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Ryan P, Odegard E, Meeds H, Lartey M, Ganu VJ, Tachi K, Yang H, Ojewale O, Boamah I, Obo-Akwa A, Antwi K, Anderson PL, Blackard JT, Kwara A. Hepatitis B virus (HBV) viremia despite tenofovir disoproxil fumarate-containing antiretroviral therapy in persons with HBV/HIV coinfection. J Clin Virol 2024; 175:105733. [PMID: 39413542 PMCID: PMC11781354 DOI: 10.1016/j.jcv.2024.105733] [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: 08/11/2024] [Revised: 09/07/2024] [Accepted: 09/30/2024] [Indexed: 10/18/2024]
Abstract
BACKGROUND The goal of treatment of hepatitis B virus (HBV) and human immunodeficiency virus (HIV) coinfection is suppression of both viruses; yet incomplete HBV suppression on tenofovir (TFV) disoproxil fumarate (TDF)-based antiretroviral therapy (ART) is common. This study investigated TFV resistance-associated mutations (RAMs) in individuals with HBV/HIV coinfection with viremia on TDF/lamivudine (3TC)-containing ART. METHODS Samples from individuals with HBV DNA levels ≥20 IU/mL in a cross-sectional study of 138 persons with HBV/HIV coinfection in Ghana were analyzed in the present study. HBV was sequenced for RAM analysis. TFV-diphosphate (TFV-DP) concentration in peripheral blood mononuclear cells (PBMCs) was used to assess ART adherence level. RESULTS Nine of 138 participants (6.5 %) had detectable HBV DNA levels ≥20 IU/mL while on ART. Seven of the nine participants had TFV-DP concentrations commensurate with 7 doses per week, and six had suppressed HIV RNA. Phylogenetic analysis revealed that eight sequences were HBV genotype E, with one genotype E/A recombinant. Ten previously-reported TFV RAMs were present in the study samples; eight were wild-type for HBV genotype E. The non-genotype-E-wild-type point mutations M267L and K333Q were found in two and one patients, respectively. No 3TC RAMs were found. CONCLUSION HBV viremia despite high adherence to TDF/3TC-based ART may be associated with the presence of TFV RAMs. These findings highlight the need for enhanced resistance monitoring and further research to examine the clinical significance of reported TFV RAMs. Individuals with HBV/HIV coinfection and TFV resistance on TDF-based ART may need alternative treatment strategies.
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Affiliation(s)
- Patrick Ryan
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Elizabeth Odegard
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Heidi Meeds
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Margaret Lartey
- Department of Medicine and Therapeutics, University of Ghana Medical School, Accra, Ghana; Department of Medicine, Korle-Bu Teaching Hospital, Accra, Ghana
| | - Vincent J Ganu
- Department of Medicine, Korle-Bu Teaching Hospital, Accra, Ghana
| | - Kenneth Tachi
- Department of Medicine and Therapeutics, University of Ghana Medical School, Accra, Ghana; Department of Medicine, Korle-Bu Teaching Hospital, Accra, Ghana
| | - Hongmei Yang
- Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Oluwayemisi Ojewale
- Department of Medicine, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Isaac Boamah
- Department of Microbiology, School of Biomedical and Allied Health Sciences, Accra, Ghana
| | - Adjoa Obo-Akwa
- Department of Medicine and Therapeutics, University of Ghana Medical School, Accra, Ghana
| | - Kenneth Antwi
- Department of Medicine, Korle-Bu Teaching Hospital, Accra, Ghana
| | - Peter L Anderson
- Colorado Antiviral Pharmacology Laboratory and Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado-Anschutz Medical Campus, Aurora, Colorado, USA
| | - Jason T Blackard
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Awewura Kwara
- Department of Medicine, University of Florida College of Medicine, Gainesville, Florida, USA; Medical Service, North Florida South Georgia Veterans Health System, Gainesville, Florida, USA.
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Lartey M, Ganu VJ, Tachi K, Yang H, Anderson PL, Langaee T, Ojewale O, Boamah I, Obo-Akwa A, Antwi K, Bushman LR, Ellison L, Kwara A. Association of tenofovir diphosphate and lamivudine triphosphate concentrations with HIV and hepatitis B virus viral suppression. AIDS 2024; 38:351-362. [PMID: 37861682 PMCID: PMC10842673 DOI: 10.1097/qad.0000000000003764] [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: 08/02/2023] [Accepted: 10/11/2023] [Indexed: 10/21/2023]
Abstract
OBJECTIVE Concentrations of tenofovir diphosphate (TFV-DP) and lamivudine triphosphate (3TC-TP) in cells are correlates of medication adherence and antiviral activity. However, studies have yet to characterize the simultaneous relationship between TFV-DP and 3TC-TP concentrations with HIV and hepatitis B virus (HBV) suppression. METHODS Individuals with HIV/HBV coinfection on tenofovir disoproxil fumarate (TDF)-containing antiretroviral therapy (ART) were enrolled. Peripheral blood mononuclear cells (PBMCs) and dried blood spots (DBS) samples were collected and steady-state TFV-DP and 3TC-TP concentrations quantified using validated methods. The relationship between patient factors, TFV-DP, and 3TC-TP concentrations in PBMCs and DBS with HBV and HIV viral suppression were examined. RESULTS Of 138 participants on TDF-containing ART for a median duration (range) of 6 (0.75-15) years, the median age was 43 years and 64% were women. Overall, 128 (92.8%) and 129 (93.5%) had suppressed HIV and HBV viral loads, respectively. Of the 128 participants with suppressed HIV, 122 (95.3%) had suppressed HBV. Self-reported ART adherence, recent change to dolutegravir-based ART, TFV-DP, and 3TC-TP concentrations in PBMCs and DBS were associated with HIV RNA suppression, while HBe antigen positivity, HIV suppression, and TFV-DP concentrations in DBS were associated with HBV DNA suppression (including six persons with HBV nonsuppression and HIV suppression). CONCLUSION Long-term TDF/3TC-conatining ART was highly efficacious in individuals with HIV/HBV coinfection. Higher TFV-DP concentrations were predictive of suppression for both viruses. Persistent HBV viremia on TDF/3TC-containg ART requires additional research, but may represent poor adherence and the need for adherence interventions or novel antivirals.
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Affiliation(s)
- Margaret Lartey
- Department of Medicine and Therapeutics, University of Ghana Medical School
- Department of Medicine, Korle-Bu Teaching Hospital, Accra, Ghana
| | - Vincent J. Ganu
- Department of Medicine, Korle-Bu Teaching Hospital, Accra, Ghana
| | - Kenneth Tachi
- Department of Medicine and Therapeutics, University of Ghana Medical School
- Department of Medicine, Korle-Bu Teaching Hospital, Accra, Ghana
| | - Hongmei Yang
- Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York
| | - Peter L. Anderson
- Colorado Antiviral Pharmacology Laboratory and Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado-Anschutz Medical Campus, Aurora, Colorado
| | - Taimour Langaee
- Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida
| | - Oluwayemisi Ojewale
- Department of Medicine, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Isaac Boamah
- Department of Microbiology, School of Biomedical and Allied Health Sciences, Accra, Ghana
| | - Adjoa Obo-Akwa
- Department of Medicine and Therapeutics, University of Ghana Medical School
| | - Kenneth Antwi
- Department of Medicine, Korle-Bu Teaching Hospital, Accra, Ghana
| | - Lane R. Bushman
- Colorado Antiviral Pharmacology Laboratory and Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado-Anschutz Medical Campus, Aurora, Colorado
| | - Lucas Ellison
- Colorado Antiviral Pharmacology Laboratory and Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado-Anschutz Medical Campus, Aurora, Colorado
| | - Awewura Kwara
- Department of Medicine, University of Florida College of Medicine, Gainesville, Florida, USA
- Medical Service, North Florida South Georgia Veterans Health System, Gainesville, Florida, USA
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Yim HJ, Kim JH, Cho YK, Kweon YO, Cho HC, Hwang JS, Lee C, Koh MS, Baek YH, Park YM, Lee JH, Kim SU, Kang MK, Park NH, Lee JS, Chon YE, Cheon GJ, Chae HB, Sohn JH, Lim YS. Non-Inferior Efficacy of Tenofovir Disoproxil to Tenofovir Disoproxil Fumarate in Virologically Suppressed Chronic Hepatitis B Patients. Drug Des Devel Ther 2022; 16:3263-3274. [PMID: 36177347 PMCID: PMC9514787 DOI: 10.2147/dddt.s376821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 09/16/2022] [Indexed: 02/05/2023] Open
Abstract
Purpose Tenofovir disoproxil (TD), modified from tenofovir disoproxil fumarate (TDF), was developed as a salt-free formulation, removing fumarate to improve the ease of oral intake by reducing the tablet's size. We evaluated the maintenance of antiviral effects and overall safety profile of TD 245 mg after switching from TDF 300 mg in patients with chronic hepatitis B (CHB). Patients and Methods CHB patients with HBV-DNA <69 IU/mL after ≥24 weeks of TDF therapy were enrolled. The primary efficacy endpoint was the HBV-DNA suppression rate (HBV-DNA <69 IU/mL) at week 48; We evaluated the non-inferiority (10% margin) of TD to TDF in terms of efficacy. Safety was assessed based on adverse events (AEs), laboratory tests, bone mineral density, and renal function abnormalities. Results Overall, 189 subjects were randomized in a 2:1 ratio, and 117 and 66 subjects in the TD and TDF groups, respectively, completed the study. In the per-protocol set, the HBV-DNA suppression rate at week 48 was 99.1% and 100% in the TD and TDF groups, respectively. The lower limit of the 97.5% one-sided confidence interval for the intergroup difference in HBV-DNA suppression rate was -2.8%, which was greater than the prespecified margin of non-inferiority. The changes in creatinine clearance from baseline to week 48 was significantly less in the TD group and in the TDF group; -0.8 ± 9.8 versus -2.4 ± 12.8 mL/min, respectively (P=0.017). Conclusion TD was non-inferior to TDF for maintaining viral suppression in CHB patients, showing the less decline of renal function.
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Affiliation(s)
- Hyung Joon Yim
- Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Seoul, Korea
| | - Ji Hoon Kim
- Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Yong Kyun Cho
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young Oh Kweon
- Department of Internal Medicine, Kyungpook National University, School of Medicine, Daegu, Korea
| | - Hyun Chin Cho
- Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Korea
| | - Jae Seok Hwang
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Changhyeong Lee
- Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, Korea
| | - Moon Soo Koh
- Department of Internal Medicine, Dongguk University Ilsan Hospital, College of Medicine, Dongguk University, Goyang, Korea
| | - Yang-Hyun Baek
- Department of Gastroenterology, DongA University College of Medicine, Busan, Korea
| | - Young-Min Park
- Department of Internal Medicine, Bundang Jesaeng General Hospital, Seongnam, Korea and Hepatology Center, Bundang Jesaeng General Hospital, Seongnam, Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea, and Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Min-Kyu Kang
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Neung Hwa Park
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - June Sung Lee
- Department of Internal Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
| | - Young Eun Chon
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Gab Jin Cheon
- Department of Medicine, GangNeung Asan Hospital, Ulsan University College of Medicine, Gangwon-do, Korea
| | - Hee Bok Chae
- Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Korea
| | - Joo Hyun Sohn
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea, and Hanyang University Guri Hospital, Guri, Korea
| | - Young-Suk Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Hall SAL, Burns GS, Anagnostou D, Vogrin S, Sundararajan V, Ratnam D, Levy MT, Lubel JS, Nicoll AJ, Strasser SI, Sievert W, Desmond PV, Ngu MC, Angus P, Sinclair M, Meredith C, Matthews G, Revill PA, Jackson K, Littlejohn M, Bowden DS, Locarnini SA, Visvanathan K, Thompson AJ. Stopping nucleot(s)ide analogues in non-cirrhotic HBeAg-negative chronic hepatitis B patients: HBsAg loss at 96 weeks is associated with low baseline HBsAg levels. Aliment Pharmacol Ther 2022; 56:310-320. [PMID: 35521992 DOI: 10.1111/apt.16968] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 03/06/2022] [Accepted: 04/28/2022] [Indexed: 01/30/2023]
Abstract
BACKGROUND AND AIMS Current guidelines recommend long-term nucleot(s)ide analogue (NA) therapy for patients with HBeAg-negative chronic hepatitis B (CHB). However, disease remission has been described after stopping NA therapy, as well as HBsAg loss. METHODS We performed a prospective multi-centre cohort study of stopping NA therapy. Inclusion criteria were HBeAg-negative CHB, the absence of cirrhosis and HBVDNA RESULTS In total, 110 patients [62% entecavir (ETV); 28% tenofovir (TDF), 10% other] were enrolled. Median age was 56 years, 57% were male, 85% were Asian, median baseline HBsAg level was 705 (214-2325) IU/ml. Virological reactivation occurred in 109/110 patients, median time to detection was 8 (4-12) weeks, and occurred earlier after stopping TDF versus ETV (median 4 vs. 12 weeks p < 0.001). At week 96, 77 (70%) remained off-treatment, 65 (59%) had ALT <2× ULN, 31 (28%) patients were in disease remission with HBVDNA <2000 IU/ml plus ALT <2× ULN and 7 (6%) patients had lost HBsAg. Baseline HBsAg ≤10 IU/ml was associated with HBsAg loss (6/9 vs. 1/101 p < 0.001). ALT >5× ULN occurred in 35 (32%); ALT flares were not associated with HBsAg loss. There were no unexpected safety issues. CONCLUSION Virological reactivation was very common after stopping NA therapy and occurred earlier after stopping TDF versus ETV. The majority of patients had ALT <2× ULN at week 96, but only one-third achieved disease remission and HBsAg loss was rare. Very low HBsAg levels at baseline were uncommon but predicted for HBsAg loss and disease remission.
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Affiliation(s)
- Samuel A L Hall
- Gastroenterology Department of St Vincent's Hospital Melbourne, Melbourne, Australia
- Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia
| | - Gareth S Burns
- Gastroenterology Department of St Vincent's Hospital Melbourne, Melbourne, Australia
- Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia
| | - Despina Anagnostou
- Gastroenterology Department of St Vincent's Hospital Melbourne, Melbourne, Australia
| | - Sara Vogrin
- Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia
| | - Vijaya Sundararajan
- Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia
- The Department of Public Health, La Trobe University, Melbourne, Australia
| | - Dilip Ratnam
- Gastroenterology & Hepatology Unit, Monash Health, Melbourne, Australia
- Monash University, Melbourne, Australia
| | - Miriam T Levy
- Gastroenterology Department of Liverpool Hospital, Sydney, Australia
| | - John S Lubel
- Department of Gastroenterology, Alfred Health, Melbourne, Australia
- Central Clinical School, Monash University, The Alfred Centre, Melbourne, Australia
| | - Amanda J Nicoll
- Gastroenterology Department of Eastern Health, Melbourne, Australia
| | - Simone I Strasser
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia
- University of Sydney, Sydney, Australia
| | - William Sievert
- Gastroenterology & Hepatology Unit, Monash Health, Melbourne, Australia
- Monash University, Melbourne, Australia
| | - Paul V Desmond
- Gastroenterology Department of St Vincent's Hospital Melbourne, Melbourne, Australia
| | - Meng C Ngu
- Gastroenterology Department of Concord Repatriation General Hospital, Sydney, Australia
| | - Peter Angus
- Department of Gastroenterology & Hepatology, Austin Health, Melbourne, Australia
- University of Melbourne, Melbourne, Australia
| | - Marie Sinclair
- Department of Gastroenterology & Hepatology, Austin Health, Melbourne, Australia
| | | | - Gail Matthews
- Department of infectious Disease, St Vincent's Hospital Sydney, Sydney, Australia
| | - Peter A Revill
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, The Doherty Institute, Melbourne, Australia
| | - Kathy Jackson
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, The Doherty Institute, Melbourne, Australia
| | - Margaret Littlejohn
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, The Doherty Institute, Melbourne, Australia
| | - D Scott Bowden
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, The Doherty Institute, Melbourne, Australia
| | - Stephen A Locarnini
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, The Doherty Institute, Melbourne, Australia
| | - Kumar Visvanathan
- Gastroenterology Department of St Vincent's Hospital Melbourne, Melbourne, Australia
- Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia
| | - Alexander J Thompson
- Gastroenterology Department of St Vincent's Hospital Melbourne, Melbourne, Australia
- Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia
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Lim JH, Yu JH, Suh YJ, Lee JW, Jin YJ. Association between HBs Ag quantification and the risk of hepatocellular carcinoma in patients treated with tenofovir disoproxil fumarate or entecavir. Medicine (Baltimore) 2021; 100:e27417. [PMID: 34596169 PMCID: PMC8483839 DOI: 10.1097/md.0000000000027417] [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] [Received: 03/16/2021] [Accepted: 09/12/2021] [Indexed: 01/05/2023] Open
Abstract
This study evaluated the clinical implications of hepatitis B surface antigen quantification (qHBs Ag) in chronic hepatitis B (CHB) patients treated with entecavir (ETV) or tenofovir disoproxil fumarate (TDF) and identified the association between qHBs Ag and the risk of hepatocellular carcinoma (HCC) in these patients.Between January 2007 and December 2018, the qHBs Ag and clinical data of 183 CHB patients who initially received ETV (n = 45, 24.6%) or TDF (n = 138, 75.4%) were analyzed.The mean follow-up period of the 183 CHB patients was 45.3 months, of which 59 (32.2%) patients showed a reduction in qHBs Ag by >50% after 1 year of antiviral treatment (ETV or TDF). The HCC development (P = .179) or qHBs Ag reduction (P = .524) were similar in the ETV and TDF groups. Patients with a ≥50% decrease in qHBs Ag had a significantly lower incidence of HCC or decompensated cirrhosis complications (P = .005). Multivariate analysis showed that a >50% reduction of qHBs Ag (hazard ratio 0.085, P = .018) and the presence of cirrhosis (hazard ratio 3.32, P = .016) were independent factors predicting the development of HCC.Patients whose qHBs Ag value decreased >50% at 1 year after antiviral treatment for CHB showed a significant decrease in HCC or decompensated cirrhosis events. A reduction in qHBs Ag could be used as a predictive factor of HCC development or critical complications in CHB patients treated with TDF or ETV.
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Affiliation(s)
- Jung Hyun Lim
- Department of Internal Medicine and Division of GI and Liver Diseases, Inha University Hospital, Inha University School of Medicine, Incheon, South Korea
| | - Jung Hwan Yu
- Department of Internal Medicine and Division of GI and Liver Diseases, Inha University Hospital, Inha University School of Medicine, Incheon, South Korea
| | - Young Ju Suh
- Department of Statistics, Inha University Hospital, Incheon, South Korea
| | - Jin-Woo Lee
- Department of Internal Medicine and Division of GI and Liver Diseases, Inha University Hospital, Inha University School of Medicine, Incheon, South Korea
| | - Young-Joo Jin
- Department of Internal Medicine and Division of GI and Liver Diseases, Inha University Hospital, Inha University School of Medicine, Incheon, South Korea
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Transaminase Elevations during Treatment of Chronic Hepatitis B Infection: Safety Considerations and Role in Achieving Functional Cure. Viruses 2021; 13:v13050745. [PMID: 33922828 PMCID: PMC8146791 DOI: 10.3390/v13050745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/20/2021] [Accepted: 04/22/2021] [Indexed: 11/17/2022] Open
Abstract
While current therapies for chronic HBV infection work well to control viremia and stop the progression of liver disease, the preferred outcome of therapy is the restoration of immune control of HBV infection, allowing therapy to be removed while maintaining effective suppression of infection and reversal of liver damage. This “functional cure” of chronic HBV infection is characterized by the absence of detectable viremia (HBV DNA) and antigenemia (HBsAg) and normal liver function and is the goal of new therapies in development. Functional cure requires removal of the ability of infected cells in the liver to produce the hepatitis B surface antigen. The increased observation of transaminase elevations with new therapies makes understanding the safety and therapeutic impact of these flares an increasingly important issue. This review examines the factors driving the appearance of transaminase elevations during therapy of chronic HBV infection and the interplay of these factors in assessing the safety and beneficial nature of these flares.
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Ferrante ND, Lo Re V. Epidemiology, Natural History, and Treatment of Hepatitis Delta Virus Infection in HIV/Hepatitis B Virus Coinfection. Curr HIV/AIDS Rep 2020; 17:405-414. [PMID: 32607773 DOI: 10.1007/s11904-020-00508-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW Limited data exist on the prevalence, determinants, and outcomes of hepatitis delta virus (HDV) infection among HIV/hepatitis B virus (HBV)-coinfected persons. This review provides current evidence on the epidemiology, natural history, and treatment of HDV infection in patients with HIV/HBV coinfection and highlights future research needs. RECENT FINDINGS Cross-sectional studies in Europe, Africa, South America, and Asia show that the prevalence of HDV among HIV/HBV-coinfected patients ranges from 1.2 to 25%. No studies have evaluated the prevalence of HDV infection among HIV/HBV-coinfected patients in the USA. HDV infection increases the risk of hepatic decompensation and hepatocellular carcinoma among HIV/HBV-coinfected patients. HDV treatment remains limited to pegylated interferon-alpha, which results in sustained virologic response in fewer than 25%. Data on the epidemiology, natural history, and treatment of HDV among HIV/HBV-coinfected persons remain limited. More research is needed to address these knowledge gaps in order to better manage HDV coinfection in HIV/HBV-coinfected patients.
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Affiliation(s)
- Nicole D Ferrante
- Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, 836 Blockley Hall, 423 Guardian Drive, Philadelphia, PA, 19104-6021, USA
| | - Vincent Lo Re
- Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, 836 Blockley Hall, 423 Guardian Drive, Philadelphia, PA, 19104-6021, USA.
- Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine University of Pennsylvania, Philadelphia, PA, USA.
- Center for AIDS Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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Complex genetic encoding of the hepatitis B virus on-drug persistence. Sci Rep 2020; 10:15574. [PMID: 32968103 PMCID: PMC7511938 DOI: 10.1038/s41598-020-72467-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 09/02/2020] [Indexed: 12/12/2022] Open
Abstract
Tenofovir disoproxil fumarate (TDF) is one of the nucleotide analogs capable of inhibiting the reverse transcriptase (RT) activity of HIV and hepatitis B virus (HBV). There is no known HBV resistance to TDF. However, detectable variation in duration of HBV persistence in patients on TDF therapy suggests the existence of genetic mechanisms of on-drug persistence that reduce TDF efficacy for some HBV strains without affording actual resistance. Here, the whole genome of intra-host HBV variants (N = 1,288) was sequenced from patients with rapid (RR, N = 5) and slow response (SR, N = 5) to TDF. Association of HBV genomic and protein polymorphic sites to RR and SR was assessed using phylogenetic analysis and Bayesian network methods. We show that, in difference to resistance to nucleotide analogs, which is mainly associated with few specific mutations in RT, the HBV on-TDF persistence is defined by genetic variations across the entire HBV genome. Analysis of the inferred 3D-structures indicates no difference in affinity of TDF binding by RT encoded by intra-host HBV variants that rapidly decline or persist in presence of TDF. This finding suggests that effectiveness of TDF recognition and binding does not contribute significantly to on-drug persistence. Differences in patterns of genetic associations to TDF response between HBV genotypes B and C and lack of a single pattern of mutations among intra-host variants sensitive to TDF indicate a complex genetic encoding of the trait. We hypothesize that there are many genetic mechanisms of on-drug persistence, which are differentially available to HBV strains. These pervasive mechanisms are insufficient to prevent viral inhibition completely but may contribute significantly to robustness of actual resistance. On-drug persistence may reduce the overall effectiveness of therapy and should be considered for development of more potent drugs.
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9
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Hall S, Howell J, Visvanathan K, Thompson A. The Yin and the Yang of Treatment for Chronic Hepatitis B-When to Start, When to Stop Nucleos(t)ide Analogue Therapy. Viruses 2020; 12:v12090934. [PMID: 32854335 PMCID: PMC7552074 DOI: 10.3390/v12090934] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 08/20/2020] [Accepted: 08/22/2020] [Indexed: 12/11/2022] Open
Abstract
Over 257 million individuals worldwide are chronically infected with the Hepatitis B Virus (HBV). Nucleos(t)ide analogues (NAs) are the first-line treatment option for most patients. Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are both potent, safe antiviral agents, have a high barrier to resistance, and are now off patent. They effectively suppress HBV replication to reduce the risk of cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Treatment is continued long-term in most patients, as NA therapy rarely induces HBsAg loss or functional cure. Two diverging paradigms in the treatment of chronic hepatitis B have recently emerged. First, the public health focussed "treat-all" strategy, advocating for early and lifelong antiviral therapy to minimise the risk of HCC as well as the risk of HBV transmission. In LMICs, this strategy may be cost saving compared to monitoring off treatment. Second, the concept of "stopping" NA therapy in patients with HBeAg-negative disease after long-term viral suppression, a personalised treatment strategy aiming for long-term immune control and even HBsAg loss off treatment. In this manuscript, we will briefly review the current standard of care approach to the management of hepatitis B, before discussing emerging evidence to support both the "treat-all" strategy, as well as the "stop" strategy, and how they may both have a role in the management of patients with chronic hepatitis B.
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Affiliation(s)
- Samuel Hall
- Gastroenterology Department, St Vincent’s Hospital Melbourne, 41 Victoria Pde, Fitzroy, VIC 3065, Australia; (J.H.); (A.T.)
- Correspondence:
| | - Jessica Howell
- Gastroenterology Department, St Vincent’s Hospital Melbourne, 41 Victoria Pde, Fitzroy, VIC 3065, Australia; (J.H.); (A.T.)
| | - Kumar Visvanathan
- Infectious Diseases Department, St Vincent’s Hospital Melbourne, 41 Victoria Pde, Fitzroy, VIC 3065, Australia;
| | - Alexander Thompson
- Gastroenterology Department, St Vincent’s Hospital Melbourne, 41 Victoria Pde, Fitzroy, VIC 3065, Australia; (J.H.); (A.T.)
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10
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Brief Report: Relationship Between ABCC4 SNPs and Hepatitis B Virus Suppression During Tenofovir-Containing Antiretroviral Therapy in Patients With HIV/HBV Coinfection. J Acquir Immune Defic Syndr 2020; 82:421-425. [PMID: 31335591 DOI: 10.1097/qai.0000000000002136] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Incomplete hepatitis B virus (HBV) suppression during antiretroviral therapy (ART) in HIV and HBV coinfected patients is common, but underlying factors are not fully elucidated. We hypothesize that genetic factors that influence nucleoside analog pharmacokinetics will affect HBV treatment response. METHODS HIV/HBV coinfected patients on tenofovir disoproxil fumarate/lamivudine (TDF/3TC)-containing ART were enrolled. Selected ABCC4 single nucleotide polymorphisms (SNPs) with known effects on nucleoside pharmacokinetics were genotyped using TaqMan assays. Relationship between ABCC4 SNPs and unsuppressed HBV DNA (HBV DNA ≥20 IU/mL) were examined. RESULTS Of the 50 participants on TDF/3TC-containing ART for a median (range) of 1.5 (1-7.4) years, 20 (40%) had unsuppressed HBV DNA. Participants with unsuppressed compared with those with suppressed HBV DNA were more likely to have negative HBe antibody, lower body mass index, and lower CD4 count at enrollment. Carriers of ABCC4 rs11568695 (G3724A) variant allele were more likely than noncarriers to have unsuppressed HBV (61.1% vs. 29.0%, P = 0.038). Among 36 patients with suppressed HIV RNA (presumed good ART adherence), ABCC4 rs11568695 variant carriers were more likely than noncarriers to have unsuppressed HBV (58.8% vs. 20.0% P = 0.021). Logistic regression analysis that included genetic and nongenetic factors identified ABCC4 rs11568695 variant allele, body mass index, and male sex as predictors of unsuppressed HBV DNA. CONCLUSIONS We identified a novel association between ABCC4 rs11568695 SNP and poor HBV treatment response. If confirmed in further studies, ABCC4 genotyping could be used to identify individuals who may need intensified HBV therapy.
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11
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Tatar B, Gül S, Köse Ş, Pala E. Long-Term Effects of Tenofovir on Liver Histopathology in Patients with Chronic Viral Hepatitis B Infection. Turk Patoloji Derg 2020; 1:154-158. [PMID: 32149362 PMCID: PMC10511254 DOI: 10.5146/tjpath.2020.01478] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 01/24/2020] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE The aim of this study to evaluate histopathological improvement and virological, serological and biochemical response rates in patients with chronic hepatitis B (CHB) who were treated with tenofovir disoproxil fumarate (TDF). MATERIAL AND METHOD A total of 91 nucleosid(t)e-naive CHB patients who received TDF were evaluated. Virological, serological and biochemical test results were assessed at baseline and every 12 weeks. Liver biopsy specimens were assessed according to the modified Ishak scoring. RESULTS The study was conducted on 52 patients. The mean age was 40±10 years and 40.4% were female. The mean follow-up period was 33±11 months. HBsAg seroclearance occurred in none of the patients. The serum level of HBV-DNA became undetectable in 94.2% of the patients. Mean histological activity index at baseline and on-treatment were 8.2±2.3 and 6.2±2.0 and the mean fibrosis scores were 2.65±1.3 and 2.33±1.1, respectively. CONCLUSION We determined that TDF therapy provided remarkably good HBV DNA suppression and biochemical response rates, but low seroconversion. Improvement of liver necroinflammation was detected, but no significant change observed in fibrosis.
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Affiliation(s)
- Bengü Tatar
- Department of Infectious Diseases and Clinical Microbiology, University of Health Sciences ,Izmir Tepecik Education and Research Hospital, Izmir, Turkey
| | - Selma Gül
- Batman State Hospital, Batman, Turkey
| | - Şükran Köse
- Department of Infectious Diseases and Clinical Microbiology, University of Health Sciences ,Izmir Tepecik Education and Research Hospital, Izmir, Turkey
| | - Emel Pala
- Department of Pathology, University of Health Sciences, Izmir Tepecik Education and Research Hospital, Izmir, Turkey
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12
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Kim DS, Jeon MY, Lee HW, Kim BK, Park JY, Kim DY, Ahn SH, Han KH, Kim SU. Influence of hepatic steatosis on the outcomes of patients with chronic hepatitis B treated with entecavir and tenofovir. Clin Mol Hepatol 2019; 25:283-293. [PMID: 30419649 PMCID: PMC6759433 DOI: 10.3350/cmh.2018.0054] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 08/17/2018] [Accepted: 09/11/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND/AIMS The influence of hepatic steatosis (HS) on chronic hepatitis B (CHB) is unclear. We evaluated the influence of the degree of HS, assessed using the controlled attenuation parameter (CAP) of transient elastography (TE), on treatment outcomes in CHB patients initiated on antiviral therapy. METHODS A total of 334 patients who were initiated on entecavir or tenofovir between 2007 and 2016 with available TE results were recruited. RESULTS Of the total study population, 146 (43.7%) patients had HS (CAP > 238 dB/m). Three-hundred-three patients (90.7%) achieved complete virological response (CVR) (hepatitis B virus DNA<12 IU/L), and 25 patients (7.5%) developed hepatocellular carcinoma (HCC). Among hepatitis B e antigen (HBeAg)-positive patients (n=172, 51.5%), 37 (21.5%) experienced HBeAg loss. On univariate analysis, CAP value was not associated with the probability of HCC development (P=0.380). However, lower CAP value was independently associated with higher probability of HBeAg loss among HBeAg-positive patients (hazard ratio [HR]=0.991, P=0.026) and with CVR achievement in the entire study population (HR=0.996, P=0.004). The cumulative incidence of HBeAg loss among HBeAg-positive patients was significantly higher in patients without HS than in those with HS (log-rank, P=0.022). CONCLUSION CAP values were not correlated with HCC development in patients initiated on entecavir and tenofovir. However, CAP values were negatively correlated with the probability of HBeAg loss among HBeAg-positive patients and with CVR achievement.
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Affiliation(s)
- David Sooik Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Mi Young Jeon
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Department of Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Department of Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Department of Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Department of Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Department of Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Department of Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Department of Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Department of Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
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13
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Liang RY, Xu JH, Si CW, Wang S, Shang J, Yu ZJ, Mao Q, Xie Q, Zhao W, Li J, Gao ZL, Wu SM, Tang H, Cheng J, Chen XY, Zhang WH, Wang H, Xu ZN, Wang L, Dai J, Yu YY. A randomized, double-blind, double-dummy, controlled, multicenter study of Qingzhong (tenofovir disoproxil fumarate) versus Viread for the treatment of chronic hepatitis B: First-stage results at week 48. Medicine (Baltimore) 2019; 98:e16778. [PMID: 31415381 PMCID: PMC6831396 DOI: 10.1097/md.0000000000016778] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Tenofovir disoproxil fumarate (TDF) has been widely recommended as a first-line antiviral agent to treat chronic hepatitis B (CHB). Qingzhong and Viread, formulations of TDF commercialized by Jiangsu Chia-tai Tianqing Pharmaceutical Co Ltd and GlaxoSmithKline, respectively, have both been approved by the State Food and Drug Administration, China. This study analyzed the efficacy and safety of these 2 TDF agents in Chinese patients with CHB. METHODS In this multicenter, randomized, double-blind, double-dummy, noninferiority phase 3 clinical trial (ClinicalTrials.gov identifier: NCT02287857), 330 Chinese patients with CHB [hepatitis B envelope antigen-positive (HBeAg) (+): 232] were randomly assigned to receive Qingzhong (group A: 161 patients) or Viread (group B: 169 patients) 300 mg once daily for 48 weeks. Subsequently, all patients were administered Qingzhong 300 mg once daily from week 49 to week 240. The primary end point was the degree of decline of plasma hepatitis B virus (HBV) DNA levels at week 48 and the secondary endpoints were viral suppression, normalization of alanine aminotransferase (ALT) levels, hepatitis B surface antigen (HBsAg)/HBeAg loss or seroconversion, and virological breakthrough. RESULTS Among patients with CHB who were HBeAg (+), the mean HBV DNA titer decreased similarly between the groups at week 48. The percentages of patients who achieved undetectable HBV DNA were similar between the groups (85.11% and 82.35% in groups A and B, respectively) and similar losses of HBeAg and HBeAg seroconversion rates were achieved. Moreover, for patients with CHB who were HBeAg (-), reductions in HBV DNA were similar. Among all patients with CHB, the rates of normalization of ALT and the loss of HBsAg were similar. The overall incidence of adverse events was comparable between the groups. CONCLUSION In conclusion, the 48-week administration of Qingzhong showed noninferior efficacy and safety profiles compared to Viread in Chinese patients with CHB.
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Affiliation(s)
- Rong-Yue Liang
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Peking
| | - Jing-Hang Xu
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Peking
| | - Chong-Wen Si
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Peking
| | - Sa Wang
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Peking
| | - Jia Shang
- Department of Infectious Diseases, Henan Provincial People's Hospital
| | - Zu-Jiang Yu
- Department of Infectious Diseases, First Affiliated Hospital of Zhengzhou University, Henan
| | - Qing Mao
- Department of Infectious Diseases, Southwest China Hospital, Chongqing
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Jiaotong University School of Medicine, Shanghai
| | - Wei Zhao
- Department of Infectious Diseases, The Second Affiliated Hospital of Southeast University
| | - Jun Li
- Department of Infectious Diseases, The First Affiliated Hospital with Nanjing Medical University, Nanjing
| | - Zhi-Liang Gao
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangdong
| | - Shan-Ming Wu
- Department of Infectious Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai
| | - Hong Tang
- Department of Infectious Diseases, West China Hospital of Sichuan University, Sichuan
| | - Jun Cheng
- Department of Infectious Diseases, Beijing Ditan Hospital
| | - Xin-Yue Chen
- Department of International Medicine, Beijing Youan Hospital, Capital Medical University, Beijing
| | - Wen-Hong Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai
| | - Hao Wang
- Department of Infectious Diseases, Peking University People's Hospital, Beijing
| | - Zhong-Nan Xu
- Jiangsu Chia-tai Tianqing Pharmaceutical Co, Ltd, Nanjing, China
| | - Ling Wang
- Jiangsu Chia-tai Tianqing Pharmaceutical Co, Ltd, Nanjing, China
| | - Jun Dai
- Jiangsu Chia-tai Tianqing Pharmaceutical Co, Ltd, Nanjing, China
| | - Yan-Yan Yu
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Peking
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14
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Tenofovir and telbivudine combination therapy rapidly decreases viral loads in immune-tolerant chronic hepatitis B patients awaiting assisted reproduction: an open-label, randomized, controlled study. Eur J Gastroenterol Hepatol 2019; 31:832-835. [PMID: 30601336 DOI: 10.1097/meg.0000000000001345] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Immune-tolerant chronic hepatitis B (CHB) patients awaiting assisted reproduction (AR) are required to initiate antiviral therapy because of laboratory safety concerns. The antiviral therapy in this group has not been well assessed. We sought to explore the efficacy and safety of the combination therapy (COM) of tenofovir (TDF) and telbivudine (LdT). PATIENTS AND METHODS In this open-label, randomized, controlled study, we enrolled and randomized hepatitis B virus e-antigen (HBeAg)-positive CHB patients awaiting AR into the study COM group and the control (TDF) group. The COM group received combination therapy of TDF and LdT, and the TDF group received a single treatment of TDF. The patients were followed up for at least 48 weeks. The primary endpoint was the proportion of patients with undetectable HBV DNA level at week 12. RESULTS A total of 121 patients were recruited into the COM group (n=60) and the TDF group (n=61). The percentages of patients with undetectable HBV DNA levels were 90.0% (54/60) in the COM group and 67.2% (41/61) (P=0.002) in the TDF group at week 12; the percentages were 96.6% (58/60) in the COM group and 85.2% (52/61) in the TDF group at week 48 (P=0.028), respectively. HBeAg seroconversion occurred in 5/60 (8.3%) patients in the COM group and 2/61 (3.3%) patients in the TDF group at week 48 (P=0.233). CONCLUSION TDF and LdT combination therapy shows a rapid antivirological response in immune-tolerant CHB patients awaiting AR, which provide an alternative for this group at AR centers. However, the HBeAg seroconversion rate is unsatisfactory in the short term.
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15
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Frequency of Hepatitis B Virus Resistance Mutations in Women Using Tenofovir Gel as Pre-Exposure Prophylaxis. Viruses 2019; 11:v11060569. [PMID: 31248149 PMCID: PMC6630952 DOI: 10.3390/v11060569] [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: 05/14/2019] [Revised: 06/12/2019] [Accepted: 06/14/2019] [Indexed: 11/17/2022] Open
Abstract
Intermittent use of a single antiretroviral agent in the presence of a replicating virus could potentially increase the development of antiviral resistance. The pericoital, before-and-after sex, dosing regimen used in the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 tenofovir gel trial meant that women who were infected with hepatitis B virus (HBV) were exposed intermittently to tenofovir during their participation. The impact of this dosing regimen on HBV resistance was assessed by amplification of the HBV polymerase region from 37 stored plasma samples of women who were HBV surface antigen positive. All samples belonged to HBV genotype A. None of the known tenofovir resistance mutations (M240V/I, L180M, A194T, V214A, N238T) were identified in any individuals. While it is reassuring that no resistance mutations were found among women using topical tenofovir, the rapidly expanding access to oral tenofovir-containing HIV pre-exposure prophylaxis (PrEP), with higher systemic exposure to the drug, makes monitoring for potential HBV drug resistance important.
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16
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Min IS, Lee CH, Shin IS, Lee NE, Son HS, Kim SB, Seo SY, Kim SH, Kim SW, Lee SO, Lee ST, Kim IH. Treatment Outcome and Renal Safety of 3-Year Tenofovir Disoproxil Fumarate Therapy in Chronic Hepatitis B Patients with Preserved Glomerular Filtration Rate. Gut Liver 2019; 13:93-103. [PMID: 30400723 PMCID: PMC6347000 DOI: 10.5009/gnl18183] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 07/02/2018] [Accepted: 07/05/2018] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND/AIMS To investigate the treatment efficacy and renal safety of long-term tenofovir disoproxil fumarate (TDF) therapy in chronic hepatitis B (CHB) patients with preserved renal function. METHODS The medical records of 919 CHB patients who were treated with TDF therapy were reviewed. All patients had preserved renal function with an estimated glomerular filtration rate (eGFR) of at least 60 mL/min/1.73 m². RESULTS A total of 426 patients (184 treatment-naïve and 242 treatment-experienced) were included for analysis. A virologic response (VR) was defined as achieving an undetectable serum hepatitis B virus (HBV) DNA level, and the overall VR was 74.9%, 86.7%, and 89.4% at the 1, 2, and 3-year follow-ups, respectively. Achieving a VR was not influenced by previous treatment experience, TDF combination therapy, or antiviral resistance. In a multivariate analysis, being hepatitis B e antigen positive at baseline and having a serum HBV DNA level ≥2,000 IU/mL at 12 months were associated with lower VR rates during the long-term TDF therapy. The overall renal impairment was 2.9%, 1.8%, and 1.7% at the 1, 2, and 3-year follow-ups, respectively. With regard to renal safety, underlying diabetes mellitus (DM) and an initial eGFR of 60 to 89 mL/min/1.73 m² were significant independent predictors of renal impairment. CONCLUSIONS TDF therapy appears to be an effective treatment option for CHB patients with a preserved GFR. However, patients with underlying DM and initial mild renal dysfunction (eGFR, 60 to 89 mL/min/1.73 m²) have an increased risk of renal impairment.
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Affiliation(s)
- In Suk Min
- Department of Internal Medicine, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - Chang Hun Lee
- Department of Internal Medicine, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - Ik Sang Shin
- Department of Internal Medicine, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - Na Eun Lee
- Department of Internal Medicine, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - Hong Seon Son
- Department of Internal Medicine, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - Seung Bum Kim
- Department of Internal Medicine, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - Seung Young Seo
- Department of Internal Medicine, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - Seong Hun Kim
- Department of Internal Medicine, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - Sang Wook Kim
- Department of Internal Medicine, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - Seung Ok Lee
- Department of Internal Medicine, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - Soo Teik Lee
- Department of Internal Medicine, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - In Hee Kim
- Department of Internal Medicine, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
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Nam JY, Chang Y, Cho H, Kang SH, Cho YY, Cho EJ, Lee JH, Yu SJ, Yoon JH, Kim YJ. Delayed viral suppression during antiviral therapy is associated with increased hepatocellular carcinoma rates in HBeAg-positive high viral load chronic hepatitis B. J Viral Hepat 2018; 25:552-560. [PMID: 29194870 DOI: 10.1111/jvh.12838] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 10/26/2017] [Indexed: 12/26/2022]
Abstract
The treatment option in chronic hepatitis B (CHB) patients with persistent low-level viremia despite entecavir or tenofovir monotherapy is unclear. This study investigated the development of hepatocellular carcinoma (HCC) or cirrhosis in hepatitis B e antigen (HBeAg)-positive high viral load CHB patients, according to the time needed to achieve complete viral suppression. A total of 325 HBeAg-positive CHB patients with high viral load who were recently started on antiviral therapy with entecavir or tenofovir were included. The enrolled patients were divided into 2 groups with 4 separate criteria based on the time needed to achieve complete viral suppression: within 1, 2, 3 or 4 years of therapy initiation. The outcomes were development of HCC and cirrhosis. The cumulative incidence of HCC was significantly higher in patients failing complete viral suppression within 1 year (hazard ratio (HR), 4.54; 95% confidence interval (CI), 1.03-19.93; P = .045) or 2 years (HR, 3.38; 95% CI, 1.24-9.23; P = .018), than patients who achieved complete viral suppression within 1 or 2 years, respectively. Cumulative incidence of cirrhosis was also significantly higher in patients failing suppression within 1 year (HR, 1.95; 95% CI, 1.04-3.66; P = .037) or 2 years (HR, 2.44; 95% CI, 1.41-4.22; P = .001). When the time for achieving viral suppression exceeded 2 years, the cumulative incidence of HCC or cirrhosis was not different regardless of viral suppression. Complete hepatitis B virus suppression within 2 years of antiviral therapy initiation is associated with risk reduction in HCC or cirrhosis development.
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Affiliation(s)
- J Y Nam
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Y Chang
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - H Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - S H Kang
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University, Wonju College of Medicine, Wonju-si, Korea
| | - Y Y Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - E J Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - J-H Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - S J Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - J-H Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Y J Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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18
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Guo X, Wu J, Wei F, Ouyang Y, Li Q, Liu K, Wang Y, Zhang Y, Chen D. Trends in hepatitis B virus resistance to nucleoside/nucleotide analogues in North China from 2009-2016: A retrospective study. Int J Antimicrob Agents 2018; 52:201-209. [PMID: 29654894 DOI: 10.1016/j.ijantimicag.2018.04.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Revised: 03/29/2018] [Accepted: 04/04/2018] [Indexed: 12/13/2022]
Abstract
Nucleos(t)ide analogues (NAs) are widely used in anti-hepatitis B virus (anti-HBV) therapy for effective inhibition of HBV replication. However, HBV resistance to NAs has emerged, resulting in virus reactivation and disease recurrence. Data on the current dynamics of HBV resistance are still rare in China. This study analysed 4491 plasma samples with HBV primary genotypic resistance mutations representative of the general HBV resistance situation in northern China from 2009-2016. We found that entecavir (ETV), representing 57.6% (12 713/22 060) of NA users in North China in 2016, has become the major NA for treating Chinese patients infected with HBV. Despite >50% of M204I/V±L180M among all HBV resistance cases annually and extensive exposure of patients to lamivudine (LAM), telbivudine (LdT) and adefovir dipivoxil (ADV), ETV resistance also showed a dramatically increased incidence, which rose to 17.1% in 2016. Moreover, A181T/V, ETV resistance mutations and multidrug resistance mutations were found more frequently in HBV genotype C compared with genotype B (21.2% vs. 8.5%, 12.4% vs. 7.9% and 5.9% vs. 3.0%, respectively), whereas M204I and N236T were more predominant in genotype B than genotype C (40.3% vs. 20.8% and 11.3% vs. 1.8%, respectively). In conclusion, we report the dynamic changes of HBV NA resistance mutation patterns and the current NA usage profile for anti-HBV treatment in North China over the past 8 years. These data provide valuable information on HBV NA resistance that is an important reference for clinicians to devise more effective treatment regimens for individual patients.
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Affiliation(s)
- Xianghua Guo
- Beijing You An Hospital, Capital Medical University, Beijing 100069, China; Beijing Institute of Hepatology, Beijing 100069, China; Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Jushan Wu
- Beijing You An Hospital, Capital Medical University, Beijing 100069, China
| | - Feili Wei
- Beijing You An Hospital, Capital Medical University, Beijing 100069, China; Beijing Institute of Hepatology, Beijing 100069, China; Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Yabo Ouyang
- Beijing You An Hospital, Capital Medical University, Beijing 100069, China; Beijing Institute of Hepatology, Beijing 100069, China; Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Qing Li
- Beijing You An Hospital, Capital Medical University, Beijing 100069, China
| | - Kai Liu
- Beijing You An Hospital, Capital Medical University, Beijing 100069, China; Beijing Institute of Hepatology, Beijing 100069, China; Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Yanjun Wang
- Beijing You An Hospital, Capital Medical University, Beijing 100069, China; Beijing Institute of Hepatology, Beijing 100069, China; Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Yulin Zhang
- Beijing You An Hospital, Capital Medical University, Beijing 100069, China.
| | - Dexi Chen
- Beijing You An Hospital, Capital Medical University, Beijing 100069, China; Beijing Institute of Hepatology, Beijing 100069, China; Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China; Organ Transplantation Center, The Affiliated Hospital of Qingdao University, Qingdao City, Shandong Province 266003, China.
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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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20
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Kayaaslan B, Akinci E, Ari A, Tufan ZK, Alpat SN, Gunal O, Tosun S, Guner R, Tabak F. A long-term multicenter study: Entecavir versus Tenofovir in treatment of nucleos(t)ide analogue-naive chronic hepatitis B patients. Clin Res Hepatol Gastroenterol 2018; 42:40-47. [PMID: 28757048 DOI: 10.1016/j.clinre.2017.06.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 06/27/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND Entecavir (ETV) and tenofovir disoproxil fumarat (TDF) are the two first-line therapies recommended in the treatment of chronic hepatitis B because of having potent antiviral effect and high genetic barriers against resistance. We aimed to compare efficacy of these drugs and to evaluate predictors of viral suppression. METHODS This multicenter retrospective study was conducted in nucleos(t)ide analogue-naive chronic hepatitis B (CHB) patients from different 6 centers. RESULTS Of the 252 patients, 166 received ETV and 86 TDF. The two groups were similar in terms of age, gender, baseline ALT levels and fibrosis scores. ETV had significantly higher baseline HBV DNA, histological activity index and lower hepatitis B early antigen (HBeAg) seropositivity. Treatment duration was longer in ETV group (P<0.001). In univariate analysis, undetectable HBV DNA and ALT normalization rates were detected significantly higher in ETV groups (P<0.001 and 0.049, respectively). There was no significant difference between groups in terms of HBeAg seroconversion, virological breakthrough, time to virological breakthrough and time to ALT normalization. Entecavir was more effective in reducing HBV DNA levels at the 3rd, 6th and 12th months of the treatment (P=0.06, 0.021 and 0.012, respectively). However, multivariate Cox regression analysis indicated that TDF therapy compared to ETV had an increased probability of achieving complete viral suppression (HR=1, 66; 95% CI 1.21-2.33; P=0.010). Hepatitis B surface antigen (HBsAg) seroconversion was occurred in only one patient in ETV group. CONCLUSION ETV leads to an early response on HBV DNA decline in the first year of the treatment. However, TDF is more successful than entecavir in achieving virological suppression.
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Affiliation(s)
- Bircan Kayaaslan
- Yildirim Beyazit University, Faculty of Medicine, Ankara Ataturk Education and Research Hospital, Department of Infectious Disease and Clinical Microbiology, Ankara, Turkey.
| | - Esragul Akinci
- Ankara Numune Education and Research Hospital, Department of Infectious Disease and Clinical Microbiology, Ankara, Turkey.
| | - Alpay Ari
- Izmir Bozyaka Education and Research Hospital, Department of Infectious Disease and Clinical Microbiology, Izmir, Turkey.
| | - Zeliha Kocak Tufan
- Yildirim Beyazit University, Faculty of Medicine, Ankara Ataturk Education and Research Hospital, Department of Infectious Disease and Clinical Microbiology, Ankara, Turkey.
| | - Saygın Nayman Alpat
- Eskisehir Osmangazi University, Faculty of Medicine, Department of Infectious Disease and Clinical Microbiology, Eskisehir, Turkey.
| | - Ozgur Gunal
- Samsun Education and Research Hospital, Department of Infectious Disease and Clinical Microbiology, Samsun, Turkey.
| | - Selma Tosun
- Izmir Bozyaka Education and Research Hospital, Department of Infectious Disease and Clinical Microbiology, Izmir, Turkey.
| | - Rahmet Guner
- Yildirim Beyazit University, Faculty of Medicine, Ankara Ataturk Education and Research Hospital, Department of Infectious Disease and Clinical Microbiology, Ankara, Turkey.
| | - Fehmi Tabak
- Istanbul University Cerrahpasa Faculty of Medicine, Department of Infectious Disease and Clinical Microbiology, Istanbul, Turkey.
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21
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Choe JY, Ko JS, Choe BH, Kim JE, Kang B, Lee KJ, Yang HR. Antiviral Efficacy of Tenofovir Monotherapy in Children with Nucleos(t)ide-naive Chronic Hepatitis B. J Korean Med Sci 2018; 33:e11. [PMID: 29215820 PMCID: PMC5729652 DOI: 10.3346/jkms.2018.33.e11] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 10/14/2017] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The purpose was to compare the efficacy between tenofovir disoproxil fumarate (TDF) and lamivudine (LMV) in children with nucleos(t)ide-naive chronic hepatitis B (CHB) infection. Patients with CHB were treated with TDF in the immune-reactive phase and compared with a historical control group of patients treated with LMV before the TDF era. METHODS Hepatitis B virus (HBV) DNA titer decrements (> 3 log₁₀ IU/mL) were monitored after treatment initiation. The treatment duration for HBV DNA clearance (< 357 IU/mL) and complete response (HBeAg loss and HBV DNA clearance) were analyzed. The follow-up period was 96 weeks. RESULTS Sixteen patients were treated with TDF and compared with a historical control group of 24 patients treated with LMV. HBV DNA decrement (> 3 log₁₀ IU/mL) was achieved in 100% (16/16) of the TDF group but in only 62.5% (15/24) of the LMV group (P = 0.005) at 48 weeks. The HBV DNA clearance (< 357 IU/mL) in the TDF and LMV groups was, respectively, as follows: 62.5% (10/16) and 25.0% (6/24) at 12 weeks (P = 0.018), 81.3% (13/16) and 37.5% (9/24) at 24 weeks (P = 0.006), 93.8% (15/16) and 50.0% (12/24) at 48 weeks (P = 0.004), and 100% (16/16) and 54.2% (13/24) at 96 weeks (P = 0.001). Complete response occurred in 41.7% (5/12) of HBeAg-positive patients in the TDF group and 28.6% (6/21) of the LMV group at 96 weeks (P = 0.443). CONCLUSION TDF monotherapy for 96 weeks produced a significantly more effective virologic response than LMV monotherapy in children with nucleos(t)ide-naive CHB.
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Affiliation(s)
- Jae Young Choe
- Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Korea
| | - Jae Sung Ko
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Byung Ho Choe
- Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Korea.
| | - Jung Eun Kim
- Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Korea
| | - Ben Kang
- Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Korea
| | - Kyung Jae Lee
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Hye Ran Yang
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
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23
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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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24
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Liu Y, Cathcart AL, Delaney WE, Kitrinos KM. Development of a digital droplet PCR assay to measure HBV DNA in patients receiving long-term TDF treatment. J Virol Methods 2017; 249:189-193. [PMID: 28923315 DOI: 10.1016/j.jviromet.2017.09.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 09/14/2017] [Accepted: 09/15/2017] [Indexed: 12/26/2022]
Abstract
The COBAS TaqMan assay has a lower limit of quantification (LLOQ) of 169 HBV copies/mL and a lower limit of detection (LLOD) of 58 copies/mL. HBV DNA below the TaqMan LLOQ is classified as target not detected (TND) (<58 copies/mL) or target detected (TD) (between 58 and 169 copies/mL). Here we have developed a more sensitive digital droplet PCR (ddPCR) assay to evaluate the impact of long-term tenofovir disoproxil fumarate (TDF) treatment in patients that did or did not achieve HBsAg seroconversion. A ddPCR assay was developed to detect HBV DNA to 8 copies/mL. HBV DNA levels in plasma from patients with or without HBsAg seroconversion were assessed by ddPCR. For patients who did not achieve HBsAg seroconversion, the majority of TD samples (33/58, 57%) were HBV DNA positive by ddPCR while (10/37, 27%) of TND samples were positive. In contrast, for patients who achieved HBsAg seroconversion, HBV DNA was rarely detected by ddPCR after HBsAg seroconversion (1/28, 3.6%). ddPCR is a sensitive method to evaluate low-level viral replication in plasma samples. Frequent detection of HBV DNA by ddPCR among patients who did not achieve HBsAg seroconversion suggests new agents may be needed to suppress low levels of replicating HBV.
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Affiliation(s)
- Yang Liu
- Gilead Sciences, Inc., Foster City, CA, USA.
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25
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Truong J, Shadbolt B, Ooi M, Chitturi S, Kaye G, Farrell GC, Teoh NC. Week 4 viral load predicts long-term suppression of hepatitis B virus DNA during antiviral therapy: improving hepatitis B treatment in the real world. Intern Med J 2017; 47:50-56. [PMID: 27571991 DOI: 10.1111/imj.13244] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Revised: 08/15/2016] [Accepted: 08/22/2016] [Indexed: 01/01/2023]
Abstract
BACKGROUND Entecavir and tenofovir potently suppress hepatitis B virus (HBV) replication so that serum HBV DNA levels <20 IU/mL can be achieved after 2 years. Despite this, inadequate suppression is reported in >20% of cases for unclear reasons. AIM We tested whether 4-week viral load (VL) assessment could improve 96-week treatment outcome. METHODS Data on all chronic hepatitis B patients treated with entecavir or tenofovir between 2005 and 2014 were entered prospectively. Full data capture included pre-treatment, weeks 4, 24, 48 and 96 HBV DNA titre, HBeAg, age, gender, antiviral agent and dose escalation. Compliance data were compiled from pharmacy records, doctors' letters and clinic bookings/attendance. Time to achieve complete viral suppression (HBV DNA < 20 IU/mL) was graphed using Kaplan-Meier curves. Factors affecting this were examined using a multivariate Cox Proportional Hazard model. RESULTS Among 156 patients treated, 72 received entecavir and 84 tenofovir. Pre-treatment HBV DNA titre, 4-week assessment and compliance impacted significantly on time to complete viral suppression. At 96 weeks, 90% of those assessed as compliant by 4-week HBV DNA had complete viral suppression versus 50% followed by 6-month VL estimation. Continuing care by the same physician was related to 4-week VL testing and optimal compliance. CONCLUSIONS Medium-term outcomes of HBV antiviral therapy are improved by early on-treatment VL testing, facilitating patient engagement and improved compliance. The observation that 90% complete viral suppression after 2 years monotherapy is achievable in a routine clinic setting questions the need for combination therapy in HBV cases with suboptimal response.
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Affiliation(s)
- J Truong
- Australian National University Medical School, Gastroenterology and Hepatology Unit, The Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - B Shadbolt
- Centre for Advances in Epidemiology and Information Technology, The Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - M Ooi
- Australian National University Medical School, Gastroenterology and Hepatology Unit, The Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - S Chitturi
- Australian National University Medical School, Gastroenterology and Hepatology Unit, The Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - G Kaye
- Australian National University Medical School, Gastroenterology and Hepatology Unit, The Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - G C Farrell
- Australian National University Medical School, Gastroenterology and Hepatology Unit, The Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - N C Teoh
- Australian National University Medical School, Gastroenterology and Hepatology Unit, The Canberra Hospital, Canberra, Australian Capital Territory, Australia
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26
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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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Cost-Effectiveness and Clinical Impact of Antiviral Strategies of HBeAg-Positive and -Negative Chronic Hepatitis B. Ann Hepatol 2017. [DOI: 10.5604/01.3001.0009.8590] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/22/2023]
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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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29
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Zhong JH, Ma L, Li LQ. Postoperative Antiviral Therapy With Nucleos(t)ide Analogs in Patients With Hepatitis B Virus--Related Hepatocellular Carcinoma. Ann Surg 2017; 265:e46-e47. [PMID: 28266988 DOI: 10.1097/sla.0000000000001224] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Affiliation(s)
- Jian-Hong Zhong
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, PR China
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30
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Sriprayoon T, Mahidol C, Ungtrakul T, Chun-On P, Soonklang K, Pongpun W, Laohapand C, Dechma J, Pothijaroen C, Auewarakul C, Tanwandee T. Efficacy and safety of entecavir versus tenofovir treatment in chronic hepatitis B patients: A randomized controlled trial. Hepatol Res 2017; 47:E161-E168. [PMID: 27176630 DOI: 10.1111/hepr.12743] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2015] [Revised: 05/08/2016] [Accepted: 05/09/2016] [Indexed: 12/25/2022]
Abstract
AIM Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are considered among the most potent antiviral agents for the treatment of chronic hepatitis B infection. We aimed to compare treatment efficacy and safety of ETV and TDF in nucleoside-naïve chronic hepatitis B patients. METHODS Inclusion criteria were compensated chronic hepatitis B patients who were either hepatitis B e antigen (HBeAg)-positive or HBeAg-negative. Exclusion criteria were co-infection with hepatitis C virus and/or HIV, concurrent malignancy, and decompensated cirrhosis. Virological, biochemical, and serological end-points at week 96 and 144 were compared. Of 400 patients, 200 patients received ETV and 200 received TDF. RESULTS There were no significant differences between the two groups in baseline characteristics including age (41.6 ± 11.5 vs. 41.2 ± 11.6, mean baseline hepatitis B virus DNA (5.91 ± 1.79 vs. 5.94 ± 1.68 log10 IU/mL), mean baseline alanine aminotransferase (68.1 ± 64.1 vs. 76.8 ± 79.8 U/L), and cirrhosis (15.5% vs. 14.5%). At week 144 of treatment, 91 and 94% of the ETV and TDF groups, respectively, achieved undetectable hepatitis B virus DNA. In HBeAg-positive patients, HBeAg seroconversion could be achieved in 27.4% and 33.7% at week 144 for ETV and TDF groups, respectively. Quantitative hepatitis B surface antigen dropped significantly over 144 weeks of treatment period but only 1.0 to 1.5% experienced hepatitis B surface antigen loss. Safety profiles were consistent with previous reports of monotherapy. CONCLUSION Both ETV and TDF showed potent antiviral activity against hepatitis B. Either ETV or TDF can be recommended as a treatment of choice for patients with chronic hepatitis B. Both drugs were safe and well tolerated.
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Affiliation(s)
- Tassanee Sriprayoon
- Chulabhorn Hospital, Bangkok, Thailand.,Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Chulabhorn Mahidol
- Chulabhorn Hospital, Bangkok, Thailand.,Chulabhorn Research Institute, Bangkok, Thailand
| | | | | | | | | | - Charlie Laohapand
- Chulabhorn Hospital, Bangkok, Thailand.,Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | | | | | - Chirayu Auewarakul
- Chulabhorn Hospital, Bangkok, Thailand.,Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Tawesak Tanwandee
- Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
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Lee S, Ahn SH, Jung KS, Kim DY, Kim BK, Kim SU, Baatarkhuu O, Ku HJ, Han K, Park JY. Tenofovir versus tenofovir plus entecavir for chronic hepatitis B with lamivudine resistance and entecavir resistance. J Viral Hepat 2017; 24:141-147. [PMID: 27766731 DOI: 10.1111/jvh.12623] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Accepted: 08/23/2016] [Indexed: 12/29/2022]
Abstract
We compared the viral suppressive efficacy of tenofovir disoproxil fumarate (TDF) mono-rescue therapy (TDF group) and TDF plus entecavir (ETV) combination-rescue therapy (TDF + ETV group) in chronic hepatitis B (CHB) patients with lamivudine resistance and entecavir resistance. One hundred and thirty-three CHB patients with lamivudine and entecavir resistance were investigated. Ninety-six patients were treated with TDF and 37 with TDF + ETV for at least 6 months. We compared the virologic response rate (HBV DNA level <20 IU/mL) between the two groups and identified the predictive factors of treatment outcome. There were no significant differences between the two groups in demographic characteristics. Up to 24 months [median: 18 (range 6-24) months], 85.4% and 89.2% of the TDF group and TDF + ETV group, respectively, achieved a virologic response (P=.068). Only the HBV DNA level at baseline was significantly associated with a virologic response in the multivariate analysis. In a subanalysis of patients with HBV DNA levels ≥4 log (IU/mL) at baseline, a higher proportion of patients in the TDF + ETV group than the TDF group achieved a virologic response (92.9% vs 68.3%; P<.001), while 90% of patients with HBV DNA (IU/mL) levels <4 log in all both TDF and TDF + ETV groups achieved a virologic response. TDF mono-rescue therapy is a reasonable option in patients with lamivudine resistance and entecavir resistance. However, the combination strategy should be considered in patients with high baseline HBV DNA levels.
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Affiliation(s)
- S Lee
- Department of Internal Medicine, Catholic Kwandong University College of Medicine, International St. Mary's Hospital, Incheon Metropolitan City, Korea
- Institute for Integrative Medicine, Catholic Kwandong University College of Medicine, International St. Mary's Hospital, Incheon Metropolitan City, Korea
| | - S H Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - K S Jung
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - D Y Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - B K Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - S U Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - O Baatarkhuu
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Department of Infectious Diseases, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - H J Ku
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - K Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - J Y Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
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32
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Liu Y, Corsa AC, Buti M, Cathcart AL, Flaherty JF, Miller MD, Kitrinos KM, Marcellin P, Gane EJ. No detectable resistance to tenofovir disoproxil fumarate in HBeAg+ and HBeAg- patients with chronic hepatitis B after 8 years of treatment. J Viral Hepat 2017; 24:68-74. [PMID: 27658343 DOI: 10.1111/jvh.12613] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 07/10/2016] [Indexed: 12/12/2022]
Abstract
A major hurdle in the long-term treatment of chronic hepatitis B (CHB) patients is to maintain viral suppression in the absence of drug resistance. To date, no evidence of resistance to tenofovir disoproxil fumarate (TDF) has been observed. A cumulative evaluation of CHB patients who qualified for resistance surveillance over 8 years of TDF treatment was conducted. Patients in studies GS-US-174-0102 (HBeAg-) and GS-US-174-0103 (HBeAg+) were randomized 2:1 to receive TDF or adefovir dipivoxil (ADV) for 48 weeks followed by open-label TDF through year 8. Population sequencing of HBV pol/RT was attempted for all TDF-treated patients at baseline and, annually if viremic, at discontinuation, or with addition of emtricitabine. Overall, 88/641 (13.7%) patients qualified for sequence analysis at one or more time points. The percentage of patients qualifying for sequence analysis declined over time, from 9 to 11% in years 1-2 to <4% over years 3-8. Forty-one episodes of virologic breakthrough (VB) occurred throughout the study, with most (n=29, 70%) associated with nonadherence to study medication. Fifty-nine per cent of VB patients with an opportunity to resuppress HBV achieved HBV DNA resuppression. A minority of patients who qualified for sequencing had polymorphic (41/165, 24.8%) or conserved (17/165, 10.3%) site changes in pol/RT, with six patients developing lamivudine and/or ADV resistance-associated mutations. No accumulation of conserved site changes was detected. The long-term treatment of CHB with TDF monotherapy maintains effective suppression of HBV DNA through 8 years, with no evidence of TDF resistance or accumulation of conserved site changes.
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Affiliation(s)
- Y Liu
- Gilead Sciences, Inc, Foster City, CA, USA
| | - A C Corsa
- Gilead Sciences, Inc, Foster City, CA, USA
| | - M Buti
- Hospital General Universitari Vall d'Hebron, Barcelona, Spain
| | | | | | - M D Miller
- Gilead Sciences, Inc, Foster City, CA, USA
| | | | - P Marcellin
- Hôpital Beaujon, University Paris-Diderot, Clichy, France
| | - E J Gane
- Auckland City Hospital, Auckland, New Zealand
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Treatment of Hepatitis B: A Concise Review. Clin Transl Gastroenterol 2016; 7:e190. [PMID: 27628420 PMCID: PMC5288592 DOI: 10.1038/ctg.2016.46] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2016] [Accepted: 07/26/2016] [Indexed: 02/07/2023] Open
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Yang J, Sheng G, Xiao D, Shi H, Wu W, Lu H, Cao H, Li L. The frequency and skewed T-cell receptor beta-chain variable patterns of peripheral CD4(+)CD25(+) regulatory T-cells are associated with hepatitis B e antigen seroconversion of chronic hepatitis B patients during antiviral treatment. Cell Mol Immunol 2016; 13:678-687. [PMID: 26899927 PMCID: PMC5037272 DOI: 10.1038/cmi.2015.100] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Revised: 11/07/2015] [Accepted: 11/08/2015] [Indexed: 02/08/2023] Open
Abstract
The frequency and T-cell receptor beta-chain variable (TCRBV) patterns of peripheral CD4(+)CD25(+) regulatory T-cells (Tregs) are ambiguously altered in chronic hepatitis B (CHB) patients following tenofovir disoproxil fumarate (TDF) treatment. Moreover, the clinical significance of these parameters in relation to hepatitis B e antigen (HBeAg) seroconversion (SC) is largely unknown. In this study, the circulation of Tregs in HBeAg-positive CHB patients was determined by flow cytometry, and the molecular profiles of frequent TCRBV patterns of Tregs were analyzed using a gene melting spectral pattern. The parameters, such as Treg frequency, the number of skewed TCRBV patterns, hepatitis B virus (HBV) DNA levels, and alanine aminotransferase (ALT) levels, were analyzed by comparing their associations in seroconverting and non-seroconverting patients following TDF treatment. The Treg frequency was significantly correlated with the ALT level in seroconverting but not in non-seroconverting patients. Similarly, skewed TCRBV patterns were remarkably associated with HBV DNA levels in the SC group. Six TCRBV families (BV3, BV11, BV12, BV14, BV20, and BV24) were more prevalent than other TCRBV members in seroconverting patients pretreated with TDF, while BV12, BV15, and BV22 were predominant in non-seroconverting patients during TDF treatment. Taken together, the preferential TCRBV patterns may be associated with immune responses related to SC. The dynamic frequency and skewed TCRBV patterns of peripheral Tregs could contribute to predicting SC in CHB patients. Moreover, the conserved TCRBV complementarity-determining region (CDR3) motif may be targeted to develop personalized immunotherapy for CHB patients.
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MESH Headings
- Adult
- Alanine Transaminase/metabolism
- Amino Acid Motifs
- Antigens, CD/metabolism
- Antiviral Agents/pharmacology
- Antiviral Agents/therapeutic use
- Complementarity Determining Regions/immunology
- Conserved Sequence
- DNA, Viral/blood
- Hepatitis B e Antigens/immunology
- Hepatitis B, Chronic/blood
- Hepatitis B, Chronic/drug therapy
- Hepatitis B, Chronic/immunology
- Hepatitis B, Chronic/virology
- Humans
- Interleukin-2 Receptor alpha Subunit/metabolism
- Kinetics
- Longitudinal Studies
- Lymphocyte Count
- Middle Aged
- Receptors, Antigen, T-Cell, alpha-beta/genetics
- Seroconversion/drug effects
- T-Lymphocytes, Regulatory/immunology
- Young Adult
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Fujita K, Iwama H, Miyoshi H, Tani J, Oura K, Tadokoro T, Sakamoto T, Nomura T, Morishita A, Yoneyama H, Masaki T. Diabetes mellitus and metformin in hepatocellular carcinoma. World J Gastroenterol 2016; 22:6100-13. [PMID: 27468203 PMCID: PMC4945972 DOI: 10.3748/wjg.v22.i27.6100] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 05/25/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death worldwide. Diabetes mellitus, a risk factor for cancer, is also globally endemic. The clinical link between these two diseases has been the subject of investigation for a century, and diabetes mellitus has been established as a risk factor for HCC. Accordingly, metformin, a first-line oral anti-diabetic, was first proposed as a candidate anti-cancer agent in 2005 in a cohort study in Scotland. Several subsequent large cohort studies and randomized controlled trials have not demonstrated significant efficacy for metformin in suppressing HCC incidence and mortality in diabetic patients; however, two recent randomized controlled trials have reported positive data for the tumor-preventive potential of metformin in non-diabetic subjects. The search for biological links between cancer and diabetes has revealed intracellular pathways that are shared by cancer and diabetes. The signal transduction mechanisms by which metformin suppresses carcinogenesis in cell lines or xenograft tissues and improves chemoresistance in cancer stem cells have also been elucidated. This review addresses the clinical and biological links between HCC and diabetes mellitus and the anti-cancer activity of metformin in clinical studies and basic experiments.
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Wang HM, Hung CH, Lee CM, Lu SN, Wang JH, Yen YH, Kee KM, Chang KC, Tseng PL, Hu TH, Chen CH. Three-year efficacy and safety of tenofovir in nucleos(t)ide analog-naïve and nucleos(t)ide analog-experienced chronic hepatitis B patients. J Gastroenterol Hepatol 2016; 31:1307-14. [PMID: 26758501 DOI: 10.1111/jgh.13294] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Revised: 12/13/2015] [Accepted: 12/31/2015] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND AIMS This study compared the efficacy and safety of tenofovir disoproxil fumarate (TDF) up to 3 years of innucleos(t)ide analog (NA)-naïve and NA-experienced chronic hepatitis B (CHB) patients. METHODS Tenofovir disoproxil fumarate-treated NA-naïve and NA-experienced CHB patients were retrospectively analyzed. RESULTS After 3 years of TDF therapy, 97.7%, 71%, and 45.5% NA-naïve patients achieved a virological response, alanine aminotransferase normalization, and hepatitis B e antigen seroconversion, respectively. Compared with NA-naïve patients, NA-experienced patients without drug resistance and infected with lamivudine/telbivudine-resistant mutants showed similar results. In contrast, patients previously infected with adefovir-resistant mutants and with a suboptimal entecavir response showed significantly lower rates of virological response and hepatitis B e antigen loss/seroconverion than NA-naïve patients. Mean estimated glomerular filtration rate markedly reduced within 12 months of TDF therapy; however, it did not decrease significantly during 12-36 months of treatment. Diabetes mellitus was an independent predictor of a ≥ 0.5 mg/dL increase above baseline in serum creatinine level, and age, hypertension, diabetes mellitus, and baseline creatinine level were independent factors for > 20% decline in estimated glomerular filtration rate from baseline. Liver stiffness measurements improved significantly, but bone mineral density did not change significantly during treatment. Hepatocellular carcinoma incidence was low at 36 months. Age of > 60 years, cirrhosis, a low baseline platelet count and a high α-fetoprotein level at 12 months were significant predictors of hepatocellular carcinoma development. CONCLUSIONS Tenofovir disoproxil fumarate is effective and safe for NA-naïve and NA-experienced CHB patients and should be used cautiously in patients with comorbidities because of a renal dysfunction risk.
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Affiliation(s)
- Hsin-Ming Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chuan-Mo Lee
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yi-Hao Yen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Kwong-Ming Kee
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Kuo-Chin Chang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Po-Lin Tseng
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
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Effects of long-term tenofovir-based combination antiretroviral therapy in HIV-hepatitis B virus coinfection on persistent hepatitis B virus viremia and the role of hepatitis B virus quasispecies diversity. AIDS 2016; 30:1597-606. [PMID: 26950313 DOI: 10.1097/qad.0000000000001080] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
OBJECTIVE Hepatitis B virus (HBV) can persist in some HIV-HBV coinfected individuals on tenofovir disoproxil fumarate (TDF)-containing combination antiretroviral therapy (cART) but HBV resistance to TDF has not been reported and the source of persistent HBV DNA on TDF is poorly understood. The aims of this study were to assess long-term HBV suppression in HIV-HBV coinfected individuals receiving TDF and investigate quasispecies variation using ultradeep pyrosequencing (UDPS). METHODS Ninety-two HIV-HBV coinfected participants on, or about to commence, TDF-containing cART were enrolled [Australia (n = 40), Thailand (n = 52)] and followed for 2 years with study visits every 6 months. HBV reverse transcriptase sequencing was performed on samples with HBV DNA more than 400 IU/ml by population-based methods and UDPS. Quasispecies diversity was assessed using Shannon entropy. RESULTS Over 24 months, viremia was detected at least once in 17% (n = 16) of the cohort. Novel mutations were not identified in on TDF samples tested by population-based sequencing (n = 19). Using UDPS, the median Shannon entropy value in samples prior to TDF in patients aviremic on TDF was not statistically different from those who were viremic on TDF (n = 50; 8.4 and 9.1, respectively, P = 0.9). Longitudinal Shannon entropy analysis of on TDF samples from five participants showed three individuals with significant changes in viral diversity over time. CONCLUSION Persistent viremia on TDF-containing cART is common but TDF-resistance was not detected. In some individuals, changes in viral diversity over time were observed on TDF which could potentially be active viral replication. Further follow-up will be needed to determine the clinical significance of detectable HBV DNA on TDF-containing cART.
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Huang M, Jie Y, Lin G, Shi H, Li X, Li X, Wu Y, Chong Y. Long-Term Efficacy of Tenofovir Disoproxil Fumarate Therapy in Nucleos(t)ide-Experienced Chronic Hepatitis B Patients. Clin Drug Investig 2016; 36:471-478. [PMID: 26992717 DOI: 10.1007/s40261-016-0392-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND OBJECTIVES Tenofovir disoproxil fumarate (TDF) therapy is a therapeutic option for nucleos(t)ide analogue (NA)-experienced chronic hepatitis B (CHB) patients infected with hepatitis B virus (HBV). In this study, we evaluated the efficacy of TDF alone compared with the efficacy of TDF plus additional NA combinations in NA-experienced CHB patients. METHODS This retrospective cohort study included 108 patients with a serum HBV DNA level above 5.0 log10 IU/ml who were treated with TDF alone (monotherapy group) or TDF combined with additional NAs (combination therapy group) for 30 months. RESULTS At month 30, both therapies resulted in the suppression of HBV DNA levels: 66 of 66 patients (100 %) in the monotherapy group and 40 of 42 patients (95.23 %) in the combination therapy group achieved virologic suppression. Kaplan-Meier curves revealed median times for virologic suppression of 3.12 months in the monotherapy group and 5.23 months in the combination therapy group (p = 0.699). The probability of virologic suppression was comparable between treatment groups. At month 6, more patients achieved normal alanine aminotransferase (ALT) levels in the monotherapy group (p = 0.029). During the treatment period, no patients experienced severe renal dysfunction. CONCLUSION TDF monotherapy and TDF plus additional NAs have comparable antiviral efficacy in CHB patients after NA treatment failure.
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Affiliation(s)
- Mingxing Huang
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, No. 600, Tianhe Road, Guangzhou, Guangdong, 510630, China
- Department of Infectious Diseases, Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China
| | - Yusheng Jie
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, No. 600, Tianhe Road, Guangzhou, Guangdong, 510630, China
| | - Guoli Lin
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, No. 600, Tianhe Road, Guangzhou, Guangdong, 510630, China
| | - Hong Shi
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, No. 600, Tianhe Road, Guangzhou, Guangdong, 510630, China
| | - Xinhua Li
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, No. 600, Tianhe Road, Guangzhou, Guangdong, 510630, China
| | - Xiangyong Li
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, No. 600, Tianhe Road, Guangzhou, Guangdong, 510630, China
| | - Yuankai Wu
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, No. 600, Tianhe Road, Guangzhou, Guangdong, 510630, China
| | - Yutian Chong
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, No. 600, Tianhe Road, Guangzhou, Guangdong, 510630, China.
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The Korean Association for the Study of the Liver (KASL). KASL clinical practice guidelines: management of chronic hepatitis B. Clin Mol Hepatol 2016; 22:18-75. [PMID: 27044762 PMCID: PMC4825166 DOI: 10.3350/cmh.2016.22.1.18] [Citation(s) in RCA: 150] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 02/22/2016] [Indexed: 01/10/2023] Open
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Treatment Outcomes With First-line Therapies With Entecavir and Tenofovir in Treatment-Naive Chronic Hepatitis B Patients in a Routine Clinical Practice. J Clin Gastroenterol 2016; 50:169-74. [PMID: 26018133 DOI: 10.1097/mcg.0000000000000345] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Given their high efficacy, entecavir (ETV) and tenofovir (TDF), are the recommended first-line therapies for chronic hepatitis B, but it is not clear whether the efficacy reported from pivotal trials is similar to the outcomes seen in routine practice. GOALS Our goal was to examine the treatment outcomes of antiviral therapy in such setting. PATIENTS AND METHODS We conducted a retrospective study of 557 consecutive treatment-naive patients who started either ETV (n=443) or TDF (n=114) at 3 US liver clinics between January 2005 and 2012. Primary study endpoint was complete viral suppression (CVS) rate (hepatitis B virus DNA<40 IU/mL). RESULTS The majority of patients in both ETV and TDF groups were Asians, hepatitis B e antigen (HBeAg) negative, male, and with similar pretreatment alanine aminotransferase and hepatitis B virus DNA levels. Similar proportions of patients in the ETV and TDF groups achieved CVS at 24 months: 87.7% versus 87.0%, respectively. Cumulative rates of virological breakthrough in the ETV and TDF groups were 1.0% versus 4.8% (P=0.26) and 3.7% versus 9.8% (P=0.04) at month 12 and 24, respectively; and all were associated with medication nonadherence. Cumulative rate of medication nonadherence was lower in the ETV than TDF group: 4.6% versus 7.8% at month 12 and 8.9% versus 16.9% at month 24, respectively. CONCLUSIONS Patients treated with either ETV or TDF achieve a similar rate of CVS at 24 months. The primary contributor to suboptimal response was medication nonadherence. Attention to medication adherence is needed in a routine clinical setting.
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Efficacy of Tenofovir-Based Combination Therapy versus Tenofovir Monotherapy in Chronic Hepatitis B Patients Presenting with Suboptimal Responses to Pretreatment: A Meta-Analysis. Gastroenterol Res Pract 2016; 2016:7214020. [PMID: 26880896 PMCID: PMC4737451 DOI: 10.1155/2016/7214020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Revised: 10/13/2015] [Accepted: 10/20/2015] [Indexed: 01/03/2023] Open
Abstract
Background/Aims. It remains unclear whether tenofovir disoproxil fumarate- (TDF-) based combination therapy produces better outcomes than TDF monotherapy in chronic hepatitis B (CHB) patients. The aim of this study was to compare the efficacy of the two regimens by performing a meta-analysis. Methods. A comprehensive literature search was performed on the comparison of TDF-based combination therapy and monotherapy for CHB patients in the PubMed, Embase, Web of Science, and the Cochrane Libraries. Both dichotomous and continuous variables were extracted and pooled outcomes were expressed as risk ratio (RR) or standard mean difference (SMD). Results. Nine eligible studies (1089 subjects in total) were included in our analysis. The proportion of patients with undetectable HBV DNA at 24, 48, and 96 weeks were similar between the two comparable groups (62.5% versus 70.9%, P = 0.086; 78.1% versus 83.7%, P = 0.118; 86.4% versus 87.9%, P = 0.626, resp.). HBV DNA reduction, rates of ALT normalization, hepatitis B e antigen (HBeAg) loss, and HBeAg seroconversion were also similar between the two groups. Conclusions. On the current data, TDF-based combination therapy seemed to be no better than those achieved by monotherapy. Further studies are needed to verify this comparison.
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Şahin E. Evaluation of antiviral resistant hepatitis B virus subpopulations in patients with chronic hepatitis B by using terminal restriction fragment length polymorphism. Virusdisease 2015; 26:267-75. [PMID: 26645037 PMCID: PMC4663704 DOI: 10.1007/s13337-015-0282-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 10/05/2015] [Indexed: 11/25/2022] Open
Abstract
Antiviral therapies with nucleotide analogues (NA) is crucial in the treatment of chronic hepatitis B as it substantially protects patients from the complications of the disease . However in most of the available NA therapies, resistance emerges in the patients' HBV populations. Therefore, detection of antiviral resistance as early as possible by means of genotypically monitoring the patients' HBV pool during NA therapy is critical to manage treatment regime. In this research study we have investigated the sensitivity and specificity of the terminal restriction fragment length polymorphism (T-RFLP) method in detecting HBV subpopulations carrying antiviral resistance mutations. For this aim, differentiation of mutant strains from wild type strains was demonstrated by PCR-RFLP method. With using recombinant plasmids containing mutant and wild type HBV genomes, we constructed artificial HBV genome populations in order to determine the sensitivity of PCR-T-RFLP method in detecting antiviral resistant minor HBV populations. Finally by comparing with the DNA sequencing method, we demonstrated the specificity of T-RFLP method in genotyping HBV populations. As a result we showed that T-RFLP is able to detect HBV subpopulations representing as low as 1 % of the whole viral population. Additionally T-RFLP showed 100 % concordance with the DNA sequencing method in genotyping HBV populations. As a conclusion, considering the other genotyping methods used in evaluating HBV populations, T-RFLP showed high sensitivity and specificity profiles in detecting antiviral resistant HBV subpopulations. Therefore T-RFLP method can be easily employed in genotypic evaluation of patients' HBV populations during the course of antiviral treatment.
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Affiliation(s)
- Ergin Şahin
- />Department of Biology, Faculty of Science, Ankara University, Tandogan, 06100 Ankara, Turkey
- />Institute of Hepatology, Ankara University, Ankara, Turkey
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De Clercq E. Current treatment of hepatitis B virus infections. Rev Med Virol 2015; 25:354-365. [PMID: 26205627 DOI: 10.1002/rmv.1849] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 06/24/2015] [Accepted: 06/25/2015] [Indexed: 01/04/2025]
Abstract
Chronic hepatitis B virus (HBV) infection remains an important global burden with an estimated 240 million HBV carriers worldwide and more than half a million people dying annually from the consequences of the HBV infection. Besides interferon and pegylated interferon, there are five antiviral drugs [lamivudine, adefovir (dipivoxil), entecavir, telbivudine, and tenofovir disoproxil fumarate] that have proved effective in the treatment of chronic hepatitis B. These five antiviral drugs interfere with viral DNA synthesis, which consists of a step reminiscent of the reverse transcriptase step in the replicative cycle of HIV. None of the antiviral drugs, or interferon, are capable of eradicating the covalently closed circular DNA, which remains settled as an episome within the virus-infected hepatocytes. In the short-term (1-3 years), the use of antiviral treatment is aimed at reducing viral DNA below levels of detection, whereas in the long term (10 years and, possibly, lifelong), treatment is aimed at reducing the progression to cirrhosis, hepatocellular carcinoma, liver decompensation, and death. As long as the virus can hide as the episomal covalently closed circular DNA, attempts to envisage a definite cure of the HBV infection may seem fortuitous.
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Affiliation(s)
- Erik De Clercq
- Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
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Murakami E, Tsuge M, Hiraga N, Kan H, Uchida T, Masaki K, Nakahara T, Ono A, Miki D, Kawaoka T, Abe H, Imamura M, Aikata H, Ochi H, Hayes CN, Akita T, Tanaka J, Chayama K. Effect of tenofovir disoproxil fumarate on drug-resistant HBV clones. J Infect 2015; 72:91-102. [PMID: 26515673 DOI: 10.1016/j.jinf.2015.09.038] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Revised: 08/23/2015] [Accepted: 09/14/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Tenofovir disoproxil fumarate (TDF) has been approved for chronic hepatitis B treatment, and favorable susceptibility of hepatitis B virus (HBV) has been indicated. However, differences in TDF susceptibility among HBV genotypes and drug-resistant strains are unclear. In this study, TDF susceptibilities between genotypes A and C were evaluated in vitro and in vivo using several drug-resistant HBV clones. METHODS HBV expression plasmids were constructed from sera of HBV carriers, and drug-resistant substitutions were introduced by site-directed mutagenesis. TDF susceptibility was evaluated by changes of core-associated HBV replication intermediates in vitro or by change of serum HBV DNA in human hepatocyte chimeric mice carrying each HBV clone in vivo. RESULTS TDF susceptibilities of lamivudine-resistant clones (rtL180M/M204V) and lamivudine plus entecavir-resistant clones (rtL180M/S202G/M204V) were similar to wild type clones in vitro. However, lamivudine plus adefovir-resistant clones (rtA181T/N236T) acquired tolerance to TDF, and the rtN236T mutation was considered to be a causal substitution for TDF resistance. Furthermore, genotypic differences in TDF susceptibility were also observed between genotypes A and C in vitro, and the differences could be confirmed in vivo (p = 0.023). CONCLUSIONS The present study indicates that TDF susceptibility varies among HBV genotypes and drug-resistant HBV clones.
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Affiliation(s)
- Eisuke Murakami
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
| | - Nobuhiko Hiraga
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hiromi Kan
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Takuro Uchida
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Keiichi Masaki
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Atsushi Ono
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hiromi Abe
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hidenori Ochi
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan
| | - C Nelson Hayes
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Tomoyuki Akita
- Department of Epidemiology, Infectious Disease Control and Prevention, Integrated Health Sciences, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Junko Tanaka
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Department of Epidemiology, Infectious Disease Control and Prevention, Integrated Health Sciences, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan.
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van Vlerken LG, Arends P, Lieveld FI, Arends JE, Brouwer WP, Siersema PD, Janssen HL, van Erpecum KJ. Real life adherence of chronic hepatitis B patients to entecavir treatment. Dig Liver Dis 2015; 47:577-83. [PMID: 25936691 DOI: 10.1016/j.dld.2015.03.024] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2014] [Revised: 03/24/2015] [Accepted: 03/28/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND Real-life prospective data on adherence to nucleos(t)ide analogues in chronic hepatitis B patients are scarce. AIMS We investigated adherence to entecavir in relation to virological response. METHODS In this prospective study, we provided 100 consecutive chronic hepatitis B patients with a medication dispenser that monitored entecavir intake during 16 weeks therapy. Hepatitis B virus (HBV) DNA was measured at baseline and after 16 weeks. Beliefs about medicines were evaluated using a questionnaire. RESULTS Adherence over 16 weeks averaged 85 ± 17%, with 70% of patients exhibiting good (i.e. ≥ 80%) adherence. Patients with poor (i.e. <80%) adherence were significantly younger (p=0.01), with more often indifferent attitudes towards entecavir (p=0.03) Viral breakthrough did not occur during the study. Adherence in patients with HBV DNA after 16 weeks > 20 IU/mL (n=18) and ≤ 20 IU/mL (n=81) averaged 83% and 91% respectively (p=0.19). In multivariate analysis, adherence was not a significant predictor of HBV DNA negativity (adjusted OR 1.02; p=0.34), after adjustment for duration of entecavir treatment (p<0.001) and HBe-status (p=0.001). CONCLUSIONS 70% of chronic hepatitis B patients exhibited good adherence to entecavir, with younger age and an indifferent attitude being risk factors for poor adherence. Poor adherence was not an independent predictor of virological response.
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Affiliation(s)
- Lotte G van Vlerken
- Department of Gastroenterology and Hepatology, University Medical Centrum Utrecht, Utrecht, The Netherlands
| | - Pauline Arends
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Faydra I Lieveld
- Department of Gastroenterology and Hepatology, University Medical Centrum Utrecht, Utrecht, The Netherlands; Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Joop E Arends
- Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Willem Pieter Brouwer
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Peter D Siersema
- Department of Gastroenterology and Hepatology, University Medical Centrum Utrecht, Utrecht, The Netherlands
| | - Harry L Janssen
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands; Liver Clinic, Toronto Western and General Hospital, University Health Network, Toronto, Canada
| | - Karel J van Erpecum
- Department of Gastroenterology and Hepatology, University Medical Centrum Utrecht, Utrecht, The Netherlands.
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46
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Baqai S, Proudfoot J, Xu R, Kane S, Clark M, Gish R. Comparable efficacy with entecavir monotherapy and tenofovir-entecavir combination in chronic hepatitis B patients. BMJ Open Gastroenterol 2015; 2:e000030. [PMID: 26462281 PMCID: PMC4599168 DOI: 10.1136/bmjgast-2015-000030] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 04/22/2015] [Accepted: 04/30/2015] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVES The long-term goal for chronic hepatitis B patients is to maintain viral suppression in order to reduce disease progression risk. Because patients with previous treatment failure may have multiple viral resistance mutations, finding effective therapy is challenging. Because recent studies have shown that the combination of entecavir and tenofovir is effective in achieving virological response in many patients with prior treatment failure and multiple drug resistance mutations, we compared outcomes with this combination versus monotherapy. METHODS With a retrospective chart review we compared results in 35 patients with previous treatment failure treated with the entecavir-tenofovir combination to results in patients treated with entecavir monotherapy. RESULTS Although combination therapy resulted in significantly faster achievement of DNA negativity compared to entecavir monotherapy, the modest ten-week advantage is unlikely to be important for most patients since entecavir resistance develops extremely slowly. Significantly more patients on combination therapy experienced viral breakthroughs, most of which were attributed to non-adherence due to difficulties with the combination regimen. CONCLUSIONS Our findings of reasonably comparable efficacy over time in the combination and monotherapy arms combined with the increased costs and compliance issues related to combination therapy weigh in favor of entecavir monotherapy in patients with previous treatment failure. However, because our study was a retrospective analysis of a small patient population, it will be important to confirm these findings with a randomised, controlled trial that compares these treatment approaches in treatment-experienced patients.
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Affiliation(s)
- Sumbella Baqai
- Department of Internal Medicine, Eden Medical Center, Castro Valley, California, USA
| | - James Proudfoot
- Biostatistics Unit, Clinical and Translational Research Institute, University of California, San Diego, San Diego, California, USA
| | - Ronghui Xu
- Department of Mathematics, University of California, San Diego, San Diego, California, USA
- Department of Family and Preventive Medicine, University of California, San Diego, San Diego, California, USA
| | - Steve Kane
- Interventional Endoscopy Services, California Pacific Medical Center, San Francisco, California, USA
| | - Margaret Clark
- Ibrahim El-Hefni Liver Biorepository, Department of Transplantation, California Pacific Medical Center, San Francisco, California, USA
| | - Robert Gish
- Liver Transplant Program, Stanford University Medical Center, Stanford, California, USA
- Hepatitis B Foundation, Doylestown, Pennsylvania, USA
- St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA
- University of Nevada, Las Vegas, Nevada, USA
- Robert G. Gish Consultants, LLC, San Diego, California, USA
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47
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Pan CQ, Chan S, Trinh H, Yao A, Bae H, Lou L. Similar efficacy and safety of tenofovir in Asians and non-Asians with chronic hepatitis B. World J Gastroenterol 2015; 21:5524-5531. [PMID: 25987775 PMCID: PMC4427674 DOI: 10.3748/wjg.v21.i18.5524] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Revised: 09/16/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To compare the efficacy and safety of tenofovir disoproxil fumarate (TDF) in Asian and non-Asian chronic hepatitis B (CHB) patients.
METHODS: The efficacy and safety of the initial 48 wk of treatment with TDF was compared in a post-hoc analysis of combined data from 217 Asians and 299 non-Asians included in Studies 102 and 103 and a post-approval, open-label trial (Study 123). Patient groups were compared according to baseline hepatitis B e antigen (HBeAg) status and viral load. The main outcome measures included the proportion of patients who achieved a hepatitis B virus (HBV) DNA level < 400 copies/mL at Week 48 of treatment. Secondary measures included: HBV DNA and alanine aminotransaminase (ALT) levels over time; proportion of patients with normal ALT levels; proportion of patients with HBeAg loss/seroconversion and proportion of patients with hepatitis B surface antigen loss/seroconversion; changes in liver histology. Safety and tolerability were evaluated by the occurrence of adverse events (AEs), serious AEs, laboratory abnormalities, discontinuation of the study drug due to AEs, or death. The primary efficacy and safety analysis set included all patients who were randomly assigned to treatment and received at least one dose of study drug.
RESULTS: At week 48, similar proportions of Asians and non-Asians reached HBV DNA < 400 copies/mL (96% of Asian and 97% of non-Asian patients with HBeAg-negative CHB and 83% of Asian and 79% of non-Asian patients with HBeAg-positive CHB had HBV DNA) and normal ALT (78% of Asian and 81% of non-Asian patients with HBeAg-negative CHB and 71% of Asian and 74% of non-Asian patients with HBeAg-positive CHB had normal ALT). On-treatment HBV DNA decline rates were similar between Asians and non-Asians regardless of baseline HBeAg status and viral load. HBV DNA decline during the first four weeks was 2.9 log10 copies/mL in HBeAg-negative Asians and non-Asians, and in HBeAg-positive non-Asians, and 3.1 log10 copies/mL in HBeAg-positive Asians. HBeAg loss and seroconversion was achieved in 14% of Asians vs 26% and 24%, respectively, in non-Asians. Liver histology improved in 77.2% of Asians and 71.5% of non-Asians. No resistance to TDF developed. No renal safety signals were observed.
CONCLUSION: TDF demonstrated similar viral suppression, normalization of ALT, improvements in liver fibrosis, and no detectable resistance in Asian and non-Asian patients regardless of baseline HBeAg status.
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Kim YW, Kwon JH, Chung E, Lee SW, Lee JY, Jang JW, Chung KW, Nam SW. Short Term Virologic Efficacies of Telbivudine versus Entecavir against Hepatitis B-Related Hepatocellular Carcinoma. Gastroenterol Res Pract 2015; 2015:181065. [PMID: 25878659 PMCID: PMC4387973 DOI: 10.1155/2015/181065] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2014] [Revised: 02/24/2015] [Accepted: 03/11/2015] [Indexed: 02/08/2023] Open
Abstract
Telbivudine has been reported to be more effective than lamivudine. However, because of the resistance rate to telbivudine (TLV), the current guidelines recommend entecavir (ETV) or tenofovir (TNV) as the first-line therapy for chronic hepatitis B. We investigated the short term virologic efficacy of TLV in comparison with ETV as the first-line agent of HBV suppression in HBV-related advanced HCC patients. A total of 86 consecutive patients with HBV-related HCC for whom antiviral treatment was initiated in Incheon St. Mary's Hospital between 2010 and 2013 were analyzed. Virologic responses were investigated on the 4th, 12th, and 24th weeks of the antiviral therapies. In patients with advanced TNM stage cancer (stage 3 or 4) and poor liver function (Child-Pugh class B or C), the virologic response rates at weeks 12 and 24 were 25% (1/4) and 42.8% (3/7) in the TLV group and 33.3% (1/3) and 33.3% (1/3) in the ETV group, respectively (P = 0.424, P = 0.800). The short term efficacy of TLV was similar to that of ETV. Since TLV is highly cost-effective, it should be considered as a first-line antiviral agent in patients with advanced HCC, poor liver function, and short life expectancies.
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Affiliation(s)
- Young Woon Kim
- Catholic Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Internal Medicine, Incheon St. Mary's Hospital, Catholic University of Korea, Bupyeong 6-dong, Bupyeong-gu, Incheon 403-720, Republic of Korea
| | - Jung Hyun Kwon
- Catholic Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Internal Medicine, Incheon St. Mary's Hospital, Catholic University of Korea, Bupyeong 6-dong, Bupyeong-gu, Incheon 403-720, Republic of Korea
| | - Eun Chung
- Catholic Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Internal Medicine, Incheon St. Mary's Hospital, Catholic University of Korea, Bupyeong 6-dong, Bupyeong-gu, Incheon 403-720, Republic of Korea
| | - Sung Won Lee
- Catholic Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Internal Medicine, Incheon St. Mary's Hospital, Catholic University of Korea, Bupyeong 6-dong, Bupyeong-gu, Incheon 403-720, Republic of Korea
| | - Jong-yul Lee
- Catholic Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Internal Medicine, Incheon St. Mary's Hospital, Catholic University of Korea, Bupyeong 6-dong, Bupyeong-gu, Incheon 403-720, Republic of Korea
| | - Jeong Won Jang
- Department of Internal Medicine, Incheon St. Mary's Hospital, Catholic University of Korea, Bupyeong 6-dong, Bupyeong-gu, Incheon 403-720, Republic of Korea
- Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Kyu Won Chung
- Catholic Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Internal Medicine, Incheon St. Mary's Hospital, Catholic University of Korea, Bupyeong 6-dong, Bupyeong-gu, Incheon 403-720, Republic of Korea
| | - Soon Woo Nam
- Catholic Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Internal Medicine, Incheon St. Mary's Hospital, Catholic University of Korea, Bupyeong 6-dong, Bupyeong-gu, Incheon 403-720, Republic of Korea
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Yang DH, Xie YJ, Zhao NF, Pan HY, Li MW, Huang HJ. Tenofovir disoproxil fumarate is superior to lamivudine plus adefovir in lamivudine-resistant chronic hepatitis B patients. World J Gastroenterol 2015; 21:2746-2753. [PMID: 25759545 PMCID: PMC4351227 DOI: 10.3748/wjg.v21.i9.2746] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2014] [Revised: 09/08/2014] [Accepted: 12/08/2014] [Indexed: 02/07/2023] Open
Abstract
AIM: To assess the efficacy of tenofovir disoproxil fumarate (TDF) in lamivudine (LAM)-resistant patients with a suboptimal response to LAM plus adefovir (ADV).
METHODS: We retrospectively analyzed the efficacy of switching to tenofovir disoproxil fumarate in suboptimal responders to lamivudine plus adefovir. Charts were reviewed for LAM-resistant chronic hepatitis B (CHB) patients who visited the Zhejiang Province People’s Hospital and The First Affiliated Hospital, College of Medicine, Zhejiang University, from June 2009 to May 2013. Patients whose serum hepatitis B virus (HBV) DNA remained detectable despite at least 6 mo of LAM plus ADV combination therapy were included. Patients with a suboptimal response to LAM plus ADV were randomized to switch to TDF monotherapy (300 mg/d orally; TDF group) or to continuation with LAM (100 mg/d orally) plus ADV (10 mg/d orally; LAM plus ADV group) and were followed for 48 wk. Serum HBV DNA was determined at baseline and weeks 4, 12, 24, 36, and 48. HBV serological markers and biochemistry were assessed at baseline and weeks 12, 24, and 48. Resistance surveillance and side effects were monitored during therapy.
RESULTS: Fifty-nine patient were randomized to switch to TDF (n = 28) or continuation with LAM plus ADV (n = 31). No significant differences were found between the groups at baseline. Prior to TDF therapy, all patients had been exposed to LAM plus ADV for a median of 11 mo (range: 6-24 mo). No difference was seen in baseline serum HBV DNA between the two groups [5.13 ± 1.08 log10 copies/mL (TDF) vs 5.04 ± 31.16 log10 copies/mL (LAM + ADV), P = 0.639]. There was no significant difference in the rates of achieving complete virological response (CVR) at week 4 between the TDF and LAM + ADV groups (17.86% vs 6.45%, P = 0.24). The rate of achieving CVR in the TDF and LAM plus ADV groups was 75% vs 16.13% at week 12, 82.14% vs 22.58% at week 24, 89.29% vs 25.81% at week 36, and 96.43% vs 29.03% at week 48, respectively (P < 0.001). The rate of alanine aminotransferase normalization was significantly higher in the TDF than in the LAM plus ADV group at week 12 (75% vs 17.86%, P < 0.001), but not at week 24 (78.57% vs 54.84%, P = 0.097) or 48 (89.26% vs 67.74%, P = 0.062). Patients were hepatitis B e antigen (HBeAg) positive at baseline. There was no significant difference in HBeAg negativity between the TDF and LAM plus ADV groups at week 48 (4% vs 0%, P = 0.481). There were no drug-related adverse effects at week 48 in either group.
CONCLUSION: Switching to TDF monotherapy was superior to continuous add-on therapy in patients with LAM-resistant CHB with a suboptimal response to LAM plus ADV.
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Abstract
For two decades, hepatitis B vaccine has been integrated into national routine childhood vaccination programs in almost all countries. The prevalence of HBsAg has decreased in children worldwide. However, there are children who miss the benefit of hepatitis B vaccine in some regions and countries. Long-term follow-up studies have revealed the clinical outcomes of chronic hepatitis B virus infection in children. A small percentage of chronically infected children develop liver cirrhosis and hepatocellular carcinoma. However, it is controversial who should be treated and when antiviral treatment should be initiated in children. Compared with adult studies, the data are insufficient to evaluate the pathogenesis of hepatitis B infection and the efficacy of antiviral treatment in childhood. New antiviral drugs have been approved for children and adults. Also, oral antiviral drugs are administered to pregnant women to reduce the hepatitis B virus mother-to-child transmission rate.
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Affiliation(s)
- Haruki Komatsu
- Department of Pediatrics, Toho University, Sakura Medical Center, 564-1 Shimoshizu Sakura, Chiba, 285-8741, Japan
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