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Broquetas T, Carrión JA. Past, present, and future of long-term treatment for hepatitis B virus. World J Gastroenterol 2023; 29:3964-3983. [PMID: 37476586 PMCID: PMC10354584 DOI: 10.3748/wjg.v29.i25.3964] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/22/2023] [Accepted: 06/06/2023] [Indexed: 06/28/2023] Open
Abstract
The estimated world prevalence of hepatitis B virus (HBV) infection is 316 million. HBV infection was identified in 1963 and nowadays is a major cause of cirrhosis and hepatocellular carcinoma (HCC) despite universal vaccination programs, and effective antiviral therapy. Long-term administration of nucleos(t)ide analogues (NA) has been the treatment of choice for chronic hepatitis B during the last decades. The NA has shown a good safety profile and high efficacy in controlling viral replication, improving histology, and decreasing the HCC incidence, decompensation, and mortality. However, the low probability of HBV surface antigen seroclearance made necessary an indefinite treatment. The knowledge, in recent years, about the different phases of the viral cycle, and the new insights into the role of the immune system have yielded an increase in new therapeutic approaches. Consequently, several clinical trials evaluating combinations of new drugs with different mechanisms of action are ongoing with promising results. This integrative literature review aims to assess the knowledge and major advances from the past of hepatitis B, the present of NA treatment and withdrawal, and the future perspectives with combined molecules to achieve a functional cure.
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Affiliation(s)
- Teresa Broquetas
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona 08003, Spain
- Institut Hospital del Mar D’Investigacions Mèdiques, PSMAR, Barcelona 08003, Spain
| | - José A Carrión
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona 08003, Spain
- Institut Hospital del Mar D’Investigacions Mèdiques, PSMAR, Barcelona 08003, Spain
- Universitat Pompeu Fabra, Facultat de Ciències de la Salut i de la Vida, Barcelona 08003, Spain
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Atarodi H, Pazouki A, Gholizadeh B, Karami R, Kabir A, Sadri G, Kassir R, Kermansaravi M. Effect of silymarin on liver size and nonalcoholic fatty liver disease in morbidly obese patients: A randomized double-blind clinical trial. JOURNAL OF RESEARCH IN MEDICAL SCIENCES : THE OFFICIAL JOURNAL OF ISFAHAN UNIVERSITY OF MEDICAL SCIENCES 2022; 27:76. [PMID: 36438071 PMCID: PMC9693701 DOI: 10.4103/jrms.jrms_683_21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 11/19/2021] [Accepted: 05/09/2022] [Indexed: 01/25/2023]
Abstract
BACKGROUND A large liver size is a factor that may increase the difficulty of bariatric surgery (BS) and unwanted complications. Some agents have been used to decrease the liver size before BS. Silymarin has been used as an antioxidant agent to improve liver function tests. This study was designed to evaluate the effects of silymarin on liver dimensions, function, and lipid profile. MATERIALS AND METHODS A double-blind randomized clinical trial was performed on 56 patients. The patients were divided into silymarin and placebo groups. Blood samples and sonographic examinations were taken from the patients before and 4 weeks after the administration of the silymarin or placebo. In the first group, 140 mg silymarin was prescribed every 8 h for 4 weeks, and the other group received placebo in the same way with the same tablet shape. After the completion of the 4-week treatment, laboratory tests and ultrasonography were carried out again. RESULTS Thirty-nine (69.6%) patients were female with a mean body mass index (BMI) of 46.2 kg/m2 and a mean age of 36.8 years. Most of the patients had a compliance of 80% and higher. The analysis did not show any significant difference in aspartate transaminase, alkaline transaminase, liver size, cholesterol, and triglyceride changes among the silymarin and placebo groups. BMI loss was slightly higher in the silymarin group although the difference was not statistically significant. CONCLUSION The present findings show that silymarin administration for 4 weeks does not affect liver size and function, but further evaluations should be carried out on the subject.
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Affiliation(s)
- Hamed Atarodi
- Minimally Invasive Surgery Research Center, Iran University of Medical Sciences, Rasool-e-Akram Hospital, Tehran, Iran
| | - Abdolreza Pazouki
- Department of Surgery, Minimally Invasive Surgery Research Center, Division of Minimally Invasive and Bariatric Surgery, Rasool-e Akram Hospital, Iran University of Medical Sciences, Tehran, Iran,Center of Excellence of European Branch of International Federation for Surgery of Obesity, Hazrat-e-Rasool Hospital, Tehran, Iran
| | - Barmak Gholizadeh
- Minimally Invasive Surgery Research Center, Iran University of Medical Sciences, Rasool-e-Akram Hospital, Tehran, Iran,Department of General Surgery, Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reza Karami
- Minimally Invasive Surgery Research Center, Iran University of Medical Sciences, Rasool-e-Akram Hospital, Tehran, Iran
| | - Ali Kabir
- Minimally Invasive Surgery Research Center, Iran University of Medical Sciences, Rasool-e-Akram Hospital, Tehran, Iran
| | - Ghazal Sadri
- Department of Radiology, Iran University of Medical Sciences, Tehran, Iran
| | - Radwan Kassir
- Department of Digestive Surgery, Chu Félix Guyon, La Réunion, Saint Denis, France
| | - Mohammad Kermansaravi
- Department of Surgery, Minimally Invasive Surgery Research Center, Division of Minimally Invasive and Bariatric Surgery, Rasool-e Akram Hospital, Iran University of Medical Sciences, Tehran, Iran,Center of Excellence of European Branch of International Federation for Surgery of Obesity, Hazrat-e-Rasool Hospital, Tehran, Iran,Address for correspondence: Dr. Mohammad Kermansaravi, Department of Surgery, Minimally Invasive Surgery Research Center, Division of Minimally Invasive and Bariatric Surgery, Rasool-e Akram Hospital, Iran University of Medical Sciences, Tehran, Iran. Center of Excellence of European Branch of International Federation for Surgery of Obesity, Hazrat-e-Rasool Hospital, Tehran, Iran. E-mail: ,
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Yin GQ, Chen KP, Gu XC. Heterogeneity of immune control in chronic hepatitis B virus infection: Clinical implications on immunity with interferon-α treatment and retreatment. World J Gastroenterol 2022; 28:5784-5800. [PMID: 36353205 PMCID: PMC9639659 DOI: 10.3748/wjg.v28.i40.5784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 09/08/2022] [Accepted: 10/10/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a global public health issue. Interferon-α (IFN-α) treatment has been used to treat hepatitis B for over 20 years, but fewer than 5% of Asians receiving IFN-α treatment achieve functional cure. Thus, IFN-α retreatment has been introduced to enhance antiviral function. In recent years, immune-related studies have found that the complex interactions between immune cells and cytokines could modulate immune response networks, in-cluding both innate and adaptive immunity, triggering immune responses that control HBV replication. However, heterogeneity of the immune system to control HBV infection, particularly HBV-specific CD8+ T cell heterogeneity, has consequ-ential effects on T cell-based immunotherapy for treating HBV infection. Altogether, the host’s genetic variants, negative-feedback regulators and HBV components affecting the immune system's ability to control HBV. In this study, we reviewed the literature on potential immune mechanisms affecting the immune control of HBV and the clinical effects of IFN-α treatment and retreatment.
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Affiliation(s)
- Guo-Qing Yin
- Center of Hepatology, Zhong-Da Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Ke-Ping Chen
- Center of Hepatology, Zhong-Da Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Xiao-Chun Gu
- Center of Hepatology, Zhong-Da Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
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Colombatto P, Coco B, Bonino F, Brunetto MR. Management and Treatment of Patients with Chronic Hepatitis B: Towards Personalized Medicine. Viruses 2022; 14:701. [PMID: 35458431 PMCID: PMC9027850 DOI: 10.3390/v14040701] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 03/22/2022] [Accepted: 03/23/2022] [Indexed: 02/07/2023] Open
Abstract
The currently available antiviral treatments (Peg-Interferon-α and Nucleos(t)ide Analogues, NA) for chronic hepatitis B (CHB) achieve a functional cure (serum HBsAg and HDV-DNA clearance) of HBV infection in a limited number of patients. Nevertheless, the continuous pharmacological suppression of viral replication by NA halts liver disease progression lowering the risk of HCC development and improving the survival. In the near future, to fully exploit the potential of old and new drugs for HBV treatment a personalized approach to the patients will be required according to an accurate definition of their virologic, immunologic and clinical profile.
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Affiliation(s)
- Piero Colombatto
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Center of the Tuscany Region for Chronic Liver Disease and Cancer, Department of Medical Specialties, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (P.C.); (B.C.)
| | - Barbara Coco
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Center of the Tuscany Region for Chronic Liver Disease and Cancer, Department of Medical Specialties, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (P.C.); (B.C.)
| | - Ferruccio Bonino
- Institute of Biostructure and Bioimaging, National Research Council, Via De Amicis 95, 80145 Naples, Italy;
| | - Maurizia R. Brunetto
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Center of the Tuscany Region for Chronic Liver Disease and Cancer, Department of Medical Specialties, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (P.C.); (B.C.)
- Institute of Biostructure and Bioimaging, National Research Council, Via De Amicis 95, 80145 Naples, Italy;
- Internal Medicine, Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56127 Pisa, Italy
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Ying SY, Hu YR, Gao GS, Lou KH, Huang Z. Interleukin-28B Polymorphisms Predict the Efficacy of Peginterferon Alpha in Patients With Chronic Hepatitis B: A Meta-Analysis. Front Med (Lausanne) 2021; 8:691365. [PMID: 34307418 PMCID: PMC8298999 DOI: 10.3389/fmed.2021.691365] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 06/11/2021] [Indexed: 12/24/2022] Open
Abstract
Background: Polyethylene glycol interferon alpha (PEG-IFN-α) is the most frequently used pharmacotherapeutic approach in patients infected with hepatitis B virus (HBV). Numerous studies have reported that interleukin-28B (IL-28B) genetic polymorphisms are related to the therapeutic efficacy of PEG-IFN-α, but the results are inconsistent. The present meta-analysis aimed to analyze the association between IL-28B genetic polymorphisms and the prognosis of patients with chronic hepatitis B (CHB) treated with PEG-IFN-α to inform clinical practice. Methods: PubMed, EBSCO, and Scopus databases were searched for relevant literature published before February 30, 2021. We calculated the crude odds ratios (ORs) with 95% confidence intervals (CIs) of the cited articles. A total of 2510 patients with CHB treated with PEG-IFN-α in 13 clinical cohort studies were analyzed. Results: The overall analysis demonstrated a potential association between IL-28B genetic polymorphisms and response to PEG-IFN-α; however, the association was not statistically significant. Furthermore, the subgroup analysis revealed that among patients with HBeAg-negative CHB, the rs12979860 CC genotype and rs8099917 TT genotype were associated with more significant treatment response to PEG-IFN-α (CC vs. non-CC: OR 2.78, 95% CI 1.00–7.76, I2 = 83%; TT vs. non-TT: OR 2.16, 95% CI 1.35–3.48, I2 = 0%). Among Asian patients with CHB, the rs12979860 CC genotype was associated with a more significant treatment response to PEG-IFN (CC vs. non-CC: OR 1.88, 95% CI 1.18–2.99, I2 = 0%). Conclusion: This meta-analysis revealed that the IL-28B rs12979860 CC genotype and rs8099917 TT genotype indicated a better treatment response than non-CC and non-TT genotypes for PEG-IFN-α in patients with CHB.
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Affiliation(s)
- Sang-Yu Ying
- Clinical Laboratory, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China.,Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, China
| | - Yao-Ren Hu
- Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, China.,Department of Hepatology, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
| | - Guo-Sheng Gao
- Clinical Laboratory, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China.,Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, China
| | - Ke-Hong Lou
- Clinical Laboratory, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China.,Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, China
| | - Zhen Huang
- Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, China.,Department of Blood Transfusion, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
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Jindal A, Vyas AK, Kumar D, Kumar G, Sharma MK, Sarin SK. Higher efficacy of pegylated interferon-α2b add-on therapy in hepatitis B envelope antigen-positive chronic hepatitis B patients on tenofovir monotherapy. Hepatol Res 2018; 48:451-458. [PMID: 29314573 DOI: 10.1111/hepr.13049] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 12/04/2017] [Accepted: 12/26/2017] [Indexed: 01/08/2023]
Abstract
AIM Monotherapy with pegylated interferon-α (Peg-IFNα) or the nucleos(t)ide analogs (NA) currently approved for treating chronic hepatitis B (CHB) has limited efficacy. Studies on the combination of Peg-IFNα/NA have shown conflicting results. We investigated whether sequentially adding on Peg-IFNα to tenofovir enhances serological response rates. METHODS Treatment-naïve, hepatitis B envelope antigen (HBeAg)-positive CHB patients with moderately elevated alanine aminotransferase (ALT; 48-200 IU/mL) were started on tenofovir (300 mg/day) and enrolled at week 12 in a 1:1 ratio to either receive Peg-IFNα2b add-on (1.5 μg/kg/week) from week 12 to 36 (n = 53) or continue tenofovir monotherapy (n = 53). Both treatment arms received tenofovir consolidation therapy until week 72. The primary end-point was HBeAg loss at week 72. RESULTS At week 72, the rate of HBeAg loss was higher in the Peg-IFNα2b add-on group (35.8%) compared to the tenofovir monotherapy group (17%) (P = 0.028; odds ratio, 2.73, 95% confidence interval, 1.09-6.79), and considerably higher in patients with a baseline hepatitis B virus (HBV)-DNA level >6 log IU/mL (32.6% vs 11.4%; P = 0.021). Rates of HBV-DNA loss (77.4% vs 71.7%; P = 0.51), ALT normalization (62.3% vs 52.8%; P = 0.32), and sustained virologic response (20.8% vs 11.3%; P = 0.18) at week 72 were comparable between the two groups. Significantly more patients in the add-on group had >3 log HBV-DNA reduction at week 36 (92.5% vs 66%; P = 0.001). Four patients treated with Peg-IFNα2b add-on achieved hepatitis B surface antigen (HBsAg) loss compared with one patient receiving tenofovir monotherapy. Decline of HBV-DNA of >2 log at week 4 led to higher HBeAg loss at week 72, independent of treatment arm. No patient had treatment-related adverse effects requiring treatment discontinuation. CONCLUSIONS Twenty-four weeks of Peg-IFNα2b as an add-on sequential regimen to tenofovir is safe and resulted in greater loss of HBeAg and HBsAg compared to tenofovir monotherapy in selected HBeAg-positive patients. Viral load reduction followed by immune modulation is a potentially useful approach.
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Affiliation(s)
- Ankur Jindal
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ashish Kumar Vyas
- Departments of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Devesh Kumar
- Department of Clinical Research, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Guresh Kumar
- Department of Clinical Research, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Manoj Kumar Sharma
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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Morçöl T, Weidner JM, Mehta A, Bell SJ, Block T. Calcium Phosphate Particles as Pulmonary Delivery System for Interferon-α in Mice. AAPS PharmSciTech 2018; 19:395-412. [PMID: 28752471 DOI: 10.1208/s12249-017-0847-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 07/10/2017] [Indexed: 01/11/2023] Open
Abstract
Systemically administered interferons are rapidly cleared from the circulation thus requiring frequent dosing to maintain the therapeutic levels of circulating interferon. This is particularly problematic for their use in the treatment of chronic diseases. The purpose of this study was to evaluate the potential of proprietary calcium phosphate (CaP) particles to deliver biologically active interferon alpha (IFNα) via the lungs into systemic circulation. Recombinant human IFNα-2a was formulated with proprietary CaP particles. In vitro biological activity of IFNα was assessed for its potential to activate IFN-induced cellular pathways in HEK-Blu-IFN α/β cell cultures. Antiviral activity was evaluated against vesicular stomatitis virus (VSV) infection of HeLa cells. Male BALB/c mice were used to evaluate the absorption of IFNα from CaP-IFNα across the lungs following intratracheal (IT) instillation. Serum IFNα concentrations up to 9 h post-treatment were determined. Data were analyzed to obtain pharmacokinetic (PK) parameters. Data from these studies indicated that IFNα formulated with CaP retains its biological activity, and it is transported into circulation in a dose-dependent manner. PK analysis showed larger than two-fold area under the serum concentration-time curve (AUC) for CaP-IFNα compared to non-formulated IFNα administered IT. The IFNα formulated with CaP had two-fold longer half-life (t1/2) and mean residence time (MRT) relative to IFNα alone administered by injection. Clearance of CaP-IFNα was slower than IFNα administered IM or IT. Relative bioavailability of CaP-IFNα was 1.3-fold of IFNα injection and twofold of IFNα administered IT. Furthermore, inhalation of aerosolized CaP did not indicate any lung toxicity in animals.
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Okada M, Enomoto M, Kawada N, Nguyen MH. Effects of antiviral therapy in patients with chronic hepatitis B and cirrhosis. Expert Rev Gastroenterol Hepatol 2017; 11:1095-1104. [PMID: 28752768 DOI: 10.1080/17474124.2017.1361822] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Hepatitis B virus (HBV) infection is the major cause of cirrhosis worldwide. The ultimate goal of current antiviral treatments for chronic hepatitis B (nucleos(t)ide analogs and interferon-α) is to prevent the development of end-stage liver diseases. Areas covered: We present a review of the current literature on antiviral therapy in patients with chronic hepatitis B and cirrhosis. Medline search was performed to identify relevant literature from 1993 through January of 2017. Expert commentary: One randomized controlled trial and a number of observational studies have shown that nucleos(t)ide analogs can decrease the incidence of hepatocellular carcinoma (HCC) in chronic hepatitis B patients with advanced fibrosis. Data from clinical trials of entecavir and tenofovir have shown that histological improvement and regression of fibrosis can be achieved in the majority of patients with chronic hepatitis B by successful viral suppression. Entecavir and tenofovir are the preferred antiviral agents for treatment of chronic hepatitis B in patients with cirrhosis due to their high antiviral potency and high genetic barrier to resistance. Pegylated interferon-α is another therapeutic option for chronic hepatitis B patients with well-compensated cirrhosis. However, interferon therapy is contraindicated in patients with decompensated cirrhosis, and evidence for reduced HCC is currently insufficient.
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Affiliation(s)
- Masako Okada
- a Department of Hepatology , Osaka City University Graduate School of Medicine , Osaka , Japan
| | - Masaru Enomoto
- a Department of Hepatology , Osaka City University Graduate School of Medicine , Osaka , Japan
| | - Norifumi Kawada
- a Department of Hepatology , Osaka City University Graduate School of Medicine , Osaka , Japan
| | - Mindie H Nguyen
- b Division of Gastroenterology and Hepatology , Stanford University Medical Center , Palo Alto , CA , USA
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Addition of nucleoside analogues to peg-IFNα-2a enhances virological response in chronic hepatitis B patients without early response to peg-IFNα-2a: a randomized controlled trial. BMC Gastroenterol 2017; 17:102. [PMID: 28854883 PMCID: PMC5577782 DOI: 10.1186/s12876-017-0657-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Accepted: 08/17/2017] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Current treatments for chronic hepatitis B (CHB) include pegylated interferon alpha (PEG-IFN-α) which is an immune modulator, and nucleos(t)ide analogs (NAs) which directly inhibit HBV DNA polymerase. With the limited efficacy of PEG-IFN-α and prolonged treatment periods associated with NAs, there is an urgent need for novel therapeutic strategies, especially for patients with a poor early response to anti-viral therapy. METHODS In this study, 178 patients with chronic hepatitis B (n = 131) and compensated (n = 47) HBV-induced cirrhosis were enrolled, 120 patients with HBeAg (+). All the patients were treated for 12 weeks with PEG-IFN-α. Among them, a total of 138 patients with a poor virological response after 12 weeks were treated for an additional 48 weeks with Peg-IFNα-2a (control) (n = 43), with Peg-IFNα-2a + entecavir (ETV) (n = 49), or Peg-IFNα-2a + adefovir dipivoxil (ADV) (n = 46), and were followed for 48 weeks after therapy. Early virological response was defined as undetectable HBV DNA after anti-viral therapy for 12 weeks. Sustained virological response (SVR) was defined as no change in therapeutic effectiveness after 6 months follow-up, and no recurrence.Therapeutic efficacy was determined by evaluating HBV DNA levels, serum and liver HBsAg levels, liver function tests and liver histology. RESULTS Patients in the Peg-IFNα-2a + ETV and Peg-IFNα-2a + ADV groups showed a significantly greater decrease in HBV DNA levels over time, and a significantly higher SVR compared to patients receiving Peg-INFα-2a monotherapy (both P values <0.05). Although patients receiving combination therapy had a significantly higher change in serum HBsAg levels compared to the monotherapy group, there was no significant difference in liver HBsAg levels between the three treatment groups. CONCLUSION This study demonstrated that in patients with a poor virological response after 12 weeks of treatment with Peg-IFNα-2a alone, addition of ADV or ETV significantly reduced HBV DNA levels, serum HBsAg levels, and increased SVR. Individualization of anti-viral therapy would ensure that only patients who do not respond to Peg-IFNα-2a would receive combination therapy. Our data have important implications for the treatment of CHB patients who fail to show an early response to Peg-IFNα-2a monotherapy. TRIAL REGISTRATION This trial was retrospectively registered on 2012 May 24 at the China Clinical Trials Registry (ChiCTR-OCC-12002196).
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10
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Domagalski K, Pawłowska M, Zaleśna A, Pilarczyk M, Rajewski P, Halota W, Tretyn A. Impact of IL28B and OAS gene family polymorphisms on interferon treatment response in Caucasian children chronically infected with hepatitis B virus. World J Gastroenterol 2016; 22:9186-9195. [PMID: 27895405 PMCID: PMC5107599 DOI: 10.3748/wjg.v22.i41.9186] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Revised: 08/31/2016] [Accepted: 09/28/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the impact of IL28B and OAS gene polymorphisms on interferon treatment responses in children with chronic hepatitis B. METHODS We enrolled 52 children (between the ages of 4 and 18) with hepatitis B e antigen-negative chronic hepatitis B (CHB), who were treated with pegylated interferon alfa for 48 wk. Single nucleotide polymorphisms in the OAS1 (rs1131476), OAS2 (rs1293747), OAS3 (rs2072136), OASL (rs10849829) and IL28B (rs12979860, rs12980275 and rs8099917) genes were studied to examine their associations with responses to IFN treatment in paediatric patients. We adopted two criteria for the therapeutic response, achieving an hepatitis B virus (HBV) DNA level < 2000 IU/mL and normalization of ALT activity (< 40 IU/L). To perform the analyses, we compared the patients in terms of achieving a partial response (PR) and a complete response (CR) upon measurement at the 24-wk post-treatment follow-up. RESULTS The PR and CR rates were 80.8% and 42.3%, respectively. Factors such as age, gender and liver histology had no impact on the type of response (partial or complete). A statistically significant relationship between higher baseline HBV DNA and ALT activity levels and lower rates of PR and CR was shown (P < 0.05). The allele association analysis revealed that only the IL-28B rs12979860 (C vs T) and IL28B rs12980275 (A vs G) markers significantly affected the achievement of PR (P = 0.021, OR = 3.3, 95%CI: 1.2-9.2 and P = 0.014, OR = 3.7, 95%CI: 1.3-10.1, respectively). However, in the genotype analysis, only IL-28B rs12980275 was significantly associated with PR (AA vs AG-GG, P = 0.014, OR = 10.9, 95%CI: 1.3-93.9). The association analysis for CR showed that the TT genotype of IL28B rs12979860 was present only in the no-CR group (P = 0.033) and the AA genotype of OASL rs10849829 was significantly more frequent in the no-CR group (P = 0.044, OR = 0.26, 95%CI: 0.07-0.88). The haplotype analysis revealed significant associations between PR and CR and OAS haplotype (P = 0.0002 and P = 0.001, respectively), but no association with IL28B haplotype was observed. CONCLUSION IL28B and OAS polymorphisms are associated with different clinical outcomes in CHB children treated with interferon.
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Abstract
Chronic hepatitis B virus (HBV) infection has a significant public health impact. There are currently 7 approved therapies for chronic HBV, including standard and pegylated interferon (IFN)-α, and 5 nucleos(t)ide analogs (NUCs). IFN offers benefits over NUCs, including a finite duration of therapy and a higher rate of clearance of hepatitis Be antigen and surface antigen. These benefits need to be weighed against the potential adverse effects of IFN therapy. Some patients should not receive IFN because of advanced liver disease or comorbidities. This article reviews the mechanisms of action, efficacy, and clinical use of IFN therapy for HBV infection.
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Affiliation(s)
- Monica A Konerman
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA
| | - Anna S Lok
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
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13
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Koumbi L. Current and future antiviral drug therapies of hepatitis B chronic infection. World J Hepatol 2015; 7:1030-1040. [PMID: 26052392 PMCID: PMC4450180 DOI: 10.4254/wjh.v7.i8.1030] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 01/12/2015] [Accepted: 02/04/2015] [Indexed: 02/06/2023] Open
Abstract
Despite significant improvement in the management of chronic hepatitis B virus (HBV) it remains a public health problem, affecting more than 350 million people worldwide. The natural course of the infection is dynamic and involves a complex interplay between the virus and the host's immune system. Currently the approved therapeutic regimens include pegylated-interferon (IFN)-α and monotherapy with five nucleos(t)ide analogues (NAs). Both antiviral treatments are not capable to eliminate the virus and do not establish long-term control of infection after treatment withdrawal. IFN therapy is of finite duration and associates with low response rates, liver decompensating and numerous side effects. NAs are well-tolerated therapies but have a high risk of drug resistance development that limits their prolonged use. The imperative for the development of new approaches for the treatment of chronic HBV infection is a challenging issue that cannot be over-sided. Research efforts are focusing on the identification and evaluation of various viral replication inhibitors that target viral replication and a number of immunomodulators that aim to restore the HBV specific immune hyporesponsiveness without inducing liver damage. This review brings together our current knowledge on the available treatment and discusses potential therapeutic approaches in the battle against chronic HBV infection.
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Affiliation(s)
- Lemonica Koumbi
- Lemonica Koumbi, Hepatology and Gastroenterology Section, Department of Medicine, Imperial College London, London W2 1PG, United Kingdom
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Goulis I, Karatapanis S, Akriviadis E, Deutsch M, Dalekos GN, Raptopoulou-Gigi M, Mimidis K, Germanidis G, Drakoulis C, Triantos C, Zintzaras E, Bakalos G, Papatheodoridis G. On-treatment prediction of sustained response to peginterferon alfa-2a for HBeAg-negative chronic hepatitis B patients. Liver Int 2015; 35:1540-8. [PMID: 25368957 DOI: 10.1111/liv.12725] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Accepted: 10/28/2014] [Indexed: 12/29/2022]
Abstract
BACKGROUND & AIMS We assessed predictors of response in HBeAg-negative chronic hepatitis B patients treated with peginterferon alfa-2a in routine clinical practice. METHODS Ninety-five HBeAg-negative patients received peginterferonalfa-2a for 48 weeks and were followed-up for 48 weeks post-treatment. Serum HBsAg and HBV DNA levels were monitored during and after therapy with valid commercial assays. Sustained response (SR) was defined as HBV DNA <2000 IU/ml at study week 96. RESULTS Twenty-two patients (23%) achieved SR and nine (9.5%) lost HBsAg. HBsAg decline was more profound in patients with SR. HBsAg decline ≥10% from baseline to week 24 was significantly associated with SR [81% (17/21) vs 37% (21/57); Odds ratio: 7.286 (2.162-24.552), P = 0.001]. The PARC rule (no decrease in HBsAg and <2 log drop in HBV DNA at week 12) was evaluated in a subset of 47 patients. Among eight patients who fulfilled the PARC rule, none achieved SR. Of the 39 patients who did not fulfil the PARC rule, 24 (62%) had HBsAg decline of ≥10% at week 24 (12 achieved SR) and 15 (38%) had HBsAg decline of <10% (1 achieved SR; negative predictive value: 93%). CONCLUSIONS In HBeAg-negative chronic hepatitis B patients treated with peginterferon alfa-2a, HBsAg decline >10% at 24 weeks is significantly associated with SR. The combination of the PARC rule and week 24 decline in HBsAg can identify almost two-thirds of patients who are unlikely to achieve SR. Clinicaltrials.gov identifier: NCT01283074.
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Affiliation(s)
- Ioannis Goulis
- 4th Department of Internal Medicine, Αristotle University of Thessaloniki Medical School, Hippokration General Hospital, Thessaloniki, Greece
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Hadziyannis SJ. Update on Hepatitis B Virus Infection: Focus on Treatment. J Clin Transl Hepatol 2014; 2:285-91. [PMID: 26355326 PMCID: PMC4521240 DOI: 10.14218/jcth.2014.00026] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Revised: 09/21/2014] [Accepted: 09/21/2014] [Indexed: 12/11/2022] Open
Abstract
This review article is an update of the current treatment strategies available for chronic hepatitis B. In addition to achieving on-therapy clinical remission and suppression of HBV replication without resistance, the ultimate goal of therapy is the development of sustained remission and HBsAg loss after discontinuation of treatment. This is the closest possible to cure outcome for hepatitis B virus (HBV) infection. These goals can be achieved by response-guided courses of pegylated interferon (peg-IFN)-alpha at rates higher than 30%, both in hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients. Review of the data regarding discontinuation of long term NA treatment in HBeAg-negative patients revealed that stopping such therapy is safe with high rates of sustained off treatment responses that appear to be immunologically induced. Decreasing hepatitis B surface antigen (HBsAg) titers under therapy to <500, particularly <100 IU/mL, and adding a course of peg-IFN to ongoing long term nucleos(t)ide analogue (NA) therapy increase the percentage of sustained responses following discontinuation of NA treatment.
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Affiliation(s)
- Stephanos J. Hadziyannis
- Liver Unit and its Molecular Biology Laboratory, National and Kapodistrian University of Athens, Evgenidion Hospital of Athens, Athens, Greece
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16
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Domagalski K, Pawłowska M, Zaleśna A, Tyczyno M, Skorupa-Kłaput M, Tretyn A, Halota W. The relationship between IL-28B polymorphisms and the response to peginterferon alfa-2a monotherapy in anti-HBe-positive patients with chronic HBV infection. Eur J Clin Microbiol Infect Dis 2014; 33:2025-33. [PMID: 24924923 DOI: 10.1007/s10096-014-2172-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Accepted: 05/21/2014] [Indexed: 12/13/2022]
Abstract
The impact of interleukin 28B (IL-28B) on the results of interferon (IFN)-based therapy in patients chronically infected with hepatitis B virus (HBV) is poorly understood. The aim of this study was to evaluate the relationship between IL-28B markers and the response to IFN monotherapy in Polish patients with anti-hepatitis B e (HBe)-positive chronic hepatitis B (CHB). We determined three single-nucleotide polymorphisms (SNPs) of IL-28B (rs12979860, rs12980275, and rs8099917) in 86 patients who were treated with pegylated interferon (PEG-IFN) for 48 weeks. The effectiveness of the therapy was evaluated based on the virological and biochemical response. The primary efficacy parameters were the HBV DNA viral load below 400 IU/ml and 2,000 IU/ml in combination with alanine aminotransferase (ALT) normalization (<40 IU/l), measured 24 weeks after the treatment. Viral load below 400 IU/ml or 2,000 IU/ml with ALT normalization was achieved by 37 % and 46 % of patients, respectively. It has been shown that the distribution of IL-28B genotypes in the dominant genetic model in patients with different therapeutic success differ significantly only for rs12979860. The IL-28B rs12979860 CC genotype was associated with lower treatment success [odds ratio (OR), 0.31; p = 0.025 and OR, 0.37; p = 0.044 for <400 IU/ml HBV DNA with <40 IU/l ALT, and <2,000 IU/ml HBV DNA with <40 IU/l ALT, respectively]. However, in the conditional logistic regression analysis adjusted by factors associated with combined response, rs12979860 was significantly associated only with <400 IU/ml HBV DNA with <40 IU/l ALT (OR, 0.24; p = 0.026). IL-28B polymorphisms have prognostic significance in assessing the treatment effectiveness based on the virological and biochemical response of patients with anti-HBe-positive CHB.
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Affiliation(s)
- K Domagalski
- Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, Toruń, Poland
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Chen X, Chen X, Chen W, Ma X, Huang J, Chen R. Extended peginterferon alfa-2a (Pegasys) therapy in Chinese patients with HBeAg-negative chronic hepatitis B. J Med Virol 2014; 86:1705-13. [PMID: 24980710 DOI: 10.1002/jmv.24013] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/06/2014] [Indexed: 12/12/2022]
Affiliation(s)
- Xuefu Chen
- Department of Infection; Guangdong General Hospital; Guangdong Academy of Medical Sciences; Guangzhou China
| | - Xiaoping Chen
- Department of Infection; Guangdong General Hospital; Guangdong Academy of Medical Sciences; Guangzhou China
| | - Wenli Chen
- Department of Infection; Guangdong General Hospital; Guangdong Academy of Medical Sciences; Guangzhou China
| | - Xiaojun Ma
- Department of Infection; Guangdong General Hospital; Guangdong Academy of Medical Sciences; Guangzhou China
| | - Jing Huang
- Department of Infection; Guangdong General Hospital; Guangdong Academy of Medical Sciences; Guangzhou China
| | - Ren Chen
- Department of Infection; Guangdong General Hospital; Guangdong Academy of Medical Sciences; Guangzhou China
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The natural course of chronic hepatitis B virus infection and its management. ADVANCES IN PHARMACOLOGY 2014; 67:247-91. [PMID: 23886003 DOI: 10.1016/b978-0-12-405880-4.00007-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Chronic infection with the hepatitis B virus (HBV) runs a long natural course during which underlying changes in liver histology can progress to cirrhosis and hepatic decompensation, as well as to hepatocellular carcinoma. Therapeutic intervention is currently aiming at suppression of HBV replication by applying a number of pharmacological agents. For an optimum use of available therapies, good knowledge of the natural course of chronic infection, as well as of the role played by several viral, host, and environmental factors, is mandatory. The larger part of this chapter deals with how to treat the various subsets of patients with chronic hepatitis B (CHB), using mainly three first-line drugs: pegylated interferon-α2a, entecavir, and tenofovir, administered either in finite courses or indefinitely. The frequency of virological, serological, biochemical, and histological responses in the various subsets of patients, both during and after stopping treatment, is reviewed. It is stressed that the application of the highly potent antivirals entecavir and tenofovir, with acceptable safety records and with a high barrier to HBV resistance, represents major progress in the treatment of CHB. Despite the hitherto important developments in the treatment of viral hepatitis B, clinical cure of chronic HBV infection with HBsAg loss is achievable only in a few treated patients while eradication of HBV infection appears unrealistic. Development of new pharmacological agents acting at multiple targets of the replicative cycle of HBV may achieve higher efficacy and even cure of CHB.
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20
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Hadziyannis E, Hadziyannis SJ. Hepatitis B surface antigen quantification in chronic hepatitis B and its clinical utility. Expert Rev Gastroenterol Hepatol 2014; 8:185-95. [PMID: 24417264 DOI: 10.1586/17474124.2014.876362] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Serum HBsAg levels have been quantified extensively in recent years with simple completely automated assays in the various phases of the natural course of chronic HBV infection, have been compared with cccDNA in the liver, with various markers of HBV replication and have been correlated with several viral, host and environmental variables. Low HBsAg levels in inactive carriers predict a spontaneous HbsAg loss. Quantification of HBsAg in serum at baseline and its decline under interferon-alfa based regimens, both in HBeAg-positive and HBeAg-negative CHB, provides important information on the prediction of sustained post-treatment outcomes and on subsequent HBsAg clearance. The value of HBsAg quantification in the monitoring of long term nucleos(t)ide analogue treatment of CHB and in the prediction of sustained response remains unclear. In this review, the most recent data regarding the overall clinical utility of HBsAg measurement in HBeAg-positive and -negative CHB and in their treatment, is critically presented.
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Affiliation(s)
- Emilia Hadziyannis
- Academic Department of Medicine, Hippokration Hospital, National and Kapodistrian University of Athens, 114 Vas. Sophias Ave, Athens 11529, Greece
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Vlachogiannakos J, Papatheodoridis GV. HBeAg-negative chronic hepatitis B: why do I treat my patients with pegylated interferon-alfa? Liver Int 2014; 34 Suppl 1:127-32. [PMID: 24373089 DOI: 10.1111/liv.12404] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
HBeAg-negative chronic hepatitis B (CHB) is the most frequent and aggressive type of CHB. The current therapeutic options for CHB include pegylated-interferon-alfa (PEG-IFNα) and nucleos(t)ide analogues (NAs). NAs are well-tolerated and safe agents that effectively inhibit viral replication, but they should be given as long-term, probably lifelong therapy, in particular in HBeAg-negative CHB. Thus, the finite, usually 48-week, duration is the main advantage of PEG-IFNα, providing sustained virological responses (SVR) off-therapy in approximately one-fourth of patients with HBeAg-negative CHB and often leading to HBsAg loss. However, the limited efficacy is the main factor restricting the use of PEG-IFNα in CHB and therefore identifying the predictors of response is of great clinical importance. No reliable baseline predictors of response to PEG-IFNα have been identified to date, but certain studies have identified satisfactory predictors of post-PEG-IFNα response using on-treatment serological markers, mostly HBsAg levels. In particular, in HBeAg-negative CHB patients mostly with genotype D a lack of decline in HBsAg levels and a lack of decrease in HBV DNA levels ≥2 log10 copies/ml at week-12 has a nearly 100% negative predictive value for SVR off-treatment and is now recommended as a stopping rule for early discontinuation of ineffective PEG-IFNα. Prolonging PEG-IFNα therapy to 96 weeks seems to provide higher SVR rates but the application and efficacy of this approach requires further study. The combination of PEG-IFNα with NAs, mostly lamivudine, has not resulted in any therapeutic benefit so far, but newer combined approaches with PEG-IFNα and NA(s) are currently under study.
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Affiliation(s)
- Jiannis Vlachogiannakos
- Academic Department of Gastroenterology, Athens University Medical School, Laiko General Hospital, Athens, Greece
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Abstract
Chronic hepatitis B virus is a serious and life threatening disease afflicting 350 million people worldwide, despite the availability of effective vaccines. Thus far, current monotherapy with conventional interferon-alpha, lamivudine and adefovir dipivoxil remains unsatisfactory. In addition, the use of conventional interferon-alpha needs to be administered subcutaneously three-times weekly and is associated with frequent adverse events. Although nucleoside/nucleotide analogs such as lamivudine and adefovir dipivoxil are well tolerated and can normalize serum alanine aminotransaminase rapidly, 1-year therapy with either lamivudine or adefovir dipivoxil results in low hepatitis B e antigen seroconversion rates. In hepatitis B e antigen-negative patients, most would relapse after lamivudine has been discontinued. Peginterferon-alpha2a, an immunomodulatory agent, is a new drug that has just completed Phase III clinical trials for the treatment of both hepatitis B e antigen-positive and -negative chronic hepatitis B virus infection. The advantage of peginterferon-alpha2a in achieving sustained virologic response over nucleoside/nucleotide analogs is particularly obvious in the hepatitis B e antigen-negative group. In both studies, sustained off-treatment response is superior to the use of monotherapy with lamivudine, and concomitant use of lamivudine and pegnterferon-alpha2a does not have advantages over the use of peginterferon-alpha2a alone. These recent data put peginterferon-alpha2a as the antihepatitis B virus therapy of choice, especially in young and motivated patients with chronic hepatitis B virus infection. However, despite the superiority of peginterferon-alpha2a over currently licensed nucleoside/nucleotide analogs, more research needs to be conducted in order to find the most optimal treatment regimen in our fight against chronic hepatitis B virus infection.
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Affiliation(s)
- Chee-Kin Hui
- Department of Medicine, Center for the Study of Liver Diseases, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong SAR, China.
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Brunetto MR, Marcellin P, Cherubini B, Yurdaydin C, Farci P, Hadziyannis SJ, Rothe V, Regep L, Bonino F. Response to peginterferon alfa-2a (40KD) in HBeAg-negative CHB: on-treatment kinetics of HBsAg serum levels vary by HBV genotype. J Hepatol 2013; 59:1153-9. [PMID: 23872601 DOI: 10.1016/j.jhep.2013.07.017] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2013] [Revised: 07/04/2013] [Accepted: 07/06/2013] [Indexed: 02/09/2023]
Abstract
BACKGROUND & AIMS We investigated whether HBV genotype influences on-treatment HBsAg kinetics and/or the end-of-treatment HBsAg levels associated with long-term virological response in HBeAg-negative chronic hepatitis B patients treated with peginterferon alfa-2a±lamivudine in the Phase III trial. METHODS All patients (n=230) who participated in long-term follow-up were included according to the availability of HBsAg level measurements. Long-term virological response was defined as HBV DNA ≤ 10,000cp/ml (1786IU/ml) at 5 years post-treatment. Genotype-specific end-of-treatment HBsAg levels associated with long-term virological response (identified by ROC analysis) were assessed in 199 patients with HBsAg measurements available at baseline and end-of-treatment. HBsAg kinetics according to genotype and long-term virological response were investigated in the 117 patients with additional samples available at weeks 12, 24, and 72. RESULTS Baseline HBsAg levels were significantly higher for A than B, C, and D genotypes (p<0.05). On-treatment HBsAg kinetics varied according to HBV genotype. The difference between responders and non-responders was greatest for genotype A from weeks 12-24; for genotypes B and D from baseline to week 12; there was no significant difference over any timeframe for genotype C. High positive predictive values for long-term virological response could be obtained by applying end-of-treatment genotype-specific cut-offs: 75%, 47%, 71%, and 75% for genotypes A (<400IU/ml), B (<50IU/ml), C (<75IU/ml), and D (<1000IU/ml), respectively. CONCLUSIONS On-treatment HBsAg kinetics vary between HBV genotypes. Genotype-specific monitoring timeframes and end-of-treatment thresholds could ameliorate response-guided treatment of HBeAg-negative chronic hepatitis B.
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Lampertico P, Viganò M, Cheroni C, Facchetti F, Invernizzi F, Valveri V, Soffredini R, Abrignani S, De Francesco R, Colombo M. IL28B polymorphisms predict interferon-related hepatitis B surface antigen seroclearance in genotype D hepatitis B e antigen-negative patients with chronic hepatitis B. Hepatology 2013; 57:890-6. [PMID: 22473858 DOI: 10.1002/hep.25749] [Citation(s) in RCA: 127] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2011] [Accepted: 03/22/2012] [Indexed: 12/12/2022]
Abstract
UNLABELLED Interleukin (IL)28B polymorphisms have been associated with interferon (IFN)-induced viral clearance in patients with chronic hepatitis C. Whether this is also true for patients with the difficult-to-cure hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) is unknown. One hundred and one HBeAg-negative patients (92% genotype D) with compensated CHB (84% males, 46 years; hepatitis B virus [HBV] DNA: 6.0 log cp/mL; alanine aminotransferase [ALT]: 136 IU/L; 42% with cirrhosis) were followed up for a median of 11 years (range, 1-17) after a median of 23 months (range, 10-48) of either standard or pegylated (Peg)-IFN-alpha therapy. A post-treatment response was defined as hepatitis B surface antigen (HBsAg) clearance with or without antibody to hepatitis B surface antigen (anti-HBs) seroconversion. The rs12979860 (C>T) genotype in the IL28B locus was assessed in serum samples by using Custom TaqMan SNP Genotyping Assays (Applied Biosystems, Carlsbad, CA). During a median of 11 years of post-treatment follow-up, 21 patients (21%) cleared serum HBsAg, including 15 who developed>10 IU/mL of anti-HBs titers. Forty-eight patients (47%) had CC genotype, 42 (42%) had CT, and 11 (11%) had TT, with the allelic frequency being 68% for C allele and 32% for T allele. The rate of serum HBsAg clearance was 29% (n=14) in CC compared to 13% (n=7) in non-CC, genotype carriers (P=0.039). Baseline HBV DNA levels<6 log cp/mL (odds ratio [OR], 11.9; 95% confidence interval [CI]: 2.8-50.6; P=0.001), ALT levels>136 IU/L (OR, 6.5; 95% CI: 1.8-22.5; P=0.003), duration of IFN (OR, 1.16; 95% CI: 1.02-1.31; P=0.021), and genotype CC (OR, 3.9; 95% CI: 1.1-13.2; P=0.025) independently predicted HBsAg clearance. CONCLUSIONS IL28B polymorphism is an additional predictor of off-therapy IFN-related HBsAg seroclearance to be used in the pretreatment stratification of HBeAg-negative patients chronically infected by genotype D of HBV.
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Affiliation(s)
- Pietro Lampertico
- Migliavacca Center for the Study of Liver Disease, First Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milano, Italy.
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Kwon JH, Kim YS, Kim SG, Jang JW, Kim TH, Jung YK, Kwon OS. The Efficacy and Safety of Peginterferon-α-2a in Korean Patients with Chronic Hepatitis B: A Multicenter Study Conducted in a Real Clinical Setting. Gut Liver 2013; 7:197-205. [PMID: 23560156 PMCID: PMC3607774 DOI: 10.5009/gnl.2013.7.2.197] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2012] [Revised: 07/06/2012] [Accepted: 07/20/2012] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND/AIMS Genotype C is the principal type of hepatitis B virus (HBV) in Koreans and is associated with poor prognosis for peginterferon α-2a therapy. The efficacy of and compliance to peginterferon α-2a therapy were investigated in Koreans with hepatitis B in a real clinical setting. METHODS Hepatitis B patients treated with peginterferon α-2a from 2008 to 2011 at four university hospitals were consecutively enrolled. RESULTS Eighty-eight patients were enrolled; 67 were hepatitis B e antigen (HBeAg)-positive. The mean treatment period was 36.1±15.2 weeks. In 26.1% of patients, treatment was discontinued due to insufficient antiviral effects and adverse events. At 24 weeks after treatment, 10/42 (23.8%) HBeAg-positive patients achieved both HBV DNA suppression to <2,000 IU/mL and HBeAg loss/seroconversion. For HBeAg-negative patients, 10/13 (76.9%) achieved HBV DNA suppression to <2,000 IU/mL at 24 weeks after treatment. During the follow-up period, 15 (30.6%) of the 49 patients who achieved HBV DNA suppression to 2,000 IU/mL developed a breakthrough HBV DNA level of >2×10(6) IU/mL. CONCLUSIONS Peginterferon α-2a therapy in Koreans with hepatitis B in a real clinical setting resulted in a lower virologic response, as compared to Western individuals, but a favorable durability. There is a need to reduce the high rate of premature discontinuation compared to the controlled studies.
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Affiliation(s)
- Jung Hyun Kwon
- Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Incheon, Korea
| | - Young Seok Kim
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital and Digestive Disease Center and Research Institute, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Sang Gyune Kim
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital and Digestive Disease Center and Research Institute, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Jeong Won Jang
- Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Incheon, Korea
| | - Tae Hun Kim
- Department of Internal Medicine, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Young Kul Jung
- Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University of Medicine and Science, Incheon, Korea
| | - Oh Sang Kwon
- Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University of Medicine and Science, Incheon, Korea
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Hadziyannis SJ, Sevastianos V, Rapti I, Vassilopoulos D, Hadziyannis E. Sustained responses and loss of HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term treatment with adefovir. Gastroenterology 2012; 143:629-636.e1. [PMID: 22659218 DOI: 10.1053/j.gastro.2012.05.039] [Citation(s) in RCA: 276] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2012] [Revised: 05/18/2012] [Accepted: 05/24/2012] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Little is known about the biochemical and virological effects of stopping long-term nucleos(t)ide analogue therapy for hepatitis B e antigen (HBeAg)-negative patients with chronic hepatitis B (CHB). METHODS We performed a cohort observational study, following 33 HBeAg-negative patients with CHB, undetectable serum HBV DNA, and normal levels of aminotransferases after long-term (4 or 5 years) treatment with adefovir dipivoxil (ADV). All patients were followed for 5.5 years; follow-up visits included measurements of serum alanine aminotransferase (ALT), hepatitis B surface antigen (HBsAg), and HBV DNA monthly for the first 6 months and every 3-6 months thereafter. Various factors were measured at baseline, the end of treatment (EOT), and following treatment to identify those associated with clearance of HBsAg. RESULTS During the first few months of the postdiscontinuation period, all patients experienced virological and 25 (76%) had biochemical relapse. During the follow-up period, 18 patients (55%) who had discontinued antiviral therapy achieved sustained response (HBV DNA level <2000 IU/L, persistently normal level of ALT). Among these, 13 (72%) cleared HBsAg. Fifteen patients (45%) with virological and/or biochemical relapse were re-treated with oral antiviral agents (11 during the first 18 months and 4 after the third year), without evidence of liver decompensation; only 1 lost HBsAg (6%). Higher pretreatment and EOT levels of ALT, no previous treatment with interferon, and lower level of HBsAg at the EOT were significantly associated with HBsAg clearance based on multivariate analysis. CONCLUSIONS In HBeAg-negative patients with CHB, it is safe and effective to discontinue ADV therapy after 4 or 5 years; 55% of patients have sustained responses, and 39% of patients lose HBsAg.
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Affiliation(s)
- Stephanos J Hadziyannis
- Department of Medicine and Hepatology, Henry Dunant Hospital, National and Kapodistrian University of Athens, Athens, Greece; Molecular Biology Laboratory of the Liver Unit at the Evgenidion Hospital, National and Kapodistrian University of Athens, Athens, Greece.
| | - Vassilios Sevastianos
- Department of Medicine and Hepatology, Henry Dunant Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Irene Rapti
- Department of Medicine and Hepatology, Henry Dunant Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios Vassilopoulos
- 2nd Academic Department of Medicine, Hippokration Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Emilia Hadziyannis
- 2nd Academic Department of Medicine, Hippokration Hospital, National and Kapodistrian University of Athens, Athens, Greece
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EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol 2012; 57:167-85. [PMID: 22436845 DOI: 10.1016/j.jhep.2012.02.010] [Citation(s) in RCA: 2398] [Impact Index Per Article: 184.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2012] [Accepted: 02/28/2012] [Indexed: 02/06/2023]
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McNutt MD, Liu S, Manatunga A, Royster EB, Raison CL, Woolwine BJ, Demetrashvili MF, Miller AH, Musselman DL. Neurobehavioral effects of interferon-α in patients with hepatitis-C: symptom dimensions and responsiveness to paroxetine. Neuropsychopharmacology 2012; 37:1444-54. [PMID: 22353759 PMCID: PMC3327849 DOI: 10.1038/npp.2011.330] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
In patients at high risk for recurrence of malignant melanoma, interferon-α (IFN-α), a stimulator of innate immunity, appears to induce distinct neurobehavioral symptom dimensions: a mood and anxiety syndrome, and a neurovegetative syndrome, of which the former is responsive to prophylactic administration of paroxetine. We sought to determine whether symptom dimensions (and treatment responsiveness) arise in patients with hepatitis C administered IFN-α and ribavirin. In a randomized, double-blind, 6-month study, 61 patients with hepatitis C eligible for therapy with IFN-α and ribavirin received the antidepressant paroxetine (n=28) or a placebo (n=33). Study medication began 2 weeks before IFN-α/ribavirin therapy. Neuropsychiatric assessments included the 10-item Montgomery-Asberg Depression Rating Scale (MADRS). The items of the MADRS were grouped into depression, anxiety, cognitive dysfunction, and neurovegetative symptom dimensions, and analyzed using a mixed model. By 2 weeks of IFN-α/ribavirin therapy, all four dimensions increased, with the symptom dimensions of anxiety and cognitive dysfunction fluctuating and worsening, respectively, in both groups over time. The depression symptom dimension was significantly lower in the paroxetine treatment group (p=0.04); severity of the neurovegetative symptom dimension was similar in both groups. Similar to patients with malignant melanoma receiving high-dose IFN-α, the depression symptom dimension is more responsive to paroxetine treatment in individuals undergoing concomitant IFN-α/ribavirin therapy. However, the anxiety, cognitive dysfunction, and neurovegetative symptom dimensions appear less responsive to prophylactic paroxetine administration. Different neurobiologic pathways may contribute to the responsiveness of IFN-α-induced symptom dimensions to antidepressant treatment, requiring relevant psychopharmacologic strategies.
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Affiliation(s)
- Marcia D McNutt
- Department of Psychology, University of Miami, Miami, FL, USA
| | - Shuling Liu
- Department of Biostatistics, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Amita Manatunga
- Department of Biostatistics, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | | | - Charles L Raison
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA,Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Bobbi J Woolwine
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA,Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Marina F Demetrashvili
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA,Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Andrew H Miller
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA,Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Dominique L Musselman
- Department of Psychiatry and Behavioral Sciences, University of Miami Leonard H Miller School of Medicine, Miami, FL, USA,Department of Psychiatry and Behavioral Sciences, Mental Health Hospital Center, University of Miami Leonard H Miller School of Medicine, 1695 NW 9th Avenue, Rm 2506, Miami, FL 33146, USA, Tel: +1 404 723 8361, Fax: +1 305 355 9072, E-mail:
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Marcellin P, Bonino F, Yurdaydin C, Hadziyannis S, Moucari R, Kapprell HP, Rothe V, Popescu M, Brunetto MR. Hepatitis B surface antigen levels: association with 5-year response to peginterferon alfa-2a in hepatitis B e-antigen-negative patients. Hepatol Int 2012; 7:88-97. [PMID: 23518903 PMCID: PMC3601258 DOI: 10.1007/s12072-012-9343-x] [Citation(s) in RCA: 126] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2011] [Accepted: 01/21/2012] [Indexed: 12/14/2022]
Abstract
Purpose To investigate the durability of response to peginterferon alfa-2a up to 5 years post-treatment and factors associated with response in hepatitis B e-antigen (HBeAg)-negative patients. Methods HBeAg-negative patients received peginterferon alfa-2a (180 μg/week) ± lamivudine (100 mg/day) for 48 weeks as part of a multicenter, randomized study. The planned 5-year efficacy analysis included patients (n = 230) enrolled in the long-term follow-up study. On-treatment hepatitis B surface antigen (HBsAg) decline kinetics were analyzed retrospectively in a subgroup of patients with HBsAg data available at baseline, weeks 12, 24, and 48 on-treatment, and 6 months post-treatment (n = 120). Receiver operating characteristic analyses identified the on-treatment HBsAg levels associated with response at 1 and 5 years post-treatment. Results HBV DNA ≤2,000 IU/mL and HBsAg clearance at 5 years post-treatment were achieved by 23 and 12% of patients, respectively. High rates of HBsAg clearance at 5 years post-treatment were achieved by patients with HBV DNA ≤2,000 IU/mL at 1 year post-treatment (28%). Rates of HBV DNA ≤2,000 IU/mL at 1 year post-treatment were 47.2 and 43.4% in patients with ≥10% decline from baseline at weeks 12 and 24, respectively, compared with 16.4% (p = 0.0003) and 13.2% (p < 0.0004) in patients with a <10% decline. Rates of HBsAg clearance at 5 years post-treatment were 22.6 and 22.4% in patients with ≥10% decline at weeks 12 and 24, respectively, compared with 7.5% (p = 0.0161) and 3.8% (p < 0.0001) in patients with <10% decline. Conclusions Peginterferon alfa-2a results in increasing rates of HBsAg clearance during post-treatment follow-up in HBeAg-negative patients. On-treatment decline in HBsAg is significantly associated with long-term post-treatment response.
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Affiliation(s)
- Patrick Marcellin
- Service d'Hépatologie and INSERM U773-CRB3, Hôpital Beaujon, University of Paris, 100 boulevard du Général Leclerc, 92110 Clichy, France
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Chen CC, Wang PC, Chang HW, Chen CF. Safety and efficacy of two-step peginterferon α-2a treatment in patients of chronic hepatitis B with acute exacerbation. J Viral Hepat 2012; 19:161-72. [PMID: 22329370 PMCID: PMC3489065 DOI: 10.1111/j.1365-2893.2011.01469.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The focus of this study was to evaluate the safety and efficacy of sequential peginterferon α-2a (Pegasys) therapy for chronic hepatitis B with acute exacerbation [ALT > 10 × upper limit of normal (ULN), bilirubin <2.0 mg/dL]. Four groups of patients categorized by HBeAg status and treatment regimens were studied since May 2007. Nineteen HBeAg-positive patients (Group 1) had received entecavir pretreatment (when ALT > 10 × ULN) plus Pegasys (180 μg/kg/week, when ALT was 5-10 × ULN) for 24 weeks. Thirteen HBeAg-negative patients (Group 2) had the same protocol for 48 weeks. In both groups, entecavir was then discontinued 14 days after the initiation of Pegasys. The results were compared, respectively, to 35 HBeAg-positive patients (Group 3) and 24 HBeAg-negative patients (Group 4), all with ALT > 5 × ULN, under continual entecavir monotherapy. The ALT levels of patients in Group 1 and 2 who had received entecavir pretreatment for a duration of 19.63 ± 3.34 days were below four times of ULN following 4 weeks of Pegasys treatment. At week 96, the rates of sustained virological response were 69.2% (9/13) and 80% (8/10), and the relapse rates were 23.1% (3/13) and 11.2% (1/9) for HBeAg-positive and HBeAg-negative patients with two-step Pegasys treatment, respectively. The HBeAg seroconversion rates were 46.2% in Group 1, and 42.1% in Group 3; HBsAg loss rates were 15.4% (2/13) in Group 1, and 30% (3/10) in Group 2, whereas none achieved HBsAg loss with entecavir monotherapy (Group 3 and 4). The two-step Pegasys treatment offers an alternative, other than the nucleos(t)ides, for treating chronic hepatitis B with acute exacerbation and provides a safe, efficacious, short-term and finite strategy.
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Affiliation(s)
- C-C Chen
- Division of Hepatology & Gastroenterology, Department of Internal Medicine, Mackay Memorial HospitalHsin-Chu, Taiwan
| | - P-C Wang
- Division of Hepatology & Gastroenterology, Department of Internal Medicine, Mackay Memorial HospitalHsin-Chu, Taiwan
| | - H-W Chang
- Division of Hepatology & Gastroenterology, Department of Internal Medicine, Mackay Memorial HospitalHsin-Chu, Taiwan
| | - C-F Chen
- Division of Hepatology & Gastroenterology, Department of Internal Medicine, Mackay Memorial HospitalHsin-Chu, Taiwan
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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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Chang M, Saab S. Interferon for Hepatitis B: Which Populations Benefit the Most. CURRENT HEPATITIS REPORTS 2011; 10:285-291. [DOI: 10.1007/s11901-011-0111-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Zhang Y, Huang X, Jiang Z, Huang X, Hu Y, Zhu D, Zhang S, Wang J, Zhang L. Simultaneous determination of metacavir and its metabolites in rat plasma using high-performance liquid chromatography with tandem mass spectrometric detection (LC-MS/MS). Biomed Chromatogr 2011; 26:363-70. [PMID: 21773980 DOI: 10.1002/bmc.1667] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2011] [Accepted: 05/16/2011] [Indexed: 11/10/2022]
Abstract
A sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of metacavir and its two metabolites in rat plasma was developed and validated. Tinidazole was used as an internal standard and plasma samples were pretreated with one-step liquid-liquid extraction. In addition, these analytes were separated using an isocratic mobile phase on a reverse-phase C18 column and analyzed by MS in the selected reaction monitoring mode. The monitored precursor to product-ion transitions for metacavir, 2',3'-dideoxyguanosine, O-methylguanine and the internal standard were m/z 266.0 → 166.0, m/z 252.0 → 152.0, m/z 166.0 → 149.0 and m/z 248.0 → 202.0, respectively. The standard curves were found to be linear in the range of 1-1000 ng/mL for metacavir, 5-5000 ng/mL for 2',3'-dideoxyguanosine and 1-1000 ng/mL for O-methylguanine in rat plasma. The precision and accuracy for both within- and between-batch determination of all analytes ranged from 2.83 to 9.19% and from 95.86 to 111.27%, respectively. No significant matrix effect was observed. This developed method was successfully applied to an in vivo pharmacokinetic study after a single intravenous dose of 20 mg/kg metacavir in rats.
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Affiliation(s)
- Yue Zhang
- Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China
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Abstract
Chronic hepatitis B (CHB) is a major public health problem affecting up to 400 million people globally. Complications of CHB including liver failure and hepatocellular carcinoma result in 1.2 million deaths per year, making CHB the 10th leading cause of mortality worldwide. The natural history of CHB is variable and complex. The past decade witnessed important developments for the therapy of hepatitis B and marked the new era of oral therapy. The ultimate goal of CHB therapy is to arrest the progression of liver injury and to prevent the development of liver failure and hepatocellular carcinoma. Currently, six agents are approved for the treatment of CHB. Each of these agents, given as monotherapy, has been shown to produce virological, biochemical, and histological benefits for both HBeAg positive and negative CHB. There are, however, limitations in spite of their efficacy. The significant side-effect profile of interferon, for example, limits its long-term use. The approved oral agents are tolerable with prolonged use but drug resistance could limit long-term monotherapy. To date, combination therapy with nucleoside analogue and pegylated interferon or two nucleos(t)ide analogues given for one year does not show superiority in durability of response compared to monotherapy. Ongoing research effort is critical to identify the ideal hepatitis B therapy that is safe, effective, and produces durable response with a finite course of therapy. It is equally important to conduct a well designed, prospective natural history study to identify predictors of disease progression. This will accurately guide treatment strategy for this important disease.
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Affiliation(s)
- Daryl T-Y Lau
- Associate Professor of Medicine, Harvard Medical School (HMS), Director of Translational Liver Research, Beth Israel Deaconess Medical Center, HMS Liver Center, Division of Gastroenterology, Department of Medicine, 110 Francis Street, Suite 4A, Boston, MA 02215.
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Abstract
Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) occurs at the late phase in hepatitis B virus (HBV) infection's natural history. The disease is characterized by progressive liver damage due to variants with mutations in the precore/core promoter region that reduce or abolish HBeAg expression. Chronic HBeAg-negative disease's prognosis is poor, with only rare incidences of spontaneous remission. Recent studies in Europe, Asia, and the United States all have reported an increased prevalence of HBeAg-negative and a decreased prevalence of HBeAg-positive chronic hepatitis; this may be related to increased awareness, decrease in new HBV infections, and aging of existing carriers. The end point of therapy for HBeAg-negative CHB patients is difficult to assess. In most studies, HBV DNA suppression and normalization of serum alanine aminotransaminase levels have been used to indicate therapeutic response. Six drugs currently are licensed for the treatment of CHB infection. These are the immunomodulatory agents (conventional interferon-alpha-2b and pegylated interferon-alpha-2a) and the nucleoside/nucleotide analogues (lamivudine, adefovir dipivoxil, entecavir, and telbivudine). Sustained treatment response rates generally are poor due to the high probability of relapse, particularly following nucleoside/nucleotide analogue therapy. As not all patients can tolerate or will respond to interferon-based therapy, maintenance therapy with nucleoside/nucleotide therapy is the alternative. However, this latter approach can lead to development of viral resistance and long-term safety concerns.
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Affiliation(s)
- Chee-Kin Hui
- George K. Lau, MD, FRCP Department of Medicine, Room 1838, Block K, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong SAR, China.
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Calvaruso V, Craxì A. Fibrosis in chronic viral hepatitis. Best Pract Res Clin Gastroenterol 2011; 25:219-30. [PMID: 21497740 DOI: 10.1016/j.bpg.2011.02.012] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2011] [Revised: 02/21/2011] [Accepted: 02/23/2011] [Indexed: 01/31/2023]
Abstract
In the last years, several studies have been performed with the aim to evaluate the real impact of antiviral treatments on fibrosis progression in patients with chronic viral hepatitis. The main goal of therapy in patients with chronic hepatitis B is viral suppression. This outcome leads to an important improvement in both hepatic inflammation and fibrosis and reduces the HCC occurrence. An histological improvement has been largely demonstrated in patient treated with oral nucleoside and nucleotide analogs achieving the rate of 72% with entecavir and tenofovir. Similarly, in patients with chronic hepatitis C, sustained virologic response to interferon therapy is associated with regression of fibrosis and lower liver decompensation and HCC occurrence. In the next future further studies will assess the real impact of the new directly anti-viral agents on liver necroinflammation and fibrosis in chronic hepatitis C.
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Affiliation(s)
- Vincenza Calvaruso
- Sezione di Gastroenterologia ed Epatologia, Di.Bi.M.I.S., University of Palermo, Piazza delle Cliniche n.2, 90127 Palermo, Italy.
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38
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Brunetto MR, Lok AS. New approaches to optimize treatment responses in chronic hepatitis B. Antivir Ther 2011; 15 Suppl 3:61-8. [PMID: 21041905 DOI: 10.3851/imp1625] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Substantial advances have been made in the treatment of chronic hepatitis B in the past decade. Currently, there are seven approved agents including two forms of interferon (conventional and pegylated), and five oral nucleoside/nucleotide analogues (lamivudine, adefovir, entecavir, telbivudine and tenofovir disoproxil fumarate). The availability of these multiple treatment options has led to expansion of treatment indications. However, the need for a long duration of treatment with some therapies, the high costs of HBV medications, the side effects associated with some treatments and the risks of drug resistance during long-term use of oral antiviral medications necessitate the careful assessment of the risk-benefit ratio prior to initiating treatment, and the evaluation of better strategies to optimize response once treatment is initiated. In this article, we review the current approaches to optimize treatment response to nucleoside/nucleotide analogue- and interferon-based therapies for chronic hepatitis B.
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Abstract
There have been numerous research milestones since the discovery of the hepatitis B virus (HBV) in the 1960s. These mark major advances in the serology and epidemiology of HBV infection, in identifying the wide clinical spectrum of acute and chronic hepatic diseases as well as the extrahepatic conditions induced by this virus, the molecular biology of the virus including its variants and mutants, its molecular diagnosis and monitoring, the host immune responses to the infecting virus, the pathogenesis and immunopathogenesis of liver disease as well as its natural course and outcome. These landmark discoveries are the firm background for current and future developments in treatment. There are three consecutive and partly overlapping chronological periods to treatment milestones beginning with recombinant standard interferon-alpha (IFN-α) in the 1980s, then oral antivirals from 1998 to the present and in 2005 pegylated IFN-α (PEG-IFN). The renewed interest in PEG-IFN-α treatment is now focused on both HBeAg-positive and HBeAg-negative chronic hepatitis B and it now also aims at HBsAg loss when associated with on-treatment monitoring of serum HBV DNA and HBsAg levels, resulting in the closest thing to a cure of hepatitis B. The impressive progress made in all aspects of hepatitis B research suggests that curative therapy may be developed for all patients and for all phases of HBV infection in the foreseeable future. However for the moment, realistic efforts should be made to make treatment as widely available and affordable as possible and to apply current therapies to significantly reduce HBV morbidity and mortality.
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Affiliation(s)
- Stephanos J Hadziyannis
- Department of Medicine and Hepatology, Henry Dunant Hospital and Liver Research Unit, Athens University, Evgenidion Hospital, Athens, Greece.
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Yokosuka O, Kurosaki M, Imazeki F, Arase Y, Tanaka Y, Chayama K, Tanaka E, Kumada H, Izumi N, Mizokami M, Kudo M. Management of hepatitis B: Consensus of the Japan Society of Hepatology 2009. Hepatol Res 2011; 41:1-21. [PMID: 21070536 DOI: 10.1111/j.1872-034x.2010.00739.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Recently, much progress has been made in the field of hepatitis B, such as natural history of the disease in relation to the amount of hepatitis B virus (HBV) DNA, genotypes of HBV influencing the natural course and treatment effects, mutations of HBV influencing the severity of the disease and development of hepatocellular carcinoma, and antiviral treatment such as nucleos(t)ide analogues and pegylated interferon. To make the consensus for the diagnosis, management and treatment of hepatitis B, a meeting was held during 45th annual meeting of Japan Society of Hepatology (JSH) in June 2009. In the meeting, recommendations and informative statements were discussed on the following subjects: (i) natural history of HBV infection; (ii) clinical implication of HBV genotypes; (iii) HBV mutations and their potential impact on pathogenesis of HBV infection; (iv) indications for antiviral treatment of chronic hepatitis B; (v) nucleos(t)ide analogues for chronic hepatitis B; and (vi) interferon therapy for chronic hepatitis B. The presenters reviewed the data on these subjects and proposed the consensus statements and recommendations. These statements were discussed among the organizers and presenters, and were approved by the participants of the meeting. In the current report, the relevant data were reviewed and the 12 consensus statements and nine recommendations on chronic hepatitis B were described.
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Affiliation(s)
- Osamu Yokosuka
- Department of Medicine and Clinical Oncology, Postgraduate School of Medicine, Chiba University, Japan
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Abstract
Current agents used in the treatment of chronic hepatitis B (CHB) can be classified into interferons-α (IFN-α: standard or pegylated) and nucleos(t)ide analogues (NUCs). NUCs are now used in most CHB patients for several reasons. They can be given to all CHB patients, even those with contraindications to IFN-α. NUCs are more convenient to use (one oral tablet daily) than IFN-α (subcutaneous injections) and are well tolerated with a good safety profile, while IFN-α has frequent and potentially severe side effects and worsens the patient's quality of life. All NUCs are potent anti-hepatitis B virus agents (all but adefovir are more potent than IFN-α) with entecavir(ETV) and tenofovir offering the highest potency and most importantly minimal to negligible risk of resistance during long-term monotherapy [corrected]. Prolongation of entecavir or tenofovir monotherapy maintains and slightly increases the initially high virological remission rates (67-76% of HBeAg-positive and 90-93% of HBeAg-negative patients) and this is expected to result in improved long-term outcomes. The need for long-term, perhaps indefinite, treatment is the main limitation of NUCs and the finite duration (48 weeks) the main advantage of IFN-α. However, only a minority of IFN-α-treated patients achieve durable sustained off-treatment responses (HBeAg-positive: 30-35%, HBeAg-negative: 20-25%), while NUCs may be safely discontinued in HBeAg-positive patients with stable HBeAg seroconversion. Because there will always be concerns for safety and family planning issues with long-term therapy, NUCs should be used judiciously and should not be prescribed in young CHB patients with mild liver disease.
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Affiliation(s)
- George V Papatheodoridis
- 2nd Department of Internal Medicine, Athens University Medical School, Hippokration General Hospital of Athens, Athens, Greece.
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Rijckborst V, ter Borg MJ, Cakaloglu Y, Ferenci P, Tabak F, Akdogan M, Simon K, Raptopoulou-Gigi M, Ormeci N, Zondervan PE, Verhey E, van Vuuren AJ, Hansen BE, Janssen HLA. A randomized trial of peginterferon alpha-2a with or without ribavirin for HBeAg-negative chronic hepatitis B. Am J Gastroenterol 2010; 105:1762-1769. [PMID: 20461068 DOI: 10.1038/ajg.2010.186] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B patients are at high risk of treatment relapse after any antiviral therapy. Combining peginterferon alpha-2a with ribavirin might improve sustained response rates. METHODS Overall, 138 HBeAg-negative chronic hepatitis B patients were randomized to receive monotherapy (peginterferon alpha-2a 180 microg weekly plus placebo) or combination therapy (peginterferon alpha-2a weekly plus ribavirin 1,000 or 1,200 mg daily, depending on body weight) for 48 weeks. Post-treatment follow-up lasted 24 weeks. Analyses were based on the modified intention-to-treat population after exclusion of five patients. RESULTS At the end of follow-up, 14 (20%) of 69 patients assigned to monotherapy and 10 (16%) of 64 assigned to combination therapy had a combined response (hepatitis B virus (HBV) DNA <10,000 copies/ml (<1,714 IU/ml) and a normal alanine aminotransferase level, P=0.49). At the end of treatment, more patients had a combined response (25 (36%) vs. 26 (41%) in the monotherapy and combination therapy group, respectively, P=0.60), but subsequently relapsed during follow-up. Serum HBV DNA and hepatitis B surface antigen (HBsAg) levels decreased during treatment (mean change at week 48 compared with baseline -3.9 vs. -2.6 log copies/ml, P<0.001 and -0.56 vs. -0.34 log IU/ml, P=0.23, respectively). HBV DNA levels relapsed after treatment discontinuation; HBsAg remained at end-of-treatment levels. In general, combination therapy was well tolerated, although it was associated with a higher risk of anemia and neutropenia. CONCLUSIONS Treatment with peginterferon alpha-2a resulted in a limited sustained response rate in HBeAg-negative chronic hepatitis B patients. Addition of ribavirin did not improve response to therapy.
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Affiliation(s)
- Vincent Rijckborst
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
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Mizokami M, Tanaka E, Chayama K, Tanaka Y, Kurosaki M, Izumi N, Arase Y, Kumada H, Imazeki F, Yokosuka O, Kudo M. JSH Consensus Kobe 2009: Diagnosis and Treatment of Hepatitis B. KANZO 2010; 51:243-260. [DOI: 10.2957/kanzo.51.243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
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Lampertico P, Aghemo A, Viganò M, Colombo M. HBV and HCV therapy. Viruses 2009; 1:484-509. [PMID: 21994557 PMCID: PMC3185503 DOI: 10.3390/v1030484] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2009] [Revised: 10/08/2009] [Accepted: 10/19/2009] [Indexed: 02/06/2023] Open
Abstract
One year of interferon therapy inhibits HBV replication in one third of the patients whereas long-term administration of oral nucleos(t)ide analogues is efficient in most of them, as long as early treatment adaptation in patients with partial virological response and resistance is provided. Following the demonstration of a more potent antiviral effect in terms of sustained virological response (SVR) rates, Pegylated-IFN coupled with Ribavirin has become the standard treatment for chronic hepatitis C, with nearly 65% of all treated patients achieving a SVR. Long-term suppression of HBV and eradication of HCV would halt the progression of chronic hepatitis to cirrhosis, hepatocellular carcinoma and liver decompensation.
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Affiliation(s)
- Pietro Lampertico
- “A.M. Migliavacca” Center for Liver Disease, First Gastroenterology Unit, Fondazione IRCCS Maggiore Hospital, Mangiagalli e Regina Elena, Università di Milano, Via F. Sforza 35, 20122 Milan, Italy
| | - Alessio Aghemo
- “A.M. Migliavacca” Center for Liver Disease, First Gastroenterology Unit, Fondazione IRCCS Maggiore Hospital, Mangiagalli e Regina Elena, Università di Milano, Via F. Sforza 35, 20122 Milan, Italy
| | - Mauro Viganò
- “A.M. Migliavacca” Center for Liver Disease, First Gastroenterology Unit, Fondazione IRCCS Maggiore Hospital, Mangiagalli e Regina Elena, Università di Milano, Via F. Sforza 35, 20122 Milan, Italy
| | - Massimo Colombo
- “A.M. Migliavacca” Center for Liver Disease, First Gastroenterology Unit, Fondazione IRCCS Maggiore Hospital, Mangiagalli e Regina Elena, Università di Milano, Via F. Sforza 35, 20122 Milan, Italy
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Ha NB, Ha NB, Garcia RT, Trinh HN, Vu AA, Nguyen HA, Nguyen KK, Levitt BS, Nguyen MH. Renal dysfunction in chronic hepatitis B patients treated with adefovir dipivoxil. Hepatology 2009; 50:727-34. [PMID: 19517525 DOI: 10.1002/hep.23044] [Citation(s) in RCA: 114] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
UNLABELLED Renal dysfunction has been reported in patients treated with adefovir dipivoxil (ADV); however, its incidence and clinical importance may be underappreciated given the lack of long-term follow-up and data outside of a clinical trial setting. Our goal was to examine the severity and incidence of renal dysfunction in a real-life setting for patients treated with ADV and whose baseline estimated glomerular filtration rate (eGFR) was >50 mL/minute. We performed a cohort study of 290 chronic hepatitis B patients: 145 patients treated with 10 mg ADV and 145 patients unexposed to ADV at two community clinics, who were matched for age (+/-10 years), sex, and baseline eGFR. The exposed and unexposed populations were well-matched with a similar mean age (46-47 years), proportion of male patients (76.5%), baseline serum creatinine (0.97-0.99 mg/dL), and baseline creatinine clearance (85.0-85.4 mL/minute). The incidence density for renal dysfunction defined by treatment termination and/or development of eGFR < or =50 mL/minute was five cases per 100 patient-years in the exposed group compared with 1.36 cases per 100 patient-years in the unexposed group (P = 0.02). The relative risk of exposed to unexposed was 3.68 (95% confidence interval 1.1-19.3). On Cox proportional hazard analysis also inclusive of sex, ADV was a significant predictor of significant renal dysfunction (hazard ratio [HR] 3.94, P = 0.03). There were also significant trends for age >50 years (HR 3.49, P = 0.087), mild renal impairment at baseline (HR 4.49, P = 0.073), and hypertension and/or diabetes mellitus (HR 2.36, P = 0.074). CONCLUSION ADV is an independent predictor for significant deterioration of renal function. Patients on ADV should be monitored, especially patients who are older, have baseline renal insufficiency, or have hypertension and/or diabetes mellitus.
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Affiliation(s)
- Nghi B Ha
- Pacific Health Foundation, San Jose, CA, USA
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Marcellin P, Bonino F, Lau GKK, Farci P, Yurdaydin C, Piratvisuth T, Jin R, Gurel S, Lu ZM, Wu J, Popescu M, Hadziyannis S. Sustained response of hepatitis B e antigen-negative patients 3 years after treatment with peginterferon alpha-2a. Gastroenterology 2009; 136:2169-2179.e1-4. [PMID: 19303414 DOI: 10.1053/j.gastro.2009.03.006] [Citation(s) in RCA: 260] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2008] [Revised: 02/23/2009] [Accepted: 03/02/2009] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B treated with peginterferon alpha-2a with or without lamivudine achieve significantly higher 6-month posttreatment rates of response compared with those treated with lamivudine alone. The durability of <or=3-year posttreatment response was investigated in this study. METHODS Patients received peginterferon alpha-2a only (180 microg once weekly; n = 177), in combination with lamivudine (100 mg daily; n = 179) or lamivudine alone (n = 181) for 48 weeks. A total of 315 patients (116, 114, and 85, respectively) participated in this posttreatment observational study. RESULTS Three years after treatment, the percentage of patients with normal alanine aminotransferase (ATL) was higher for patients treated with peginterferon alpha-2a (31%) than with lamivudine (18%; P = 0.032). Similarly, 28% of patients treated with peginterferon had hepatitis B virus (HBV) DNA levels <or= 10,000 copies/mL versus 15% of patients treated with lamivudine (P = .039). Peginterferon alpha-2a treatment and high baseline ALT level were independent baseline predictors of long-term virologic response (P = .040 and P = .01, respectively). Of the patients who had been treated with a peginterferon alpha-2a-containing regimen, 8.7% cleared hepatitis B surface antigen (HBsAg; 44% of those with undetectable HBV at 3-year posttreatment follow-up) compared with none treated with lamivudine alone. CONCLUSIONS Biochemical and virologic responses were sustained for <or=3 years in approximately 25% of patients given a 48-week course of peginterferon alpha-2a, with or without lamivudine. The increased rate of HBsAg clearance in patients with HBeAg-negative chronic hepatitis B supports the use of peginterferon alpha-2a as a first-line treatment.
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Affiliation(s)
- Patrick Marcellin
- Service d'Hépatologie, U773-CRB3, Hôpital Beaujon, University of Paris, Clichy, France.
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Manesis EK, Papatheodoridis GV, Touloumi G, Karafoulidou A, Ketikoglou J, Kitis GE, Antoniou A, Kanatakis S, Koutsounas SJ, Vafiadis I. Natural course of treated and untreated chronic HCV infection: results of the nationwide Hepnet.Greece cohort study. Aliment Pharmacol Ther 2009; 29:1121-1130. [PMID: 19222410 DOI: 10.1111/j.1365-2036.2009.03974.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Interferon (IFN-alpha)-based regimens have been used with varying success in the treatment of chronic hepatitis C (CHC) for over two decades. The effect of such treatments on the natural course of CHC has been evaluated in small clinical trials with conflicting results. AIM To investigate the natural course of IFNalpha-based-treated and untreated patients with CHC by analysing data from the HEPNET.GREECE study. METHODS We retrospectively analysed 1738 patients from 25 Greek Centres (median age 40.1; males 57.6%; cirrhosis 9.2%), 734 untreated and 993 treated with IFNalpha-based regimens [44.7% sustained viral response (SVR)], followed-up for median 25.2 and 46.8 months, respectively. RESULTS During follow-up, 48 patients developed liver decompensation and 24 HCC. Older age was significantly related to disease progression (HR = 2.6 per 10 years of increasing age). Stratified by baseline cirrhosis, Cox analysis showed that patients with SVR, but not without SVR, had significantly lower hazard for events compared with nontreated patients (HR = 0.16; P < 0.001), whereas the detrimental effect of older age remained highly significant. Separate group analysis demonstrated that in cirrhosis, the beneficial effect of treatment was evident even without SVR. Treatment effect interacted significantly with age, indicating that older patients, mainly noncirrhotic, gained the most benefit. CONCLUSIONS IFNalpha-based treatment does alter the natural course of CHC. A protective effect is mostly present in patients with SVR, but older patients, at higher risk of events, gain the greatest benefit. In established cirrhosis, treatment carries a protective effect even among those without SVR.
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Abstract
UNLABELLED Alpha interferon is the only licensed drug for hepatitis B with immunomodulatory as well as viral inhibitory properties. Potential advantages of interferon compared to nucleoside analogs include a lack of drug resistance, a finite and defined treatment course, and a higher likelihood for hepatitis B surface antigen (HBsAg) clearance. Approximately 30% of hepatitis B e antigen (HBeAg)-positive and 40% of HBeAg-negative cases have a sustained virological response (when defined as HBeAg seroconversion and/or hepatitis B virus (HBV) DNA levels below 20,000 copies/mL, respectively) 6 months after completion of a 48-week course of peginterferon alfa-2a These responses remain durable in 80% and 50% of cases, respectively, when evaluated several years later. Recent studies have shown that changes in HBsAg and HBeAg concentration during treatment predict sustained virological response and serial monitoring of HBsAg is helpful in predicting HBsAg clearance. HBeAg-positive patients with genotype A have higher rates of HBeAg and HBsAg clearance, whereas HBeAg-negative patients with genotype D have the lowest rate of response to interferon therapy. Long-term follow-up of virological responders to either standard alpha interferon or peginterferon has demonstrated a progressive increase in the rate of HBsAg clearance, particularly in patients who were initially HBeAg-positive. Future studies need to address if specific virological benchmarks during therapy can be used to tailor treatment duration. CONCLUSION Peginterferon alfa has a place as first-line therapy of hepatitis B in patients who are carefully selected on the basis of pretreatment serum HBV DNA and aminotransferase levels, safety considerations, and viral genotype.
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Affiliation(s)
- Robert Perrillo
- Hepatology Division, Baylor University Medical Center; Dallas, TX 75246, USA.
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Tea polyphenols exerts anti-hepatitis B virus effects in a stably HBV-transfected cell line. ACTA ACUST UNITED AC 2009; 29:169-72. [DOI: 10.1007/s11596-009-0206-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2008] [Indexed: 11/25/2022]
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Abstract
In 2007, the world celebrated the 50th anniversary of the discovery of interferon (IFN) by Isaacs and Lindenmann. Subsequently, the IFN-alpha gene was cloned, fully sequenced and IFN-alpha was produced in recombinant form. Recombinant IFN-alpha is now used as the basis for treatment of chronic hepatitis C virus infection and can also be used to treat certain forms of chronic hepatitis B virus infections. IFNs have also been used in other viral infections, although with less success. The antiviral mechanisms of IFNs are reviewed in this chapter as well as the utility of IFNs in the treatment of persistent viral infections.
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Affiliation(s)
- Hans-Georg Kräusslich
- Hygiene Institute Department of Virology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, Heidelberg, 69120 Germany
| | - Ralf Bartenschlager
- Hygiene Institute Department of Virology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, Heidelberg, 69120 Germany
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