the performance of 12-week stopping rules of no decline in HBsAg with a < 2log10 decline in HBV DNA and a < 10% log10 decline in HBsAg showed modest negative predictive values of 80% and 66%, respectively, for achieving sustained response. CONCLUSION Outcomes in CHB patients treated with peginterferon in a clinical setting are similar to those demonstrated in clinical trials. Application of the early stopping rule based on HBsAg quantification may allow individualization of therapy, particularly in HBeAg-positive patients.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Piyawat Komolmit
- Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | | | | | | | | | - Tawesak Tanwandee
- Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
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Brouwer WP, Sonneveld MJ, Xie Q, Guo S, Zhang N, Zeuzem S, Tabak F, Zhang Q, Simon K, Akarca US, Streinu-Cercel A, Hansen BE, Janssen HLA. Peginterferon add-on results in more HBsAg decline compared to monotherapy in HBeAg-positive chronic hepatitis B patients. J Viral Hepat 2016; 23:419-26. [PMID: 26403919 DOI: 10.1111/jvh.12468] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 08/25/2015] [Indexed: 01/04/2023]
Abstract
It is unknown whether peginterferon (PEG-IFN) add-on to entecavir (ETV) leads to more HBsAg decline compared to PEG-IFN monotherapy or combination therapy, and whether ETV therapy may prevent HBsAg increase after PEG-IFN cessation. We performed a post hoc analysis of 396 HBeAg-positive patients treated for 72 weeks with ETV + 24 weeks PEG-IFN add-on from week 24 to 48 (add-on, n = 85), 72 weeks with ETV monotherapy (n = 90), 52 weeks with PEG-IFN monotherapy (n = 111) and 52 weeks PEG-IFN + lamivudine (combination, n = 110) within 2 randomized trials. HBsAg decline was assessed at the end of PEG-IFN (EOP) and 6 months after PEG-IFN (EOF) discontinuation. Differences in baseline characteristics were accounted for using inversed probability of treatment weights. At EOP, a HBsAg reduction of ≥1log10 IU/mL was more frequently achieved for patients in the add-on or combination therapy arms (both 36%), compared to PEG-IFN mono (20%) or ETV (8%) (add-on vs PEG-IFN mono P = 0.050). At EOF, the HBsAg reduction ≥1log10 IU/mL was only sustained in patients treated with ETV consolidation (add-on vs combination and PEG-IFN mono: 40% vs 23% and 18%, P = 0.029 and P = 0.003, respectively). For add-on, combination, PEG-IFN mono and ETV, the mean HBsAg-level change at EOF was -0.84, -0.81, -0.68 and -0.33 log10 IU/mL, respectively (P > 0.05 for PEG-IFN arms). HBeAg loss at EOF was 36%, 31%, 33% and 20%, respectively (P > 0.05). PEG-IFN add-on for 24 weeks results in more on-treatment HBsAg decline than does 52 weeks of PEG-IFN monotherapy. ETV therapy may maintain the HBsAg reduction achieved with PEG-IFN.
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Affiliation(s)
- W P Brouwer
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - M J Sonneveld
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Q Xie
- Infectious Diseases, Ruijin Hospital, Jiaotong University, Shanghai, China
| | - S Guo
- Infectious Diseases, Ruijin Hospital, Jiaotong University, Shanghai, China
| | - N Zhang
- Gastroenterology and Hepatology, Zhong Shan Hospital, Fu Dan University, Shanghai, China
| | - S Zeuzem
- Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany
| | - F Tabak
- Cerrahpasa Medical Faculty, Istanbul, Turkey
| | - Q Zhang
- Gastroenterology and Hepatology, Shanghai Public Health Center, Fu Dan University, Shanghai, China
| | - K Simon
- Division of Infectious Diseases and Hepatology, Wroclaw Medical University, Wroclaw, Poland
| | - U S Akarca
- Ege Üniversitesi Tip Fakultesi, Bornova, Turkey
| | - A Streinu-Cercel
- Department of Gastroenterology, Fundeni Cinical Institute, Bucharest, Romania
| | - B E Hansen
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.,Department of Public Health, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - H L A Janssen
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.,Toronto Center for Liver Disease, Toronto Western and General Hospital, University Health Network, Toronto, ON, Canada
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Fan R, Sun J, Yuan Q, Xie Q, Bai X, Ning Q, Cheng J, Yu Y, Niu J, Shi G, Wang H, Tan D, Wan M, Chen S, Xu M, Chen X, Tang H, Sheng J, Lu F, Jia J, Zhuang H, Xia N, Hou J. Baseline quantitative hepatitis B core antibody titre alone strongly predicts HBeAg seroconversion across chronic hepatitis B patients treated with peginterferon or nucleos(t)ide analogues. Gut 2016; 65:313-20. [PMID: 25586058 PMCID: PMC4752655 DOI: 10.1136/gutjnl-2014-308546] [Citation(s) in RCA: 100] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Revised: 12/05/2014] [Accepted: 12/23/2014] [Indexed: 02/06/2023]
Abstract
OBJECTIVE The investigation regarding the clinical significance of quantitative hepatitis B core antibody (anti-HBc) during chronic hepatitis B (CHB) treatment is limited. The aim of this study was to determine the performance of anti-HBc as a predictor for hepatitis B e antigen (HBeAg) seroconversion in HBeAg-positive CHB patients treated with peginterferon (Peg-IFN) or nucleos(t)ide analogues (NUCs), respectively. DESIGN This was a retrospective cohort study consisting of 231 and 560 patients enrolled in two phase IV, multicentre, randomised, controlled trials treated with Peg-IFN or NUC-based therapy for up to 2 years, respectively. Quantitative anti-HBc evaluation was conducted for all the available samples in the two trials by using a newly developed double-sandwich anti-HBc immunoassay. RESULTS At the end of trials, 99 (42.9%) and 137 (24.5%) patients achieved HBeAg seroconversion in the Peg-IFN and NUC cohorts, respectively. We defined 4.4 log10 IU/mL, with a maximum sum of sensitivity and specificity, as the optimal cut-off value of baseline anti-HBc level to predict HBeAg seroconversion for both Peg-IFN and NUC. Patients with baseline anti-HBc ≥4.4 log10 IU/mL and baseline HBV DNA <9 log10 copies/mL had 65.8% (50/76) and 37.1% (52/140) rates of HBeAg seroconversion in the Peg-IFN and NUC cohorts, respectively. In pooled analysis, other than treatment strategy, the baseline anti-HBc level was the best independent predictor for HBeAg seroconversion (OR 2.178; 95% CI 1.577 to 3.009; p<0.001). CONCLUSIONS Baseline anti-HBc titre is a useful predictor of Peg-IFN and NUC therapy efficacy in HBeAg-positive CHB patients, which could be used for optimising the antiviral therapy of CHB.
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Affiliation(s)
- Rong Fan
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jian Sun
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Quan Yuan
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Jiaotong University School of Medicine, Shanghai, China
| | - Xuefan Bai
- Department of Infectious Diseases, Tangdu Hospital, Xi'an, China
| | - Qin Ning
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Cheng
- Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yanyan Yu
- Department of Infectious Diseases, First Hospital of Peking University, Beijing, China
| | - Junqi Niu
- Department of Hepatology, First Hospital, Jilin University, Changchun, China
| | - Guangfeng Shi
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Hao Wang
- Hepatology Unit, Peking University People's Hospital, Beijing, China
| | - Deming Tan
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, China
| | - Mobin Wan
- Department of Infectious Diseases, Changhai Hospital, Shanghai, China
| | - Shijun Chen
- Ji'nan Infectious Diseases Hospital, Ji'nan, China
| | - Min Xu
- 8th People's Hospital, Guangzhou, China
| | - Xinyue Chen
- Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Hong Tang
- Department of Infectious Diseases, West China Hospital, Chengdu, China
| | - Jifang Sheng
- Department of Infectious Diseases, Zhejiang University 1st Affiliated Hospital, Hangzhou, China
| | - Fengmin Lu
- Department of Microbiology, Health science Center, Peking University, Beijing, China
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Hui Zhuang
- Department of Microbiology, Health science Center, Peking University, Beijing, China
| | - Ningshao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China
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Brahmania M, Feld J, Arif A, Janssen HLA. New therapeutic agents for chronic hepatitis B. THE LANCET. INFECTIOUS DISEASES 2016; 16:e10-21. [PMID: 26795693 DOI: 10.1016/s1473-3099(15)00436-3] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Revised: 10/13/2015] [Accepted: 11/03/2015] [Indexed: 12/11/2022]
Abstract
The treatment goal for chronic hepatitis B is true eradication of the hepatitis B virus, but this is rarely achieved with first-line treatment regimens because of an inability to disrupt covalently closed circular DNA and an inadequate host immune response. Therefore, new antiviral agents are needed to target various stages of the hepatitis B virus lifecycle and modulation of the immune system. This Review provides a summary of available regimens with their strengths and limitations, and highlights future therapeutic strategies to target the virus and host immune response. These new agents can hopefully lead to a finite duration of treatment, and provide a functional and durable cure for chronic hepatitis B infection.
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Affiliation(s)
- Mayur Brahmania
- Toronto Centre for Liver Diseases, Toronto Western Hospital, University Health Network, Toronto, ON, Canada
| | - Jordan Feld
- Toronto Centre for Liver Diseases, Toronto Western Hospital, University Health Network, Toronto, ON, Canada
| | - Ambreen Arif
- Toronto Centre for Liver Diseases, Toronto Western Hospital, University Health Network, Toronto, ON, Canada
| | - Harry L A Janssen
- Toronto Centre for Liver Diseases, Toronto Western Hospital, University Health Network, Toronto, ON, Canada; Department of Gastroenterology and Hepatology, Erasmus Medical Center University Hospital, Rotterdam, Netherlands.
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Wong GLH, Chan HLY, Chan HY, Tse CH, Chim AML, Lo AOS, Wong VWS. Serum interferon-inducible protein 10 levels predict hepatitis B s antigen seroclearance in patients with chronic hepatitis B. Aliment Pharmacol Ther 2016; 43:145-53. [PMID: 26526395 DOI: 10.1111/apt.13447] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2015] [Revised: 09/08/2015] [Accepted: 10/06/2015] [Indexed: 12/15/2022]
Abstract
BACKGROUND Hepatitis B s antigen (HBsAg) seroclearance is regarded as the optimal virological end-point. AIM To investigate the dynamic changes in serum cytokine levels around the time of HBsAg seroclearance. METHODS This was a case-control study. Consecutive patients with chronic hepatitis B (CHB) who lost HBsAg were matched with those remained positive for HBsAg with same age, gender, HBeAg status and presence of cirrhosis in 1:2 ratio. Relevant serum cytokines [interleukin (IL)-2, IL-3, IL-4, IL-7, IL-9, IL-10, IL-12, IL-15, IL-21 interferon-γ, tumour necrosis factor-α (TNF-α), granulocyte macrophage colony-stimulating factor (GM-CSF) and interferon-inducible protein 10 (IP-10)] were assayed at the time (Year 0) and 3 years before (Year -3) HBsAg seroclearance. RESULTS Seventy-one and 142 CHB patients who did and did not achieve HBsAg seroclearance were included. Mean age was 48 ± 11 years; 76% were male, 20% had positive HBeAg, 99 (46%) patients received anti-viral therapy, and mean baseline HBV DNA was 3.78 ± 2.28 log IU/mL vs. 4.36 ± 2.13 log IU/mL respectively (P = 0.05). In those who achieved HBsAg seroclearance, serum IL-15 and GM-CSF levels decreased significantly from Year -3 to Year 0 (P = 0.017 and 0.05 respectively). When compared to controls, only serum IP-10 level was significantly lower at Year 0 than at Year -3 in patients with HBsAg seroclearance. Lower serum IP-10 level at Year 0 was the only factor associated with HBsAg seroclearance. There was no correlation between serum IP-10 and HBsAg levels around the time of HBsAg seroclearance. CONCLUSION Lower serum IP-10 level at Year 0 was the only factor associated with HBsAg seroclearance.
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Affiliation(s)
- G L-H Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.,State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - H L-Y Chan
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.,State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - H-Y Chan
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.,State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - C-H Tse
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.,State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - A M-L Chim
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
| | - A O-S Lo
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
| | - V W-S Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.,State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
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Liang TJ, Block TM, McMahon BJ, Ghany MG, Urban S, Guo JT, Locarnini S, Zoulim F, Chang KM, Lok AS. Present and future therapies of hepatitis B: From discovery to cure. Hepatology 2015; 62:1893-908. [PMID: 26239691 PMCID: PMC4681668 DOI: 10.1002/hep.28025] [Citation(s) in RCA: 246] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2015] [Accepted: 07/31/2015] [Indexed: 12/11/2022]
Abstract
UNLABELLED Hepatitis B virus (HBV) is a significant global pathogen, infecting more than 240 million people worldwide. While treatment for HBV has improved, HBV patients often require lifelong therapies and cure is still a challenging goal. Recent advances in technologies and pharmaceutical sciences have heralded a new horizon of innovative therapeutic approaches that are bringing us closer to the possibility of a functional cure of chronic HBV infection. In this article, we review the current state of science in HBV therapy and highlight new and exciting therapeutic strategies spurred by recent scientific advances. Some of these therapies have already entered into clinical phase, and we will likely see more of them moving along the development pipeline. CONCLUSION With growing interest in developing and efforts to develop more effective therapies for HBV, the challenging goal of a cure may be well within reach in the near future.
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Affiliation(s)
- T. Jake Liang
- Liver Diseases Branch, NIDDK, NIH, Bethesda, MD. USA
| | | | - Brian J. McMahon
- National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Anchorage, AK. USA
| | - Marc G. Ghany
- Liver Diseases Branch, NIDDK, NIH, Bethesda, MD. USA
| | - Stephan Urban
- Dept of Infectious Diseases, Molecular Virology and German Center for Infection Diseases (DZIF), Univ Hospital Heidelberg, Heidelberg, Germany
| | - Ju-Tao Guo
- Baruch S. Blumberg Institute, Doylestown, PA. USA
| | | | - Fabien Zoulim
- Victorian Infectious Diseases Reference Laboratory, Doherty Institute, Melbourne, VIC, Australia
| | - Kyong-Mi Chang
- Dept of Medicine, Philadelphia VAMC & University of Pennsylvania, Philadelphia, PA. USA
| | - Anna S. Lok
- Div of Gastroenterology and Hepatology, Univ of Michigan, Ann Arbor, MI. USA
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Martin P, Lau DTY, Nguyen MH, Janssen HLA, Dieterich DT, Peters MG, Jacobson IM. A Treatment Algorithm for the Management of Chronic Hepatitis B Virus Infection in the United States: 2015 Update. Clin Gastroenterol Hepatol 2015; 13:2071-87.e16. [PMID: 26188135 DOI: 10.1016/j.cgh.2015.07.007] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 07/01/2015] [Accepted: 07/09/2015] [Indexed: 02/07/2023]
Abstract
Chronic hepatitis B (CHB) continues to be an important public health problem worldwide, including in the United States. An algorithm for managing CHB was developed by a panel of United States hepatologists in 2004 and subsequently updated in 2006 and 2008. Since 2008, additional data on long-term safety and efficacy of licensed therapies have become available and have better defined therapeutic options for CHB. The evidence indicates that potent antiviral therapy can lead to regression of extensive fibrosis or even cirrhosis, thus potentially altering the natural history of CHB. In addition, appropriate choice of antiviral agent can minimize the risk of resistance. This updated algorithm for managing CHB is based primarily on evidence from the scientific literature. Where data were lacking, the panel relied on clinical experience and consensus expert opinion. The primary aim of antiviral therapy for CHB is durable suppression of serum hepatitis B virus (HBV) DNA to low or undetectable levels. CHB patients who have HBV DNA >2000 IU/mL, elevated alanine aminotransferase level, and any degree of fibrosis should receive antiviral therapy regardless of their hepatitis B e antigen status. CHB patients with HBV DNA >2000 IU/mL and elevated alanine aminotransferase level but no evidence of fibrosis may also be considered for antiviral therapy. Approved antiviral therapies for CHB are interferon alfa-2b, peginterferon alfa-2a, lamivudine, adefovir, entecavir, telbivudine, and tenofovir, although the preferred first-line treatment choices are peginterferon alfa-2a, entecavir, and tenofovir. In determining choice of therapy, considerations include efficacy, safety, rate of resistance, method of administration, duration, and cost.
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Affiliation(s)
- Paul Martin
- Division of Hepatology, University of Miami School of Medicine, Miami, Florida.
| | - Daryl T-Y Lau
- Liver Center, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, California
| | - Harry L A Janssen
- Toronto Centre for Liver Diseases, University Health Network, Toronto, Canada
| | | | - Marion G Peters
- Division of Gastroenterology, University of California, San Francisco, San Francisco, California
| | - Ira M Jacobson
- Department of Medicine, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, New York
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Comparative effectiveness of antiviral treatment for hepatitis B: a systematic review and Bayesian network meta-analysis. Eur J Gastroenterol Hepatol 2015; 27:882-94. [PMID: 25919772 DOI: 10.1097/meg.0000000000000376] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
OBJECTIVE A wide variety of competing drugs are available to patients for the treatment of chronic hepatitis B. We update a recent meta-analysis to include additional trial evidence with the aim of determining which treatment is the most effective. METHODS Twelve monotherapy or combination therapy were evaluated in treatment-naive individuals with hepatitis B e antigen (HBeAg) positive or negative patients. Databases were searched for randomized controlled trials in the first year of therapy. Bayesian random effects network meta-analysis was used to calculate the pairwise odds ratios, 95% credible intervals and ranking of six surrogate outcomes. RESULTS In total, 22 studies were identified (7508 patients): 12 studies analysed HBeAg-positive patients, six analysed HBeAg-negative patients, and four evaluated both. Tenofovir was most effective at increasing efficacy in HBeAg-positive patients, ranking first for three outcomes and increased odds of undetectable levels of hepatitis B virus (HBV) DNA compared with seven other therapies (such as lamivudine: odds ratio 33.0; 95% credible interval 7.0-292.7). For HBeAg-negative patients, the large network (seven therapies) ranked entecavir alone or in combination with tenofovir highly for reduction in HBV DNA and histologic improvement. In the smaller network (three therapies), tenofovir ranked first for undetectable HBV DNA and histologic improvement. No data existed to directly or indirectly compare these treatments. CONCLUSION For HBeAg-positive patients tenofovir is the most effective at increasing efficacy, whereas for HBeAg-negative patients, either tenofovir or entecavir is most effective. Further research should focus on strengthening the network connections, in particular comparing tenofovir and entecavir in HBeAg-negative patients.
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Brouwer WP, Xie Q, Sonneveld MJ, Zhang N, Zhang Q, Tabak F, Streinu-Cercel A, Wang JY, Idilman R, Reesink HW, Diculescu M, Simon K, Voiculescu M, Akdogan M, Mazur W, Reijnders JGP, Verhey E, Hansen BE, Janssen HLA. Adding pegylated interferon to entecavir for hepatitis B e antigen-positive chronic hepatitis B: A multicenter randomized trial (ARES study). Hepatology 2015; 61:1512-22. [PMID: 25348661 DOI: 10.1002/hep.27586] [Citation(s) in RCA: 131] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Accepted: 10/24/2014] [Indexed: 01/05/2023]
Abstract
UNLABELLED Entecavir (ETV) is a potent inhibitor of hepatitis B viral replication, but long-term therapy may be required. We investigated whether adding on pegylated interferon (Peg-IFN) to ETV therapy enhances serological response rates. In this global investigator-initiated, open-label, multicenter, randomized trial, hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients with compensated liver disease started on ETV monotherapy (0.5 mg/day) and were randomized in a 1:1 ratio to either Peg-IFN add-on therapy (180 µg/week) from week 24 to 48 (n = 85) or to continue ETV monotherapy (n = 90). Response was defined as HBeAg loss with HBV DNA <200 IU/mL at week 48. Responders discontinued ETV at week 72. All patients were followed until week 96. Response was achieved in 16 of 85 (19%) patients allocated to the add-on arm versus 9 of 90 (10%) in the monotherapy arm (P = 0.095). Adjusted for HBV DNA levels before randomized therapy, Peg-IFN add-on was significantly associated with response (odds ratio: 4.8; 95% confidence interval: 1.6-14.0; P = 0.004). Eleven (13%) of the add-on-treated patients achieved disease remission after ETV cessation versus 2 of 90 (2%) of those treated with monotherapy (P = 0.007), which was 79% (11 of 14) versus 25% (2 of 8) of those who discontinued ETV (P = 0.014). At week 96, 22 (26%) patients assigned add-on versus 12 (13%) assigned monotherapy achieved HBeAg seroconversion (P = 0.036). Peg-IFN add-on led to significantly more decline in hepatitis B surface antigen, HBeAg, and HBV DNA (all P < 0.001). Combination therapy was well tolerated. CONCLUSION Although the primary endpoint was not reached, 24 weeks of Peg-IFN add-on therapy led to a higher proportion of HBeAg response, compared to ETV monotherapy. Add-on therapy resulted in more viral decline and appeared to prevent relapse after stopping ETV. Hence, Peg-IFN add-on therapy may facilitate the discontinuation of nucleos(t)ide analogs.
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Affiliation(s)
- Willem Pieter Brouwer
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
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Kasırga E. Lamivudine resistance in children with chronic hepatitis B. World J Hepatol 2015; 7:896-902. [PMID: 25937866 PMCID: PMC4411531 DOI: 10.4254/wjh.v7.i6.896] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Revised: 10/31/2014] [Accepted: 01/20/2015] [Indexed: 02/06/2023] Open
Abstract
Currently, although lamivudine (LAM) has a low genetic barrier, only interferon-alpha and LAM are available as a first-line treatment in children with chronic hepatitis B (CHB). LAM is a potent inhibitor of hepatitis B virus-deoxyribonucleic acid (HBV-DNA) polymerase replication by termination of the proviral HBV-DNA chain. LAM has a good safety and tolerability profile in CHB patients with hepatic decompensation. However, the main disadvantages of this HBV reverse transcriptase inhibitor are: (1) pre-existing covalently closed circular DNA cannot be eradicated by LAM, thus relapse after therapy withdrawal is frequent; and (2) although the longer LAM treatment induced the higher seroconversion rate, the risk of viral resistance increased through the selection of YMDD (tyrosine, methionine, aspartate, aspartate) motif. Insufficient suppression of viral replication leads to the emergence of resistant strains that could result in virological breakthrough which is usually followed by biochemical breakthrough. Mutant strains affects additional resistance and cross resistance, leading to drug resistance in a significant number of CHB patients. In this case, efficacy of more powerful anti-viral agents with higher genetic barrier against development of resistance is diminished. Furthermore, strains that are resistant to LAM could bring about vaccine escape mutants, decreasing the efficacy of HBV vaccine. A more potent drug with a high genetic barrier to resistance needs to be approved as the first-line treatment option for CHB in children.
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Wu H, Zhao G, Qian F, Liu K, Xie J, Zhou H, Xu J, Xu Y, Han Y, Xie Q, Wang H. Association of IL28B polymorphisms with peginterferon treatment response in Chinese Han patients with HBeAg-positive chronic hepatitis B. Liver Int 2015; 35:473-81. [PMID: 24517415 DOI: 10.1111/liv.12491] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Accepted: 02/03/2014] [Indexed: 12/25/2022]
Abstract
AIMS To investigate whether IL28B polymorphisms could affect the treatment response to peginterferon alpha (PEG-IFN) in chronic hepatitis B (CHB) patients in the Chinese Han population. METHODS A total of 212 hepatitis B e antigen (HBeAg)-positive patients treated with PEG-IFN monotherapy were enrolled in this study. Genotype analysis was performed for IL28B rs12980275, rs12979860 and rs8099917 using the MassArray system. Response was defined as cases showing normal aminotransferase (ALT) levels, HBV DNA level < 200 IU/ml and HBeAg seroconversion after 48 weeks of PEG-IFN therapy. RESULTS The patients were infected with hepatitis B virus (HBV) genotype B (44.8%) and C (55.2%) with a total response rate of 34.9%. For the three SNPs, there were significant differences between the response (R) and non-response (NR) groups both in allele frequencies and genotype distributions. IL28B genotype was independently associated with R for AA vs. N-AA (OR 2.70, 95% CL 1.21-6.01; P = 0.015) at rs12980275 after adjustment for sex, age, HBV genotype, baseline levels of HBV DNA and ALT. There were similar results for rs12979860 CC vs. N-CC (OR 2.56, 95% CL 1.15-5.67; P = 0.021) and rs8099917 TT vs. N-TT (OR 2.80, 95% CL 1.23-6.39; P = 0.015) respectively. Furthermore, one block formed by rs12980275 and rs12979860 was identified in this study. In multivariate analyses, the most common haplotype A-C was independently associated with high rates of R (OR 2.53, 95% CL 1.20-5.34; P = 0.015). CONCLUSIONS Our study suggested that genetic variations in IL28B may play a critical role in PEG-IFN efficacy in HBeAg-positive CHB patients in Han Chinese.
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Affiliation(s)
- Haiqing Wu
- Department of Infectious Diseases, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Cardiology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, China
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Cost effectiveness of response-guided therapy with peginterferon in the treatment of chronic hepatitis B. Clin Gastroenterol Hepatol 2015; 13:377-385.e5. [PMID: 24993366 DOI: 10.1016/j.cgh.2014.06.022] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2013] [Revised: 06/01/2014] [Accepted: 06/10/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The high prevalence of chronic hepatitis B in Asian countries produces a substantial economic burden. Peginterferon has immunomodulatory effects and a finite course for treatment of hepatitis B, but also a high cost and side effects. The recent introduction of a 12-week stopping rule (stopping treatment after 12 weeks) has increased its appeal as a first-line treatment for hepatitis B. We aimed to determine the cost effectiveness of the 12-week stopping rule for peginterferon in hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients. METHODS We used Markov modeling, with data from the Hong Kong population, to compare the cost effectiveness of peginterferon therapy with a 12-week stopping rule vs conventional therapy (48 weeks) and with other antiviral agents. RESULTS For HBeAg-positive patients, stopping peginterferon therapy after 12 weeks had the lowest cost-effectiveness ratio (CER), of $9501/quality-adjusted life-year (QALY), compared with no treatment, making it the most cost-effective option. Conventional (48-week) peginterferon treatment had a CER of $9664/QALY. For HBeAg-negative patients, entecavir had the lowest CER ($34,310/QALY). Entecavir was more cost effective than either peginterferon strategies (CERs of $37,423/QALY for 12 weeks of peginterferon and $38,474/QALY for 48 weeks of treatment). CONCLUSIONS The 12-week stopping rule increases the cost effectiveness of peginterferon therapy, and is the most cost-effective treatment for HBeAg-positive patients. The need for long-term antiviral therapy for HBeAg-negative patients makes entecavir the most cost-effective strategy.
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Wang H, Wu H, Bao S, Xiang X, Zhao G, Liu K, Li F, Xu Y, An B, Zhou H, Lu J, Xie Q. Association of IPS1 polymorphisms with peginterferon efficacy in chronic hepatitis B with HBeAg-positive in the Chinese population. INFECTION GENETICS AND EVOLUTION 2015; 31:161-8. [PMID: 25640825 DOI: 10.1016/j.meegid.2015.01.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Revised: 01/11/2015] [Accepted: 01/19/2015] [Indexed: 12/25/2022]
Abstract
AIMS To investigate whether IPS1 polymorphisms affect peginterferon alpha (PEG-IFN) efficacy in chronic hepatitis B (CHB) patients using a tag- single nucleotide polymorphism (SNP) approach. METHODS A total of 212 hepatitis B e antigen (HBeAg)-positive patients treated with a 48weeks of PEG-IFN monotherapy were enrolled initially and 127 patients were followed for 48weeks posttreatment. Genotype analysis was performed for 10 tag-SNPs in IPS1. RESULTS The end of virological response (EVR) rate was 45.8% (97/212) and the sustained virological response (SVR) rate was 45.7% (58/127). Meanwhile, 35.4% (75/212) achieved HBeAg seroconversion at the end of treatment. In a multivariate analysis, the rs2464 CC genotype was independently associated with EVR (OR 2.21, 95% CI 1.23-3.98, P=0.008) and SVR (OR 2.34, 95% CI 1.05-5.20, P=0.037) after adjustment for sex, age, HBV genotype, baseline levels of HBV DNA and ALT. Meanwhile, rs2464 CC genotype were also independently associated with decline of HBsAg levels below 1500IU/mL at 12weeks of treatment (OR 2.52, 95% CI 1.01-6.29, P=0.047). Furthermore, three SNPs were found to be independently associated with HBeAg seroconversion at the end of treatment. (1) The rs2326369 CC genotype was independently associated with no HBeAg seroconversion (OR 0.52, 95% CI 0.29-0.95, P=0.034); (2) The rs6515831 TT genotype was independently associated with HBeAg seroconversion (OR 2.11, 95% CI 1.14-3.90, P=0.017); (3) The rs2464 CC genotype was independently associated with HBeAg seroconversion (OR 2.36, 95% CI 1.26-4.42, P=0.007). CONCLUSIONS Polymorphisms in IPS1 are independently associated with treatment response to PEG-IFN among Chinese HBeAg-positive CHB patients.
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Affiliation(s)
- Hui Wang
- Department of Infectious Diseases, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Haiqing Wu
- Department of Infectious Diseases, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Department of Cardiology, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Shisan Bao
- Discipline of Pathology, School of Medical Sciences and The Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia
| | - Xiaogang Xiang
- Department of Infectious Diseases, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Gangde Zhao
- Department of Infectious Diseases, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Kehui Liu
- Department of Infectious Diseases, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Fengdi Li
- Department of Infectious Diseases, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yumin Xu
- Department of Infectious Diseases, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Baoyan An
- Department of Infectious Diseases, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Huijuan Zhou
- Department of Infectious Diseases, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jie Lu
- Department of Infectious Diseases, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qing Xie
- Department of Infectious Diseases, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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Wong GLH, Wong VWS, Chan HLY. Combination therapy of interferon and nucleotide/nucleoside analogues for chronic hepatitis B. J Viral Hepat 2014; 21:825-34. [PMID: 25402543 DOI: 10.1111/jvh.12341] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Accepted: 09/09/2014] [Indexed: 12/12/2022]
Abstract
Chronic hepatitis B is one of the leading causes of cirrhosis and hepatocellular carcinoma globally. At present, seven drugs, including two interferons and five oral nucleos(t)ide analogues (NAs), have been approved for the treatment of chronic hepatitis B. Interferon works by immunomodulation, but is successful in less than a third of treated patients and is a relatively weak antiviral. NAs directly suppress the hepatitis B virus but have limited durability. Based on current data, combination of NA and interferon results in greater viral suppression but does not translate to off-treatment sustained response. Concomitant or sequential treatment also does not make a difference. Combining telbivudine and interferon also runs the risk of severe peripheral neuropathy. On the other hand, interferon switch or additional therapy in patients well controlled with NAs appears to improve the durability of off-treatment response. This article reviews current data on interferon and NA combination and discusses potential future developments.
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Affiliation(s)
- G L-H Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China; State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
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van Campenhout MJH, Janssen HLA. How to achieve immune control in chronic hepatitis B? Hepatol Int 2014; 9:9-16. [PMID: 25788374 DOI: 10.1007/s12072-014-9571-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Accepted: 08/06/2014] [Indexed: 12/23/2022]
Abstract
Chronic hepatitis B infection remains a major global health problem despite the existence of an effective vaccine. The current treatment options are either nucleos(t)ide analog therapy, which inhibits viral replication, or peginterferon-α, which has mainly immunomodulatory effects. However, treatment-induced HBeAg seroconversion with suppressed viral replication is mostly not sustainable, and loss of HBsAg is a rarely achieved endpoint. In addition, the hepatitis B virus persists in hepatocytes even after HBsAg clearance as covalently closed circular DNA is not eliminated from the hepatocytes. Because the course of chronic hepatitis B is determined by an ongoing interaction between the virus and the host immune system, immunomodulation may be the most logical approach in attempting to accomplish control or even cure of chronic hepatitis B. In the last years, methods for measuring the degree of immune control have been a major area of interest, with an important role for monitoring of HBsAg levels. In addition, new immunomodulatory agents are being developed and tested, providing promising options for future treatment.
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Affiliation(s)
- Margo J H van Campenhout
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
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A Randomized, Open-Label Clinical Study of Combined Pegylated Interferon Alfa-2a (40KD) and Entecavir Treatment for Hepatitis B "e" Antigen-Positive Chronic Hepatitis B. Clin Infect Dis 2014; 59:1714-23. [DOI: 10.1093/cid/ciu702] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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