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Abstract
It has been reported that liver fibrosis could be reversed after eliminating liver injuries. This article systematically summarizes the evidence of fibrosis regression based on histology, liver stiffness, and serum biomarkers, and discusses several clinically relevant challenges. Evidence from liver biopsy has been regarded as the gold standard in the assessment of fibrosis regression. Semi-quantitative staging and grading systems are traditionally and routinely used to define regression. Recently, the predominantly regressive, indeterminate, and predominantly progressive score was proposed, based on the regressive features from "hepatic repair complex", to provide additional information regarding the quality of fibrosis. For non-invasive assessment, although liver stiffness and serum biomarkers could be applied to reflect the dynamic changes of liver fibrosis, other confounding factors such as liver inflammation have to be considered. In conclusion, both histology and non-invasive methods can provide evidence regarding fibrosis regression. The predictive value of fibrosis regression in long-term prognosis warrants further investigation.
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Damiris K, Tafesh ZH, Pyrsopoulos N. Efficacy and safety of anti-hepatic fibrosis drugs. World J Gastroenterol 2020; 26:6304-6321. [PMID: 33244194 PMCID: PMC7656211 DOI: 10.3748/wjg.v26.i41.6304] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 09/30/2020] [Accepted: 10/20/2020] [Indexed: 02/06/2023] Open
Abstract
Recent progress in our understanding of the pathways linked to progression from hepatic insult to cirrhosis has led to numerous novel therapies being investigated as potential cures and inhibitors of hepatic fibrogenesis. Liver cirrhosis is the final result of prolonged fibrosis, which is an intimate balance between fibrogenesis and fibrinolysis. A number of these complex mechanisms are shared across the various etiologies of liver disease. Thankfully, investigation has yielded some promising results in regard to reversal of fibrosis, particularly the indirect benefits associated with antiviral therapy for the treatment of hepatitis B and C and the farnesoid receptor agonist for the treatment of primary biliary cholangitis and metabolic associated fatty liver disease. A majority of current clinical research is focused on targeting metabolic associated fatty liver disease and its progression to metabolic steatohepatitis and ultimately cirrhosis, with some hope of potential standardized therapeutics in the near future. With our ever-evolving understanding of the underlying pathophysiology, these therapeutics focus on either controlling the primary disease (the initial trigger of fibrogenesis), interrupting receptor ligand interactions and other intracellular communications, inhibiting fibrogenesis, or even promoting resolution of fibrosis. It is imperative to thoroughly test these potential therapies with the rigorous standards of clinical therapeutic trials in order to ensure the highest standards of patient safety. In this article we will briefly review the key pathophysiological pathways that lead to liver fibrosis and present current clinical and experimental evidence that has shown reversibility of liver fibrosis and cirrhosis, while commenting on therapeutic safety.
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Affiliation(s)
- Konstantinos Damiris
- Department of Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07103, United States
| | - Zaid H Tafesh
- Medicine-Gastroenterology and Hepatology, Rutgers-New Jersey Medical School, Newark, NJ 07103, United States
| | - Nikolaos Pyrsopoulos
- Medicine-Gastroenterology and Hepatology, Rutgers-New Jersey Medical School, Newark, NJ 07103, United States
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3
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Adverse events of nucleos(t)ide analogues for chronic hepatitis B: a systematic review. J Gastroenterol 2020; 55:496-514. [PMID: 32185517 PMCID: PMC7188775 DOI: 10.1007/s00535-020-01680-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 02/26/2020] [Indexed: 02/04/2023]
Abstract
Nucleos(t)ide analogues (NAs) are the main drug category used in chronic hepatitis B (CHB) treatment. Despite the fact that NAs have a favourable safety profile, undesired adverse events (AEs) may occur during the treatment of CHB. Given the eminent number of patients currently receiving NAs, even a small risk of any of these toxicities can represent a major medical issue. The main objective of this review was to analyse information available on AEs associated with the use of NAs in published studies. We choose the following MesH terms for this systematic review: chronic hepatitis B, side effects and treatment. All articles published from 1 January 1990 up to 19 February 2018 in MEDLINE of PubMed, EMBASE, the Cochrane Library and LILACS databases were searched. A total of 120 articles were selected for analysis, comprising 6419 patients treated with lamivudine (LAM), 5947 with entecavir (ETV), 3566 with tenofovir disoproxil fumarate (TDF), 3096 with telbivudine (LdT), 1178 with adefovir dipivoxil (ADV) and 876 with tenofovir alafenamide (TAF). The most common AEs in all NAs assessed were abdominal pain/discomfort, nasopharyngitis/upper respiratory tract infections, fatigue, and headache. TAF displays the highest density of AEs per patient treated among NAs (1.14 AE/treated patient). In conclusion, treatment of CHB with NAs is safe, with a low incidence of AEs. Despite the general understanding TAF being safer than TDF, the number of patients treated with TAF still is too small in comparison to other NAs to consolidate an accurate safety profile. PROSPERO Registration No. CRD42018086471.
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Nagaoki Y, Aikata H, Daijyo K, Teraoka Y, Honda F, Nakamura Y, Hatooka M, Morio K, Fujino H, Nakahara T, Kawaoka T, Miki D, Tsuge M, Hiramatsu A, Imamura M, Kawakami Y, Ochi H, Chayama K. Risk factors for exacerbation of gastroesophageal varices and portosystemic encephalopathy during treatment with nucleos(t)ide analogs for hepatitis B virus-related cirrhosis. Hepatol Res 2018; 48:264-274. [PMID: 29114970 DOI: 10.1111/hepr.12996] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 10/11/2017] [Accepted: 11/03/2017] [Indexed: 12/18/2022]
Abstract
AIM The aim of this study was to determine the risk factors for worsening of gastroesophageal varices (GEVs) and development of portosystemic encephalopathy in patients with hepatitis B virus (HBV)-related cirrhosis during nucleos(t)ide analog (NA) treatment. METHODS One hundred and thirty-seven patients with HBV-related cirrhosis were enrolled in this retrospective cohort study. Findings of portal hemodynamics with computed tomography, liver function, and endoscopic examinations during NA treatment were assessed. RESULTS Among 137 patients, feeding vessels for GEVs (left gastric vein, posterior gastric vein, and short gastric vein) were present in 56 (41%) patients, and extrahepatic portosystemic shunt (paraesophageal vein, paraumbilicul vein, and splenorenal shunt) were present in 36 (26%) patients at the start of NA treatment. Although NA treatment was successful, significant improvements were not observed in portosystemic collateral vessels 3 years after NA treatment and GEVs were exacerbated in 48 (35%) patients. The cumulative 5- and 10-year exacerbation rate of GEVs was 27% and 50%, respectively. By multivariate analysis, the existence of feeding vessels for GEVs at the start of NA treatment was the independent predictive factor for the exacerbation of GEVs (P < 0.001). Eight patients who had extrahepatic portosystemic shunt at the start of NA treatment developed portosystemic encephalopathy during follow-up. The 3- and 5-year incidence of that was 5% and 8%, respectively. CONCLUSIONS The presence of portosystemic collateral vessels at the start of NA treatment increases the risk of GEVs worsening and development of portosystemic encephalopathy in patients with HBV-related cirrhosis, despite improvement of liver function and success in reducing viral loads with NA treatment.
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Affiliation(s)
- Yuko Nagaoki
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, 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
| | - Kana Daijyo
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Yuji Teraoka
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Fumi Honda
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Yuki Nakamura
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Masahiro Hatooka
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Kei Morio
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Hatsue Fujino
- 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
| | - 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
| | - Daiki Miki
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan.,Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, 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
| | - Akira Hiramatsu
- 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
| | - Yoshiiku Kawakami
- 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, RIKEN Center for Integrative Medical Sciences, 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, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
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5
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Li Q, Chen L, Zhou Y. Changes of FibroScan, APRI, and FIB-4 in chronic hepatitis B patients with significant liver histological changes receiving 3-year entecavir therapy. Clin Exp Med 2018; 18:273-282. [PMID: 29350286 DOI: 10.1007/s10238-018-0486-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Accepted: 01/04/2018] [Indexed: 12/17/2022]
Abstract
Noninvasive fibrosis tests have been used widely for evaluation of liver fibrosis in patients with chronic hepatitis B (CHB). We aimed to investigate the influence of antiviral treatment on FibroScan, APRI, and FIB-4 in CHB patients with significant liver histological changes (SLHC) defined as inflammatory grade ≥ A2 and/or fibrosis stage ≥ F2. A total of 104 CHB patients with SLHC at the baseline were included. FibroScan, APRI, and FIB-4 values were compared before and after 3-year entecavir (ETV) treatment. Liver stiffness measurement values decreased significantly after 3-year ETV treatment in cirrhosis group (from 13.6 to 9.6 kPa, p = 0.018), significant fibrosis group (from 8.4 to 5.8 kPa, p = 0.001), and mild fibrosis group (from 5.5 to 4 kPa, p < 0.001). APRI decreased significantly after 3-year ETV treatment in patients with cirrhosis (from 0.80 to 0.25, p < 0.001), patients with significant fibrosis (from 0.54 to 0.24, p < 0.001), and those with mild fibrosis (from 0.35 to 0.23, p < 0.001). FIB-4 decreased significantly after 3-year ETV treatment in patients with cirrhosis (from 1.27 to 0.81, p = 0.007) and significant fibrosis (from 1.12 to 0.78, p < 0.001), while did not decrease significantly in patients with mild fibrosis (from 0.90 to 0.80, p = 0.389). FibroScan, APRI, and FIB-4 values decreased significantly after 3-year ETV treatment in CHB patients, which indicates that these noninvasive fibrosis tests might be useful for monitoring regression of liver fibrosis and assessing treatment efficacy during long-term ETV treatment.
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Affiliation(s)
- Qiang Li
- Department of Liver Disease, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China. .,Department of Infectious Disease, Huashan Hospital, Fudan University, Shanghai, 200040, China.
| | - Liang Chen
- Department of Liver Disease, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China
| | - Yu Zhou
- Department of Infectious Disease, Ruian People's Hospital, Wenzhou, 310000, Zhejiang, China.
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Cost-Effectiveness Comparison Between the Response-Guided Therapies and Monotherapies of Nucleos(t)ide Analogues for Chronic Hepatitis B Patients in China. Clin Drug Investig 2017; 37:233-247. [PMID: 27928739 DOI: 10.1007/s40261-016-0486-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND OBJECTIVE Nucleos(t)ide analogue (NA) monotherapies are typically used as the primary treatment for chronic hepatitis B (CHB) patients, including lamivudine (LAM), telbivudine (TBV), adefovir (ADV), entecavir (ETV) and tenofovir (TDF). For high-resistance NAs (LAM, TBV, ADV), they can generate excellent clinical outcomes by using response-guided therapy; however, their pharmacoeconomic profiles remain unclear in China. We aimed to evaluate the cost effectiveness between response-guided therapies and monotherapies of NAs for Chinese hepatitis B e-antigen (HBeAg)-positive and -negative CHB patients. METHODS We constructed a Markov model to simulate CHB progression associated with 12 treatment strategies using effectiveness and cost data from the published literature. We measured the lifetime costs, quality adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs). One-way sensitivity (especially to extend the range of the TDF price) and probabilistic sensitivity analyses were used to explore the uncertainties of the model. RESULTS For both HBeAg-positive and -negative patients, no treatment strategy generated the lowest lifetime costs (US$31,185-US$31,338) and QALYs (7.54-7.58). ETV and TDF monotherapies were not dominated by other treatments, whereas, the ICER of ETV monotherapy was the lowest (US$6112/QALY-US$8533/QALY). For each high-resistance NA, compared with its monotherapy, the ICERs of its response-guided therapies were below the willingness-to-pay threshold of US$22,833/QALY. Additionally, TDF monotherapy was the preferred treatment when its price dropped to US$1820/year or lower. CONCLUSION Among 12 treatment strategies evaluated, ETV monotherapy is the most cost-effective treatment for treatment-naive CHB patients in China. The response-guided therapies of high-resistance NAs are more cost-effective than their monotherapies.
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Abstract
Great strides have been made in hepatitis B virus (HBV)-related fibrosis and cirrhosis. Available evidence indicates that HBV viral suppression causes regression of advanced fibrosis and even cirrhosis, and therefore should be attempted in all patients with advanced fibrosis and cirrhosis. The preferred agents in patients with cirrhosis are entecavir and tenofovir, primarily because the risk of breakthrough is low. HBV viral suppression leads to improved clinical outcomes even in patients with cirrhosis and complications. The risk of hepatocellular carcinoma is reduced, but not eliminated. Thus, patients with HBV cirrhosis should continue to have routine screening for hepatocellular carcinoma, even after viral suppression.
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Affiliation(s)
- Don C Rockey
- Department of Internal Medicine, The Medical University of South Carolina, 96 Jonathan Lucas Street, 803 CSB, Charleston, SC 29425, USA.
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8
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Bermingham SL, Hughes R, Fenu E, Sawyer LM, Boxall E, T Kennedy P, Dusheiko G, Hill-Cawthorne G, Thomas H. Cost-Effectiveness Analysis of Alternative Antiviral Strategies for the Treatment of HBeAg-Positive and HBeAg-Negative Chronic Hepatitis B in the United Kingdom. VALUE IN HEALTH : THE JOURNAL OF THE INTERNATIONAL SOCIETY FOR PHARMACOECONOMICS AND OUTCOMES RESEARCH 2015; 18:800-809. [PMID: 26409607 DOI: 10.1016/j.jval.2015.05.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Revised: 04/24/2015] [Accepted: 05/28/2015] [Indexed: 06/05/2023]
Abstract
BACKGROUND Seven drugs are licensed for the treatment of chronic hepatitis B (CHB) in the United Kingdom. Which initial treatment, secondary therapy, and whether antivirals should be given alone or in combination are questions of considerable uncertainty. OBJECTIVE The aim of this model was to undertake a comprehensive economic evaluation of all antiviral treatments for CHB to recommend the most cost-effective therapeutic sequence. METHODS We developed a probabilistic Markov model to compare the cost-effectiveness of all clinically relevant antiviral treatment sequences for nucleos(t)ide-naive adults with hepatitis B e-antigen (HBeAg)-positive or HBeAg-negative CHB. Relative rates of HBeAg seroconversion and viral suppression were obtained from a network meta-analysis. Data on mortality, antiviral drug resistance, durability of response, adverse events, and costs were obtained from published literature. Results are reported in terms of lifetime costs, quality-adjusted life-years (QALYs), and expected net benefit. RESULTS In the base-case analysis, pegylated interferon alpha-2a (peg-IFN α-2a) followed by tenofovir disoproxil fumarate was most effective and cost-effective in HBeAg-positive patients, with a cost of £7488 per QALY gained compared with no treatment. In HBeAg-negative patients, peg-IFN α-2a followed by entecavir was most effective and cost-effective, with a cost of £6981 per QALY gained. The model was robust to a wide range of sensitivity analyses. CONCLUSIONS Peg-IFN α-2a followed by tenofovir disoproxil fumarate or entecavir is the most effective antiviral treatment strategy for people with both variants of CHB. At a cost of less than £10,000 per QALY gained, these sequences are considered cost-effective in England and Wales. The results of this analysis were used to inform 2013 National Institute for Health and Care Excellence guideline recommendations.
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Affiliation(s)
| | - Ralph Hughes
- Royal College of Physicians, National Clinical Guideline Centre, London, UK
| | - Elisabetta Fenu
- Royal College of Physicians, National Clinical Guideline Centre, London, UK
| | | | - Elizabeth Boxall
- Virology Laboratory, Health Protection Agency, Microbiology Services Division, Heartlands Hospital, Birmingham, UK
| | | | - Geoff Dusheiko
- UCL Institute of Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Grant Hill-Cawthorne
- Marie Bashir Institute for Infectious Diseases and Biosecurity, Sydney School of Public Health, University of Sydney, Sydney, Australia
| | - Howard Thomas
- Section of Hepatology and Gastroenterology, Department of Medicine, Imperial College, London, UK
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Yo IK, Kwon OS, Park JW, Lee JJ, Lee JH, Won IS, Na SY, Jang PK, Park PH, Choi DJ, Kim YS, Kim JH. The factors associated with longitudinal changes in liver stiffness in patients with chronic hepatitis B. Clin Mol Hepatol 2015; 21:32-40. [PMID: 25834800 PMCID: PMC4379195 DOI: 10.3350/cmh.2015.21.1.32] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Revised: 10/22/2014] [Accepted: 12/11/2014] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/AIMS Liver stiffness (LS) as assessed by transient elastography (TE) can change longitudinally in patients with chronic hepatitis B (CHB). The aim of this study was to identify the factors that improve LS. METHODS Between April 2007 and December 2012, 151 patients with CHB who underwent two TE procedures with an interval of about 2 years were enrolled. Ninety-six of the 151 patients were treated with nucleos(t)ide analogues [the antiviral therapy (+) group], while the remaining 55 patients were not [the antiviral therapy (-) group]. The two groups of patients were stratified according to whether they exhibited an improvement or a deterioration in LS during the study period (defined as an LS change of ≤0 or >0 kPa, respectively, over a 1-year period), and their data were compared. RESULTS No differences were observed between the antiviral therapy (+) and (-) groups with respect to either their clinical characteristics or their initial LS. The observed LS improvement was significantly greater in the antiviral therapy (+) group than in the antiviral therapy (-) group (-3.0 vs. 0.98 kPa, P=0.011). In the antiviral therapy (+) group, the initial LS was higher in the LS improvement group (n=63) than in the LS deterioration group (n=33; 7.9 vs. 4.8 kPa, P<0.001). However, there were no differences in any other clinical characteristic. In the antiviral therapy (-) group, the initial LS was also higher in the LS improvement group (n=29) than in the LS deterioration group (n=26; 8.3 vs. 6.5 kPa, P=0.021), with no differences in any other clinical characteristic. CONCLUSIONS A higher initial LS was the only factor associated with LS improvement in patients with CHB in this study.
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Affiliation(s)
- In Ku Yo
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Korea
| | - Oh Sang Kwon
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Korea
| | - Jin Woong Park
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Korea
| | - Jong Joon Lee
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Korea
| | - Jung Hyun Lee
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Korea
| | - In Sik Won
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Korea
| | - Sun Young Na
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Korea
| | - Pil Kyu Jang
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Korea
| | - Pyung Hwa Park
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Korea
| | - Duck Joo Choi
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Korea
| | - Yun Soo Kim
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Korea
| | - Ju Hyun Kim
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Korea
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Soriano V, McMahon B. Strategic use of lamivudine in the management of chronic hepatitis B. Antiviral Res 2013; 100:435-8. [PMID: 24050850 DOI: 10.1016/j.antiviral.2013.08.026] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Revised: 08/29/2013] [Accepted: 08/30/2013] [Indexed: 02/08/2023]
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11
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Reversal of cirrhosis: an achievable goal of hepatitis B antiviral therapy. J Hepatol 2013; 59:880-1. [PMID: 23673137 DOI: 10.1016/j.jhep.2013.05.007] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Accepted: 05/05/2013] [Indexed: 02/07/2023]
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12
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Marcellin P, Asselah T. Long-term therapy for chronic hepatitis B: hepatitis B virus DNA suppression leading to cirrhosis reversal. J Gastroenterol Hepatol 2013; 28:912-23. [PMID: 23573915 DOI: 10.1111/jgh.12213] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/26/2013] [Indexed: 02/06/2023]
Abstract
Since the licensing of the first treatment for chronic hepatitis B in the nucleoside/tide analog class almost 15 years ago, considerable progress has been made in improving drug efficacy and safety with highly potent nucleoside/tide analogs exhibiting a high barrier to resistance. Physicians are now able to treat patients safely for many years and to be able to see convincing improvements in histology, including regression of fibrosis and even reversal of cirrhosis. The robust data that have been generated help us build confidence that we can now offer patients with chronic hepatitis B long-term, disease-modifying therapy that can alter the natural course of disease and help prevent the morbidity and mortality associated with it.
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Affiliation(s)
- Patrick Marcellin
- Service d'Hépatologie, Hôpital Beaujon, University of Paris, Clichy, France.
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13
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Du X, Wang J, Shao L, Hu X, Yang C, Shen L, Weng X, Zhang W. Histological improvement of long-term antiviral therapy in chronic hepatitis B patients with persistently normal alanine aminotransferase levels. J Viral Hepat 2013; 20:328-35. [PMID: 23565615 DOI: 10.1111/jvh.12034] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2012] [Accepted: 09/01/2012] [Indexed: 12/11/2022]
Abstract
The aim of this study was to evaluate the histological outcomes of chronic hepatitis B (CHB) patients with persistently normal alanine aminotransferase (ALT) levels after long-term antiviral therapy. Paired liver biopsies before and after lamivudine (LAM) treatment in CHB patients with normal and elevated ALT levels were compared. Histological response was defined as a 1-point decrease according to the Scheuer scoring system, without worsening of fibrosis between pretreatment and posttreatment biopsies. Among the 48 patients who underwent paired liver biopsies, 17 had persistently normal baseline ALT level and 31 had elevated ALT level. The median age of the patients was 44 years and 72.9% of the patients were male. The median duration of antiviral treatment was 44.5 months (range 14-104). Long-term follow-up of liver biopsies revealed that 82.4% of patients in the normal ALT group and 61.3% in the elevated ALT group had a baseline fibrosis score of 4, which was reduced to 17.6% and 38.7% after long-term therapy, respectively, indicating reversal of cirrhosis in a large proportion of both groups, especially in patients with normal baseline ALT levels. Long-term antiviral treatment could achieve significant histological improvement in CHB patients with fibrosis or cirrhosis, regardless of ALT level.
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Affiliation(s)
- X Du
- Department of Infectious Diseases, Beilun People's Hospital, Ningbo, China
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14
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Abstract
Hepatitis B virus (HBV) has been classified into 10 genotypes (A-J) according to genome sequence divergence. HBV genotypes have a distinct geographical distribution. As chronic HBV infection is endemic in the Asian region, genotypes B and C prevail there, and genotypes A and D are mainly found in the western world and Europe. Genotypes A, B, C, and D have been studied most extensively. In Europe and Asia, most patients with genotypes A and B have acute hepatitis B; however, some mutants may tend to cause fulminant hepatitis B. Many studies have indicated that the severity and outcomes of chronic hepatitis B infections are more serious in patients with genotypes C and D than in those with genotypes A and B. Cirrhosis and hepatocellular carcinoma (HCC) are more frequently diagnosed in carriers of genotypes C and D than in those of genotypes A and B. Accumulating evidence indicated that higher plasma HBV DNA levels, infection with HBV genotype C, as well as mutations at 1653T, 1753V, and A1762T/G1764A are independently associated with the risk of HCC in Asian men. However, the therapeutic responses differ with regard to the different HBV genotypes. For example, the response to interferon-α treatment in patients with genotypes A and B was better than that in patients with genotypes C, D, and mixed genotypes. Some studies have shown seroconversion after treatment, i.e., genotypes A and C may switch to genotypes D and B, respectively. Some reports indicated a correlation between the emergence of the hepatitis B e antigen-negative variant in patients with genotypes C and D and worsening of liver injury without sustained response. In order to provide better treatment options for these poorly responding patients, further studies, e.g, novel immunomodulatory therapies, are required. Many studies have shown that HBV genotypes have remarkable clinical and epidemical differences; however, HBV sub-genotypes, mixed genotype infections, and the effect of different genotypes on the treatment of HBV infections require further studies.
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Affiliation(s)
- Ying-Hui Shi
- Qingdao YH Virus Institute, Shandong, China. yinghui_777＠163.com
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Sueki R, Maekawa S, Miura M, Kadokura M, Komase K, Shindo H, Kanayama A, Ohmori T, Shindo K, Amemiya F, Nakayama Y, Uetake T, Inoue T, Sakamoto M, Enomoto N. Correlation between pretreatment viral sequences and the emergence of lamivudine resistance in hepatitis B virus infection. J Med Virol 2012; 84:1360-8. [PMID: 22825814 DOI: 10.1002/jmv.23314] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The emergence of amino acid or nucleotide substitutions leads to lamivudine resistance in hepatitis B virus (HBV) infected patients. The aim of this study was to investigate whether viral sequences help predict the emergence of lamivudine resistance. The study subjects comprised 59 consecutive patients infected with HBV treated with daily therapy of 100 mg lamivudine. Among those, 32 patients with adequate pretreatment serum preservation were investigated for the correlation between viral amino acid substitutions and the appearance of lamivudine resistance with consideration of clinical background by determining dominant HBV full open reading frames. Viral resistance to lamivudine emerged in 28 of 59 patients (47%) in a median period of 2.45 years. Sequence comparisons of HBV genomes between patients who later developed lamivudine resistance and patients who did not revealed the existence of significant differences between the two groups in the pre-S1 84 (P = 0.042), pre-S2 1 (P = 0.017) and 22 (P = 0.015), and polymerase tp 95 (P = 0.046), judged by a log-rank test. Viral sequence analyses revealed the presence of amino acid substitutions in HBV pre-S1 and pre-S2 that may be associated with the emergence of lamivudine resistance during chronic HBV infection.
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Affiliation(s)
- Ryota Sueki
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
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Sohrabpour AA, Mohamadnejad M, Malekzadeh R. Review article: the reversibility of cirrhosis. Aliment Pharmacol Ther 2012; 36:824-832. [PMID: 22966946 DOI: 10.1111/apt.12044] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2012] [Revised: 04/18/2012] [Accepted: 08/22/2012] [Indexed: 02/06/2023]
Abstract
BACKGROUND Cirrhosis is the end result of many types of chronic liver diseases. Recent developments in the understanding of the process of hepatic fibrogenesis have revealed that the process is a dynamic one and a capacity for recovery from any degree of fibrosis including those associated with cirrhosis is plausible. AIM To review current evidence of histopathological reversibility following drug therapy of more common aetiologies of cirrhosis. METHODS A PubMed search was performed and the evidence for histopathological regression of advanced fibrosis/cirrhosis following drug therapy was reviewed as of the end of February 2012. RESULTS There is abundant clinical evidence in support of the idea of the reversibility of cirrhosis in patients with different aetiologies of advanced hepatic disease including viral, autoimmune and metabolic/infiltrative liver disease. CONCLUSIONS The concept of cirrhosis has changed from being a form of static and irreversible entity to a dynamic and reversible diseases stage. Novel therapeutic strategies are under investigation to target specific steps in the process of fibrogenesis with the aim of reversing advanced fibrosis/cirrhosis.
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Affiliation(s)
- A A Sohrabpour
- Digestive Disease Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
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18
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Fasano M, Lampertico P, Marzano A, Di Marco V, Niro GA, Brancaccio G, Marengo A, Scotto G, Brunetto MR, Gaeta GB, Rizzetto M, Angarano G, Santantonio T. HBV DNA suppression and HBsAg clearance in HBeAg negative chronic hepatitis B patients on lamivudine therapy for over 5 years. J Hepatol 2012; 56:1254-8. [PMID: 22343167 DOI: 10.1016/j.jhep.2012.01.022] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2011] [Revised: 01/19/2012] [Accepted: 01/23/2012] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS In long-term responder patients, it is unclear whether lamivudine (LAM) monotherapy should be continued or switched to a high-genetic-barrier analogue. This study aims at assessing LAM efficacy over a 5-year period and the residual risk of drug resistance. The rate of HBsAg clearance and LAM long-term safety profile were also evaluated. METHODS One hundred and ninety-one patients with chronic HBeAg-negative hepatitis B successfully treated with LAM monotherapy for at least 5 years were included. Biochemical and virological tests were assessed every 3 months in all patients and HBsAg quantification was performed in 45/191. Reverse-transcriptase (RT) region was directly sequenced in virological breakthrough patients. RESULTS One hundred and ninety-one patients (148 males, median age 53 years, 72 with compensated cirrhosis) responding to 60-month LAM monotherapy continued to receive LAM monotherapy beyond the initial 5 years and were followed for an additional 36-month median period (range 1-108). Virological response was maintained in 128/191 patients (67%) and HBsAg clearance was observed in 15/128 (11.7%) after a 32-month median period (range 1-65). The 63 remaining patients (33%) showed virological breakthrough after a 15-month median treatment (range 1-78). RT region analysis was performed in 38/63 breakthrough patients and LAM resistant mutations were found in 37/38. No significant side effects were observed. CONCLUSIONS In long-term responder patients, continuation of LAM monotherapy resulted in persistent viral suppression in most cases with undetectable HBV DNA by real-time PCR; moreover, 11.7% of these patients cleared HBsAg. Selection of LAM resistance, however, can still occur even after successful long-term therapy, thus emphasising the importance of a careful virological monitoring.
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Affiliation(s)
- Massimo Fasano
- Clinic of Infectious Diseases, University of Bari, Policlinico, Bari, Italy
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Brown A, Goodman Z. Hepatitis B-associated fibrosis and fibrosis/cirrhosis regression with nucleoside and nucleotide analogs. Expert Rev Gastroenterol Hepatol 2012; 6:187-98. [PMID: 22375524 DOI: 10.1586/egh.12.4] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hepatitis B virus (HBV) infection currently accounts for approximately 600,000 deaths per year resulting from progression of liver fibrosis to cirrhosis and hepatocellular carcinoma. Treatment of chronic hepatitis B with antiviral agents aims to improve survival through the reduction of HBV DNA to undetectable levels and the resultant prevention of disease progression. In recent years, observations in various disease areas have shown that liver fibrosis can be reversed if the underlying cause of the liver damage is effectively addressed. In line with these observations, there is now considerable evidence to suggest that effective sustained suppression of HBV replication with long-term anti-HBV treatment can result in measurable improvements in liver fibrosis over time, even in patients with advanced cirrhosis. This review article provides an overview of currently available data on regression of fibrosis and cirrhosis in patients with chronic hepatitis B treated with nucleoside and nucleotide analog inhibitors of HBV.
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Affiliation(s)
- Ashley Brown
- Department of Hepatology, Imperial College Healthcare NHS Trust, London, UK.
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Gish R, Jia JD, Locarnini S, Zoulim F. Selection of chronic hepatitis B therapy with high barrier to resistance. THE LANCET. INFECTIOUS DISEASES 2012; 12:341-53. [PMID: 22326017 DOI: 10.1016/s1473-3099(11)70314-0] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Antiviral drug resistance is a crucial factor that frequently determines the success of long-term therapy for chronic hepatitis B. The development of resistance to nucleos(t)ide analogues has been associated with exacerbations in liver disease and increased risk of emergence of multidrug resistance. The selection of a potent nucleos(t)ide analogue with a high barrier to resistance as a first-line therapy, such as entecavir or tenofovir, provides the best chance of achieving long-term treatment goals and should be used wherever possible. The barrier to resistance of a given nucleos(t)ide analogue is influenced by genetic barrier, drug potency, patient adherence, pharmacological barrier, viral fitness, mechanism of action, and cross-resistance. In countries with limited health-care resources, the selection of a therapy with a high barrier to resistance is not always possible and alternative strategies for preventing resistance might be needed, although limited data are available to support these strategies.
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Affiliation(s)
- Robert Gish
- Center for Hepatobiliary Disease and Abdominal Transplantation, UC San Diego Health System, San Diego, CA, USA
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21
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Lok ASF, Negro F. Hepatitis B and D. SCHIFF'S DISEASES OF THE LIVER 2011:537-581. [DOI: 10.1002/9781119950509.ch24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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22
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Post SE, Sodhi NK, Peng CH, Wan K, Pollack HJ. A simulation shows that early treatment of chronic hepatitis B infection can cut deaths and be cost-effective. Health Aff (Millwood) 2011; 30:340-8. [PMID: 21289356 DOI: 10.1377/hlthaff.2008.0905] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Chronic hepatitis B affects between 800,000 and two million people in the United States and causes 4,000 deaths each year. Yet the costs and benefits of treatment have not been fully evaluated. Using a model that simulates disease progression, we compare treatment programs for hepatitis B that start at an early stage of the disease to treatment that begins at a late stage. Our analysis concludes that early hepatitis B care can improve health, reduce premature deaths, and prevent expensive complications, making it highly cost-effective in the long term. Our results demonstrate the importance of screening for hepatitis B among at-risk groups and then linking screening to treatment. They also illustrate how predictive models can be used to evaluate strategies for improving access to care.
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Affiliation(s)
- Sarah E Post
- University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
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Fung J, Lai CL, Seto WK, Yuen MF. Nucleoside/nucleotide analogues in the treatment of chronic hepatitis B. J Antimicrob Chemother 2011; 66:2715-25. [PMID: 21965435 DOI: 10.1093/jac/dkr388] [Citation(s) in RCA: 137] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The current available agents for the treatment of chronic hepatitis B (CHB) include immunomodulatory agents, such as interferon-α and pegylated interferon-α, and oral nucleoside/nucleotide analogues (NAs), including lamivudine, adefovir, telbivudine, entecavir and tenofovir. The NAs work mainly by inhibiting hepatitis B virus (HBV) DNA polymerase activity and thus suppress HBV replication. Oral NAs have become the mainstay of CHB treatment, mainly due to their profound viral suppressive effects and also due in part to the ease of single daily dosing and lack of significant side effects. One major drawback of NA therapy is the development of drug resistance mutations with long-term treatment. Lamivudine, the first oral NA approved for CHB patients, is associated with high rates of drug resistance, with resultant virological relapse and biochemical flare. Fortunately, newer and more potent NAs, such as entecavir and tenofovir, have very low resistance rates, with potent and durable viral suppression. This review is aimed at the current developments in NAs for CHB treatment, detailing the mechanisms of antiviral activity of the different agents, the efficacy of viral suppression, the achievement of treatment endpoints, the development of drug resistance and the optimal strategies for using these drugs.
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Affiliation(s)
- James Fung
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong SAR
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Zhu CW, Wang HY, Fang H. Antiviral therapy in patients with hepatitis B virus-related cirrhosis. Shijie Huaren Xiaohua Zazhi 2011; 19:1592-1597. [DOI: 10.11569/wcjd.v19.i15.1592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Antiviral therapy can lead to biochemical remission, histological improvement, and even complete reversibility of liver cirrhosis in patients with hepatitis B virus-related cirrhosis, thereby significantly reducing the incidence of hepatic decompensation, hepatocellular carcinoma and liver disease-related death. Interferon alpha is not contraindicated in compensated cirrhosis and can be used in finite treatment for 6 or 12 months. Long-term treatment with nucleoside/nucleotide analogues is recommended for both compensated and decompensated cirrhosis. Biochemical and virological changes should be carefully monitored during antiviral treatment to promptly find viral breakthrough and prevent hepatitis B recurrence and liver failure. In addition, hepatocellular carcinoma is required to be screened in all cirrhotic patients.
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Adefovir and lamivudine in combination compared with adefovir monotherapy in HBeAg-negative adults with chronic hepatitis B virus infection and clinical or virologic resistance to lamivudine: a retrospective, multicenter, nonrandomized, open-label study. Clin Ther 2009; 30:317-23. [PMID: 18343270 DOI: 10.1016/j.clinthera.2008.02.012] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2007] [Indexed: 02/06/2023]
Abstract
OBJECTIVES The aim of this study was to assess the therapeutic effectiveness of adefovir dipivoxil (ADV), administered in combination with lamivudine (LAM) or as monotherapy, and the rate of resistance to ADV, in hepatitis B e antigen (HBeAg)-negative adult patients with chronic hepatitis B virus (HBV) infection and clinical or virologic resistance to LAM. Furthermore, we evaluated in these selected patients the clinical co-variates associated with a sustained virologic response. METHODS Data from adult outpatients aged >18 years with chronic HBV infection and clinical or virologic resistance to LAM were used in this retrospective, multicenter, nonrandomized, open-label study. Patients were selected if they received ADV 10 mg PO QD + LAM 100 mg QD PO or ADV 10 mg PO QD as monotherapy for 24 to 32 months between June 2003 and July 2006. End points were the proportions of patients who achieved virologic response (undetectable HBV-DNA [<3.3 log(10) copies/mL]) and biochemical response (normalization [<40 IU/L] of alanine aminotransferase [ALT]), and the proportions in whom resistance to ADV (rebound serum HBV-DNA >1 log(10) copies/mL compared with on-treatment nadir, as confirmed on molecular analysis) was found. HBV-DNA and ALT levels were checked every month during the first 3 months of treatment and every 3 months thereafter until 28 months. Data from each center were stored in a centralized database and analyzed by a blinded independent investigator. RESULTS Data from 70 patients were included (48 men, 22 women; median age, 51 years; ADV + LAM, 36 patients; ADV monotherapy, 34). The median duration of the pharmacologic treatment in the 2 groups of patients was 28 months (range, 24-32 months). By month 3, virologic response was achieved in 30 patients (83%) in the ADV + LAM group and in 26 patients (76%) in the ADV monotherapy group. At 12 months, virologic response was achieved in 5 additional patients in the ADV + LAM group and 2 additional patients in the ADV monotherapy group. Biochemical response was found to be time dependent: in the 2 groups, the rates of biochemical response were, respectively, 56% and 54% at month 3, 80% and 71% at month 6, and 96% and 79% at month 12, persisting up to the end of the study period. The rates of clinical resistance to ADV were 3% with ADV + LAM and 18% with ADV monotherapy (with a 6% rate of resistance due to rtA181 mutation in the monotherapy group). Logistic regression analysis found that pre-treatment levels of HBV-DNA <5 log(10) copies/mL, ALT levels >150 IU/L, an inflammation score >7, and a fibrosis score <2 were the strongest covariates independently associated with a sustained virologic response in both groups of patients. No adverse events were reported in any of the patients. CONCLUSION ADV, administered in combination with LAM or as monotherapy, appeared to be effective in this small, selected group of HBeAg-negative patients with clinical or virologic resistance to LAM, especially in those with low pretreatment HBV-DNA levels, high ALT levels, and low fibrosis scores.
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Almeida AM, Silva DID, Guerra Jr AA, Silva GD, Acurcio FDA. Revisão sistemática da eficácia do interferon alfa (convencional, peguilado) e lamivudina para o tratamento da hepatite crônica B. CAD SAUDE PUBLICA 2009; 25:1667-77. [PMID: 19649408 DOI: 10.1590/s0102-311x2009000800003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
A hepatite crônica B constitui um grave problema de saúde pública e vem demonstrando crescentes gastos com financiamento de medicamentos de dispensação em caráter excepcional e de alto custo no Sistema Único de Saúde (SUS). O objetivo do estudo foi comparar a eficácia do interferon (convencional; peguilado - PEG2a) e lamivudina (LAM) para o tratamento da hepatite crônica B, pelo método de revisão sistemática selecionando ensaios clínicos randomizados e controlados identificados nas bases PubMed e LILACS. As medidas de resultado consideradas foram resposta virológica, soroconversão, resposta bioquímica, resposta histológica e efeitos adversos. Foram selecionados 35 artigos. A presença ou ausência do HBeAg e os níveis de alanina amino transferase (ALT) no pré-tratamento demonstraram papel fundamental na indicação terapêutica inicial. O tratamento com interferons convencionais permite a inativação da doença por longos períodos de tempo, podendo resultar em soroconversão HBsAg. O PEG 2a demonstrou eficácia superior ao interferon e LAM e efeitos colaterais semelhantes ao interferon. A LAM apresenta vantagem de ser sensível para os pacientes HBeAg negativo e apresenta como maior desvantagem o desenvolvimento de resistência.
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Scarsi KK, Darin KM. Chronic Hepatitis B Infection: Principles of Therapy. J Pharm Pract 2009; 22:359-387. [DOI: 10.1177/0897190008328692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Chronic hepatitis B is a global health concern in many resource-limited settings due to perinatal or pediatric hepatitis B virus transmission. In the United States, pediatric infection has been virtually eliminated due to maternal screening during pregnancy and the availability of an effective vaccine. However, young adults remain an at-risk group for hepatitis B virus infection due to sexual transmission and injection drug use. The frequency of progression from acute hepatitis B virus infection to chronic hepatitis B infection depends on multiple factors, including host immune function and age at time of hepatitis B virus infection. Fortunately, there are 7 currently approved therapies for chronic hepatitis B infection, and several emerging therapies that show promise. Despite the availability of these agents, many clinical questions still surround chronic hepatitis B therapy including when to start therapy, which agent is ideal for first and second line therapy, the appropriate duration of therapy, and the role of combination antiviral therapy. This review focuses on agents available for chronic hepatitis B management, including pharmacology, safety and efficacy data, monitoring parameters, and the role for each in chronic hepatitis B therapy in adult patients.
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Affiliation(s)
- Kimberly K. Scarsi
- Northwestern University Feinberg School of Medicine, Division of Infectious Diseases, Chicago,
| | - Kristin M. Darin
- Northwestern University Feinberg School of Medicine, Division of Infectious Diseases, Chicago
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28
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Abstract
Nucleoside or nucleotide analogs (NUCs) are a major step forward in the treatment of hepatitis B virus (HBV) infection. Apart from their proven antiviral efficacy, these drugs have proved able to significantly improve liver fibrosis as short-term treatment. Using different definitions of fibrosis regression, after 1 year of treatment, improvement in liver fibrosis was observed among HBe antigen (HBeAg)-positive naive patients: 35-61% with lamivudine; 41% with adefovir; 68% with telbivudine; 39% with entecavir; and 74% with tenofovir. Among HBeAg-negative patients, after 1 year of treatment, improvement in liver fibrosis was seen in: 36-46% with lamivudine; 48% with adefovir; 56% with telbivudine; 36% with entecavir; and 71% with tenofovir. Long-term treatment is often required with NUCs; the response continue to improve over time, reaching up to 63% of patients with lamivudine and 71% of patients with adefovir, although the development of antiviral drug resistance can blunt any histological improvement. Also, there is now growing evidence that non-invasive methods of fibrosis diagnosis, such as surrogate markers, are likely to become as important as liver biopsy for taking the initial decision to biopsy and for treatment, and in the follow-up of treated chronic HBV patients.
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Affiliation(s)
- Jules L Dienstag
- Gastrointestinal Unit (Medical Services), Massachusetts General Hospital, and Department of Medicine and Office of the Dean for Medical Education, Harvard Medical School, Boston 02114, USA.
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30
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Carosi G, Rizzetto M. Treatment of chronic hepatitis B: recommendations from an Italian workshop. Dig Liver Dis 2008; 40:603-617. [PMID: 18499540 DOI: 10.1016/j.dld.2008.03.011] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2008] [Revised: 03/03/2008] [Accepted: 03/04/2008] [Indexed: 12/11/2022]
Abstract
The changing scenario of hepatitis B virus therapy has encouraged the organisation of a workshop, endorsed by three Italian scientific societies, aimed at defining the current recommendations for hepatitis B virus treatment. Liver histology and stage of disease remain fundamental for treatment decisions; interferon and nucleoside/nucleotide analogues-based therapy represent different strategies for different phases of the hepatitis B virus disease. The recommendations defined: new and lower cut-off of hepatitis B virus-DNA for eligibility to therapy according to disease stage, how to optimise the use of nucleoside/nucleotide analogues and to individualise the monitoring of response and what to do with treatment failures. Specific recommendations have also been given for cirrhosis patients, those immune suppressed and co-infected with HIV and other hepatitis viruses.
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Affiliation(s)
- G Carosi
- Department of Infectious and Tropical Diseases, University of Brescia, AO Spedali Civili, Brescia, Italy.
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31
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Leemans WF, Ter Borg MJ, de Man RA. Review article: Success and failure of nucleoside and nucleotide analogues in chronic hepatitis B. Aliment Pharmacol Ther 2007; 26 Suppl 2:171-82. [PMID: 18081660 DOI: 10.1111/j.1365-2036.2007.03481.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Strong suppression of viral replication and normalization of alanine aminotransferase is feasible with nucleos(t)ide analogues. It is estimated viral replication and liver inflammation can be controlled in 90% of patients with chronic hepatitis B with the current available treatments. AIM To review the studies currently available on the management of chronic hepatitis B with nucleos(t)ide analogues. RESULTS Although very potent, nucleos(t)ide analogues are not effective in every patient. Some factors are known to influence treatment outcome, but many host and viral factors are still unknown. Stopping rules have to be defined to assess treatment efficacy in an early stage and change the regimen. Discontinuation of nucleos(t)ide analogues is often followed by reactivation of HBV. Data on the risk factors for relapse are necessary in order to decide if treatment can be safely discontinued. Another major drawback of nucleos(t)ide analogues is the emergence of resistance. The efficacy of compounds for the treatment of mutant virus and the impact of cross-resistance is largely unknown. The use of combination therapy to prevent resistance looks promising, but has to be proven. CONCLUSIONS HBV has become a treatable disease, however much research is needed to optimize treatment for individual patients and treatment failures.
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Affiliation(s)
- W F Leemans
- Department of Gastroenterology & Hepatology, Erasmus Medical Center, University Medical Center, Rotterdam, The Netherlands
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Gérolami R, Borentain P, Colson P, Norguet E, Gérolami A, Tamalet C. Efficacy of hepatitis B virus (HBV) vaccination in treating lamivudine-resistant HBV reactivation following hepatitis B surface antigen seroconversion. Liver Int 2007; 27:1417-21. [PMID: 18036104 DOI: 10.1111/j.1478-3231.2007.01541.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
BACKGROUND HBsAg vaccination might help to control HBV replication following nucleos(t)ide analog therapy. We tested HBsAg vaccine in a patient who developed lamivudine resistance. PATIENT AND RESULTS An HBeAg negative HBV chronically-infected patient developed HBsAg seroconversion after 3 years of treatment by lamivudine. However, the control of HBV replication was transient and HBV DNA could be detected in the serum one year after lamivudine was stopped. Concurrently, the anti-HBs antibodies (HBsAb) titre had decreased from more than 100 IU/L to 23 IU/L. Due to the presence of rtM204V resistance mutation, lamivudine was not reintroduced and the patient was treated by HBsAg vaccination. After three injections, HBV DNA was no more detectable and the HBsAb titre reached more than 200 IU/L. CONCLUSION This observation suggests that a regular follow up of patients presenting HBsAg seroconversion following lamivudine therapy is necessary. In these patients, a low titre of HBsAb may not prevent from lamivudine-resistant HBV reactivation. Evaluation of HBsAg vaccination to maintain HBsAb at a high titre in these patients deserves further studies.
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Affiliation(s)
- René Gérolami
- Service d'Hépato-gastroentérologie, Centre Hospitalier Universitaire Conception, Marseille, France.
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Stornaiuolo G, Stanzione M, Brancaccio G, Cuomo G, Precone V, Di Biase S, Felaco FM, Piccinino F, Gaeta GB. Viral blips during long-term treatment with standard or double dose lamivudine in HBe antigen negative chronic hepatitis B. World J Gastroenterol 2007; 13:5642-7. [PMID: 17948940 PMCID: PMC4172745 DOI: 10.3748/wjg.v13.i42.5642] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate safety and effect on hepatitis B virus (HBV) suppression of a long-term treatment with lamivudine (LAM) at standard (100 mg/d) or double (200 mg/d) dose in chronic hepatitis B.
METHODS: This was a case study with matched controls (1:3) in patients with chronic hepatitis B with anti-HBe antibodies.
RESULTS: Twelve patients received LAM 200 mg/d and 35 LAM 100 mg/d, for a median of 28 mo. A primary response (PR; i.e., negative HBV-DNA with Amplicor assay) was achieved in 100% of LAM-200 patients and 83% of LAM-100 patients. A virological breakthrough occurred in 16.7 and 24.7%, respectively, of the PR-patients, with the appearance of typical LAM resistance mutations in all but one patient. Viremia blips (i.e., transient HBV-DNA below 80 IU/mL in patients who tested negative at Amplicor assay) were detected using a real time polymerase chain reaction (PCR) and occurred in seven out of nine patients with subsequent BT and in four out of 32 patients with end-of-study response (77.7% vs 12.5%; P = 0.001) at chi-square test). At the end of the study, 51.4% of LAM-100 patients and 83.3% of LAM-200 patients had remained stably HBV-DNA negative. Double-dose LAM was well tolerated.
CONCLUSION: Long-term treatment of anti-HBe positive chronic hepatitis B with double dose lamivudine causes a more profound and stable viral suppression as compared to conventional treatment.
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Abstract
Hepatitis B virus (HBV) is the most common cause of chronic hepatitis and end-stage liver disease worldwide. Untreated, chronic hepatitis B acquired early in life results in cirrhosis, liver failure, or hepatocellular carcinoma in up to 40% of individuals. Until recently, the options for a patient who had end-stage hepatitis B cirrhosis were severely limited, but during the past 15 years great strides have been made in prevention and treatment of hepatitis B cirrhosis. This article reviews recent advances in the understanding of the natural history, prevention, and medical management of HBV-related end-stage liver disease.
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Affiliation(s)
- Ilan S Weisberg
- Division of Gastroenterology and Hepatology, New York Weill Cornell Medical Center, 525 E. 68th Street, New York, NY 10021, USA
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Thomas HC. Best practice in the treatment of chronic hepatitis B: a summary of the European Viral Hepatitis Educational Initiative (EVHEI). J Hepatol 2007; 47:588-97. [PMID: 17697725 DOI: 10.1016/j.jhep.2007.07.017] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2007] [Revised: 07/18/2007] [Accepted: 07/18/2007] [Indexed: 12/12/2022]
Abstract
Hepatitis B causes acute and chronic hepatitis, the latter resulting in cirrhosis and hepatocellular carcinoma. There are four phases of infection: during the phases of immune tolerance and immune control of the virus, no treatment is recommended but in the phases of immune clearance and immune escape, viraemia with biopsy evidence of significant fibrosis requires anti-viral therapy. The areas of agreement and disagreement between the various consensus statements are discussed. Health economic issues indicate that a trial of pegylated interferon should be offered in non-cirrhotic cases, particularly those that are HBe antigen positive, followed in those that do not establish a sustained viral response, by long term viral suppressive therapy with nucleoside analogues singly or in combination. The indications for treatment and methods of follow-up, as well as issues of viral resistance are discussed.
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Affiliation(s)
- Howard C Thomas
- Department of Hepatology and Gastroenterology, St. Mary's Hospital Campus, Imperial College, London, UK.
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36
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Yoo BC, Kim JH, Kim TH, Koh KC, Um SH, Kim YS, Lee KS, Han BH, Chon CY, Han JY, Ryu SH, Kim HC, Byun KS, Hwang SG, Kim BI, Cho M, Yoo K, Lee HJ, Hwang JS, Kim YS, Lee YS, Choi SK, Lee YJ, Yang JM, Park JW, Lee MS, Kim DG, Chung YH, Cho SH, Choi JY, Kweon YO, Lee HY, Jeong SH, Yoo HW, Lee HS. Clevudine is highly efficacious in hepatitis B e antigen-negative chronic hepatitis B with durable off-therapy viral suppression. Hepatology 2007; 46:1041-8. [PMID: 17647293 DOI: 10.1002/hep.21800] [Citation(s) in RCA: 96] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
UNLABELLED Clevudine is a pyrimidine analog with potent and sustained antiviral activity against HBV. In the present study, we evaluated the safety and efficacy of clevudine 30 mg daily for 24 weeks and assessed the durability of antiviral response for 24 weeks after cessation of dosing in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (e-CHB). We randomized a total of 86 patients (3:1) to receive clevudine 30 mg (n = 63) or placebo (n = 23) daily for 24 weeks. We followed patients for an additional 24 weeks after withdrawal of treatment. The median changes in HBV DNA from baseline were -4.25 and -0.48 log(10) copies/mL at week 24 in the clevudine and placebo groups, respectively (P < 0.0001). Viral suppression in the clevudine group was sustained after withdrawal of therapy, with 3.11 log(10) reduction at week 48. At week 24 and week 48, 92.1% and 16.4% of patients in the clevudine group had undetectable serum HBV DNA levels by Amplicor PCR assay (<300 copies/mL). The proportion of patients who achieved ALT normalization was 74.6% and 33.3% in the clevudine and placebo groups at week 24, respectively (P = 0.0006). ALT normalization in the clevudine group was well-maintained during the post-treatment follow-up period. The incidence of adverse events was similar in the 2 groups. No resistance to clevudine was detected during treatment. CONCLUSION A 24-week clevudine therapy was well-tolerated and showed potent and sustained antiviral effect without evidence of viral resistance in e-CHB patients. However, treatment for longer than 24 weeks would be needed to achieve durable remission.
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Affiliation(s)
- Byung Chul Yoo
- Sungkyunkwan University Samsung Medical Center, Seoul, South Korea
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37
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Abstract
Chronic hepatitis B remains a treatment challenge despite the availability of new nucleoside analogs. This is due to the persistence of viral infection during therapy, which exposes the patient to the risk of developing antiviral drug resistance. Therefore, new polymerase inhibitors are needed to manage resistance to existing drugs and new trials of combination therapy are required to delay drug resistance. In the future, antiviral agents targeting other steps of the viral life cycle will be needed to achieve antiviral synergy and prevent antiviral drug resistance. Immune modulators are also expected to enhance antiviral response and to achieve sustained response. Discovery of new antiviral drugs and design of new treatment strategies are, therefore, needed to manage this disease, which is still the main cause of cirrhosis and hepatocellular carcinoma worldwide.
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Affiliation(s)
- Fabien Zoulim
- INSERM, U871, 151 cours Albert Thomas, 69424 Lyon cedex 03, France.
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Rizzetto M, Zoulim F. Viral Hepatitis. TEXTBOOK OF HEPATOLOGY 2007:819-956. [DOI: 10.1002/9780470691861.ch9a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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39
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Abstract
Hepatitis B virus (HBV) infection is still the most common cause of hepatocellular carcinoma and liver cirrhosis world wide. Recently, however, there has been quite dramatic improvement in the understanding of HBV associated liver disease and its treatment. It has become clear that high viral replication is a major risk factor for the development of both cirrhosis and hepatocellular carcinoma. Early studies have shown lamivudine lowers the risk of HBV associated complications. There are currently three nucleos(t)ides licensed, in addition to interferon, and there are more drugs coming to the market soon. Interferon or its pegylated counterpart are still the only options for treatment with defined end points, while nucleos(t)ides therapy is used mostly for long term treatment. Combination therapies have not been shown to be superior to monotherapy in naïve patients, however, the outcome depends on how the end point is defined. Interferon plus lamivudine achieves a higher viral suppression than either treatment alone, even though Hbe-seroconversion was not different after a one year treatment. HBV-genotypes emerge as relevant factors, with genotypes "A" and "B" responding relatively well to interferon, achieving up to 20% HBsAg clearance in the case of genotype "A". In addition to having a defined treatment duration, interferon has the advantage of lacking resistance selection, which is a major drawback for lamivudine and the other nucleos(t)ides. The emergence of resistance against adefovir and entecavir is somewhat slower in naïve compared to lamivudine resistant patients. Adefovir has a low resistance profile with 3%, 9%, 18%, and 28% after 2, 3, 4, and 5 years, respectively, while entecavir has rarely produced resistance in naïve patients for up to 3 years.
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Affiliation(s)
- Hans L Tillmann
- University of Leipzig, Philipp-Rosenthal Street 27, Leipzig 04103, Germany.
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Manesis EK, Hadziyannis ES, Angelopoulou OP, Hadziyannis SJ. Prediction of treatment-related HBsAg loss in HBeAG-negative chronic hepatitis B: a clue from serum HBsAg levels. Antivir Ther 2007; 12:73-82. [PMID: 17503750 DOI: 10.1177/135965350701200107] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2025]
Abstract
BACKGROUND Quantification of HBsAg in serum may be of clinical importance in predicting HBsAg seroconversion and complete response to treatment. METHODS Serum HBsAg was quantified by ADVIA Centaur in 63 patients with HBeAg-negative chronic hepatitis B (CHBe-). A total of 42 had received interferon-alpha2b (IFN-alpha2b) (median 12.1 months; 19 sustained responders including 12 HBsAg-seroconvertors; 23 non-sustained responders) and 21 were on lamivudine (LAM) (median 33.0 months). Measurements were done at baseline, during and at the end of treatment, and during and at the end of follow-up. RESULTS Baseline median [interquartile range (IQR)] HBsAg levels in all patients were 3286 (1602-7458) IU/ml, not different between IFN- and LAM-treated (P = 0.139). IFN significantly depressed HBsAg in all patients except IFN non-responders, but HBsAg decline persisted only in sustained responders. Low pretreatment HBsAg level was the only significant prognostic variable of HBsAg seroconversion by multivariate analysis. LAM treatment also suppressed HBsAg levels but at a significantly slower rate compared with IFN (P = 0.022). The median (IQR) estimated time to HBsAg undetectability (ETU-HBsAg), derived from best curve fitting, was 127 (87.6-263.5) months for LAM virological responders and 65.3 (36.3-95.0) months for IFN sustained responders (P = 0.002). In 12 HBsAg seroconvertors, ETU-HBsAg was similar to the real time of HBsAg loss (P = 0.525) and seroconversion (0.056). CONCLUSIONS In CHBe-, IFN induces a sharper decrease in serum HBsAg compared with LAM and low pretreatment levels are significantly associated with HBsAg serocon-version. Serial HBsAg measurements may be useful for prediction of HBsAg loss and our data suggest that to achieve this, 5.4 years of sustained response to IFN or 10.6 years of effective LAM therapy are probably needed.
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Affiliation(s)
- Emanuel K Manesis
- Academic Department of Medicine, Hippokration General Hospital, Athens, Greece.
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41
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Vray M, Debonne JM, Sire JM, Tran N, Chevalier B, Plantier JC, Fall F, Vernet G, Simon F, Mb PS. Molecular epidemiology of hepatitis B virus in Dakar, Sénégal. J Med Virol 2006; 78:329-34. [PMID: 16419106 DOI: 10.1002/jmv.20544] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Using DNA chip technology and real-time quantitative PCR, molecular profile of HBV strains infecting blood donors and patients in Dakar, Sénégal was studied. All HBsAg-positive blood donors (n = 175) and all patients who presented with chronic hepatitis B (n = 29) between 1st June 2003 and 31st July 2003 were studied. One patient, a blood donor, was coinfected by HCV, and nine patients had anti-HDV antibodies. Few persons in either group were HBeAg-positive. Viral load values were relatively low but correlated with biochemical abnormalities. Patients were infected mainly by genotype E (72%). Patients infected by genotype A (28%) tended to be younger than other patients. There was no significant difference between the blood donors and the patients with hepatitis B as regards virological markers, including viral load, when the HBV genotype was taken into account. The BCP A1762T and G1764A mutations were found in four patients and one patient, respectively; the two mutations were never found in the same patient. The W28* mutation at position 1896 of the core was detected in 19 of the 32 genotyped patients, 18 (83%) of whom had genotype E infection. ALT levels were not influenced by HBV mutations. This study shows a low frequency of clinical signs in HBsAg-positive blood donors, a relatively low level of viral replication, and a high frequency of pre-core mutants in this West African population. These results underline the importance of molecular characterization of HBV infection as specific treatments become available in this region.
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Affiliation(s)
- Muriel Vray
- Unité d'Epidémiologie des Maladies Emergentes, Institut Pasteur, Paris, France.
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Abstract
PURPOSE OF REVIEW This review aims to provide a concise summary of relevant developments in the treatment and prevention of viral hepatitis based on publications between December 2004 and November 2005. RECENT FINDINGS Long-term therapy with lamivudine was shown to reduce the incidence of adverse clinical outcomes in patients with chronic hepatitis B. This benefit was, however, diminished in patients with viral breakthrough. Combination therapy (peginterferon or telbivudine plus lamivudine) decreased the risk of antiviral resistance but did not improve response compared with monotherapy. Entecavir and tenofovir were shown to be effective in suppressing lamivudine-resistant hepatitis B. A shorter duration of peginterferon-ribavirin treatment was shown to be feasible in genotype 2/3 hepatitis C patients. Relapsers to previous standard interferon-based therapy had higher sustained virological response rates than previous non-responders when retreated with peginterferon-ribavirin. Hepatitis C patients with advanced liver disease may achieve sustained virological response with peginterferon-ribavirin treatment, but the complication rate was high. SUMMARY New insights into the management of viral hepatitis have been gained over the past year. The problem of antiviral resistance in chronic hepatitis B is real and treatment options need to keep evolving. Advances have been made in hepatitis C treatment including patients with genotypes 2 or 3 infection and decompensated cirrhosis.
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Affiliation(s)
- Stephen N Wong
- Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, 48109, USA
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43
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Zoulim F. Antiviral therapy of chronic hepatitis B. Antiviral Res 2006; 71:206-15. [PMID: 16716414 DOI: 10.1016/j.antiviral.2006.04.003] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2006] [Revised: 03/31/2006] [Accepted: 04/03/2006] [Indexed: 01/04/2023]
Abstract
Treatment of chronic hepatitis B remains a clinical challenge. Long-term viral suppression is a major goal of antiviral therapy to improve the clinical outcome of the patients. Antiviral treatment of chronic hepatitis B relies currently on immune modulators such as interferon alpha and its pegylated form, and viral polymerase inhibitors. Because of the slow kinetics of viral clearance and the spontaneous viral genome variability, viral mutants resistant to nucleoside analogs may be selected. However, the development of new antiviral agents is rapidly improving the offing of therapy of chronic hepatitis B. These new therapeutic advances are reviewed in this manuscript.
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Affiliation(s)
- Fabien Zoulim
- Liver Department, Hôtel Dieu, INSERM Unit 271, 151 Cours Albert Thomas, 69003 Lyon, France.
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44
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Zoulim F, Poynard T, Degos F, Slama A, Al Hasnaoui A, Blin P, Mercier F, Deny P, Landais P, Parvaz P, Trépo C. A prospective study of the evolution of lamivudine resistance mutations in patients with chronic hepatitis B treated with lamivudine. J Viral Hepat 2006; 13:278-88. [PMID: 16611195 PMCID: PMC2233898 DOI: 10.1111/j.1365-2893.2005.00712.x] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Lamivudine resistance has been described in subjects with chronic hepatitis B infections, associated with mutations in the viral polymerase gene. The objective of this study was to estimate the emergence rate of lamivudine-resistant viral strains and their consequences over a 2-year period. We evaluated 283 lamivudine-naïve subjects with chronic hepatitis B. Clinical and virological features were assessed at inclusion and every 6 months thereafter. Viral DNA was characterized using polymerase chain reaction (PCR)-based sequencing. Potential risk factors for the emergence of lamivudine resistance mutations were assessed using logistic regression analysis. The annualized incidence rate for viral polymerase mutations was 22%. The only independent risk factor identified was high viral load, at inclusion. Detectable viral DNA and elevated transaminases were more frequent in subjects harbouring mutant viral strains, and these underwent a lower rate of hepatitis B e seroconversion. All subjects responded favourably to treatment, with no difference in symptoms between the two groups. This prospective cohort study identified lamivudine-resistant mutations emerging in 22% of subjects, yearly, which were apparently not associated with clinical aggravation over the study period.
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Affiliation(s)
- Fabien Zoulim
- Virus des hépatites et pathologies associées
INSERM : U271Université Claude Bernard - Lyon ICentre de Recherche Inserm
151, Cours Albert Thomas
69424 LYON CEDEX 03,FR
- * Correspondence should be adressed to: Fabien Zoulim
| | - Thierry Poynard
- Service d'hépato-gastro-entérologie
AP-HPHôpital de La Pitié-SalpêtrièreUniversité Pierre et Marie Curie - Paris VI47-83, boulevard de l'Hôpital
75651 PARIS Cedex 13,FR
| | - Françoise Degos
- Service d'hépato-gastro-entérologie
AP-HPHôpital BeaujonClichy,FR
| | - Alain Slama
- GlaxoSmithKline Laboratory
GlaxoSmithKlineMarly-Le-Roi,FR
| | | | - Patrick Blin
- Epidemiology department
IcareMassy,FR
- Département de pharmacologie
Université de BordeauxBordeaux,FR
| | | | - Paul Deny
- Laboratoire de virologie
AP-HPHôpital AvicenneUniversité Paris-Nord - Paris XIIIBobigny,FR
| | - Paul Landais
- Service de Biostatistique et d'Informatique Médicale
CHU Necker-Enfants MaladesParis,FR
| | | | - Christian Trépo
- Virus des hépatites et pathologies associées
INSERM : U271Université Claude Bernard - Lyon ICentre de Recherche Inserm
151, Cours Albert Thomas
69424 LYON CEDEX 03,FR
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45
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Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, DeHertogh D, Wilber R, Zink RC, Cross A, Colonno R, Fernandes L. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2006; 354:1011-20. [PMID: 16525138 DOI: 10.1056/nejmoa051287] [Citation(s) in RCA: 907] [Impact Index Per Article: 47.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Entecavir is a potent and selective antiviral agent that has demonstrated efficacy in phase 2 studies in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. METHODS In this phase 3, double-blind trial, we randomly assigned 648 patients with HBeAg-negative chronic hepatitis B who had not previously been treated with a nucleoside analogue to receive 0.5 mg of entecavir or 100 mg of lamivudine once daily for a minimum of 52 weeks. The primary efficacy end point was histologic improvement (a decrease by at least two points in the Knodell necroinflammatory score, without worsening of fibrosis). RESULTS Histologic improvement after 48 weeks of treatment occurred in 208 of 296 patients in the entecavir group who had adequate baseline liver-biopsy specimens that could be evaluated (70 percent), as compared with 174 of 287 such patients in the lamivudine group (61 percent, P=0.01). More patients in the entecavir group than in the lamivudine group had undetectable serum hepatitis B virus (HBV) DNA levels according to a polymerase-chain-reaction assay (90 percent vs. 72 percent, P<0.001) and normalization of alanine aminotransferase levels (78 percent vs. 71 percent, P=0.045). The mean reduction in serum HBV DNA levels from baseline to week 48 was greater with entecavir than with lamivudine (5.0 vs. 4.5 log [on a base-10 scale] copies per milliliter, P<0.001). There was no evidence of resistance to entecavir. Safety and adverse-event profiles were similar in the two groups. CONCLUSIONS Among patients with HBeAg-negative chronic hepatitis B who had not previously been treated with a nucleoside analogue, the rates of histologic improvement, virologic response, and normalization of alanine aminotransferase levels were significantly higher at 48 weeks with entecavir than with lamivudine. The safety profile of the two agents was similar, and there was no evidence of viral resistance to entecavir. (ClinicalTrials.gov number, NCT00035789.).
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Okanoue T, Minami M. Update of research and management of hepatitis B. J Gastroenterol 2006; 41:107-18. [PMID: 16568369 DOI: 10.1007/s00535-006-1774-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2006] [Accepted: 01/13/2006] [Indexed: 02/04/2023]
Affiliation(s)
- Takeshi Okanoue
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Hirokoji, Kawaramachi, Kamigyo-ku, Kyoto 602-8566, Japan
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Yim HJ, Lok ASF. Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in 2005. Hepatology 2006; 43:S173-81. [PMID: 16447285 DOI: 10.1002/hep.20956] [Citation(s) in RCA: 367] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Remarkable progress has been made in our understanding of the natural history of chronic hepatitis B virus (HBV) infection in the past 25 years. Availability of sensitive HBV DNA assays and application of sophisticated immunological techniques led to the recognition that HBV replication persists throughout the course of chronic HBV infection, and host immune response plays a pivotal role in HBV-related liver disease. Knowledge of the HBV genome organization and replication cycle led to the unraveling of HBV genotypes and molecular variants, which contribute to the heterogeneity in outcome of chronic HBV infection. The natural course of chronic HBV infection is now perceived as consisting of 4 phases: immune tolerance, immune clearance [hepatitis B e antigen (HBeAg)-positive chronic hepatitis], inactive carrier state, and reactivation (HBeAg-negative chronic hepatitis B). Understanding the dynamic nature of chronic HBV infection is crucial in the management of HBV carriers and underscores the need for long-term monitoring. Accumulating evidence indicates that antiviral therapy can prevent progression of HBV-related liver disease, particularly among patients with sustained response. Newer antiviral therapies with improved efficacy and decreased risk of resistance may lead to a complete revision of the chapter on the natural history of chronic HBV infection on the occasion of the golden jubilee of Hepatology.
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Affiliation(s)
- Hyung Joon Yim
- Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109-0362, USA
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48
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Chan HLY, Wong VWS, Hui AY, Tsang SWC, Chan JLY, Chan HY, Wong GLH, Sung JJY. Long-term lamivudine treatment is associated with a good maintained response in severe acute exacerbation of chronic HBeAg-negative hepatitis B. Antivir Ther 2006; 11:465-471. [PMID: 16856620 DOI: 10.1177/135965350601100404] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B is difficult to treat and there is little long-term data for lamivudine treatment of severe acute exacerbation. We report a prospective, consecutive cohort of severe acute exacerbation of HBeAg-negative chronic hepatitis B patients treated by lamivudine between 1999 and 2004. All patients had respectively increased alanine aminotransferase and serum bilirubin to at least 10 and 2 times the upper limit of laboratory normal. Thirty-two patients were treated with lamivudine for 130 +/- 58 (range 48-217) weeks. Five patients had evidence of virological breakthrough (HBV DNA >10,000 copies/ml) during lamivudine treatment. The cumulative probability of maintained response without any virological breakthrough was 94% (95% confidence interval [CI], 86-100%) at year 1, 94% (95% CI, 82-100%) at year 2 and 71% (95% CI, 41-100%) at year 3. At the last follow-up visit, 31 (97%) lamivudine patients had HBV DNA <10,000 copies/ml. The prevalence of lamivudine resistance mutation was 1 in 32 patients (3%; 95% CI, 0-9%) at year 1, 1 in 17 patients (6%; 95% CI, 0-17%) at year 2, 1 in 9 patients (11%, 95% CI, 0-32%) at year 3 and 1 in 4 patients (25%; 95% CI, 0-67%) at year 4 of lamivudine treatment. In conclusion, extended lamivudine treatment is associated with a high maintained virological response and a low rate of drug resistance in severe acute exacerbation of HBeAg-negative chronic hepatitis B.
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Affiliation(s)
- Henry Lik-Yuen Chan
- Department of Medicine and Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.
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49
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Lampertico P, Viganò M, Manenti E, Iavarone M, Lunghi G, Colombo M. Adefovir rapidly suppresses hepatitis B in HBeAg-negative patients developing genotypic resistance to lamivudine. Hepatology 2005; 42:1414-9. [PMID: 16317671 DOI: 10.1002/hep.20939] [Citation(s) in RCA: 228] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Progression of hepatitis B in patients with lamivudine-resistant strains is slowed down by adefovir dipivoxil (ADV). Whether the time point of ADV administration (genotypic vs. phenotypic resistance) influences the outcome of therapy is unknown. We compared the outcome of ADV therapy in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B patients with genotypic and phenotypic resistance to lamivudine. Ten milligrams of ADV was administered daily for 2 years to 46 HBeAg-negative patients at the time of phenotypic resistance (group A, >6 log(10) copies/mL of hepatitis B virus [HBV] DNA and high alanine aminotransferase [ALT] levels) and 28 patients at the time of genotypic resistance (group B, 3-6 log(10) copies/mL of HBV-DNA and normal ALT). HBV DNA was assessed every 2 months using Versant 3.0 assay, and lamivudine resistance was confirmed via INNO-LiPA assay in all patients. By month 3, HBV DNA tested negative in all patients from group B compared with only 20 (46%) in group A (P < .0001). The 2-year rates of virological response were 100% in the former patients and 78% in the latter ones (P < .0001). ALT levels remained persistently normal in all group B patients, whereas in group A patients they normalized at rates of 50% at month 6 (P < .0001), 72% at month 12 (P < .01), and 93% at month 24. None of the patients developed ADV resistance or ADV-related side effects. In conclusion, to optimize antiviral treatment in HBeAg-negative patients selecting resistant strains to lamivudine, ADV should be added to lamivudine as soon as genotypic resistance is detected.
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Affiliation(s)
- Pietro Lampertico
- Department of Gastroenterology and Endocrinology, AM and A Migliavacca Center for Liver Disease, IRCCS Maggiore Hospital, Fondazione Policlinico, Mangiagalli e Regina Elena, University of Milan, Italy
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50
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