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Shinde S, Bigogno CM, Simmons A, Kathuria N, Ghose A, Apte V, Lapitan P, Makker S, Caglayan A, Boussios S. Precision oncology through next generation sequencing in hepatocellular carcinoma. Heliyon 2025; 11:e42054. [PMID: 39927143 PMCID: PMC11804570 DOI: 10.1016/j.heliyon.2025.e42054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 01/08/2025] [Accepted: 01/15/2025] [Indexed: 02/11/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a primary liver cancer that originates from underlying inflammation, often associated with Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infections. Despite the availability of treatments, there are high rates of tumour relapse due to the development of drug resistance in infected cells. Next-Generation Sequencing (NGS) plays a crucial role in overcoming this issue by sequencing both viral and host genomes to identify mutations and genetic heterogeneity. The knowledge gained from sequencing is then utilised to develop countermeasures against these mutants through different combination therapies. Advances in NGS have led to sequencing with higher accuracy and throughput, thereby enabling personalized and effective treatments. The purpose of this article is to highlight how NGS has contributed to precision medicine in HCC and the possible integration of artificial intelligence (AI) to bolster the advancement.
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Affiliation(s)
- Sayali Shinde
- Barts Cancer Institute, Queen Mary University of London, Cancer Research UK Barts Centre, London, UK
| | - Carola Maria Bigogno
- Department of Medical Oncology, St. Bartholomew's Hospital, Barts Health NHS Trust, London, UK
- British Oncology Network for Undergraduate Societies (BONUS), UK
| | - Ana Simmons
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- QIAGEN Manchester, Manchester, UK
| | - Nikita Kathuria
- Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Aruni Ghose
- Department of Medical Oncology, St. Bartholomew's Hospital, Barts Health NHS Trust, London, UK
- Department of Medical Oncology, Medway NHS Foundation Trust, Kent, UK
- Department of Medical Oncology, Mount Vernon Cancer Centre, East and North Hertfordshire NHS Trust, London, UK
| | - Vedika Apte
- University College London Medical School, London, UK
- University College London Oncology Society, London, UK
| | - Patricia Lapitan
- School of Medical Sciences, The University of Manchester, Manchester, UK
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Surrey, UK
- University College London Cancer Institute, London, UK
| | - Shania Makker
- University College London Cancer Institute, London, UK
- Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Barts and the London Oncology Society, London, UK
| | - Aydin Caglayan
- Department of Medical Oncology, Medway NHS Foundation Trust, Kent, UK
| | - Stergios Boussios
- Department of Medical Oncology, Medway NHS Foundation Trust, Kent, UK
- Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, King's College London, Strand, London, UK
- Kent and Medway Medical School, University of Kent, Canterbury, UK
- Faculty of Medicine, Health, and Social Care, Canterbury Christ Church University, Canterbury, UK
- AELIA Organization, 9th Km Thessaloniki–Thermi, 57001 Thessaloniki, Greece
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Itokawa N, Atsukawa M, Tsubota A, Ishikawa T, Toyoda H, Takaguchi K, Watanabe T, Ogawa C, Hiraoka A, Okubo H, Uojima H, Chuma M, Nozaki A, Kato K, Mikami S, Tani J, Morishita A, Tada T, Asano T, Senoh T, Oikawa T, Okubo T, Kumada T, Iwakiri K. Kinetics of the hepatitis B core-related antigen and treatment responses in chronic hepatitis B patients treated with tenofovir alafenamide. Hepatol Res 2024; 54:993-1003. [PMID: 38685853 DOI: 10.1111/hepr.14052] [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: 12/20/2023] [Revised: 04/02/2024] [Accepted: 04/15/2024] [Indexed: 05/02/2024]
Abstract
AIM An association between hepatitis B core-related antigen (HBcrAg) kinetics and hepatocarcinogenesis during nucleoside (t)id analog (NA) treatment has recently been reported. HBcrAg kinetics and factors associated with HBcrAg response during tenofovir alafenamide (TAF) administration remain unclear. In this multicenter retrospective study, we aimed to clarify the efficacy and safety of TAF in treatment-naïve patients with chronic hepatitis B, focusing on the reduction in HBcrAg levels. METHODS Patients were treated with TAF monotherapy for 96 weeks, and the kinetics of HBcrAg during treatment and the factors associated with HBcrAg response (defined as a change in HBcrAg of -1 log IU/mL from baseline) were evaluated. RESULTS The study population comprised 241 patients, 36.9% of whom were HBeAg-positive. The median baseline HBcrAg level was 4.7 log IU/mL. The median change in HBcrAg from baseline was -1.1 log IU/mL at 96 weeks after treatment. The HBcrAg response rate at 96 weeks was 56.6% (43/76). Multivariate analysis revealed high alanine transaminase level as an independent baseline factor associated with HBcrAg response at 96 weeks of treatment (p = 4.53 × 10-6). No correlation was found between the HBcrAg and hepatitis B surface antigen kinetics in patients treated with TAF monotherapy. CONCLUSIONS In TAF monotherapy for patients with chronic hepatitis B, HBcrAg levels were significantly decreased and baseline alanine transaminase level is an important factor associated with HBcrAg reduction. As no correlation was found between HBcrAg and reduced hepatitis B surface antigen levels in this study, HBcrAg kinetics in addition to hepatitis B surface antigen may need to be monitored during TAF treatment.
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Affiliation(s)
- Norio Itokawa
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
| | - Masanori Atsukawa
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
| | - Akihito Tsubota
- Project Research Units (PRU) Research Center for Medical Science The Jikei University School of Medicine, Tokyo, Japan
| | - Toru Ishikawa
- Department of Hepatology, Saiseikai Niigata Hospital, Niigata, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Koichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Tsunamasa Watanabe
- Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
| | - Chikara Ogawa
- Department of Gastroenterology and Hepatology, Takamatsu Red Cross Hospital, Takamatsu, Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Hironao Okubo
- Department of Gastroenterology, Juntendo University Nerima Hospital, Tokyo, Japan
| | - Haruki Uojima
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Makoto Chuma
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Akito Nozaki
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Keizo Kato
- Division of Gastroenterology and Hepatology, Shinmatusdo Central General Hospital, Matsudo, Japan
| | - Shigeru Mikami
- Department of Internal Medicine, Division of Gastroenterology, Kikkoman General Hospital, Noda, Japan
| | - Joji Tani
- Department of Gastroenterology, Kagawa University Graduate School of Medicine, Kagawa, Japan
| | - Asahiro Morishita
- Department of Gastroenterology, Kagawa University Graduate School of Medicine, Kagawa, Japan
| | - Toshifumi Tada
- Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Hyogo, Japan
| | - Toru Asano
- Department of Internal Medicine, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan
| | - Tomonori Senoh
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Tsunekazu Oikawa
- Department of Gastroenterology and Hepatology, The Jikei University School of Medicine, Tokyo, Japan
| | - Tomomi Okubo
- Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Chiba, Japan
| | - Takashi Kumada
- Department of Nursing, Gifu Kyoritsu University, Ogaki, Japan
| | - Katsuhiko Iwakiri
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
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Xie C, Lu D. Evolution and diversity of the hepatitis B virus genome: Clinical implications. Virology 2024; 598:110197. [PMID: 39098184 DOI: 10.1016/j.virol.2024.110197] [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: 05/23/2024] [Revised: 07/14/2024] [Accepted: 07/30/2024] [Indexed: 08/06/2024]
Abstract
Hepatitis B virus (HBV) infection remains a significant global health burden. The genetic variation of HBV is complex. HBV can be divided into nine genotypes, which show significant differences in geographical distribution, clinical manifestations, transmission routes and treatment response. In recent years, substantial progress has been made through various research methods in understanding the development, pathogenesis, and antiviral treatment response of clinical disease associated with HBV genetic variants. This progress provides important theoretical support for a deeper understanding of the natural history of HBV infection, virus detection, drug treatment, vaccine development, mother-to-child transmission, and surveillance management. This review summarizes the mechanisms of HBV diversity, discusses methods used to detect viral diversity in current studies, and the impact of viral genome variation during infection on the development of clinical disease.
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Affiliation(s)
- Chengzuo Xie
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Daiqiang Lu
- Institute of Molecular and Medical Virology, Key Laboratory of Ministry of Education for Viral Pathogenesis & Infection Prevention and Control, School of Medicine, Jinan University, Guangzhou, Guangdong Province, 510632, China.
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Maung ST, Decharatanachart P, Treeprasertsuk S, Chaiteerakij R. Risk Factors for Development of Cirrhosis in Chronic Viral Hepatitis B Patients Who Had Persistent Viral Suppression With Antiviral Therapy. J Clin Exp Hepatol 2024; 14:101388. [PMID: 38523735 PMCID: PMC10956063 DOI: 10.1016/j.jceh.2024.101388] [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: 09/13/2023] [Accepted: 02/24/2024] [Indexed: 03/26/2024] Open
Abstract
BACKGROUND AND AIMS Chronic viral hepatitis B (CHB)-infected patients occasionally develop cirrhosis despite having persistent viral suppression with antiviral therapy. We aimed to identify risk factors for developing cirrhosis in hepatitis B virus (HBV)-suppressed patients. METHODS We conducted a case-control study involving 120 noncirrhotic CHB-infected patients achieving viral suppression with antiviral treatment, with 40 cases developing cirrhosis and 80 age-, sex-, and Fibrosis-4 (FIB-4)-matched controls. Clinical and laboratory data at viral suppression, including body mass index (BMI), comorbidities, pretreatment HBV viral load, HBe antigen status, hepatitis C virus (HCV) and HIV coinfections, liver chemistries, and AST to Platelets Ratio Index (APRI) values, were retrospectively abstracted. Risk factors for cirrhosis post-HBV suppression were identified using Cox proportional hazard analysis. RESULTS Case and control groups had similar ages (51.4 ± 9.9 vs. 51.4 ± 10.2 years), proportions of males (80% vs. 80%), and FIB-4 values (1.32 vs. 1.31). The cirrhosis group showed significantly higher BMI (25.1 vs. 22.7, P = 0.01) and more diabetes prevalence (50.0% vs. 26.3%, P = 0.01), while other comorbidities and laboratory parameters were comparable (P > 0.05). By univariate analysis, BMI >23 kg/m2, diabetes, and APRI >0.7 were significantly associated with cirrhosis, with hazard ratios (HRs) (95%CI) of 2.99 (1.46-6.13), 2.31 (1.23-4.36), and 2.71 (1.05-6.99), P = 0.003, 0.010, and 0.039, respectively. In multivariate analyses adjusted for APRI, BMI>23 kg/m2 remained significantly associated with cirrhosis (aHR: 2.76, P = 0.006), while diabetes showed borderline significance (aHR: 1.99, P = 0.072). CONCLUSIONS In HBV-infected patients achieving viral suppression with therapy, a BMI >23 kg/m2 increases the risk of cirrhosis. Therefore, a comprehensive approach addressing metabolic factors is imperative for preventing disease progression in HBV-infected patients.
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Affiliation(s)
- Soe T. Maung
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Ma Har Myaing Hospital, Yangon, Myanmar
| | | | - Sombat Treeprasertsuk
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Roongruedee Chaiteerakij
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Center of Excellence for Innovation and Endoscopy in Gastrointestinal Oncology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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Giannakopoulou E, Pardali V, Edwards TC, Woodson M, Tajwar R, Tavis JE, Zoidis G. Identification and assessment of the 1,6-dihydroxy-pyridin-2-one moiety as privileged scaffold for HBV ribonuclease H inhibition. Antiviral Res 2024; 223:105833. [PMID: 38325606 PMCID: PMC11533872 DOI: 10.1016/j.antiviral.2024.105833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 01/20/2024] [Accepted: 02/02/2024] [Indexed: 02/09/2024]
Abstract
The Hepatitis B Virus (HBV) ribonuclease H (RNase H) although promising remains an unexploited therapeutic target. HBV RNase H inhibition causes premature termination of viral minus-polarity DNA strands, prevents the synthesis of the viral positive-polarity DNA strand, and causes accumulation of RNA:DNA heteroduplexes within viral capsids. As part of our ongoing research to develop more potent anti-HBV RNase H inhibitors, we designed, synthesized and analyzed a library of 18 novel compounds (17 N-hydroyxpyridinedione (HPD) imine derivatives and 1 barbituric acid analogue) as potential leads for HBV treatment development. In cell assays, fourteen HPDs showed significant anti-HBV activity with EC50s from 1.1 to 2.5 μM and selectivity indices (SI) of up to 58. Three of them exhibited more than 3-fold improvement in the SI over the best previous HPD imine (SI = 13). To gain insight to the interaction between the tested compounds and the active site of HBV RNase H, docking experiments were undertaken. In almost all binding poses, the novel HPDs coordinated both active site Mg2+ ions via their oxygen trident. Furthermore, the novel HPDs displayed high cell permeability and solubility as well as good drug-like properties. These results reveal that HPD imines can be significantly active and selective HBV inhibitors, and that the HPD scaffold merits further development towards anti-HBV agents.
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Affiliation(s)
- Erofili Giannakopoulou
- School of Health Sciences, Department of Pharmacy, Division of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771, Athens, Greece
| | - Vasiliki Pardali
- School of Health Sciences, Department of Pharmacy, Division of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771, Athens, Greece
| | - Tiffany C Edwards
- Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, United States
| | - Molly Woodson
- Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, United States
| | - Razia Tajwar
- Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, United States
| | - John E Tavis
- Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, United States
| | - Grigoris Zoidis
- School of Health Sciences, Department of Pharmacy, Division of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771, Athens, Greece.
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Jones T, Tavis JE, Li Q, Riabova O, Monakhova N, Bradley DP, Lane TR, Makarov V, Ekins S. Antiviral Evaluation of Dispirotripiperazines against Hepatitis B Virus. J Med Chem 2023; 66:12459-12467. [PMID: 37611244 PMCID: PMC11017374 DOI: 10.1021/acs.jmedchem.3c00974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/25/2023]
Abstract
Hepatitis B virus (HBV) is a hepatotropic DNA virus that replicates by reverse transcription. It chronically infects >296 million people worldwide, including ∼850,000 in the USA, and kills 820,000 annually worldwide. Current nucleos(t)ide analogue (NA) or pegylated interferon α therapies do not eradicate the virus and would benefit from a complementary antiviral drug. We performed a preliminary screen of 28 dispirotripiperazines against HBV, identifying 9 hits with EC50 of 0.7-25 μM. Compound 11826096 displays the most potent activity and represents a promising lead for future optimization. While the mechanism of action is unknown, preliminary assays limit possible targets to activities involved in RNA accumulation, translation, capsid assembly, and/or capsid stability. In addition, we built machine learning models to determine if they were able to predict the activity of this series of compounds. The novelty of these molecules indicated they were outside of the applicability domain of these models.
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Affiliation(s)
- Thane Jones
- Collaborations Pharmaceuticals Inc., 840 Main Campus Dr., Lab 3510, Raleigh, NC, USA
| | - John E. Tavis
- Saint Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO, USA
| | - Qilan Li
- Saint Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO, USA
| | - Olga Riabova
- Research Center of Biotechnology RAS, Leninsky Prospekt 33-2, 119071, Moscow, Russia
| | - Natalia Monakhova
- Research Center of Biotechnology RAS, Leninsky Prospekt 33-2, 119071, Moscow, Russia
| | - Daniel P. Bradley
- Saint Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO, USA
| | - Thomas R. Lane
- Collaborations Pharmaceuticals Inc., 840 Main Campus Dr., Lab 3510, Raleigh, NC, USA
| | - Vadim Makarov
- Research Center of Biotechnology RAS, Leninsky Prospekt 33-2, 119071, Moscow, Russia
| | - Sean Ekins
- Collaborations Pharmaceuticals Inc., 840 Main Campus Dr., Lab 3510, Raleigh, NC, USA
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Kim DY, Kim YR, Suh C, Yoon DH, Yang DH, Park Y, Eom HS, Lee JO, Kwak JY, Kang HJ, Hyun SY, Jo JC, Chang MH, Yoo KH, Lim SN, Shin HJ, Kim WS, Kim IH, Kim MK, Kim HJ, Lee WS, Mun YC, Kim JS. A Prospective Study of Preemptive Tenofovir Disoproxil Fumarate Therapy in HBsAg-Positive Patients With Diffuse Large B-Cell Lymphoma Receiving Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone. Am J Gastroenterol 2023; 118:1373-1380. [PMID: 36728217 DOI: 10.14309/ajg.0000000000002185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 12/28/2022] [Indexed: 02/03/2023]
Abstract
INTRODUCTION This prospective study aimed to investigate the efficacy and safety of preemptive antiviral therapy with tenofovir disoproxil fumarate (TDF) for HBsAg-positive patients with newly diagnosed diffuse large B-cell lymphoma receiving rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. METHODS We enrolled 73 patients from 20 institutions. The primary end point was the absolute risk of hepatitis B virus (HBV)-related hepatitis during preemptive TDF therapy and for 24 weeks after withdrawal from TDF. Hepatitis was defined as a more than 3-fold increase in serum alanine aminotransferase from baseline or an alanine aminotransferase level of ≥100 U/L. HBV-related hepatitis was defined as hepatitis with an increase in serum HBV-DNA to >10 times that of the pre-exacerbation baseline or an absolute increase of ≥20,000 IU/mL compared with the baseline. RESULTS No patient developed HBV reactivation or HBV-related hepatitis during preemptive antiviral therapy (until 48 weeks after completion of R-CHOP chemotherapy) with TDF. All adverse events were grade 1 or 2. HBV reactivation was reported in 17 (23.3%) patients. All HBV reactivation was developed at a median of 90 days after withdrawal from TDF (range, 37-214 days). Six (8.2%) patients developed HBV-related hepatitis at a median of 88 days after withdrawal from TDF (range, 37-183 days). DISCUSSION Preemptive TDF therapy in HBsAg-positive patients with diffuse large B-cell lymphoma receiving R-CHOP chemotherapy was safe and effective for preventing HBV-related hepatitis. However, a long-term maintenance strategy of preemptive TDF therapy should be recommended because of the relatively high rate of HBV-related hepatitis after withdrawal from TDF ( ClinicalTrials.gov ID: NCT02354846).
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Affiliation(s)
- Do Young Kim
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, Korea
| | - Yu Ri Kim
- Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, Korea
| | - Cheolwon Suh
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Dok Hyun Yoon
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Deok-Hwan Yang
- Department of Hematology/Oncology, Chonnam National University Hwasun Hospital, Jeollanam-do, Korea
| | - Yong Park
- Department of Internal Medicine, Korea University Medical Center, Seoul, Korea
| | - Hyeon Seok Eom
- Hematology-Oncology Clinic, National Cancer Center, Goyang, Korea
| | - Jeong-Ok Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Jae-Yong Kwak
- Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Korea
| | - Hye Jin Kang
- Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Shin Young Hyun
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jae-Cheol Jo
- Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Myung Hee Chang
- Department of Internal Medicine, National Health Insurance Corporation Ilsan Hospital, Goyang, Korea
| | - Kwai Han Yoo
- Departments of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea
| | - Sung-Nam Lim
- Department of Internal Medicine, Inje University Haeundae Paik Hospital, Busan, Korea
| | - Ho-Jin Shin
- Department of Internal Medicine, Pusan National University School of Medicine, Pusan National University Hospital, Busan, Korea
| | - Won Seog Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - In-Ho Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Min Kyung Kim
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Hyo Jung Kim
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, Anyang, Korea
| | - Won-Sik Lee
- Department of Internal Medicine, Inje University Busan Paik Hospital, Busan, Korea
| | - Yeung-Chul Mun
- Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Korea
| | - Jin Seok Kim
- Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, Korea
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Kim JH, Kim JH, Choe WH, Kwon SY, Yoo BC, Yoon EL, Kang SH. Switching from Tenofovir-Based Combination Therapy to Tenofovir Monotherapy in Multidrug-Experienced Chronic Hepatitis B Patients: a 5-Year Experience at Two Centers. Antimicrob Agents Chemother 2022; 66:e0027522. [PMID: 35867571 PMCID: PMC9380523 DOI: 10.1128/aac.00275-22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 06/27/2022] [Indexed: 01/16/2023] Open
Abstract
Patients with chronic hepatitis B (CHB) who were administered tenofovir disoproxil fumarate (TDF)-based combination therapy after receiving multiple drugs are frequently switched to TDF monotherapy in South Korea. We evaluated the efficacy and safety of switching to TDF monotherapy from TDF-based combination therapy over 5 years. This was a retrospective study of multidrug-experienced CHB patients who switched from TDF-based combination therapy to TDF monotherapy after achieving a virologic response (VR; <20 IU/mL) at Konkuk University Hospital and Sanggye Paik Hospital. The biochemical response was defined as a normalized serum ALT level during follow-up. Each patient was assessed from the date of switching to TDF monotherapy to the date of the last follow-up over 5 years. A total of 39 patients who received at least one antiviral therapy before TDF-based combination therapy were analyzed. The median duration of VR before switching to TDF monotherapy was 18 months and the median duration of TDF monotherapy was 55 months. In this study, except for one patient who had poor compliance, all patients maintained a VR. Three patients had a temporarily increased HBV DNA level and 91.2% of the patients showed a biochemical response. Switching multidrug-experienced patients to TDF monotherapy is generally safe and effective.
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Affiliation(s)
- Jung Hun Kim
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, South Korea
| | - Jeong Han Kim
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, South Korea
- Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, South Korea
| | - Won Hyeok Choe
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, South Korea
| | - So Young Kwon
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, South Korea
| | - Byung-chul Yoo
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, South Korea
| | - Eileen L. Yoon
- Department of Internal Medicine, Inje University Sanggye Paik Hospital, Seoul, South Korea
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, South Korea
| | - Seong Hee Kang
- Department of Internal Medicine, Inje University Sanggye Paik Hospital, Seoul, South Korea
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Dunn R, Wetten A, McPherson S, Donnelly MC. Viral hepatitis in 2021: The challenges remaining and how we should tackle them. World J Gastroenterol 2022; 28:76-95. [PMID: 35125820 PMCID: PMC8793011 DOI: 10.3748/wjg.v28.i1.76] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 06/26/2021] [Accepted: 12/22/2021] [Indexed: 02/06/2023] Open
Abstract
Viral hepatitis results in 1.4 million deaths annually. The World Health Organization (WHO) set an ambitious target to eliminate viral hepatitis by 2030, but significant challenges remain. These include inequalities in access to healthcare, reaching at risk populations and providing access to screening and effective treatment. Stigma around viral hepatitis persists and must be addressed. The WHO goal of global elimination by 2030 is a worthy aim, but remains ambitious and the coronavirus 2019 pandemic undoubtedly has set back progress. This review article will focus on hepatitis A to E, highlighting problems that have been resolved in the field over the past decade, those that remain to be resolved and suggest directions for future problem solving and research.
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Affiliation(s)
- Rebecca Dunn
- Gastroenterology, University Hospital of North Tees, Stockton on Tees TS198PE, United Kingdom
| | - Aaron Wetten
- Liver Unit, Freeman Hospital, Newcastle NE77DN, United Kingdom
- Translational and Clinical Research Institute, Newcastle University, Newcastle NE17RU, United Kingdom
| | - Stuart McPherson
- Liver Unit, Freeman Hospital, Newcastle NE77DN, United Kingdom
- Translational and Clinical Research Institute, Newcastle University, Newcastle NE17RU, United Kingdom
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10
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Fischer MG, Newman W, Hammer K, Rohrich M, Lo TS. Comparison of Renal Function Between Tenofovir Disoproxil Fumarate and Other Nucleos(t)ide Reverse Transcriptase Inhibitors in Patients With Hepatitis B Virus Infection. Fed Pract 2021; 38:363-367. [PMID: 34733088 DOI: 10.12788/fp.0169] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) have become a standard treatment for both HIV and hepatitis B virus (HBV) infections. Tenofovir disoproxil fumarate (TDF) has been associated with kidney injury and possible long-term damage in patients with HIV. Few studies have examined whether this holds true for patients treated for HBV. Methods Data were gathered from the Veterans Health Administration Corporate Data Warehouse between July 1, 2005 and July 31, 2015. Patients aged ≥ 18 years with HBV infection and prescribed a NRTI for > 1 month were included in the study and followed for 36 months. Patients with HIV infection were excluded, and patients treated with combination TDF/emtricitabine were analyzed separately from patients receiving only TDF. A linear mixed model was used to examine the effects of time and specific agent on renal function, which was measured with estimated glomerular filtration rate (eGFR) at various time intervals. Results There were 413 incidences of NRTI use in 308 subjects during the 10 years of the study with 39 cases of TDF use. There was a significant fixed effect of time, with eGFR reduction of 4.6 mL/min (P < .001) over the course of the study for the full cohort, but the effects of each medication were not significant. Conclusions This multicenter, retrospective study did not demonstrate an association between TDF use and a greater degree of kidney injury compared with other NRTIs in patients with HBV, but further studies are warranted.
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Affiliation(s)
- Matthew G Fischer
- At the time of the study, was Chief of Endocrinology and was a Pharmacy Resident; is Associate Chief of Staff/Research and Development; is Chief of Pharmacy; is Chief of Infectious Disease; all at Fargo Veterans Affairs Health Care System in North Dakota. Kimberly Hammer is Associate Professor, Internal Medicine Department, University of North Dakota School of Medicine and Health Sciences. Matthew Fischer is a Clinical Pharmacy Practitioner at Veterans Affairs Northern California Health Care System in Mather
| | - William Newman
- At the time of the study, was Chief of Endocrinology and was a Pharmacy Resident; is Associate Chief of Staff/Research and Development; is Chief of Pharmacy; is Chief of Infectious Disease; all at Fargo Veterans Affairs Health Care System in North Dakota. Kimberly Hammer is Associate Professor, Internal Medicine Department, University of North Dakota School of Medicine and Health Sciences. Matthew Fischer is a Clinical Pharmacy Practitioner at Veterans Affairs Northern California Health Care System in Mather
| | - Kimberly Hammer
- At the time of the study, was Chief of Endocrinology and was a Pharmacy Resident; is Associate Chief of Staff/Research and Development; is Chief of Pharmacy; is Chief of Infectious Disease; all at Fargo Veterans Affairs Health Care System in North Dakota. Kimberly Hammer is Associate Professor, Internal Medicine Department, University of North Dakota School of Medicine and Health Sciences. Matthew Fischer is a Clinical Pharmacy Practitioner at Veterans Affairs Northern California Health Care System in Mather
| | - Melissa Rohrich
- At the time of the study, was Chief of Endocrinology and was a Pharmacy Resident; is Associate Chief of Staff/Research and Development; is Chief of Pharmacy; is Chief of Infectious Disease; all at Fargo Veterans Affairs Health Care System in North Dakota. Kimberly Hammer is Associate Professor, Internal Medicine Department, University of North Dakota School of Medicine and Health Sciences. Matthew Fischer is a Clinical Pharmacy Practitioner at Veterans Affairs Northern California Health Care System in Mather
| | - Tze Shien Lo
- At the time of the study, was Chief of Endocrinology and was a Pharmacy Resident; is Associate Chief of Staff/Research and Development; is Chief of Pharmacy; is Chief of Infectious Disease; all at Fargo Veterans Affairs Health Care System in North Dakota. Kimberly Hammer is Associate Professor, Internal Medicine Department, University of North Dakota School of Medicine and Health Sciences. Matthew Fischer is a Clinical Pharmacy Practitioner at Veterans Affairs Northern California Health Care System in Mather
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Yamashige D, Hosaka T, Suzuki F, Fujiyama S, Kawamura Y, Sezaki H, Akuta N, Kobayashi M, Suzuki Y, Saitoh S, Arase Y, Ikeda K, Kobayashi M, Kumada H. Effectiveness of tenofovir alafenamide for chronic hepatitis B patients with a poor response to the previously used nucleos(t)ide analogs. J Gastroenterol 2021; 56:1008-1021. [PMID: 34596753 DOI: 10.1007/s00535-021-01826-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 09/10/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND Few studies have demonstrated the potency of tenofovir alafenamide (TAF) in patients with poor response to other nucleos(t)ide analogs (NAs). METHODS We conducted a retrospective study comprising consecutive 40 patients exhibiting a poor response to other NAs, who subsequently received TAF-containing regimens. The primary outcome was the prevalence of virological response (VR) at each time and maintained virological response (MVR) under TAF-containing regimens until week 96. RESULTS In the entire cohort, the prevalence of MVR was 71.1% (27/38). Further, poor tenofovir disoproxil fumarate (TDF) response was significantly associated with a lower prevalence of MVR (p = 0.014). In TDF-naïve patients, the prevalence of MVR was 92.3% (12/13) and 62.5% (5/8) in patients with lamivudine resistance (LAM-r) and entecavir resistance (ETV-r), respectively. Further, viral load and HBeAg status at baseline were associated with a lower prevalence of MVR (p = 0.013). Among the seven patients with prior TDF exposure, 2 patients achieved MVR. Among them, one patient with development of viral breakthrough during TDF/LAM achieved MVR after switching to TAF/ETV. In contrast, one of the five patients with non-MVR had three substitutions (rtS106C, rtD134N/S, and rtL269I) of quadruple mutations in addition to ETV-r. Other patients with rtA181T + rtN236T also could not achieve MVR. CONCLUSION TAF exhibited high antiviral potency in patients with LAM-r and ETV-r. However, TAF potency was associated with previous TDF response, viral load, and HBeAg status at baseline. Additionally, a quadruple mutation may impact tenofovir resistance; however, further studies are needed to verify this.
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Affiliation(s)
- Daiki Yamashige
- Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Tetsuya Hosaka
- Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan.
| | - Fumitaka Suzuki
- Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Shunichiro Fujiyama
- Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Yusuke Kawamura
- Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Hitomi Sezaki
- Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Norio Akuta
- Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Masahiro Kobayashi
- Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Yoshiyuki Suzuki
- Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Satoshi Saitoh
- Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Yasuji Arase
- Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Kenji Ikeda
- Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Mariko Kobayashi
- Research Institute for Hepatology, Toranomon Hospital, Kawasaki, Japan
| | - Hiromitsu Kumada
- Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan
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12
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Wassner C, Bradley N, Lee Y. A Review and Clinical Understanding of Tenofovir: Tenofovir Disoproxil Fumarate versus Tenofovir Alafenamide. J Int Assoc Provid AIDS Care 2021; 19:2325958220919231. [PMID: 32295453 PMCID: PMC7163232 DOI: 10.1177/2325958220919231] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
HIV is a serious chronic medical condition. Significant improvements in antiretroviral
therapy have led to a transformation in its management. No curative treatment is available
for HIV, and lifelong therapy is required with a combination of agents to control viral
replication and prevent complications. Some of the older agents are notorious for many
side effects, making patient compliance difficult, which is critical to preventing HIV
resistance. Tenofovir is one of the newer, more tolerable, nucleotide reverse
transcriptase inhibitors on the market; is a mainstay of many antiretroviral therapy
combinations; and is now available in 2 different formulations, tenofovir disoproxil
fumarate (TDF) and, the more recent, tenofovir alafenamide (TAF). These 2 formulations
have very different pharmacokinetics, which seem to affect their efficacy and safety. This
manuscript provides insight into the history of TDF and TAF development, their unique
pharmacokinetics and pharmacology, clinically important adverse effects, monitoring,
interactions, resistance, review of clinical studies, and guideline recommendations and
clinical applications for tenofovir’s various indications.
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Affiliation(s)
- Chanie Wassner
- Department of Pharmacy, NYU Langone Hospital, Brooklyn, NY, USA
| | - Nicole Bradley
- College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA
| | - Yuman Lee
- College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA
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13
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Suzuki F, Sezaki H, Hosaka T, Suzuki Y, Fujiyama S, Kawamura Y, Akuta N, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Kobayashi M, Mineta R, Suzuki Y, Kumada H. Virologic analysis of tenofovir resistance in a patient with chronic hepatitis B experiencing viral breakthrough during combination treatment with tenofovir disoproxil fumarate and entecavir. Hepatol Res 2021; 51:503-508. [PMID: 33462964 DOI: 10.1111/hepr.13618] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 12/15/2020] [Accepted: 12/31/2020] [Indexed: 12/30/2022]
Abstract
Tenofovir disoproxil fumarate (TDF) is widely used to treat hepatitis B virus (HBV) patients worldwide. We previously reported a patient with CHB and cirrhosis in whom viral breakthrough occurred during combination therapy with TDF and entecavir (ETV) against ETV-resistant virus. A recent Korean report showed that two patients with viral breakthrough during treatment with TDF-containing regimens were found to carry five reverse transcriptase (rt) mutations ([rt]S106C[C], rtH126Y[Y], rtD134E[E], rtM204I/V, and rtL269I [I]), with the C, Y, E, and I mutations being associated with tenofovir resistance. We report the clinical course up to September 2019 in our patient, and compare the HBV mutations to those of the two Korean patients. Four mutations (rtS106C, rtD134N/S[N/S], rtM204V, and rtL269I) plus ETV resistance (rtL180M and rtS202G) existed when she developed viral breakthrough during ETV and TDF combination therapy in April 2013. Moreover, three mutations (rtS106C, rtD134N, and rtL269I) existed at baseline. Our patient's father is Korean. Considering these factors, patients with these three or four mutations (CYEI or CN/SI) at baseline could experience tenofovir resistance in addition to lamivudine (LAM) or ETV resistance. In addition, HBV DNA levels fluctuated during tenofovir alafenamide (TAF) and LAM therapy in our patient, although treatment was switched from LAM, TDF, and ETV to LAM and TAF combination therapy in April 2018. In conclusion, three mutations (CN/SI) plus ETV resistance (rtL180M, rtM204V, and rtS202G) can cause tenofovir resistance. Long-term therapy with tenofovir against ETV-resistant virus has the potential to induce viral breakthrough and resistance, necessitating careful follow-up.
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Affiliation(s)
- Fumitaka Suzuki
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan.,Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Hitomi Sezaki
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | - Tetsuya Hosaka
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | | | | | | | - Norio Akuta
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | | | - Satoshi Saitoh
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | - Yasuji Arase
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | - Kenji Ikeda
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | - Mariko Kobayashi
- Research Institute for Hepatology, Toranomon Branch Hospital, Kawasaki, Japan
| | - Rie Mineta
- Research Institute for Hepatology, Toranomon Branch Hospital, Kawasaki, Japan
| | - Yukiko Suzuki
- Research Institute for Hepatology, Toranomon Branch Hospital, Kawasaki, Japan
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14
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Li Q, Edwards TC, Ponzar NL, Tavis JE. A mid-throughput HBV replication inhibition assay capable of detecting ribonuclease H inhibitors. J Virol Methods 2021; 292:114127. [PMID: 33766659 DOI: 10.1016/j.jviromet.2021.114127] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 01/28/2021] [Accepted: 03/08/2021] [Indexed: 12/19/2022]
Abstract
The hepatitis B virus (HBV) ribonuclease H (RNaseH) is a promising but unexploited drug target. Inhibiting the RNaseH blocks viral reverse transcription by truncating the minus-polarity DNA strand, causing accumulation of RNA:DNA heteroduplexes, and abrogating plus-polarity DNA synthesis. Screening for RNaseH inhibitors is complicated by the presence of the minus-polarity DNA strand even when replication is fully inhibited because this residual DNA can be detected by standard screening assays that measure reduction in total HBV DNA accumulation. We previously developed a strand-preferential qPCR assay that detects RNaseH replication inhibitors by measuring preferential suppression of the viral plus-polarity DNA strand. However, this assay employed cells grown in 6- or 12-well plates and hence was of very low throughput. Here, we adapted the assay to a 96-well format and conducted a proof-of-principle screen of 727 compounds. The newly developed assay is a valuable tool for anti-HBV drug discovery, particularly when screening for RNaseH inhibitors.
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Affiliation(s)
- Qilan Li
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA; Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, MO, USA.
| | - Tiffany C Edwards
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA; Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, MO, USA.
| | - Nathan L Ponzar
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA; Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, MO, USA.
| | - John E Tavis
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA; Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, MO, USA.
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15
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Itokawa N, Atsukawa M, Tsubota A, Takaguchi K, Nakamuta M, Hiraoka A, Kato K, Abe H, Mikami S, Shimada N, Chuma M, Akito N, Uojima H, Ogawa C, Asano T, Tani J, Morishita A, Senoh T, Yamashita N, Oikawa T, Matsumoto Y, Koeda M, Yoshida Y, Tanabe T, Okubo T, Arai T, Hayama K, Iwashita AN, Kondo C, Tada T, Toyoda H, Kumada T, Iwakiri K. Sequential therapy from entecavir to tenofovir alafenamide versus continuous entecavir monotherapy for patients with chronic hepatitis B. JGH OPEN 2021; 5:34-40. [PMID: 33490611 PMCID: PMC7812481 DOI: 10.1002/jgh3.12443] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 09/21/2020] [Accepted: 10/19/2020] [Indexed: 12/24/2022]
Abstract
Background and Aim Although tenofovir alafenamide (TAF), as well as entecavir (ETV), is widely used as first‐line treatment for patients with chronic hepatitis B, there are only a few studies comparing sequential therapy from ETV to TAF and continuous ETV monotherapy in patients with maintained virologic response to ETV. Methods In a retrospective multicenter study, we investigated the efficacy and safety of sequential therapy from ETV to TAF (ETV‐TAF group) and compared them with continuous ETV monotherapy (ETV group), using propensity score matching, in chronic hepatitis B patients. Results From 442 patients, we analyzed 142 patients from each group comprising 71 patients matched for several data, including age, HBV genotype, hepatitis B envelope antigen, cirrhosis, alanine aminotransferase, platelet count, prior ETV monotherapy period, and hepatitis B surface antigen (HBsAg) change during prior ETV monotherapy. In the ETV‐TAF group, HBsAg levels significantly decreased from baseline to 48 weeks after switching to TAF (−0.02 log IU/mL, P = 0.038). HBcrAg levels also significantly decreased after switching to TAF (−0.1 log IU/mL, P = 0.004). However, there were no significant differences in the reduction of HBsAg and HBcrAg levels between the ETV‐TAF and ETV groups. There was no significant difference in the change of estimated glomerular filtration rate levels from baseline to 48 weeks between the two groups. Conclusions The present study indicated that the efficacy, especially of the HBsAg‐reducing action, and safety of sequential therapy from ETV to TAF were similar to those of continuous ETV monotherapy among chronic hepatitis B patients with maintained virologic response to ETV.
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Affiliation(s)
- Norio Itokawa
- Department of Internal Medicine, Division of Gastroenterology Nippon Medical School Chiba Hokusoh Hospital Chiba Japan
| | - Masanori Atsukawa
- Department of Internal Medicine, Division of Gastroenterology Nippon Medical School Chiba Hokusoh Hospital Chiba Japan.,Department of Internal Medicine, Division of Gastroenterology and Hepatology Nippon Medical School Tokyo Japan
| | - Akihito Tsubota
- Core Research Facilities The Jikei University School of Medicine Tokyo Japan
| | - Koichi Takaguchi
- Department of Hepatology Kagawa Prefectural Central Hospital Takamatsu Japan
| | - Makoto Nakamuta
- Department of Gastroenterology National Hospital Organization Kyushu Medical Center Fukuoka Japan
| | - Atsushi Hiraoka
- Gastroenterology Center Ehime Prefectural Central Hospital Matsuyama Japan
| | - Keizo Kato
- Division of Gastroenterology and Hepatology Shinmatusdo Central General Hospital Matsudo Japan
| | - Hiroshi Abe
- Division of Gastroenterology and Hepatology Shinmatusdo Central General Hospital Matsudo Japan
| | - Shigeru Mikami
- Department of Internal Medicine, Division of Gastroenterology Kikkoman General Hospital Noda Japan
| | - Noritomo Shimada
- Department of Internal Medicine, Division of Gastroenterology and Hepatology Otakanomori Hospital Chiba Japan
| | - Makoto Chuma
- Gastroenterological Center Yokohama City University Medical Center Yokohama Japan
| | - Nozaki Akito
- Gastroenterological Center Yokohama City University Medical Center Yokohama Japan
| | - Haruki Uojima
- Department of Gastroenterology Kitasato University School of Medicine Kanagawa Japan
| | - Chikara Ogawa
- Department of Gastroenterology and Hepatology Takamatsu Red Cross Hospital Takamatsu Japan
| | - Toru Asano
- Department of Internal Medicine, Division of Gastroenterology and Hepatology Tokyo Metropolitan Bokutoh Hospital Tokyo Japan
| | - Joji Tani
- Department of Gastroenterology Kagawa University Graduate School of Medicine Kagawa Japan
| | - Asahiro Morishita
- Department of Gastroenterology Kagawa University Graduate School of Medicine Kagawa Japan
| | - Tomonori Senoh
- Department of Hepatology Kagawa Prefectural Central Hospital Takamatsu Japan
| | - Naoki Yamashita
- Department of Gastroenterology National Hospital Organization Kyushu Medical Center Fukuoka Japan
| | - Tsunekazu Oikawa
- Department of Gastroenterology and Hepatology The Jikei University School of Medicine Tokyo Japan
| | - Yoshihiro Matsumoto
- Department of Gastroenterology and Hepatology Jikei University School of Medicine Kashiwa Hospital Chiba Japan
| | - Mai Koeda
- Department of Internal Medicine, Division of Gastroenterology Nippon Medical School Chiba Hokusoh Hospital Chiba Japan
| | - Yuji Yoshida
- Department of Internal Medicine, Division of Gastroenterology Nippon Medical School Chiba Hokusoh Hospital Chiba Japan
| | - Tomohide Tanabe
- Department of Internal Medicine, Division of Gastroenterology and Hepatology Nippon Medical School Tokyo Japan
| | - Tomomi Okubo
- Department of Internal Medicine, Division of Gastroenterology Nippon Medical School Chiba Hokusoh Hospital Chiba Japan
| | - Taeang Arai
- Department of Internal Medicine, Division of Gastroenterology and Hepatology Nippon Medical School Tokyo Japan
| | - Korenobu Hayama
- Department of Internal Medicine, Division of Gastroenterology and Hepatology Nippon Medical School Tokyo Japan
| | - Ai-Nakagawa Iwashita
- Department of Internal Medicine, Division of Gastroenterology and Hepatology Nippon Medical School Tokyo Japan
| | - Chisa Kondo
- Department of Internal Medicine, Division of Gastroenterology and Hepatology Nippon Medical School Tokyo Japan
| | - Toshifumi Tada
- Department of Gastroenterology Ogaki Municipal Hospital Gifu Japan
| | - Hidenori Toyoda
- Department of Gastroenterology Ogaki Municipal Hospital Gifu Japan
| | | | - Katsuhiko Iwakiri
- Department of Internal Medicine, Division of Gastroenterology and Hepatology Nippon Medical School Tokyo Japan
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16
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Udompap P, Tanwandee T, Gani R. Affordability of Antiviral Therapy in Asia-Pacific Countries and Its Impact on Public Health Outcomes. Clin Liver Dis (Hoboken) 2021; 16:249-253. [PMID: 33489097 PMCID: PMC7805294 DOI: 10.1002/cld.977] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 04/20/2020] [Accepted: 04/22/2020] [Indexed: 02/04/2023] Open
Affiliation(s)
- Prowpanga Udompap
- Department of MedicineUniversity of MinnesotaMinneapolisMN,Division of GastroenterologyDepartment of MedicineFaculty of Medicine Siriraj HospitalMahidol UniversityBangkokThailand
| | - Tawesak Tanwandee
- Division of GastroenterologyDepartment of MedicineFaculty of Medicine Siriraj HospitalMahidol UniversityBangkokThailand
| | - Rino Gani
- Hepatobiliary DivisionDepartment of Internal MedicineFaculty of MedicineUniversity of IndonesiaCipto Mangunkusumo HospitalJakartaIndonesia
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17
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Itokawa N, Atsukawa M, Tsubota A, Shimada N, Toyoda H, Takaguchi K, Hiraoka A, Senoh T, Koeda M, Yoshida Y, Okubo T, Arai T, Hayama K, Nakagawa-Iwashita A, Kondo C, Iwakiri K. Factors Associated with Hepatitis B Surface Antigen Kinetics and Responses in Pegylated Interferon Alpha-2a Monotherapy for Patients with Chronic Hepatitis B. Intern Med 2021; 60:507-516. [PMID: 33583931 PMCID: PMC7946504 DOI: 10.2169/internalmedicine.5432-20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Objective Pegylated-interferon monotherapy is the standard treatment for patients with chronic hepatitis B; however, the factors associated with its therapeutic effects remain unclear. Methods Patients with chronic hepatitis B were treated with pegylated interferon α-2a for 48 weeks. We evaluated the kinetics of hepatitis B surface antigen (HBsAg) during treatment and follow-up periods and the factors associated with an HBsAg response (defined as a change in HBsAg of ≥-1 log IU/mL from baseline). Results The study population comprised 50 patients. The median baseline levels of hepatitis B virus DNA and HBsAg were 5.00 and 3.40 log IU/mL. The median values of HBsAg reduction from baseline were -0.44 (n=48), -0.41 (n=40), and -0.68 (n=11) log IU/mL at the end of treatment and at 48 and 144 weeks post-treatment, respectively. The rates of HBsAg response were 24.0% and 22.5% at the end of treatment and at 48 weeks post-treatment, respectively. A multivariate analysis identified HBsAg <3.00 log IU/mL as an independent baseline factor contributing to the HBsAg response at the end of treatment and 48 weeks post-treatment (p=1.07×10-2 and 4.42×10-2, respectively). There were significant differences in the reduction of the HBsAg levels at 12 weeks of treatment and in the incidence of serum ALT increase during treatment between patients with and without an HBsAg response. Conclusion These findings suggest that the baseline HBsAg level, HBsAg kinetics at 12 weeks of treatment, and ALT increase during treatment are important factors contributing to the HBsAg response in pegylated interferon α-2a monotherapy for patients with chronic hepatitis B.
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Affiliation(s)
- Norio Itokawa
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Japan
| | - Masanori Atsukawa
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Japan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Japan
| | - Akihito Tsubota
- Core Research Facilities, The Jikei University School of Medicine, Japan
| | - Noritomo Shimada
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Otakanomori Hospital, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Japan
| | - Koichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central Hospital, Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Japan
| | - Tomonori Senoh
- Department of Hepatology, Kagawa Prefectural Central Hospital, Japan
| | - Mai Koeda
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Japan
| | - Yuji Yoshida
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Japan
| | - Tomomi Okubo
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Japan
| | - Taeang Arai
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Japan
| | - Korenobu Hayama
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Japan
| | - Ai Nakagawa-Iwashita
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Japan
| | - Chisa Kondo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Japan
| | - Katsuhiko Iwakiri
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Japan
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18
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Chen K, Chang C, Lee J, Yang C. Tenofovir disoproxil fumarate for patients with chronic hepatitis B who suboptimal response to non‐tenofovir disoproxil fumarate nucleos(t)ide analogs therapy. ADVANCES IN DIGESTIVE MEDICINE 2020. [DOI: 10.1002/aid2.13171] [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: 11/11/2022]
Affiliation(s)
- Kwei‐Ming Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Show Chwan Memorial Hospital Changhua Taiwan
| | - Chi‐Hsien Chang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Show Chwan Memorial Hospital Changhua Taiwan
| | - Jyong‐Hong Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Show Chwan Memorial Hospital Changhua Taiwan
| | - Chi‐Chieh Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Show Chwan Memorial Hospital Changhua Taiwan
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Japan Society of Hepatology Guidelines for the Management of Hepatitis B Virus Infection: 2019 update. Hepatol Res 2020; 50:892-923. [PMID: 32343469 DOI: 10.1111/hepr.13504] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 03/16/2020] [Accepted: 03/22/2020] [Indexed: 02/06/2023]
Abstract
The Drafting Committee for Hepatitis Management Guidelines established by the Japan Society of Hepatology published the first version of the Guidelines for the Management of Hepatitis B in 2013 (first English version in 2014), and has since been publishing updates to the Guidelines as new drugs become available, with the latest original Japanese version being Version 3.1. Herein, the Drafting Committee publishes the second English version that contains all the changes made since the first English version of the guidelines was published in 2014. This 2019 version covers: (i) the nucleos(t)ide analogs, tenofovir disoproxil fumarate and tenofovir alafenamide; (ii) updates to treatment recommendations and management of drug-resistant hepatitis B virus that reflect the new availability of these drugs; and (iii) new information about hepatitis B virus reactivation with each update. This latest update also contains information about treatment goals, indications for treatment and cessation of nucleos(t)ide analog therapy, most of which were covered by the first version.
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Lampertico P, Berg T, Buti M, Pathil A, Petersen J, Ryder SD, Zoulim F, Botros I, Flaherty JF, Jump B, Op den Brouw ML, van Troostenburg A, Ramroth H. Treatment with tenofovir disoproxil fumarate or entecavir in chronic hepatitis B virus-infected patients with renal impairment: results from a 7-year, multicentre retrospective cohort study. Aliment Pharmacol Ther 2020; 52:500-512. [PMID: 32583915 PMCID: PMC7383725 DOI: 10.1111/apt.15901] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 04/02/2020] [Accepted: 05/30/2020] [Indexed: 01/09/2023]
Abstract
BACKGROUND Limited data exist regarding tenofovir disoproxil fumarate (TDF) safety and effectiveness in chronic hepatitis B virus-infected (CHB) patients with renal impairment (RI). AIMS To compare real-world data on renal safety and effectiveness of TDF vs entecavir (ETV) in CHB patients with moderate-to-severe RI. METHODS Retrospective, non-interventional, cohort study analysing medical records for TDF/ETV-treated CHB patients (54 European centres). Included patients experienced moderate-to-severe RI (creatinine clearance 20-60 mL/min [Cockcroft-Gault]) either before TDF/ETV initiation ('before' subgroup [baseline = treatment initiation]) or after TDF/ETV initiation ('after' subgroup [baseline = first RI occurrence]). The primary objective was TDF safety, particularly renal-related adverse events of special interest (AESI). TDF and ETV safety and effectiveness were compared and multivariate analyses were performed using inverse probability treatment weighting. RESULTS 'Before' subgroup included 107 TDF- and 91 ETV-treated patients; 'after' subgroup included 212 TDF- and 77 ETV-treated patients. Mean baseline creatinine clearance was higher for TDF- vs ETV-treated patients (both subgroups). Median follow-up was 3.1 years (both treatments). AESI were more frequent with TDF vs ETV ('before': 18.7% vs 8.8%; 'after': 9.9% vs 3.9%); however, differences were not significant by multivariate analysis. Only TDF-treated patients experienced renal tubular dysfunction (6.5% 'before'; 1.9% 'after') as well as renal adverse events leading to treatment discontinuation (8.4% 'before'; 7.1% 'after'). Effectiveness was similar between treatments. CONCLUSIONS Overall safety was similar for TDF vs ETV (both subgroups). Given that renal tubular dysfunction occurred with TDF and not with ETV, renal safety concerns may be greater with TDF in CHB patients with RI.
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Park S, Park ES, Koo JE, Park YK, Lee AR, Dezhbord M, Cho ES, Ahn SH, Kim DH, Lee JH, Lee HC, Kim KH. Entecavir-resistant hepatitis B virus decreases surface antigenicity: A full genome and functional characterization. Liver Int 2020; 40:1564-1577. [PMID: 32216026 DOI: 10.1111/liv.14446] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Revised: 02/17/2020] [Accepted: 03/17/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Since polymerase and surface genes overlap in hepatitis B virus (HBV), an antiviral-induced mutation in the polymerase gene may alter the surface antigenicity in patients with chronic hepatitis B (CHB), but this possibility has not been clearly confirmed. This study aimed to determine the drug susceptibility and surface antigenicity of the patient-derived mutants. PATIENTS AND METHODS Full-length HBV genomes isolated from four entecavir-resistant CHB patients were cloned and sequenced. Around 10 clones of full-length HBV obtained from each patient were analysed and registered in the NCBI GenBank. Representative clones were further characterized by in vitro drug susceptibility and surface antigenicity assays. RESULTS The rtL180M + rtM204V mutations were common among all the clones analysed. Additionally, the ETV resistance mutations rtT184A/L, rtS202G and rtM250V were found among three patients. Most of the ETV-resistant mutants had amino acid alterations within the known epitopes recognized by T- and B-cells in the HBV surface and core antigens. The in vitro drug susceptibility assay showed that all tested clones were resistant to ETV treatment. However, they were all susceptible to ADV and TDF. More importantly, the rtI169T mutation in the RT domain, led to the sF161L mutation in the overlapping S gene, which decreased in surface antigenicity. CONCLUSIONS The ETV resistance mutations can affect the antigenicity of the HBsAg proteins due to changes in the overlapping sequence of this surface antigen. Thus, the apparent decline or disappearance of HBsAg needs to be interpreted cautiously in patients with previous or current antiviral resistance mutations.
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Affiliation(s)
- Soree Park
- Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Korea
| | - Eun-Sook Park
- Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Korea
| | - Ja Eun Koo
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Yong Kwang Park
- Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Korea
| | - Ah Ram Lee
- Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Korea
| | - Mehrangiz Dezhbord
- Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Korea
| | - Eun Sook Cho
- Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Korea
| | - Sung Hyun Ahn
- Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Korea
| | - Doo Hyun Kim
- Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Han Chu Lee
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Kyun-Hwan Kim
- Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Korea.,Department of Precision Medicine, Sungkyunkwan University School of Medicine, Suwon, Korea
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Woo HY, Park JY, Bae SH, Kim CW, Jang JY, Tak WY, Kim DJ, Kim IH, Heo J, Ahn SH. Entecavir+tenofovir vs. lamivudine/telbivudine+adefovir in chronic hepatitis B patients with prior suboptimal response. Clin Mol Hepatol 2020; 26:352-363. [PMID: 32460460 PMCID: PMC7364362 DOI: 10.3350/cmh.2019.0044n] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 04/06/2020] [Accepted: 04/07/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/AIMS Suboptimal responses to lamivudine or telbivudine plus adefovir (LAM/LdT+ADV) rescue therapy are common in patients with LAM-resistant hepatitis B virus (HBV) infections. We compared patients switched to entecavir plus tenofovir (ETV+TDF) to those maintained on LAM/LdT+ADV. METHODS This prospective randomized controlled trial examined 91 patients whose serum HBV DNA levels were greater than 60 IU/mL after at least 24 weeks of treatment with LAM/LdT+ADV for LAM-resistant HBV. Patients were randomized to receive a new treatment (ETV+TDF, n=45) or maintained on the same treatment (LAM/LdT+ADV, n=46) for 48 weeks. Patients with baseline ADV resistance were excluded. RESULTS Compared to LAM/LdT+ADV group, ETV+TDF group had more patients with a virologic response (42/45 [93.33%] vs. 3/46 [6.52%], P<0.001) and had a greater mean reduction in serum HBV DNA level from baseline (-4.16 vs. -0.37 log10 IU/mL, P<0.001). Multivariate analysis indicated that high baseline HBV DNA level (P=0.005) and LAM/LdT+ADV maintenance therapy (P=0.001) were negatively associated with virologic response. At week 48, additional ADV- or ETV-associated mutations were cleared in ETV+TDF group, but such mutations were present in 4.3% of patients in LAM/LdT+ADV group (P=0.106). The two groups had similar rates of adverse events. CONCLUSION ETV+TDF combination treatment led to a significantly higher rate of virologic response compared to LAM/LdT+ADV combination treatment in patients with LAM-resistant HBV who had suboptimal responses to LAM/LdT+ADV regardless of HBV genotypic resistance profile (NCT01597934).
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Affiliation(s)
- Hyun Young Woo
- Department of Internal Medicine, College of Medicine, Pusan National University, Busan, Korea
- Medical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Si Hyun Bae
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Chang Wook Kim
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jae Young Jang
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Won Young Tak
- Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea
| | - Dong Joon Kim
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Korea
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Korea
| | - In Hee Kim
- Department of Internal Medicine, Chonbuk National University Hospital, Chonbuk National University College of Medicine, Chonju, Korea
| | - Jeong Heo
- Department of Internal Medicine, College of Medicine, Pusan National University, Busan, Korea
- Medical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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Deng H, Liang S, Xu M, Zhuo L, Gao H, Chen K, Shi Y, Li H, Jiao Q, Lin L, Lei Y, Liu H. Clinical efficacy and safety in telbivudine- or tenofovir-treated hepatitis B e antigen-positive pregnant women. Antivir Ther 2020; 25:33-41. [PMID: 32049069 DOI: 10.3851/imp3345] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/05/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Telbivudine (LdT) and tenofovir (TDF) are widely used in pregnant women to prevent vertical transmission; however, limited data are available on the differences in clinical efficacy and safety between the two drugs. METHODS A total of 307 hepatitis B e antigen (HBeAg)-positive pregnant women with complete follow-up data were enrolled, the patients with alanine aminotransferase (ALT) levels <1×ULN at baseline were enrolled to cohort 1 for treatment from 28 ±4 weeks gestation to delivery, while ALT levels >1×ULN at baseline were enrolled to cohort 2 for treatment from 28 ±4 weeks gestation and continued after delivery. The clinical efficacy and safety was compared in LdT- and TDF-treated patients. In addition, 32 patients in cohort 1 were analysed for nucleoside analogue (NA)-related resistance mutations at baseline and after delivery. RESULTS The results showed that HBV DNA levels were significantly lower at delivery than at baseline (P<0.001), but the decreases in HBV DNA, ALT, total bilirubin and total bile acid levels did not differ between the LdT- and TDF-treated patients at different time points (P>0.05) in the two cohorts. However, gastrointestinal adverse effects (vomiting) occurred more frequently in TDF-treated than LdT-treated patients (6.6% versus 0.0%; P=0.001). The results of NA-related resistance mutations analysis in cohort 1 revealed that short-term LdT or TDF treatment did not significantly change the NA-related resistance mutations (P>0.05). CONCLUSIONS This study revealed that the clinical efficacy in LdT- or TDF-treated HBeAg-positive Chinese pregnant women is similar, and gastrointestinal adverse effects occurred more frequently in TDF-treated patients.
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Affiliation(s)
- Haohui Deng
- Department of Infectious Diseases Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Shuzhen Liang
- Community Health Service Center of Lin He Street, Guangzhou, China
| | - Min Xu
- Department of Infectious Diseases Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Li Zhuo
- Department of Infectious Diseases Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Hongbo Gao
- Department of Infectious Diseases Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Keng Chen
- Department of Infectious Diseases Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yuming Shi
- Department of Infectious Diseases Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Huihui Li
- Department of Infectious Diseases Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Qian Jiao
- Department of Infectious Diseases Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Liansheng Lin
- Department of Infectious Diseases Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yan Lei
- Department of Infectious Diseases Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Huiyuan Liu
- Department of Infectious Diseases Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
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Tafesh ZH, Brown RS. Management of Virologic Failure in Patients with Chronic Hepatitis B Treated with Nucleos(t)ide Analogues. CURRENT HEPATOLOGY REPORTS 2019; 18:363-369. [DOI: 10.1007/s11901-019-00483-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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25
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Vittal A, Ghany MG. WHO Guidelines for Prevention, Care and Treatment of Individuals Infected with HBV: A US Perspective. Clin Liver Dis 2019; 23:417-432. [PMID: 31266617 PMCID: PMC9616205 DOI: 10.1016/j.cld.2019.04.008] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The prevalence of chronic hepatitis B (CHB) differs globally. CHB is responsible for 30% of all deaths from cirrhosis and 40% from hepatocellular carcinoma. The WHO developed guidelines in 2015 on prevention, care, and treatment of chronic HBV infection targeted to program managers in all health care settings, particularly in low- and middle-income countries. Several of the recommendations differ from those of the major Liver Societies, including the American Association for the Study of Liver Diseases (AASLD). This review highlights key differences between the AASLD and WHO guidelines and discusses the impact on management of CHB.
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Manne V, Gochanour E, Kowdley KV. Current perspectives into the evaluation and management of hepatitis B: a review. Hepatobiliary Surg Nutr 2019; 8:361-369. [PMID: 31489305 DOI: 10.21037/hbsn.2019.02.09] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Hepatitis B is a widespread disease which affects millions of people worldwide. Chronic hepatitis B (CHB) can lead to significant morbidity and mortality due to complications such as cirrhosis and hepatocellular carcinoma. The pathophysiology of hepatitis is critical to diagnosing CHB. Deciding which patients with CHB should be treated is an important decision as treatment can often lead to better outcomes in the appropriate patient population. The nucleos(t)ide analog inhibitors entecavir and tenofovir are currently the mainstay of treatment as they are able to successfully suppress the virus and lead to fewer complications. Novel therapies are currently being developed which may offer a potential cure for this disease in the future.
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Affiliation(s)
- Vignan Manne
- Liver Care Network, Swedish Medical Center, Seattle, WA, USA
| | - Eric Gochanour
- Liver Care Network, Swedish Medical Center, Seattle, WA, USA
| | - Kris V Kowdley
- Liver Care Network, Swedish Medical Center, Seattle, WA, USA
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27
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Lim YS, Gwak GY, Choi J, Lee YS, Byun KS, Kim YJ, Yoo BC, Kwon SY, Lee HC. Monotherapy with tenofovir disoproxil fumarate for adefovir-resistant vs. entecavir-resistant chronic hepatitis B: A 5-year clinical trial. J Hepatol 2019; 71:35-44. [PMID: 30876946 DOI: 10.1016/j.jhep.2019.02.021] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Revised: 02/06/2019] [Accepted: 02/22/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS Tenofovir disoproxil fumarate (TDF) monotherapy has displayed non-inferior efficacy to TDF plus entecavir (ETV) combination therapy in patients with hepatitis B virus (HBV) resistant to ETV and/or adefovir (ADV). Nonetheless, the virologic response rate was suboptimal in patients receiving up to 144 weeks of TDF monotherapy. We aimed to assess the efficacy and safety of TDF monotherapy given for up to 240 weeks. METHODS One trial enrolled patients with ETV resistance without ADV resistance (n = 90), and another trial included patients with ADV resistance (n = 102). Most patients (91.2%) also had lamivudine resistance. Patients were randomized 1:1 to receive TDF monotherapy or TDF + ETV combination therapy for 48 weeks, and then TDF monotherapy until week 240. We compared efficacy between the studies and safety in the pooled population at 240 weeks. RESULTS At week 240, the proportion of patients with serum HBV DNA <15 IU/ml was not significantly different between the ETV and ADV resistance groups in the full analysis set (84.4% vs. 73.5%; p = 0.07), which was significantly different by on-treatment analysis (92.7% vs. 79.8%; p = 0.02). Virologic blips associated with poor medication adherence occurred in 7 patients throughout the 240 weeks. None developed additional HBV resistance mutations. Among the 170 HBV e antigen (HBeAg)-positive patients at baseline, 12 (7.1%) achieved HBeAg seroconversion at week 240. None achieved HBV surface antigen seroclearance. Significant decreases from baseline were observed at week 240 in the estimated glomerular filtration rate (-3.21 ml/min/1.73 m2 by the CKD-EPI equation, p <0.001) and bone mineral density (g/cm2) at the femur (-2.48%, p <0.001). CONCLUSIONS Up to 240 weeks of TDF monotherapy provided an increasing virologic response rate in heavily pretreated patients with HBV resistant to ETV and/or ADV. However, it was associated with poor serological responses and decreasing renal function and bone mineral density. (ClinicalTrials.gov No, NCT01639066 and NCT01639092). LAY SUMMARY In patients chronically infected with hepatitis B virus resistant to multiple drugs including lamivudine, entecavir, and/or adefovir, tenofovir disoproxil fumarate (TDF) monotherapy showed non-inferior efficacy compared with the combination therapy of TDF plus entecavir. Nonetheless, short-term TDF monotherapy was associated with suboptimal virologic response, and its long-term safety was uncertain. This study displayed that 240 weeks of TDF monotherapy provided a virologic response in most of those patients, but it was associated with poor serological responses and decreasing renal function and bone mineral density.
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Affiliation(s)
- Young-Suk Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
| | - Geum-Youn Gwak
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jonggi Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yung Sang Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kwan Soo Byun
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Byung Chul Yoo
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Republic of Korea
| | - So Young Kwon
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Republic of Korea
| | - Han Chu Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
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Chan HLY. Okuda lecture: Challenges of hepatitis B in the era of antiviral therapy. J Gastroenterol Hepatol 2019; 34:501-506. [PMID: 30402981 DOI: 10.1111/jgh.14534] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 10/25/2018] [Accepted: 10/30/2018] [Indexed: 12/13/2022]
Abstract
Nucleos(t)ide analogs (NAs) are effective, safe, and convenient antiviral therapy to suppress replication of hepatitis B virus, which can be translated into improved long-term outcome of chronic hepatitis B patients. The current recommended first-line NAs, namely, entecavir and tenofovir, are largely free from problems of drug resistance. Nonetheless, there are still a few challenges in the era of NA. First, the risk of hepatocellular carcinoma can only be reduced but not eliminated, particularly among cirrhotic patients. For cirrhotic patients who have persistent low-level viremia on NA, that is, partial responders, the risk of hepatocellular carcinoma is higher than those with complete viral suppression. The best strategy to manage partial responders to entecavir or tenofovir is uncertain. Second, immune-tolerant patients are very difficult to treat with NA. A significant proportion of immune-tolerant patients will have detectable viremia despite a few years of continuous NA treatment, and the rate of hepatitis B e-antigen seroconversion is very low. Third, most patients need long-term treatment as NA cannot eliminate covalently closed circular DNA in the hepatocytes. Some patients can consider stop NA according to treatment guidelines, but viral and clinical relapses often occur after treatment cessation. There is no concrete consensus on when one should stop NA in a hepatitis B e-antigen-negative patient among different treatment guidelines. New biomarkers such as hepatitis B surface antigen level can be used to select patients to stop NA, but the data are still preliminary.
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Affiliation(s)
- Henry Lik Yuen Chan
- Department of Medicine and Therapeutics, Institute of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong
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Li X, Luo J, Zhu C, Wu Y, Li Z, Jie Y, Zhang Y, Lin G, Li X, Zhang Y, Shu X. Efficacy of tenofovir disoproxil fumarate switch therapy in chronic hepatitis B patients with suboptimal response to adefovir-based combination therapy. Exp Ther Med 2019; 17:1196-1205. [PMID: 30679993 PMCID: PMC6327499 DOI: 10.3892/etm.2018.7081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 09/06/2018] [Indexed: 02/05/2023] Open
Abstract
In the present study, the efficacy and safety of tenofovir disoproxil fumarate (TDF) switch therapy were assessed in patients with chronic hepatitis B exhibiting a suboptimal response to adefovir (ADV)-based combination therapy. First, the efficacy of the TDF switch therapy was retrospectively evaluated in 50 patients with chronic hepatitis B who failed to respond to ADV-based combination treatment. Among those, 48 patients with a median age of 35 years were hepatitis B e antigen (HBeAg)-positive and 17, 14 and 19 patients were previously treated with lamivudine (LAM) plus ADV, telbivudine plus ADV and entecavir (ETV) plus ADV, respectively. A total of 41 patients were treated with TDF alone and 9 with TDF plus ETV. The median time of follow-up was 102 weeks. The primary end-point was the cumulative probability of achieving a complete virologic response (CVR). The secondary end-points were the rate of alanine aminotransferase (ALT) normalization, HBeAg seroconversion in HBeAg-positive patients, and the plasma levels of creatinine and creatine kinase. The mean serum hepatitis B virus DNA levels prior to initiation of the TDF switch therapy were 4.8±1.6 log10IU/ml. The cumulative probability of achieving a VR at 24, 48, 96 and 108 weeks was 52.0, 76.0, 89.8 and 94.9%, respectively. The cumulative probability of normalization of ALT at 12, 24, 36, 48, 60,72, 84, 96, 108, 120 and 132 weeks was 34, 44, 50, 58, 66, 70, 74, 80, 90, 92 and 94%, respectively. HBeAg seroconversion was achieved in 5 patients. During the follow-up, 6 patients suffered from a virologic breakthrough, 3 patients failed to respond to the TDF treatment and the remaining patients were able to obtain VR following the continuation of TDF treatment. Slightly elevated serum levels of creatinine were observed in one patient, whereas creatine kinase activity did not increase in any of the subjects. In conclusion, TDF switch therapy is efficient and safe for patients with chronic hepatitis B with a suboptimal response to ADV-based combination therapy.
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Affiliation(s)
- Xiangyong Li
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Jie Luo
- Department of Hepatology, Shenzhen Luohu People's Hospital, Shenzhen, Guangdong 518020, P.R. China
| | - Changhao Zhu
- Intensive Care Unit, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Yuankai Wu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Zhanyi Li
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Yusheng Jie
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Yeqiong Zhang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Guoli Lin
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Xinhua Li
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Ying Zhang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
- Correspondence to: Dr Ying Zhang or Dr Xin Shu, Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, Guangdong 510630, P.R. China, E-mail: , E-mail:
| | - Xin Shu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
- Correspondence to: Dr Ying Zhang or Dr Xin Shu, Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, Guangdong 510630, P.R. China, E-mail: , E-mail:
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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 2019; 118:7-38. [PMID: 30527436 DOI: 10.1016/j.jfma.2018.11.008] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [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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31
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Aziz M, Aziz H, Waheed Y, Gill ML. Predictors of Therapeutic Outcome to Nucleotide Reverse Transcriptase Inhibitor in Hepatitis B Patients. Viral Immunol 2018; 31:632-638. [PMID: 30285571 DOI: 10.1089/vim.2018.0022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Hepatitis B is a clinically important public health issue. Infection leads to hepatocellular carcinoma. Therefore, patients need antiviral therapy for prolonged period to prevent the complication of the disease. Data concerning chronic hepatitis B (CHB) patients with high hepatitis B virus (HBV) DNA are limited. The aim of the study was to check the efficacy of the nucleoside reverse transcriptase inhibitors (tenofovir) in terms of suppression of HBV DNA. The secondary end point in the study is to evaluate trends of predictive variables that predict outcome of treatment. In this specific study, we evaluated 140 CHB male and female patients, of these 110 completed 48 weeks of treatment. On the basis of hepatitis B e antigen (HBeAg), patients were stratified; HBV DNA and hepatitis B surface antigen (HBsAg) levels were measured along with liver function tests. All enrolled patients were given tenofovir disoproxil fumarate 300 mg daily before breakfast. Overall, 69.1% of patients showed virologic response. HBeAg-negative patient group showed 68% viral suppression and HBeAg-positive patient group showed 45.9% over 24 months of treatment, while at 48 months it was shown to be 76.7% and 54.1%, respectively. None of the patients suffered HBsAg loss during the 48 months. Baseline high HBV DNA level was found as a significant predictor of response (OR, 1.9; 95% CI = 1.23-3.9, p = 0.005). None of the patients observed had serious adverse events. Mutations in the RT region of polymerase gene are shown to be associated with resistance to antiviral drugs. Among patients suffering with chronic HBV infection, HBeAg-negative patient group have better virologic response as compared with HBeAg-positive group. Higher concentration of HBV DNA at baseline has negative prediction for sustained viral suppression. The A-B motif interdomain rtL122F mutation was found in nonresponder patients in our study. Another mutation rtN248H observed in E motif considered to have effect on DNA primer grip, which forms part of binding pocket.
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Affiliation(s)
- Muneba Aziz
- 1 Maroof International Hospital , Islamabad, Pakistan
- 2 Allied Hospital , Faisalabad, Pakistan
| | - Hafsa Aziz
- 3 Diagnostic Labs, Nuclear Medicine Oncology and Radiotherapy Institute , Islamabad, Pakistan
| | - Yasir Waheed
- 4 Foundation University Islamabad , Islamabad, Pakistan
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32
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Kim DY, Park JY. Step-down strategy in antiviral resistant chronic hepatitis B patients who achieved viral suppression with rescue combination therapy. Future Virol 2018. [DOI: 10.2217/fvl-2018-0078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
In the treatment of chronic hepatitis B (CHB) patients with drug resistance, rescue combination therapy leads to viral suppression in almost all patients. However, once it is achieved, lifelong maintenance especially, by using combination therapy is not always possible in a significant proportion of patients. At present, there is no consensus on whether it is possible to switch to monotherapy from combination therapy. However, there is robust evidence to support step-down therapy, which involves switching from combination therapy to monotherapy in antiviral resistant CHB patients who achieve complete viral response from combination therapy. We review the evidence in favor of switching to monotherapy in antiviral resistant CHB patients who achieve complete viral response by combination therapy.
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Affiliation(s)
- Dong Yun Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
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No Resistance to Tenofovir Alafenamide Detected through 96 Weeks of Treatment in Patients with Chronic Hepatitis B Infection. Antimicrob Agents Chemother 2018; 62:AAC.01064-18. [PMID: 30038044 DOI: 10.1128/aac.01064-18] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 06/14/2018] [Indexed: 12/19/2022] Open
Abstract
Tenofovir alafenamide (TAF) has shown equivalent efficacy and improved safety profiles for patients with chronic hepatitis B (CHB) compared to tenofovir disoproxil fumarate (TDF). However, limited data are available for its resistance profiles. In two clinical trials, 1,298 hepatitis E antigen-positive and -negative patients with CHB were randomized 2:1 and treated with TAF (n = 866) or TDF (n = 432). Baseline nucleos(t)ide analog resistance substitutions in HBV polymerase/reverse transcriptase (Pol/RT) were assessed using INNO-LiPA Multi-DR v2/v3. Resistance surveillance was conducted for patients with viremia (HBV DNA ≥ 69IU/ml) by HBV Pol/RT sequencing at week 96 or at discontinuation. In vitro phenotypic analysis was performed for patients with conserved site substitutions or virologic breakthrough while adherent to the study drug. At baseline, the majority of patients harbored virus with wild-type Pol/RT (89.2%), with 10.8% harboring resistance associated mutations. A similar percentage of patients in the TAF or TDF groups qualified for sequence analysis through week 96 (TAF, 11.1%; TDF, 10.9%). Of these, a small percentage of patients experienced virologic breakthrough (TAF, 2.8%; TDF, 3.2%) that was often associated with drug nonadherence (TAF, 30%; TDF, 50%). Across treatment groups, 132 patients qualified for sequence analysis through week 96, with nearly half having no sequence changes from baseline (43.2%). Most sequence changes occurred at polymorphic positions, and no isolates showed a reduction in susceptibility in vitro After 96 weeks, the proportion of patients achieving virus suppression (HBV DNA < 69 IU/ml) was similar across treatment groups, and no substitutions associated with resistance to TAF or TDF were detected. (These studies have been registered at ClinicalTrials.gov under identifiers NCT01940471 and NCT01940341.).
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Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, Brown RS, Bzowej NH, Wong JB. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018; 67:1560-1599. [PMID: 29405329 PMCID: PMC5975958 DOI: 10.1002/hep.29800] [Citation(s) in RCA: 2788] [Impact Index Per Article: 398.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 01/11/2018] [Indexed: 12/11/2022]
Affiliation(s)
- Norah A Terrault
- Division of Gastroenterology/Hepatology, University of California San Francisco, San Francisco, CA
| | - Anna S F Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI
| | - Brian J McMahon
- Liver Diseases and Hepatitis Program, Alaska NativeTribal Health Consortium, Anchorage, AK
| | - Kyong-Mi Chang
- Division of Gastroenterology, Corporal Michael J. Crescenz VA Medical Center & University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | - Jessica P Hwang
- Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Maureen M Jonas
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA
| | - Robert S Brown
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY
| | | | - John B Wong
- Division of Clinical Decision Making, Tufts Medical Center, Tufts University School of Medicine, Boston, MA
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No longer 'written off' - times have changed for the BBV-infected dental professional. Br Dent J 2018; 222:47-52. [PMID: 28084394 DOI: 10.1038/sj.bdj.2017.36] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/03/2016] [Indexed: 12/28/2022]
Abstract
There is a recognised potential risk of transmission of blood-borne viruses (BBVs) from infected healthcare workers to patients during exposure prone procedures (EPPs). The restrictions placed on performance of EPPs by infected clinicians in the UK have had a particularly significant impact on dentists because of the exposure-prone nature of most dental procedures and the difficulties in identifying alternative career pathways in the profession that do not involve EPPs. More recently, the significant positive impact of antiviral drugs on viral load, together with a re-categorisation of EPPs in dentistry have resulted in evolution of the guidance with a consequent significant improvement to the career prospects of dentists infected with BBVs. This paper provides an update for practitioners on the progress that has been made and outlines the current position with respect to practice restrictions.
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Kim DY, Lee HW, Song JE, Kim BK, Kim SU, Kim DY, Ahn SH, Han KH, Park JY. Switching from tenofovir and nucleoside analogue therapy to tenofovir monotherapy in virologically suppressed chronic hepatitis B patients with antiviral resistance. J Med Virol 2018; 90:497-502. [PMID: 29077211 DOI: 10.1002/jmv.24986] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 09/27/2017] [Indexed: 12/30/2022]
Abstract
It is unclear whether chronic hepatitis B (CHB) patients with antiviral resistance, who achieve a complete virologic response (CVR) with tenofovir disoproxil fumarate (TDF) and nucleoside analogue (NUC) combination therapy, maintain CVR if switched to TDF monotherapy. We investigated the persistence of CVR after cessation of NUC in virologically suppressed antiviral resistant CHB patients using TDF+NUC combination therapy. This study recruited 76 antiviral-resistant CHB patients showing CVR on TDF+entecavir (ETV) (n = 52), TDF+lamivudine (LAM; n = 14), and TDF+telbivudine (LdT; n = 10) combination therapy, who were switched to TDF monotherapy as step-down therapy. At baseline, 47 patients were male and the median age was 53.0 years (range: 30-78 years); 72.3% cases were hepatitis B e antigen-positive (HBeAg+) and 23.7% were of liver cirrhosis. The median duration of TDF+NUC combination therapy was 20.8 months (range: 3-46 months). At a median follow-up of 24.7 months (range: 12-48 months) after switching to TDF monotherapy, all 76 patients maintained CVR, regardless of the duration of combination therapy and the type of prior NUC and antiviral resistance. Renal dysfunction was not observed during the treatment period. The step-down strategy of switching from TDF+NUC combination therapy to TDF monotherapy in virologically suppressed CHB patients with antiviral resistance should be considered.
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Affiliation(s)
- Dong Yun Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
| | - Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Jeong Eun Song
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Yonsei Liver Center, Severance Hospital, Seoul, South Korea
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37
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Evaluating the efficacy of switching from lamivudine plus adefovir to tenofovir disoproxil fumarate monotherapy in lamivudine-resistant stable hepatitis B patients. PLoS One 2018; 13:e0190581. [PMID: 29329305 PMCID: PMC5766122 DOI: 10.1371/journal.pone.0190581] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 12/15/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The efficacy of switching to tenofovir disoproxil fumarate (TDF) monotherapy from lamivudine (LAM) plus adefovir dipivoxil (ADV) combination therapy (stable switching) in patients with LAM-resistant chronic hepatitis B (CHB) and undetectable hepatitis B virus (HBV) DNA is not clear. METHODS In this non-inferiority trial, patients with LAM-resistant CHB and undetectable serum HBV DNA (<20 IU/mL) for >6 months after initiating LAM+ADV combination therapy were randomized (1:2) either to continue the combination therapy (LAM+ADV group, n = 58) or switched to TDF monotherapy (TDF group, n = 111). They were followed-up with serum biochemistry tests and HBV DNA measurement at 12-week intervals for 96 weeks. The primary endpoint of this study was the proportion of patients with viral reactivation at week 96. RESULTS Patients with CHB enrolled in this study (n = 169) included 74 patients with compensated liver cirrhosis. In total, 9 patients (4 in the LAM+ADV group and 5 in the TDF group) dropped-out from the study. After a mean follow-up period of 96 weeks, the proportion of HBV reactivation observed was 6.8% (4/58) in the LAM+ADV group and 4.5% (5/111) in the TDF group by using intention-to-treat analysis (difference, -2.3%; 95% CI, -9.84-5.24%). None of the subjects in either group experienced viral reactivation based on per protocol analysis. No serious adverse reactions were observed. In the subgroup analysis for estimated glomerular filtration rate (eGFR) before and after treatment, decreased eGFR was observed only in the TDF group with cirrhosis (85.22 vs. 79.83 mL/min/1.73 m2, p = 0.000). CONCLUSIONS Stable switching to TDF monotherapy yielded non-inferior results at 96 weeks compared to the results obtained with LAM+ADV combination therapy in patients with LAM-resistant CHB and undetectable HBV DNA. However, TDF monotherapy in patients with cirrhosis requires close attention with respect to renal function. TRIAL REGISTRATION ClinicalTrials.gov NCT01732367.
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38
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Kimberlin DW. Antiviral Agents. PRINCIPLES AND PRACTICE OF PEDIATRIC INFECTIOUS DISEASES 2018:1551-1567.e6. [DOI: 10.1016/b978-0-323-40181-4.00295-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Saxena V, Terrault NA. Recurrent Primary Disease After Liver Transplantation. ZAKIM AND BOYER'S HEPATOLOGY 2018:784-815.e14. [DOI: 10.1016/b978-0-323-37591-7.00053-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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40
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Lee SH, Cheon GJ, Kim HS, Kim SG, Kim YS, Jeong SW, Jang JY, Kim BS, Jun BG, Don Kim Y, Jun DW, Sohn JH, Kim TY, Lee BS. Tenofovir disoproxil fumarate monotherapy is superior to entecavir-adefovir combination therapy in patients with suboptimal response to lamivudine-adefovir therapy for nucleoside-resistant HBV: a 96-week prospective multicentre trial. Antivir Ther 2018; 23:219-227. [PMID: 28436380 DOI: 10.3851/imp3169] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/07/2017] [Indexed: 10/19/2022]
Abstract
BACKGROUND A complete virological response is closely related to the long-term outcome of patients with chronic hepatitis B and prevention of emerging HBV mutations. We aimed to evaluate the efficacy of tenofovir disoproxil fumarate (TDF) monotherapy compared to entecavir-adefovir dipivoxil (ETV-ADV) combination therapy in patients with suboptimal responses to long-term lamivudine-adefovir dipivoxil (LAM-ADV) therapy for nucleoside analogue-resistant chronic hepatitis B. METHODS Patients (n=60) were randomized to TDF monotherapy or ETV-ADV combination therapy for 96 weeks. All patients had the rt204I/V mutation and serum HBV DNA was measured (>60 IU/ml) during LAM-ADV therapy. The primary end point was a complete virological response (HBV DNA <20 IU/ml) at week 96. RESULTS The median duration of prior LAM-ADV rescue therapy was 43 (7-108) months. A complete virological response was achieved in 86.6% and 53.3% of patients in the TDF and ETV-ADV groups, respectively, at week 96 (P=0.005). Reduction in serum HBV DNA was significantly greater in the TDF group than in ETV-ADV group (-3.2 ±1.2 versus -2.6 ±1.2; P=0.01). Hepatitis B e antigen loss (22.2% versus 16.6%; P=0.731) and biochemical responses (76.7% versus 73.3%; P=0.766) were not different between the TDF and ETV-ADV groups. No newly emerged mutations were detected. Both therapies demonstrated favourable safety profiles. CONCLUSIONS TDF therapy achieved a better complete virological response than ETV-ADV therapy in chronic hepatitis B patients with suboptimal response to long-term LAM-ADV rescue therapy. (KCT0000627).
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Affiliation(s)
- Sae Hwan Lee
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Gab Jin Cheon
- Department of Internal Medicine, University of Ulsan College of Medicine, Gangneung Asan Hospital, Gangneung, Korea
| | - Hong Soo Kim
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Sang Gyune Kim
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Young Seok Kim
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Soung Won Jeong
- Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul, Korea
| | - Jae Young Jang
- Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul, Korea
| | - Boo Sung Kim
- Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul, Korea
| | - Baek Gyu Jun
- Department of Internal Medicine, University of Ulsan College of Medicine, Gangneung Asan Hospital, Gangneung, Korea
| | - Young Don Kim
- Department of Internal Medicine, University of Ulsan College of Medicine, Gangneung Asan Hospital, Gangneung, Korea
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University Seoul Hospital, Seoul, Korea
| | - Joo Hyun Sohn
- Department of Internal Medicine, Hanyang University Guri Hospital, Guri, Korea
| | - Tae Yeob Kim
- Institute of Medical Science, Hanyang University, Seoul, Korea
| | - Byung Seok Lee
- Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Korea
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Park J, Jung KS, Lee HW, Kim BK, Kim SU, Kim DY, Ahn SH, Han KH, Park JY. Effects of Entecavir and Tenofovir on Renal Function in Patients with Hepatitis B Virus-Related Compensated and Decompensated Cirrhosis. Gut Liver 2017; 11:828-834. [PMID: 28651305 PMCID: PMC5669599 DOI: 10.5009/gnl16484] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 12/17/2016] [Accepted: 01/18/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/AIMS The renal effects of nucleos(t)ide analogs in patients with chronic hepatitis B are controversial. We aimed to compare the impact of entecavir (ETV) and tenofovir (TDF) on renal function in patients with hepatitis B virus (HBV)-related cirrhosis. METHODS We performed a retrospective cohort study of 235 consecutive treatment-naïve patients with HBV-related cirrhosis who were treated with ETV or TDF between December 2012 and November 2013 at Severance Hospital, Seoul, Korea. RESULTS Compensated cirrhosis was noted in 183 patients (ETV 130, TDF 53), and decompensated cirrhosis was noted in 52 patients (ETV 32, TDF 20). There were no significant changes in estimated glomerular filtration rates (eGFR) from baseline in either the ETV- or TDF-treated groups at week 96 (Chronic Kidney Disease Epidemiology Collaboration, ETV -1.68% and TDF -5.03%, p=0.358). Using a multivariate analysis, the significant factors associated with a decrease in eGFR >20% were baseline eGFR, diabetes mellitus (DM), and the use of diuretics. The use of antiviral agents and baseline decompensation were not determined to be significant factors. CONCLUSIONS In patients with HBV-related cirrhosis, TDF has shown similar renal safety to that of ETV over a 2-year period. Renal function should be closely monitored, especially in patients who exhibit decreasing eGFR, DM, and the use of diuretics.
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Affiliation(s)
- Jihye Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
| | - Kyu Sik Jung
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
| | - Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
- Yonsei Liver Center, Yonsei University Health System, Seoul,
Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
- Yonsei Liver Center, Yonsei University Health System, Seoul,
Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
- Yonsei Liver Center, Yonsei University Health System, Seoul,
Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
- Yonsei Liver Center, Yonsei University Health System, Seoul,
Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
- Yonsei Liver Center, Yonsei University Health System, Seoul,
Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
- Yonsei Liver Center, Yonsei University Health System, Seoul,
Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
- Yonsei Liver Center, Yonsei University Health System, Seoul,
Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
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Evolution of drug-resistant mutations in HBV genomes in patients with treatment failure during the past seven years (2010-2016). Virus Genes 2017; 54:41-47. [PMID: 29119303 DOI: 10.1007/s11262-017-1518-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 11/01/2017] [Indexed: 02/06/2023]
Abstract
The objective of this study was to analyze the prevalence of drug-resistant HBV mutants in patients with treatment failure during the past seven years (2010-2016). 4055 HBV-infected patients who underwent HBV polymerase gene mutation test from 2010 to 2016 were enrolled. The nucleos(t)ide analogues (NAs) resistance mutation positions, including rtL180, rtA181, rtT184, rtS202, rtM204, rtI233, rtN236, rtI169, rtV173, and rtM250 were analyzed. Genotypic resistance mutations were detected in 30.8% (1248/4055) of the patients with treatment failure. Rates of drug-resistant mutations associated with LAM, ADV, ETV, and multidrug were 27.23% (1104/4055), 9.67% (392/4055), 3.69% (150/4055), and 0.79% (32/4055). Among the primary NA-resistant mutations, rtM204I (13.44%, 545/4055) occurred more frequently, followed by rtM204V, rtN236T, rtA181T, and rtA181V. For single-base mutations, rtL180M and rtA181V increased gradually during the past seven years, while rtM204I/V and rtN236T decreased after 2015. The development of drug-resistant mutations positively correlated with the consumption of ETV (r = 0.964, P = 0.002), and weakly correlated with that of LAM (r = 0.679, P = 0.109) and ADV (r = 0.429, P = 0.354). Moreover, single-base mutation rtA181V and multi-base mutations (rtL180M + M204I and rtL180M + M204V + M204I) were more common in HBV genotype C than those in genotype B (1.94% vs. 0.66%, 1.84% vs. 0.16%, 1.02% vs. 0.16%, respectively). NA-related mutations in HBV RT region increased in the past seven years, especially for LAM. Frequencies of rtL180M and rtA181T/V increased gradually in the past seven years, to which we should pay more attention.
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Rodríguez M, Pascasio JM, Fraga E, Fuentes J, Prieto M, Sánchez-Antolín G, Calleja JL, Molina E, García-Buey ML, Blanco MÁ, Salmerón J, Bonet ML, Pons JA, González JM, Casado MÁ, Jorquera F, the TENOSIMP-B Research Group. Tenofovir vs lamivudine plus adefovir in chronic hepatitis B: TENOSIMP-B study. World J Gastroenterol 2017; 23:7459-7469. [PMID: 29151700 PMCID: PMC5685852 DOI: 10.3748/wjg.v23.i41.7459] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2017] [Revised: 05/22/2017] [Accepted: 06/19/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To demonstrate the non-inferiority (15% non-inferiority limit) of monotherapy with tenofovir disoproxil fumarate (TDF) vs the combination of lamivudine (LAM) plus adefovir dipivoxil (ADV) in the maintenance of virologic response in patients with chronic hepatitis B (CHB) and prior failure with LAM.
METHODS This study was a Phase IV prospective, randomized, open, controlled study with 2 parallel groups (TDF and LAM+ADV) of adult patients with hepatitis B e antigen (HBeAg)-negative CHB, prior failure with LAM, on treatment with LAM+ADV for at least 6 mo, without prior resistance to ADV and with an undetectable viral load at the start of the study, in 14 Spanish hospitals. The follow-up time for each patient was 48 wk after randomization, with quarterly visits in which the viral load, biochemical and serological parameters, adverse effects, adherence to treatment and consumption of hospital resources were analysed.
RESULTS Forty-six patients were evaluated [median age: 55.4 years (30.2-75.2); 84.8% male], including 22 patients with TDF and 24 with LAM+ADV. During study development, hepatitis B virus DNA (HBV-DNA) remained undetectable, all patients remained HBeAg negative, and hepatitis B surface antigen (HBsAg) positive. Alanine aminotransferase (ALT) values at the end of the study were similar in the 2 groups (25.1 ± 7.65, TDF vs 24.22 ± 8.38, LAM+ADV, P = 0.646). No significant changes were observed in creatinine or serum phosphorus values in either group. No significant differences between the 2 groups were noted in the identification of adverse effects (AEs) (53.8%, TDF vs 37.5%, LAM+ADV, P = 0.170), and none of the AEs which occurred were serious. Treatment adherence was 95.5% and 83.3% in the TDF and the LAM+ADV groups, respectively (P = 0.488). The costs associated with hospital resource consumption were significantly lower with the TDF treatment than the LAM+ADV treatment (€4943 ± 1059 vs €5811 ± 1538, respectively, P < 0.001).
CONCLUSION TDF monotherapy proved to be safe and not inferior to the LAM+ADV combination therapy in maintaining virologic response in patients with CHB and previous LAM failure. In addition, the use of TDF generated a significant savings in hospital costs.
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Affiliation(s)
- Manuel Rodríguez
- Division of Gastroenterology and Hepatology. Hospital Universitario Central de Asturias, Oviedo 33011, Spain
| | - Juan Manuel Pascasio
- Unit for the Clinical Management of Digestive Diseases, IBIS, Hospital Universitario Virgen del Rocío, Sevilla 41013, Spain and CIBERehd
| | - Enrique Fraga
- Liver Transplantation and Hepatology Unit, Gastroenterology Service, Hospital Universitario Reina Sofía, Córdoba 14004, Spain
| | - Javier Fuentes
- Digestive Medicine Service, Hospital Universitario Miguel Servet, Zaragoza 50009, Spain
| | - Martín Prieto
- Hepatology Unit, Digestive Medicine Service, Hospital Universitari i Politècnic La Fe, Valencia 46026, Spain and CIBERehd
| | | | - José Luis Calleja
- Liver Unit, Hospital Universitario Puerta de Hierro de Majadahonda, Universidad Autónoma de Madrid, Madrid 28049, Spain
| | - Esther Molina
- Digestive Medicine Service, Hospital Clínico de Santiago de Compostela, La Coruña 15706, Spain
| | | | - María Ángeles Blanco
- Digestive Medicine Service, Hospital General Universitario Gregorio Marañón, Madrid 28007, España
| | - Javier Salmerón
- Digestive Medicine Unit, Complejo Hospitalario de Granada, Granada 18014, Spain
| | - María Lucía Bonet
- Digestive Medicine Service, Hospital Universitario Son Espases, Palma de Mallorca 07120, Spain
| | - José Antonio Pons
- Hepatology Unit, IMIB Hospital Universitario Virgen de la Arrixaca, Murcia 30120, Spain
| | - José Manuel González
- Digestive Medicine Service, Hospital Clínico Universitario de Valladolid, Valladolid 47003, Spain
| | | | - Francisco Jorquera
- Division of Gastroenterology and Hepatology, Complejo Asistencial Universitario de León, León 24001, Spain CIBERehd and IBIOMED León
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Yamamoto T, Maruyama Y, Ohashi N, Yasuda H, Shinozaki M. Hypophosphatemia predicts a failure to recover from adefovir-related renal injury after dose reduction in lamivudine-resistant hepatitis B patients. Hepatol Res 2017; 47:1272-1281. [PMID: 28079295 DOI: 10.1111/hepr.12865] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 12/24/2016] [Accepted: 01/09/2017] [Indexed: 02/08/2023]
Abstract
AIM In chronic hepatitis B patients receiving 10 mg adefovir, dose reduction is recommended when renal injury appears. However, recovery is not always achieved and markers that recommend switching to another antiviral agent are unknown. We investigated adefovir-related renal injury, recovery after dose reduction, and their predictors. METHODS The renal injury in 77 chronic hepatitis B patients receiving 10 mg adefovir and recovery after dose reduction to alternate day administration in those with adefovir-related renal injury were assessed. The predictors for >20% estimated glomerular filtration rate (eGFR) decline following treatment with 10 mg adefovir and for >20% eGFR recovery after dose reduction were investigated. RESULTS The adefovir dose was reduced in 26 patients (34%) at 59 ± 30 (mean ± standard deviation) months of 10 mg adefovir treatment because of decreases in eGFR (cumulative incidence 27%), serum phosphorus (9%), and uric acid (16%) levels, and increases in alkaline phosphatase (20%), bone type alkaline phosphatase (18%), urinary α1-microglobulin (18%), and urinary N-acetyl-β-D-glucosaminidase (18%) levels. The only significant predictor for >20% eGFR decline was age ≥50 years at the start of 10 mg adefovir treatment. The cumulative eGFR recovery rate was 42% at 42 ± 27 months after dose reduction, and ≥2.5 mg/dL serum phosphorus level at dose reduction was the only significant predictor for >20% eGFR recovery after dose reduction. CONCLUSION Patients aged ≥50 years are predisposed to adefovir-related renal injury and switching to another antiviral agent rather than adefovir dose reduction is recommended when hypophosphatemia is observed.
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Affiliation(s)
- Tatsuo Yamamoto
- Department of Nephrology, Fujieda Municipal General Hospital, Fujieda, Japan
| | - Yasuhiko Maruyama
- Department of Gastroenterology, Fujieda Municipal General Hospital, Fujieda, Japan
| | - Naro Ohashi
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hideo Yasuda
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Masami Shinozaki
- Department of Gastroenterology, Numazu City Hospital, Numazu, Japan
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Zhou J, Liu YY, Lian JS, Pan LF, Yang JL, Huang JR. Efficacy and Safety of Tenofovir Disoproxil Treatment for Chronic Hepatitis B Patients with Genotypic Resistance to Other Nucleoside Analogues: A Prospective Study. Chin Med J (Engl) 2017; 130:914-919. [PMID: 28397720 PMCID: PMC5407037 DOI: 10.4103/0366-6999.204107] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background: Tenofovir disoproxil (TDF) is a promising salvage therapy for patients with chronic hepatitis B (CHB) who failed regimens of other nucleoside analogues (NAs). In this study, we aimed to investigate the clinical efficacy and safety of TDF monotherapy in Chinese CHB patients with genotypic resistance. Methods: A total of 33 CHB patients who had failed treatment with other NAs and had genotypic resistance were switched to TDF monotherapy for 48 weeks. Patients’ demographic data (age, sex, history of hepatitis B virus [HBV] therapy), laboratory testing results (hepatitis B e antigen [HBeAg] status, HBV DNA levels, alanine aminotransferase [ALT] levels, serum creatinine, urinary protein, genotypic assay), clinical symptoms, and liver color ultrasound examinations were collected for evaluation at day 0 (baseline) and the 12th, 24th, 36th, and 48th weeks after initiating treatment. Statistical analyses were carried out using rank sum test or rank correlation. Results: With regard to efficacy, the study found that all patients who switched to TDF monotherapy had undetectable HBV DNA levels after 48 weeks. In addition, patients with lower baseline HBV DNA levels realized earlier virological undetectability (rs = 0.39, P = 0.030). ALT levels were normal in 30 of 33 patients (91%). HBeAg negative conversion occurred in 7 of 25 patients (28%), among whom HBeAg seroconversion (12%) and HBeAg seroclearance (16%) occurred. The time of complete virological response was significantly affected by the number of resistance loci (rs = 0.36, P = 0.040). Concerning safety, the study found that no adverse events were observed during the 48 weeks. Conclusion: TDF monotherapy is an effective and safe salvage treatment for CHB patients who are resistant to other NAs.
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Affiliation(s)
- Jing Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003; Department of Infectious Disease, The First People's Hospital of Yongkang, Jinhua, Zhejiang 321300, China
| | - Yue-Ying Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, China
| | - Jiang-Shan Lian
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, China
| | - Li-Fang Pan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, China
| | - Jian-Le Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, China
| | - Jian-Rong Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, China
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46
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Evolutionary trends of resistance mutational patterns of HBV reverse transcriptase over years (2002–2012) of different treatment regimens: The legacy of lamivudine/adefovir combination treatment. Antiviral Res 2017; 143:62-68. [DOI: 10.1016/j.antiviral.2017.03.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 03/10/2017] [Indexed: 02/07/2023]
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47
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Yuan G, Hu C, Zhou Y, Liu J, Huang H, Li Y, Yang D, Zhou F, Zhang YY, Zhou Y. A different inhibitor is required for overcoming entecavir resistance: a comparison of four rescue therapies in a retrospective study. Br J Clin Pharmacol 2017; 83:2259-2265. [PMID: 28511283 DOI: 10.1111/bcp.13330] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2017] [Revised: 05/03/2017] [Accepted: 05/14/2017] [Indexed: 01/02/2023] Open
Abstract
AIMS Little clinical data are available regarding re-establishing the effective inhibition of entecavir (ETV)-resistant mutants. In this retrospective study, we aimed to compare the efficacies of four treatment regimens as rescue therapy for those chronic hepatitis B (CHB) patients with ETV resistance. METHODS A total of 65 patients with ETV resistance were assigned either with tenofovir disoproxil fumarate (TDF) monotherapy (n = 21), ETV (0.5 mg) plus adefovir (ADV) combination therapy (n = 19), ETV (1.0 mg) monotherapy (n = 11) or ETV (0.5 mg) plus TDF combination therapy (n = 14). The efficacy and safety of four treatment regimens were compared. RESULTS There were no significant differences among the four study groups in baseline characteristics, including HBV DNA levels (χ2 = 0.749, P = 0.862) and hepatitis B e antigen-positivity (χ2 = 0.099, P = 0.992). The median reduction in serum HBV DNA level from baseline at week 48 was -2.37 ± 1.07 log10 IU ml-1 , -2.16 ± 0.81 log10 IU ml-1 , -1.17 ± 1.23 log10 IU ml-1 and -2.49 ± 1.10 log10 IU ml-1 , respectively (F = 4.078, P = 0.011). The TDF group and ETV (0.5 mg) + TDF group have the highest undetectable HBV DNA rate (76.19% vs. 78.57%) compared to the ETV (0.5 mg) + ADV group and the ETV (1.0 mg) group (63.16% vs. 18.18%, respectively). Two patients in the ETV (1.0 mg) group experienced virological breakthrough at week 48 and was attributed to poor drug adherence. CONCLUSIONS TDF monotherapy appeared to deliver the highest undetectable HBV DNA rate in patients with ETV resistance, and ADV plus ETV combination therapy could be another choice for patients with financial restraint.
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Affiliation(s)
- Guosheng Yuan
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Chengguang Hu
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yuchen Zhou
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Junwei Liu
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Huaping Huang
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yuan Li
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Dinghua Yang
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Fuyuan Zhou
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | | | - Yuanping Zhou
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Lim L, Thompson A, Patterson S, George J, Strasser S, Lee A, Sievert W, Nicoll A, Desmond P, Roberts S, Marion K, Bowden S, Locarnini S, Angus P. Five-year efficacy and safety of tenofovir-based salvage therapy for patients with chronic hepatitis B who previously failed LAM/ADV therapy. Liver Int 2017; 37:827-835. [PMID: 27896895 DOI: 10.1111/liv.13331] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Accepted: 11/14/2016] [Indexed: 02/13/2023]
Abstract
BACKGROUND Multidrug-resistant HBV continues to be an important clinical problem. The TDF-109 study demonstrated that TDF±LAM is an effective salvage therapy through 96 weeks for LAM-resistant patients who previously failed ADV add-on or switch therapy. We evaluated the 5-year efficacy and safety outcomes in patients receiving long-term TDF±LAM in the TDF-109 study. METHODS A total of 59 patients completed the first phase of the TDF-109 study and 54/59 were rolled over into a long-term prospective open-label study of TDF±LAM 300 mg daily. RESULTS Results are reported at the end of year 5 of treatment. At year 5, 75% (45/59) had achieved viral suppression by intent-to-treat analysis. Per-protocol assessment revealed 83% (45/54) were HBV DNA undetectable. Nine patients remained HBV DNA detectable, however 8/9 had very low HBV DNA levels (<264IU/mL) and did not meet virological criteria for virological breakthrough (VBT). One patient experienced VBT, but this was in the setting of documented non-compliance. The response was independent of baseline LAM therapy or mutations conferring ADV resistance. Four patients discontinued TDF, one patient was lost to follow-up and one died from hepatocellular carcinoma. CONCLUSIONS Long-term TDF treatment appears to be safe and effective in patients with prior failure of LAM and a suboptimal response to ADV therapy. These findings confirm that TDF has a high genetic barrier to resistance is active against multidrug-resistant HBV, and should be the preferred oral anti-HBV agent in CHB patients who fail treatment with LAM and ADV.
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Affiliation(s)
- Lucy Lim
- Liver Transplant & Gastroenterology Department, Austin Health, Melbourne, VIC, Australia.,Gastroenterology Department, St Vincent's Hospital, Melbourne, VIC, Australia.,Molecular Research & Development Laboratory, Victorian Infectious Diseases Reference Laboratory, Melbourne, VIC, Australia.,University of Melbourne, Melbourne, VIC, Australia
| | - Alexander Thompson
- Gastroenterology Department, St Vincent's Hospital, Melbourne, VIC, Australia.,Molecular Research & Development Laboratory, Victorian Infectious Diseases Reference Laboratory, Melbourne, VIC, Australia.,University of Melbourne, Melbourne, VIC, Australia
| | - Scott Patterson
- Liver Transplant & Gastroenterology Department, Austin Health, Melbourne, VIC, Australia
| | - Jacob George
- Storr Liver Centre, Westmead Millennium Institute for Medical Research, Westmead Hospital & University of Sydney, Sydney, NSW, Australia
| | - Simone Strasser
- AW Morrow Gastroenterology & Liver Centre, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
| | - Alice Lee
- Gastroenterology Department, Concord Hospital, Sydney, NSW, Australia
| | - William Sievert
- Gastroenterology Department, Monash Medical Centre, Melbourne, VIC, Australia
| | - Amanda Nicoll
- Gastroenterology & Hepatology Department, Royal Melbourne Hospital, Melbourne, VIC, Australia.,Gastroenterology Department, Eastern Health, Melbourne, VIC, Australia
| | - Paul Desmond
- Gastroenterology Department, St Vincent's Hospital, Melbourne, VIC, Australia.,University of Melbourne, Melbourne, VIC, Australia
| | - Stuart Roberts
- Gastroenterology Department, Alfred Hospital, Melbourne, VIC, Australia
| | - Kaye Marion
- Mathematical & Geospatial Sciences Department, RMIT University, Melbourne, VIC, Australia
| | - Scott Bowden
- Molecular Research & Development Laboratory, Victorian Infectious Diseases Reference Laboratory, Melbourne, VIC, Australia
| | - Stephen Locarnini
- Molecular Research & Development Laboratory, Victorian Infectious Diseases Reference Laboratory, Melbourne, VIC, Australia.,University of Melbourne, Melbourne, VIC, Australia
| | - Peter Angus
- Liver Transplant & Gastroenterology Department, Austin Health, Melbourne, VIC, Australia.,University of Melbourne, Melbourne, VIC, Australia
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Fasano M, Maggi P, Leone A, Volpe A, Fiore JR, Angarano G, Santantonio TA. Long-term efficacy and safety of switching from lamivudine+adefovir to tenofovir disoproxil fumarate in virologically suppressed patients. Dig Liver Dis 2017; 49:530-534. [PMID: 28179096 DOI: 10.1016/j.dld.2017.01.140] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 01/05/2017] [Accepted: 01/06/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Tenofovir disoproxil fumarate (TDF) is recommended as first-line monotherapy for nucleos(t)ide (NA)-naïve chronic hepatitis B (CHB) patients and as a second-line rescue therapy for NA-experienced patients with a previous treatment failure. However, data regarding the efficacy of TDF monotherapy in patients with lamivudine resistance (LAM-R) successfully treated with LAM+adefovir (ADV) are limited. Herein, the efficacy and safety of switching from LAM+ADV to TDF monotherapy in clinical practice have been evaluated. METHODS Sixty LAM-R HBeAg-negative CHB patients treated with ADV add-on therapy and stable viral suppression, were switched to TDF monotherapy and prospectively evaluated for virological response, liver and renal function, and bone mineral density. RESULTS During a median period of 57 months of TDF monotherapy, all patients maintained a virological response, four of whom cleared HBsAg (6.6%) and discontinued treatment. Monitoring of renal function showed no case of the Fanconi syndrome, no significant alterations of median serum creatinine, eGFR and phosphate levels, although a reduction of TDF dosage was required in five patients (8.3%). Despite the stable virological suppression, five cirrhotic patients and one CHB patient developed hepatocellular carcinoma. CONCLUSIONS Our results demonstrate the efficacy of switching to TDF monotherapy in virologically suppressed CHB patients receiving long-term LAM+ADV therapy, with a low rate of adverse events.
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Affiliation(s)
- Massimo Fasano
- Clinic of Infectious Diseases, University of Foggia, Italy
| | - Paolo Maggi
- Clinic of Infectious Diseases, University of Bari, Italy
| | - Armando Leone
- Clinic of Infectious Diseases, University of Bari, Italy
| | - Anna Volpe
- Clinic of Infectious Diseases, University of Bari, Italy
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50
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Suzuki F, Suzuki Y, Hosaka T, Sezaki H, Akuta N, Fujiyama S, Kawamura Y, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Kobayashi M, Mineta R, Suzuki Y, Kumada H. Efficacy of long-term tenofovir-based rescue therapy in patients with chronic hepatitis B refractory to nucleoside/nucleotide analogs. J Gastroenterol 2017; 52:641-651. [PMID: 27699721 DOI: 10.1007/s00535-016-1270-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2016] [Accepted: 09/20/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND Few studies have investigated the efficacy of long-term tenofovir disoproxil fumarate (TDF)-based rescue therapy in patients with chronic hepatitis B refractory to nucleoside/nucleotide analogs. METHODS We retrospectively analyzed 40 Japanese patients with chronic hepatitis B refractory to nucleoside/nucleotide analogs who received TDF-based rescue therapy [TDF monotherapy, TDF plus lamivudine (LAM) combination therapy, or TDF plus entecavir (ETV) combination therapy] followed up for a median of 45 months (range 14-99 months). Viral response, changes in hepatitis B surface antigen levels from the baseline, and viral breakthrough during therapy were analyzed. RESULTS The proportion of patients with undetectable serum hepatitis B virus (HBV) DNA levels (less than 2.1 log copies per milliliter) (viral response) during TDF-based rescue therapy was 68, 78, 85, 88, 83, 81, 88, and 100 % at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, and 4 years respectively. There were no differences in the viral response rate between the TDF plus LAM group and the TDF plus ETV group. The mean reduction from the baseline in hepatitis B surface antigen levels in patients with LAM-resistant HBV was greater than the reductions in patients with adefovir dipivoxil (ADV)-resistant or ETV-resistant HBV at 2 and 3 years (P = 0.024, and P = 0.025 respectively). However, two patients with ADV- or ETV-resistant HBV at the baseline developed viral breakthrough during TDF-based rescue therapy. CONCLUSIONS Long-term therapy with a TDF-based rescue regimen demonstrated high viral suppression in patients in whom LAM plus ADV combination therapy, ETV plus ADV combination therapy, or ETV monotherapy had failed. However, patients with ADV- or ETV-resistant HBV at the baseline may develop viral breakthrough and resistance, and careful follow-up is advised.
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Affiliation(s)
- Fumitaka Suzuki
- Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan.
- Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
| | - Yoshiyuki Suzuki
- Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Tetsuya Hosaka
- Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Hitomi Sezaki
- Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Norio Akuta
- Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Shunichiro Fujiyama
- Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Yusuke Kawamura
- Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Masahiro Kobayashi
- Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Satoshi Saitoh
- Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Yasuji Arase
- Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Kenji Ikeda
- Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Mariko Kobayashi
- Research Institute for Hepatology, Toranomon Branch Hospital, Kawasaki, Japan
| | - Rie Mineta
- Research Institute for Hepatology, Toranomon Branch Hospital, Kawasaki, Japan
| | - Yukiko Suzuki
- Research Institute for Hepatology, Toranomon Branch Hospital, Kawasaki, Japan
| | - Hiromitsu Kumada
- Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan
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