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Liang X, Xie Q, Shang J, Tang H, Xu M, Meng Q, Zhang J, Gao P, Sheng J, Wang H, Jia J, Wang G, Wu S, Ping J, Hou J. Tenofovir disoproxil fumarate for multiple nucleos(t)ide analogues treatment failure hepatitis B: Is monotherapy enough? J Gastroenterol Hepatol 2022; 37:471-479. [PMID: 34894002 PMCID: PMC9303406 DOI: 10.1111/jgh.15757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 11/10/2021] [Accepted: 12/01/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND AIM Tenofovir disoproxil fumarate (TDF) is a first-line treatment for chronic hepatitis B virus (HBV) infection for its high potency and a low rate of drug resistance. This study investigated the efficacy and safety of TDF in Chinese patients with chronic hepatitis B (CHB) infection after treatment failure with multiple nucleos(t)ide analogues (NAs). METHODS Patients included were aged 18-65 years, with treatment failure with multiple NAs (serum HBV DNA > 200 IU/mL after more than two different NA treatments). The primary endpoint was proportion of patients with serum HBV DNA < 20 IU/mL at Week 144 of TDF monotherapy. Secondary endpoints and safety were also assessed. RESULTS Overall, 213 patients were enrolled. At Week 144, mean HBV DNA decreased significantly from baseline (4.4 vs 1.4 log10 IU/mL), with 77.0% patients (95% confidence interval: 71.1, 82.9) achieving serum HBV DNA < 20 IU/mL. Three (1.4%) patients experienced virological breakthrough during TDF monotherapy, without hepatitis flare. At Week 144, 15.3% and 4.7% patients (hepatitis B e antigen [HBeAg]-positive at baseline) experienced HBeAg loss and HBeAg seroconversion, respectively; 68.3% patients achieved normalized alanine aminotransferase levels. Overall, 58.7% patients experienced more than one adverse event (AE). Most common AEs were upper respiratory tract infection and blood creatine phosphokinase increase; 8.5% patients experienced study drug-related AEs; 9.4% patients experienced serious AEs (none were TDF-related). Among renal safety parameters, overall trend of mean serum phosphorous level remained stable, while mean estimated glomerular filtration rate increased slightly. CONCLUSIONS Tenofovir disoproxil fumarate monotherapy is efficacious in CHB patients with multiple NAs treatment failure with no new safety findings.
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Affiliation(s)
- Xieer Liang
- Nanfang HospitalSouthern Medical UniversityGuangzhouChina
| | - Qing Xie
- School of MedicineRuijin Hospital Affiliated to Jiaotong UniversityShanghaiChina
| | - Jia Shang
- Department of Infectious DiseasesHenan Provincial People's HospitalZhengzhouChina
| | - Hong Tang
- West China Hospital of Sichuan UniversityChengduChina
| | - Min Xu
- Guangzhou Eighth Municipal People's HospitalGuangzhouChina
| | - Qinghua Meng
- Beijing You‐An HospitalCapital Medical UniversityBeijingChina
| | - Jiming Zhang
- Huashan Hospital Affiliated to Fudan UniversityShanghaiChina
| | - Pujun Gao
- The First Hospital of Jilin UniversityChangchunChina
| | - Jifang Sheng
- Department of Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
| | - Hao Wang
- Peking University People's HospitalBeijingChina
| | - Jidong Jia
- Beijing Friendship HospitalCapital Medical UniversityBeijingChina
| | | | - Shunquan Wu
- GlaxoSmithKline R&D Company LimitedShanghaiChina
| | - Jingna Ping
- GlaxoSmithKline R&D Company LimitedShanghaiChina
| | - Jinlin Hou
- Nanfang HospitalSouthern Medical UniversityGuangzhouChina
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Paro EDL, Puchnick A, Szejnfeld J, Goldman SM. Use of diffusion-weighted imaging in the noninvasive diagnostic of obstructed biliary ducts. Abdom Radiol (NY) 2021; 46:268-279. [PMID: 32666232 DOI: 10.1007/s00261-020-02636-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 06/22/2020] [Accepted: 07/04/2020] [Indexed: 11/27/2022]
Abstract
OBJECTIVE This study sought to evaluate the role of diffusion-weighted imaging (DWI) in differentiation between obstructed and unobstructed bile ducts in patients undergoing magnetic resonance imaging (MRI). METHODS Eighty-four patients, 40 males and 44 females (mean age: 56.4 ± 15.1 years), undergoing MRI with DWI (0-50-500-700) were evaluated and divided into two groups: 58 with abnormal laboratory tests (obstructed group) and 26 with normal laboratory values (unobstructed group). Laboratory tests were total bilirubin, alkaline phosphatase, and gamma-glutamyltransferase. Median ADC values were calculated and correlated with laboratory tests and degree of bile-duct dilatation (absent, moderate, or severe). The persistence of signal on DWI (b500 and b700) in the biliary tract was evaluated. Bilirubin values were tested for correlation with bile-duct ADC values and persistence of b700 signal. For statistical analysis, Student t test, chi-square test and Wilcoxon-Mann-Whitney test were used. ADC maps were plotted for three levels of the biliary tree, and a receiver operating characteristic (ROC) curve was calculated. RESULTS In the obstructed group, 15 patients had severe dilatation, 24 had moderate dilatation, and 19 had no appreciable dilatation; 38 patients had persistent signal on b700 images. In the unobstructed group, 23 patients had no dilatation and 3 had moderate dilatation; 4 patients had persistent signal on b700 images. Correlation was found between degree of bile-duct dilatation, bilirubin levels, persistence of b700 signal, and ADC map values. The calculated ADC map cutoff value (353 10-6 mm2/s) was able to differentiate the obstructed and unobstructed groups with 92.3% sensitivity, 81% specificity, and 91.9% accuracy. CONCLUSIONS DWI is able to distinguish patients with obstructed versus unobstructed bile ducts, regardless of the degree of dilatation, correlating with clinical and laboratory findings.
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Affiliation(s)
- Eliane Donato Leite Paro
- Department of Diagnostic Imaging, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), Rua Napoleão de Barros, 800, Vila Clementino, São Paulo, SP, 04024-002, Brazil.
| | - Andrea Puchnick
- Department of Diagnostic Imaging, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), Rua Napoleão de Barros, 800, Vila Clementino, São Paulo, SP, 04024-002, Brazil
| | - Jacob Szejnfeld
- Department of Diagnostic Imaging, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), Rua Napoleão de Barros, 800, Vila Clementino, São Paulo, SP, 04024-002, Brazil
| | - Suzan Menasce Goldman
- Department of Diagnostic Imaging, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), Rua Napoleão de Barros, 800, Vila Clementino, São Paulo, SP, 04024-002, Brazil
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Chen K, Chang C, Lee J, Yang C. Tenofovir disoproxil fumarate for patients with chronic hepatitis B who suboptimal response to non‐tenofovir disoproxil fumarate nucleos(t)ide analogs therapy. ADVANCES IN DIGESTIVE MEDICINE 2020. [DOI: 10.1002/aid2.13171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Kwei‐Ming Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Show Chwan Memorial Hospital Changhua Taiwan
| | - Chi‐Hsien Chang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Show Chwan Memorial Hospital Changhua Taiwan
| | - Jyong‐Hong Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Show Chwan Memorial Hospital Changhua Taiwan
| | - Chi‐Chieh Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Show Chwan Memorial Hospital Changhua Taiwan
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Woo HY, Park JY, Bae SH, Kim CW, Jang JY, Tak WY, Kim DJ, Kim IH, Heo J, Ahn SH. Entecavir+tenofovir vs. lamivudine/telbivudine+adefovir in chronic hepatitis B patients with prior suboptimal response. Clin Mol Hepatol 2020; 26:352-363. [PMID: 32460460 PMCID: PMC7364362 DOI: 10.3350/cmh.2019.0044n] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 04/06/2020] [Accepted: 04/07/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/AIMS Suboptimal responses to lamivudine or telbivudine plus adefovir (LAM/LdT+ADV) rescue therapy are common in patients with LAM-resistant hepatitis B virus (HBV) infections. We compared patients switched to entecavir plus tenofovir (ETV+TDF) to those maintained on LAM/LdT+ADV. METHODS This prospective randomized controlled trial examined 91 patients whose serum HBV DNA levels were greater than 60 IU/mL after at least 24 weeks of treatment with LAM/LdT+ADV for LAM-resistant HBV. Patients were randomized to receive a new treatment (ETV+TDF, n=45) or maintained on the same treatment (LAM/LdT+ADV, n=46) for 48 weeks. Patients with baseline ADV resistance were excluded. RESULTS Compared to LAM/LdT+ADV group, ETV+TDF group had more patients with a virologic response (42/45 [93.33%] vs. 3/46 [6.52%], P<0.001) and had a greater mean reduction in serum HBV DNA level from baseline (-4.16 vs. -0.37 log10 IU/mL, P<0.001). Multivariate analysis indicated that high baseline HBV DNA level (P=0.005) and LAM/LdT+ADV maintenance therapy (P=0.001) were negatively associated with virologic response. At week 48, additional ADV- or ETV-associated mutations were cleared in ETV+TDF group, but such mutations were present in 4.3% of patients in LAM/LdT+ADV group (P=0.106). The two groups had similar rates of adverse events. CONCLUSION ETV+TDF combination treatment led to a significantly higher rate of virologic response compared to LAM/LdT+ADV combination treatment in patients with LAM-resistant HBV who had suboptimal responses to LAM/LdT+ADV regardless of HBV genotypic resistance profile (NCT01597934).
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Affiliation(s)
- Hyun Young Woo
- Department of Internal Medicine, College of Medicine, Pusan National University, Busan, Korea
- Medical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Si Hyun Bae
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Chang Wook Kim
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jae Young Jang
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Won Young Tak
- Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea
| | - Dong Joon Kim
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Korea
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Korea
| | - In Hee Kim
- Department of Internal Medicine, Chonbuk National University Hospital, Chonbuk National University College of Medicine, Chonju, Korea
| | - Jeong Heo
- Department of Internal Medicine, College of Medicine, Pusan National University, Busan, Korea
- Medical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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Ciclopirox inhibits Hepatitis B Virus secretion by blocking capsid assembly. Nat Commun 2019; 10:2184. [PMID: 31097716 PMCID: PMC6522524 DOI: 10.1038/s41467-019-10200-5] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 04/25/2019] [Indexed: 12/13/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection can cause cirrhosis and hepatocellular carcinoma and is therefore a serious public health problem. Infected patients are currently treated with nucleoside/nucleotide analogs and interferon α, but this approach is not curative. Here, we screen 978 FDA-approved compounds for their ability to inhibit HBV replication in HBV-expressing HepG2.2.15 cells. We find that ciclopirox, a synthetic antifungal agent, strongly inhibits HBV replication in cells and in mice by blocking HBV capsid assembly. The crystal structure of the HBV core protein and ciclopirox complex reveals a unique binding mode at dimer-dimer interfaces. Ciclopirox synergizes with nucleoside/nucleotide analogs to prevent HBV replication in cells and in a humanized liver mouse model. Therefore, orally-administered ciclopirox may provide a novel opportunity to combat chronic HBV infection by blocking HBV capsid assembly.
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Cho WH, Lee HJ, Bang KB, Kim SB, Song IH. Development of tenofovir disoproxil fumarate resistance after complete viral suppression in a patient with treatment-naïve chronic hepatitis B: A case report and review of the literature. World J Gastroenterol 2018; 24:1919-1924. [PMID: 29740207 PMCID: PMC5937209 DOI: 10.3748/wjg.v24.i17.1919] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 04/01/2018] [Accepted: 04/15/2018] [Indexed: 02/06/2023] Open
Abstract
Tenofovir disoproxil fumarate (TDF) is a potent nucleotide analogue that is recommended as first-line therapy for patients with chronic hepatitis B. The results of a longitudinal study of TDF treatment demonstrated no development of resistance. We observed one treatment-naïve chronic hepatitis B (CHB) patient who developed TDF resistance after complete viral suppression during long-term TDF treatment. A 37-year-old HBeAg-positive man received TDF 300 mg/d for 43 mo. The hepatitis B virus (HBV) DNA titer was 8 log10 copies/mL at baseline and became undetectable at 16 mo after treatment. However, the HBV DNA titer rebounded to 7.5 log10 copies/mL at 43 mo after treatment. We performed full sequencing to find mutation sites associated with virologic breakthrough. The results showed 9 mutation sites, most of which had not been well-known as mutation sites. We changed the therapy from tenofovir to entecavir with a regimen of 0.5 mg once daily. After 4 mo, the HBV DNA titer decreased to 267 copies/mL, and the liver enzyme levels were normalized.
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Affiliation(s)
- Woo Hee Cho
- Department of Internal Medicine, Dankook University College of Medicine, Cheonan 31116, South Korea
| | - Hyun Jae Lee
- Department of Internal Medicine, Dankook University College of Medicine, Cheonan 31116, South Korea
| | - Ki Bae Bang
- Department of Internal Medicine, Dankook University College of Medicine, Cheonan 31116, South Korea
| | - Seok Bae Kim
- Department of Internal Medicine, Dankook University College of Medicine, Cheonan 31116, South Korea
| | - Il Han Song
- Department of Internal Medicine, Dankook University College of Medicine, Cheonan 31116, South Korea
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Jeon HJ, Jung SW, Park NH, Yang Y, Noh JH, Ahn JS, Kim HR, Lee JH, Shin JW. Efficacy of tenofovir-based rescue therapy for chronic hepatitis B patients with resistance to lamivudine and entecavir. Clin Mol Hepatol 2017; 23:230-238. [PMID: 28669175 PMCID: PMC5628011 DOI: 10.3350/cmh.2017.0003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Revised: 03/28/2017] [Accepted: 04/05/2017] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND/AIMS Tenofovir disoproxil fumarate (TDF) monotherapy for 48 weeks provided a virological response comparable to that of TDF and entecavir (ETV) combination therapy in patients infected with ETV-resistant hepatitis B virus (HBV). Little long-term data in routine clinical practice are available regarding the optimal treatment of patients with ETV-resistant HBV. METHODS We investigated the long-term antiviral efficacy of combination therapy of TDF+lamivudine (LAM) or TDF+ETV compared to that of TDF monotherapy in 73 patients with resistance to both LAM and ETV. RESULTS Patients were treated with TDF monotherapy (n=12), TDF+LAM (n=19), or TDF+ETV (n=42) for more than 6 months. The median duration of TDF-based rescue therapy was 37 months. Virologic response (VR) was found in 63 patients (86.3%). The rates of VR among the three groups (TDF monotherapy, TDF+LAM, and TDF+ETV) were not statistically different (log-rank P=0.200) at 12 months (59.3%, 78.9%, and 51.8%, respectively) or at 24 months (88.4%, 94.7%, and 84.2%). In addition, treatment efficacy of TDF-based combination or TDF monotherapy was not statistically different with ETV-resistant strains or exposure to other antiviral agents. In multivariate analysis, only lower baseline HBV DNA level was an independent predictor for VR (hazard ratio, 0.723; 95% confidence interval, 0.627-0.834; P<0.001). CONCLUSIONS TDF monotherapy was as effective as combination therapy of TDF+LAM or TDF+ETV in maintaining long-term viral suppression in chronic hepatitis B patients with resistance to both LAM and ETV. HBV DNA level at the start of TDF rescue therapy was the only independent predictor of subsequent VR.
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Affiliation(s)
- Hee-Jeong Jeon
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Seok Won Jung
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Neung Hwa Park
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea.,Department of Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Yujin Yang
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Jin-Hee Noh
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Jae-Sung Ahn
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Hyung Rae Kim
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Jae Ho Lee
- Department of Anesthesiology and Pain Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Jung Woo Shin
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
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Zoulim F, Białkowska-Warzecha J, Diculescu MM, Goldis AE, Heyne R, Mach T, Marcellin P, Petersen J, Simon K, Bendahmane S, Klauck I, Wasiak W, Janssen HLA. Entecavir plus tenofovir combination therapy for chronic hepatitis B in patients with previous nucleos(t)ide treatment failure. Hepatol Int 2016; 10:779-788. [PMID: 27206517 DOI: 10.1007/s12072-016-9737-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 04/24/2016] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS In patients with chronic hepatitis B (CHB) who have failed on other nucleos(t)ide analogs (NUCs), the combination of entecavir (ETV) plus tenofovir disoproxil fumarate (TDF), two potent agents with non-overlapping resistance profiles, may provide a single rescue regimen. METHODS In this single-arm, open-label study, 92 CHB patients with a primary non-response, partial response, or virologic breakthrough on their current NUC were switched to ETV (1 mg) plus TDF (300 mg) and treated for 96 weeks. RESULTS At baseline, 62 % of patients were HBeAg(+) and mean HBV DNA was 4.4 log10IU/mL. Patients had received ≥1 line of prior NUC therapy, with the latest regimen consisting of monotherapy with ETV (53 %), lamivudine (LVD 22 %), TDF (12 %), adefovir (ADV 4 %), or telbivudine (2 %), or combinations of these agents (7 %); 58 % had evidence of single- or multidrug resistance mutations (LVD 52 %, ETV 26 %; ADV 7 %). Response rates for HBV DNA <50 IU/mL were 76 % (70/92) at week 48 (primary endpoint), and 85 % (78/92) at week 96, including 80 % (16/20) in prior LVD failures, 100 % (4/4) in ADV failures, 82 % (9/11) in TDF failures, and 88 % (42/48) in ETV failures. No treatment-emergent resistance to ETV or ADV was observed. ETV/TDF was well tolerated, with no significant renal or additive toxicities observed. CONCLUSIONS In NUC-experienced patients who have failed prior NUC therapy, ETV/TDF was well tolerated and effective, achieving virologic suppression through 96 weeks in the majority (85 %), irrespective of prior NUC exposure, without occurrence of treatment-emergent resistance to either agent.
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Affiliation(s)
- Fabien Zoulim
- Hepatology Department, Hospices Civils de Lyon, INSERM U1052, INSERM, Lyon University, 151 Cours Albert Thomas, 69424, Lyon Cedex 03, France.
| | | | - Mircea Mihai Diculescu
- Centre of Gastroenterology and Hepatology, Fundeni Clinical Institute, Bucharest, Romania
| | | | | | - Tomasz Mach
- Department of Gastroenterology and Hepatology, Jagiellonian University, Krakow, Poland
| | - Patrick Marcellin
- Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, University of Paris 7, Paris, France
- INSERM Unité 773, Centre de Recherches Claude Bernard sur les Hépatites Virales, Clichy, France
| | - Jörg Petersen
- IFI Institute for Interdisciplinary Medicine, Asklepios Klinik St Georg, Hamburg, Germany
| | - Krzysztof Simon
- Division of Infectious Diseases and Hepatology, Wrocław Medical University, Wrocław, Poland
| | | | | | | | - Harry L A Janssen
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Liver Clinic, Toronto Western and General Hospital, University Health Network, Toronto, Canada
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Liu Y, Zhang Y, Yuan J, Zeng W, Zhang G, Yao S, Li H, Yang M, Deng Y, Zou R, Li S, Xiao J. Efficacy of tenofovir disoproxil fumarate therapy in Chinese chronic hepatitis B patients after multiple antiviral failures. Hepatol Res 2015; 45:E43-52. [PMID: 25429855 DOI: 10.1111/hepr.12454] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2014] [Revised: 11/20/2014] [Accepted: 11/21/2014] [Indexed: 02/08/2023]
Abstract
AIM In this prospective study, we aimed to evaluate the efficacy and safety of tenofovir disoproxil fumarate (TDF) in Chinese chronic hepatitis B (CHB) patients after multiple nucleoside/nucleotide analog (NA) treatment failures. METHODS A total of 115 Chinese CHB patients with suboptimal response to two or more NA treatments were included in this study. All patients were changed to TDF (300 mg/day, oral administration) antiviral treatment for at least 72 weeks. Hepatitis B virus (HBV) polymerase (P) gene mutation screening for each patient was performed. In addition, virological, biochemical responses and estimated glomerular filtration rate (eGFR) of each patient at weeks 12, 24, 48 and 72 of TDF treatment were evaluated. RESULTS Seventy-six out of 115 patients had drug-resistance mutations (R(+) ), including 27 with adefovir (ADV)-associated mutations (35.5%) and 49 with lamivudine (LMV)-associated mutations (64.5%). For all included patients, complete viral response (CVR) of HBV DNA (<100 IU/mL) was 57.4%, 69.6%, 74.8% and 86.1% at weeks 12, 24, 48 and 72 of TDF treatment, respectively. Alanine aminotransferase normalization and hepatitis B e-antigen seroclearance occurred in 77.3% and 23.2%, respectively, after 72-week TDF treatment. CVR at weeks 12, 24 and 48 was observed more commonly in patients with baseline HBV DNA of less than 10(6) IU/mL. There was no significant reduction of eGFR induced by the TDF treatment. CONCLUSION Seventy-two-week treatment with TDF in Chinese CHB patients with previously multiple NA treatment failures exhibited effective and safe outcomes, which were independent of baseline mutations conferring ADV or LMV resistance.
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Affiliation(s)
- Yingxia Liu
- State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Ying Zhang
- State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Jing Yuan
- State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Wen Zeng
- State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Guoliang Zhang
- State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Simin Yao
- State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Huijuan Li
- State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Min Yang
- State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Yong Deng
- State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Rongrong Zou
- State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Shaxi Li
- State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Jia Xiao
- State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
- Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China
- Department of Anatomy, The University of Hong Kong, Hong Kong, China
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Park JG, Park SY. Entecavir plus tenofovir versus entecavir plus adefovir in chronic hepatitis B patients with a suboptimal response to lamivudine and adefovir combination therapy. Clin Mol Hepatol 2015; 21:242-8. [PMID: 26523269 PMCID: PMC4612285 DOI: 10.3350/cmh.2015.21.3.242] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Revised: 08/20/2015] [Accepted: 08/25/2015] [Indexed: 12/22/2022] Open
Abstract
Background/Aims We compared the efficacies of entecavir (ETV) plus tenofovir (TDF) and ETV plus adefovir (ADV) in chronic hepatitis B (CHB) patients with genotypic resistance to lamivudine (LAM) who showed a suboptimal response to LAM and ADV combination therapy. Methods We reviewed 63 CHB patients with genotypic resistance to LAM who showed a suboptimal response to LAM and ADV combination therapy. Among these patients, 30 were treated with ETV + ADV and 33 were treated with ETV + TDF for 12 months. Results The only baseline characteristic that differed significantly between the two groups was the ETV resistance profile. The rate of a virologic response [serum hepatitis B virus (HBV) DNA level of <20 IU/mL] was significant higher for ETV+TDF than for ETV+ADV over 12 months (57.6% vs. 23.3%, P=0.006, at 6 months; 84.8% vs. 26.7%, P<0.001, at 12 months). The probability of a virologic response was significantly increased in ETV+TDF (P<0.001, OR=54.78, 95% CI=7.15-419.54) and decreased in patients with higher baseline viral loads (P=0.001, OR=0.18, 95% CI=0.07-0.50) in multivariate analysis. No serious adverse event occurred during the study period. Conclusions In patients with CHB who showed a suboptimal response to LAM and ADV combination therapy, ETV+TDF was superior to ETV+ADV in achieving a virologic response regardless of the HBV resistance profile. Further large-scale and long-term follow-up prospective studies are needed to explain these results.
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Affiliation(s)
- Jung Gil Park
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, CHA University, CHA Gumi Medical Center, Gumi, Korea
| | - Soo Young Park
- Division of Gastroenterology and Hepatology, Department of Internal Medicine School of Medicine, Kyungpook National University, Daegu, Korea
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Park JH, Ahn SJ, Cho HJ, Kim SS, Cheong JY, Cho SW. Clinical course of partial virological responders under prolonged entecavir monotherapy in patients with chronic hepatitis B. J Med Virol 2015; 88:252-9. [PMID: 26178822 DOI: 10.1002/jmv.24330] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/08/2015] [Indexed: 12/19/2022]
Abstract
Studies about long-term entecavir (ETV) therapy for partial virological response (PVR) are lacking. This study aimed to assess the clinical course of PVR patients receiving ETV therapy and analyze the efficacy of tenofovir (TDF). We retrospectively evaluated 130 patients who showed a PVR to ETV. Among these patients, 102 were nucleot(s)ide analogue (NUC)-naïve and 28 were lamivudine (LAM)-experienced. The cumulative rates of VR were 54.1%, 70.8%, and 83.7% for the NUC-naïve group and 37.0%, 42.8%, and 42.8% for the LAM-experienced group after 24, 36, and 48 months of ETV therapy, respectively (P = 0.008). Low HBV DNA level at 12 months (P < 0.001) and absence of a LAM treatment history (P = 0.031) were significant associated factors for VR. In VR prediction at 36 months of ETV therapy in NUC-naïve patients, HBV DNA level <95 IU/ml at 12 months showed a 92.9% sensitivity and a 78.3% specificity (AUROC, 0.909; P < 0.001). ETV resistance did not develop in NUC-naïve patients with HBV DNA levels <95 IU/ml at 12 months. The cumulative probability of VR in patients who switched to or additionally received TDF was 91.3% at 15 months. Prolonged ETV therapy induced a VR without the risk of ETV resistance in NUC-naïve patients with HBV DNA levels <95 IU/ml at 12 months. All patients with LAM-experienced or NUC-naïve with HBV DNA levels ≥95 IU/ml at 12 months should be switched to TDF rescue therapy.
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Affiliation(s)
- Joo Han Park
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea
| | - Seon Joo Ahn
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea
| | - Hyo Jung Cho
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea
| | - Soon Sun Kim
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea
| | - Jae Youn Cheong
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea
| | - Sung Won Cho
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea
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12
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The case of chronic hepatitis B treatment with tenofovir: an update for nephrologists. J Nephrol 2015; 28:393-402. [DOI: 10.1007/s40620-015-0214-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Accepted: 05/22/2015] [Indexed: 12/29/2022]
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13
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Wang G, Liu Y, Qiu P, Zhou SF, Xu L, Wen P, Wen J, Xiao X. Cost-effectiveness analysis of lamivudine, telbivudine, and entecavir in treatment of chronic hepatitis B with adefovir dipivoxil resistance. DRUG DESIGN DEVELOPMENT AND THERAPY 2015; 9:2839-46. [PMID: 26082614 PMCID: PMC4459610 DOI: 10.2147/dddt.s73150] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The purpose of this study was to analyze the cost-effectiveness of lamivudine (LMV), telbivudine (LdT), and entecavir (ETV) in treatment of chronic hepatitis B with adefovir dipivoxil (ADV) resistance. Two hundred and fifty-two patients were recruited and screened for resistance to ADV and randomly assigned into three groups: LMV + ADV, LdT + ADV, and ETV + ADV. The ratio of biochemical response, virological response, seroconversion of hepatitis Be antigen (HBeAg)/hepatitis Be antibody (HBeAb), viral breakthrough, and the cost and effectiveness of treatments were analyzed. A comparison of the results of the ratio of biochemical response, virological response and seroconversion of HBeAg/HBeAb, showed no statistical difference between the three groups, with the economic cost of LMV + ADV the lowest, LdT + ADV the middle, and ETV + ADV the highest. The side effects of the three plans are all rare and tolerable. LMV + ADV is the optimal rescue strategy, and LdT + ADV the alternative selection in the economically less developed regions, while ETV + ADV was used in the economically developed regions.
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Affiliation(s)
- Guiliang Wang
- Department of Digestive Internal Medicine, Gannan Medical University Pingxiang Hospital, Pingxiang, People's Republic of China ; Department of Digestive Internal Medicine, 307 Hospital of PLA, Beijing, People's Republic of China
| | - Yan Liu
- Department of Digestive Internal Medicine, 307 Hospital of PLA, Beijing, People's Republic of China
| | - Ping Qiu
- Department of Digestive Internal Medicine, Gannan Medical University Pingxiang Hospital, Pingxiang, People's Republic of China
| | - Shu-Feng Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA ; Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, People's Republic of China
| | - Linfang Xu
- Department of Digestive Internal Medicine, Gannan Medical University Pingxiang Hospital, Pingxiang, People's Republic of China
| | - Ping Wen
- Department of Digestive Internal Medicine, Gannan Medical University Pingxiang Hospital, Pingxiang, People's Republic of China
| | - Jianbo Wen
- Department of Digestive Internal Medicine, Gannan Medical University Pingxiang Hospital, Pingxiang, People's Republic of China
| | - Xianzhong Xiao
- Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, People's Republic of China
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14
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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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Zhang Q, Han T, Nie CY, Ha FS, Liu L, Liu H. Tenofovir rescue regimen following prior suboptimal response to entecavir and adefovir combination therapy in chronic hepatitis B patients exposed to multiple treatment failures. J Med Virol 2015; 87:1013-21. [PMID: 25716029 DOI: 10.1002/jmv.24153] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/07/2015] [Indexed: 12/16/2022]
Abstract
In clinical practice, establishing a subsequent optimum treatment for chronic hepatitis B patients with a history of multiple NAs treatment failures, including a suboptimal response to a final therapy with combined ETV and ADV, is a complicated but crucial challenge. This study investigated the efficacy and safety of a tenofovir rescue regimen in these patients. A total of six eligible patients were enrolled and were switched to a tenofovir rescue regimen. At baseline, the genotypes and genotypic mutations of the reverse transcriptase and surface gene were determined by ultra-deep pyrosequencing, and further clonal analyses of the reverse transcriptase domain were performed to identify multidrug-resistant HBV strains. In addition, HBV DNA levels, serology, and biochemistry parameters were monitored at baseline and every 3 months, and abdominal ultrasonography was performed at baseline and every 6 months. All patients were confirmed to harbor LAM-related resistant HBV strains. After switching to the tenofovir rescue treatment, all patients had an undetectable level of HBV DNA within 6 months and achieved normalization of the ALT level within 9 months. These virological and biochemical responses persisted until the end of the observation period. None of the patients developed clinical deterioration or any adverse events related to the tenofovir therapy during the median 16.5-month follow-up. In conclusion, the tenofovir rescue regimen can be employed confidently as a highly effective and safe treatment choice following a suboptimal response to ETV plus ADV therapy for a subset of chronic hepatitis B patients with a history of multiple unsuccessful antiviral treatments.
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Affiliation(s)
- Qian Zhang
- The Third Central Clinical College of Tianjin Medical University, Tianjin, China; Department of Hepatology, Tianjin Third Central Hospital, Tianjin, China
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Fung S, Gordon SC, Krastev Z, Horban A, Petersen J, Sperl J, Gane E, Jacobson IM, Yee LJ, Dinh P, Martins EB, Flaherty JF, Kitrinos KM, Dusheiko G, Trinh H, Flisiak R, Rustgi VK, Buti M, Marcellin P. Tenofovir disoproxil fumarate in Asian or Pacific Islander chronic hepatitis B patients with high viral load (≥ 9 log10 copies/ml). Liver Int 2015; 35:422-8. [PMID: 25277773 DOI: 10.1111/liv.12694] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Accepted: 09/17/2014] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS We evaluated the antiviral response of Asian or Pacific Islander (API) patients with chronic hepatitis B (CHB) who had baseline high viral load (HVL), defined as pre-treatment hepatitis B virus (HBV) DNA ≥9 log10 copies/ml, following up to 288 weeks of tenofovir disoproxil fumarate (TDF) treatment. METHODS A total of 205 HBeAg-negative and HBeAg-positive self-described API patients received 48 weeks of TDF 300 mg (HVL n = 18) or adefovir dipivoxil 10 mg (HVL n = 15) in a blinded fashion, followed by open-label TDF for an additional 240 weeks. The proportions of HVL vs. non-HVL patients with HBV DNA <400 copies/ml were compared. Mean declines in HBV DNA were evaluated in API vs. non-API patients. RESULTS Throughout the first 72 weeks of treatment, a smaller proportion of HVL API patients reached HBV DNA <400 copies/ml than non-HVL API patients. However, after this timepoint similar proportions of HVL and non-HVL API patients achieved HBV DNA <400 copies/ml (100% vs. 97%, respectively), which was maintained through week 288, where 92% of HVL patients and 99% of non-HVL API patients on treatment had HBV DNA <400 copies/ml. During the 288 weeks of treatment, API patients had similar mean HBV DNA declines as non-API patients, regardless of whether patients were HVL or non-HVL. No API HVL patient had persistent viremia at week 288. No resistance was detected among HVL or non-HVL patients. CONCLUSIONS API patients with HVL CHB achieve HBV DNA <400 copies/ml with long-term TDF treatment; however, achieving viral suppression may take longer for HVL patients relative to non-HVL API patients.
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Kim HJ, Cho JY, Kim YJ, Gwak GY, Paik YH, Choi MS, Koh KC, Paik SW, Yoo BC, Lee JH. Long-term efficacy of tenofovir disoproxil fumarate therapy after multiple nucleos(t)ide analogue failure in chronic hepatitis B patients. Korean J Intern Med 2015; 30:32-41. [PMID: 25589833 PMCID: PMC4293561 DOI: 10.3904/kjim.2015.30.1.32] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Revised: 07/08/2014] [Accepted: 08/01/2014] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND/AIMS The efficacy of tenofovir disoproxil fumarate (TDF) for the treatment of chronic hepatitis B (CHB) patients following prior treatment failure with multiple nucleos(t)ide analogues (NAs) is not well defined, especially in Asian populations. In this study we investigated the efficacy and safety of TDF rescue therapy in CHB patients after multiple NA treatment failure. METHODS The study retrospectively analyzed 52 CHB patients who experienced failure with two or more NAs and who were switched to regimens containing TDF. The efficacy and safety assessments included hepatitis B virus (HBV) DNA undetectability, hepatitis B envelop antigen (HBeAg) seroclearance, alanine transaminase (ALT) normalization and changes in serum creatinine and phosphorus levels. RESULTS The mean HBV DNA level at baseline was 5.4 ± 1.76 log10 IU/mL. At a median duration of 34.5 months of TDF treatment, the cumulative probabilities of achieving complete virological response (CVR) were 25.0%, 51.8%, 74.2%, and 96.7% at 6, 12, 24, and 48 months, respectively. HBeAg seroclearance occurred in seven of 48 patients (14.6%). ALT levels were normalized in 27 of 31 patients (87.1%) with elevated ALT at baseline. Lower levels of HBV DNA at baseline were significantly associated with increased CVR rates (p < 0.001). However, CVR rates did not differ between TDF monotherapy or combination therapy with other NAs, and were not affected by mutations associated with resistance to NAs. No significant adverse events were observed. CONCLUSIONS TDF is an efficient and safe rescue therapy for CHB patients after treatment failure with multiple NAs.
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Affiliation(s)
- Hyo Jin Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ju-Yeon Cho
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yu Jin Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Geum-Youn Gwak
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yong-Han Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Moon Seok Choi
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kwang Cheol Koh
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seung Woon Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Byung Chul Yoo
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Joon Hyeok Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Alsohaibani F, Alturaif N, Abdulshakour A, Alghamdi S, Alshaibani A, Alashgar H, Alkahtani K, Kagevi I. Tenofovir in the treatment of naïve and refractory chronic Hepatitis B: A single center experience in Saudi Arabia. Saudi J Gastroenterol 2015; 21:295-9. [PMID: 26458856 PMCID: PMC4632254 DOI: 10.4103/1319-3767.164189] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND/AIMS Tenofovir disoproxil fumarate (TDF) is a nucleotide analog used in the treatment of chronic hepatitis B (CHB) infection. This study evaluated the efficacy of TDF in achieving undetectable HBV DNA after 48 weeks of treatment in a Saudi cohort of CHB patients. PATIENTS AND METHODS This retrospective study included patients treated at a tertiary care center in Saudi Arabia from January 2009 to December 2012. Of the 68 eligible patients, 51 were treatment naïve and 17 were treatment-refractory. Twenty-three patients tested positive for HBeAg. The remaining 45 patients were HBeAg-negative. RESULTS The mean HBV DNA viral load decreased from 95 million IU/mL at baseline to 263 IU/mL after 48 weeks of treatment (P < 0.001). Overall, 62% of patients achieved a complete virological response (CVR) and 37% a partial virological response (PVR). Respective CVR and PVR rates according to subgroup were: HBeAg-positive (21.7% and 78.3%) and HBeAg-negative (84.4% and 15.6%). At 48 weeks, HBV DNA was undetectable in 66.7% of treatment-naÏve and 53% of treatment-refractory patients (P = 0.3). Seroconversion occurred in 13 (57%) of HBeAg-positive patients. Two (3%) of the HBeAg-negative patients lost HBsAg at follow up. Mean alanine aminotransferase decreased significantly from 134 U/L before treatment to 37 U/L at 48 weeks (P < 0.001). Significant adverse events were not encountered during the study period. CONCLUSION Forty-eight weeks of treatment with TDF reduced HBV DNA to undetectable levels in more than half of our patients regardless of whether they were treatment-naïve or refractory. HBeAg-negative (vs positive) patients experienced a better response rate.
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Affiliation(s)
- Fahad Alsohaibani
- Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia,Address for correspondence: Dr. Fahad Alsohaibani, Department of Medicine, King Faisal Specialist Hospital and Research Centre, MBC 46 P.O Box 3354, Riyadh 11211, Saudi Arabia. E-mail:
| | - Noura Alturaif
- Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Ahmed Abdulshakour
- Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Saad Alghamdi
- Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Alfadel Alshaibani
- Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Hamad Alashgar
- Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Khalid Alkahtani
- Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Ingvar Kagevi
- Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
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Bang KB, Kim HJ. Management of antiviral drug resistance in chronic hepatitis B. World J Gastroenterol 2014; 20:11641-11649. [PMID: 25206270 PMCID: PMC4155356 DOI: 10.3748/wjg.v20.i33.11641] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Revised: 01/10/2014] [Accepted: 05/28/2014] [Indexed: 02/07/2023] Open
Abstract
Rescue antiviral treatment for patients with resistance to preexisting nucleos(t)ide analogues remains a clinical challenge. The correct choice of a first-line treatment of high potency and with a high genetic barrier to achieve sustained long-term suppression of viral replication provides the best chance of preventing treatment failure and the emergence of drug resistance. The management of treatment failure and drug resistance requires a precise and accurate clinical and virologic monitoring. Combination treatment with antiviral drugs that belong to different groups is associated with a lower chance of developing resistance to rescue drugs. To guarantee better control of viral replication in patients with drug resistance, the addition of another drug without a cross resistance profile should be given as early as possible, preferably at the time when genotypic resistance emerges. Long-term surveillance for treatment efficacy and possible emergence of drug resistance should be continued to prevent the emergence of multidrug-resistant strains.
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Suzuki F, Sezaki H, Akuta N, Suzuki Y, Kawamura Y, Hosaka T, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Kobayashi M, Watahiki S, Mineta R, Suzuki Y, Kumada H. Virologic breakthrough in a patient with chronic hepatitis B by combination treatment with tenofovir disoproxil fumarate and entecavir. DRUG DESIGN DEVELOPMENT AND THERAPY 2014; 8:869-73. [PMID: 25061278 PMCID: PMC4085295 DOI: 10.2147/dddt.s65349] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Tenofovir disoproxil fumarate (TDF) is widely used to treat hepatitis B virus (HBV) patients in the USA and Europe. No confirmed report of resistance selection during treatment with TDF in treatment-naïve and nucleoside/nucleotide analog-treated chronic hepatitis B patients has yet been reported. Here, we report for the first time a patient with chronic hepatitis B and cirrhosis who emerged with virologic breakthrough during combination therapy with TDF and entecavir (ETV), against ETV-resistant virus. A 51-year-old Japanese woman with hepatitis B e-antigen (HBeAg), whose genotype was C, received ETV monotherapy continuously followed by TDF and ETV combination therapy, because her HBV DNA levels had been >3.5 log copies/mL. At the start of combination therapy, amino acid substitutions of the reverse transcriptase (rt) gene, rtL180M, rtT184I/M, and rtM204V, were detected. After this, serum HBV DNA decreased to less than 2.1 log copies/mL and remained at this level until 31 months of combination therapy, when it again began to increase. Amino acid substitutions of rtL180M, rtS202G, and rtM204V emerged and were associated with an increase in serum HBV DNA at virologic breakthrough. Long-term therapy with TDF against the ETV-resistant virus has the potential to induce virologic breakthrough and resistance, and careful follow-up should be carried out.
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Affiliation(s)
- Fumitaka Suzuki
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan ; Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Hitomi Sezaki
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | - Norio Akuta
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | | | | | - Tetsuya Hosaka
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | | | - Satoshi Saitoh
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | - Yasuji Arase
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | - Kenji Ikeda
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | - Mariko Kobayashi
- Research Institute for Hepatology, Toranomon Branch Hospital, Kawasaki, Japan
| | - Sachiyo Watahiki
- Research Institute for Hepatology, Toranomon Branch Hospital, Kawasaki, Japan
| | - Rie Mineta
- Research Institute for Hepatology, Toranomon Branch Hospital, Kawasaki, Japan
| | - Yukiko Suzuki
- Research Institute for Hepatology, Toranomon Branch Hospital, Kawasaki, Japan
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Cholongitas E, Papatheodoridis GV. Review of the pharmacological management of hepatitis B viral infection before and after liver transplantation. World J Gastroenterol 2013; 19:9189-9197. [PMID: 24409047 PMCID: PMC3882393 DOI: 10.3748/wjg.v19.i48.9189] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2013] [Revised: 10/29/2013] [Accepted: 11/19/2013] [Indexed: 02/06/2023] Open
Abstract
The progress in treatment against hepatitis B virus (HBV) with the development of effective and well tolerated nucleotide analogues (NAs) has improved the outcome of patients with HBV decompensated cirrhosis and has prevented post-transplant HBV recurrence. This review summarizes updated issues related to the management of patients with HBV infection before and after liver transplantation (LT). A literature search using the PubMed/Medline databases and consensus documents was performed. Pre-transplant therapy has been initially based on lamivudine, but entecavir and tenofovir represent the currently recommended first-line NAs for the treatment of patients with HBV decompensated cirrhosis. After LT, the combination of HBV immunoglobulin (HBIG) and NA is considered as the standard of care for prophylaxis against HBV recurrence. The combination of HBIG and lamivudine is related to higher rates of HBV recurrence, compared to the HBIG and entecavir or tenofovir combination. In HBIG-free prophylactic regimens, entecavir and tenofovir should be the first-line options. The choice of treatment for HBV recurrence depends on prior prophylactic therapy, but entecavir and tenofovir seem to be the most attractive options. Finally, liver grafts from hepatitis B core antibody (anti-HBc) positive donors can be safely used in hepatitis B surface antigen negative, preferentially anti-HBc/anti-hepatitis B surface antibody positive recipients.
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Srivastava M, Rungta S, Dixit VK, Shukla SK, Singh TB, Jain AK. Predictors of survival in hepatitis B virus related decompensated cirrhosis on tenofovir therapy: an Indian perspective. Antiviral Res 2013; 100:300-5. [PMID: 24012998 DOI: 10.1016/j.antiviral.2013.08.020] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2013] [Revised: 08/21/2013] [Accepted: 08/27/2013] [Indexed: 12/12/2022]
Abstract
Decompensated cirrhosis has low survival rate compared to compensated state. Effective viral suppression due to antiviral therapy (tenofovir) has been shown to slow disease progression and may delay the burden of liver transplantation. We aimed to evaluate the usefulness of various prognostic indicators in predicting the 24-months survival in HBV related decompensated cirrhosis after tenofovir therapy and to evaluate the post-treatment outcome. Ninety-six HBV related decompensated patients on antiviral (tenofovir) therapy were prospectively studied for 24months survival and mortality. Cutoff levels for several prognostic indicators were generated by ROC. Prediction of overall probability of mortality was also calculated. The overall probability of survival observed at 12months was 0.947 whereas at 24months it was found to be 0.833. According to Cox proportional hazards model, the univariate analysis revealed cutoff of >7.4logcopies/ml for HBV DNA, >1.2mg/dl for serum creatinine, >3.7mg/dl for total bilirubin, ⩽0.75 for platelets count, >10 for CTP and >20 for MELD as predictors of poor survival. Multivariate analysis showed MELD score of >20 was the most robust predictor of mortality, with 58 times higher risk (HR: 58.73, p<0.001). Post-treatment response with tenofovir for 24months significantly improved the hepatic functions and reverses decompensation and showed incredible efficacy in improvement of hepatic functional status with reduced viremia in a great majority of decompensated cirrhosis subjects having high MELD and HBV DNA level.
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Affiliation(s)
- Manjita Srivastava
- Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, U.P., India
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Yim HJ, Hwang SG. Options for the management of antiviral resistance during hepatitis B therapy: reflections on battles over a decade. Clin Mol Hepatol 2013; 19:195-209. [PMID: 24133659 PMCID: PMC3796671 DOI: 10.3350/cmh.2013.19.3.195] [Citation(s) in RCA: 26] [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: 07/31/2013] [Accepted: 08/18/2013] [Indexed: 12/14/2022] Open
Abstract
Although much advancement has been achieved in the treatment of chronic hepatitis B, antiviral resistance is still a challenging issue. Previous generation antiviral agents have already developed resistance in a number of patients, and it is still being used especially in resource limited countries. Once antiviral resistance occurs, it predisposes to subsequent resistance, resulting in multidrug resistance. Therefore, prevention of initial antiviral resistance is the most important strategy, and appropriate choice and modification of therapy would be the cornerstone in avoiding treatment failures. Until now, management of antiviral resistance has been evolving from sequential therapy to combination therapy. In the era of tenofovir, the paradigm shifts again, and we have to decide when to switch and when to combine on the basis of newly emerging clinical data. We expect future eradication of chronic hepatitis B virus infection by proper prevention and optimal management of antiviral resistance.
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Affiliation(s)
- Hyung Joon Yim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
- Antiviral Resistance Study Group, Korea
| | - Seong Gyu Hwang
- Department of Internal Medicine, CHA University School of Medicine, Seongnam, Korea
- Antiviral Resistance Study Group, Korea
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