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Tamai H, Ida Y, Kawashima A, Shingaki N, Shimizu R, Moribata K, Nasu T, Maekita T, Iguchi M, Kato J, Nakao T, Kitano M. Simeprevir-Based Triple Therapy with Reduced Doses of Pegylated Interferon α-2a Plus Ribavirin for Interferon Ineligible Patients with Genotype 1b Hepatitis C Virus. Gut Liver 2018; 11:551-558. [PMID: 28506030 PMCID: PMC5491091 DOI: 10.5009/gnl16525] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 12/10/2016] [Accepted: 12/23/2016] [Indexed: 12/28/2022] Open
Abstract
Background/Aims The present study aimed to evaluate the safety and efficacy of simeprevir-based triple therapy with reduced doses of pegylated interferon (PEG-IFN) and ribavirin for interferon (IFN) ineligible patients, such as elderly and/or cirrhotic patients, and to elucidate the factors contributing to a sustained virologic response (SVR). Methods One hundred IFN ineligible patients infected with genotype 1b hepatitis C virus (HCV) were treated. Simeprevir (100 mg) was given orally together with reduced doses of PEG-IFN-α 2a (90 μg), and ribavirin (200 mg less than the recommended dose). Results The patients’ median age was 70 years, and 70 patients were cirrhotic. Three patients (3%) discontinued treatment due to adverse events. The SVR rate was 64%. Factors that significantly contributed to the SVR included the γ-glutamyl transferase and α-fetoprotein levels, interleukin-28B (IL28B) polymorphism status, and the level and reduction of HCV RNA at weeks 2 and 4. The multivariate analysis showed that the IL28B polymorphism status was the only independent factor that predicted the SVR, with a positive predictive value of 77%. Conclusions Simeprevir-based triple therapy with reduced doses of PEG-IFN and ribavirin was safe and effective for IFN ineligible patients infected with genotype 1b HCV. IL28B polymorphism status was a useful predictor of the SVR.
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Affiliation(s)
- Hideyuki Tamai
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Yoshiyuki Ida
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Akira Kawashima
- Department of Internal Medicine, Naga Municipal Hospital, Wakayama, Japan
| | - Naoki Shingaki
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Ryo Shimizu
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Kosaku Moribata
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Tetsushi Nasu
- Department of Internal Medicine, Naga Municipal Hospital, Wakayama, Japan
| | - Takao Maekita
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Mikitaka Iguchi
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Jun Kato
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Taisei Nakao
- Department of Internal Medicine, Naga Municipal Hospital, Wakayama, Japan
| | - Masayuki Kitano
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
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Jung CH, Um SH, Kim TH, Yim SY, Suh SJ, Yim HJ, Seo YS, Choi HS, Chun HJ. Treatment Response and Long-Term Outcome of Peginterferon α and Ribavirin Therapy in Korean Patients with Chronic Hepatitis C. Gut Liver 2017; 10:808-17. [PMID: 27114417 PMCID: PMC5003206 DOI: 10.5009/gnl15360] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 10/15/2015] [Accepted: 10/27/2015] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND/AIMS Peginterferon plus ribavirin remains a standard therapy for patients with chronic hepatitis C (CHC) in Korea. We investigated the efficacy and long-term outcome of peginterferon and ribavirin therapy in Korean patients with CHC, particularly in relation to the stage of liver fibrosis. METHODS The incidence of sustained virological response (SVR), hepatic decompensation, hepatocellular carcinoma, and liver-related death was analyzed in 304 patients with CHC; the patients were followed up for a median of 54 months. RESULTS Among patients with HCV genotype 1, the SVR rate was 36.7% (18/49) and 67% (69/103) for patients with and without cirrhosis, respectively (p<0.001). For patients with non-1 HCV genotypes, the SVR rates were 86.0% (37/43) in cirrhotic patients and 86.2% (94/109) in noncirrhotic patients. SVR significantly reduced the risk of liverrelated death, hepatic decompensation, and hepatocellular carcinoma, which had hazard ratios of 0.27, 0.16, and 0.22, respectively (all p<0.05). However, despite the SVR rate, patients with advanced fibrosis were still at risk of developing liver-related complications. CONCLUSIONS A relatively high SVR rate was achieved by peginterferon plus ribavirin therapy in Korean patients with CHC, which improved their long-term outcomes. However, all CHC patients with advanced hepatic fibrosis should receive close follow-up observations, even after successful antiviral treatment.
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Affiliation(s)
- Chang Ho Jung
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Soon Ho Um
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Tae Hyung Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Sun Young Yim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Sang Jun Suh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Hyung Joon Yim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Yeon Seok Seo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Hyuk Soon Choi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Hoon Jai Chun
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
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Velosa J. Why is viral eradication so important in patients with HCV-related cirrhosis? Antivir Ther 2016; 22:1-12. [PMID: 27553973 DOI: 10.3851/imp3077] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/18/2016] [Indexed: 02/07/2023]
Abstract
Approximately one-third of patients infected with chronic HCV have cirrhosis, and this is likely to increase in the near future. The risk of complications, mainly the development of hepatocellular carcinoma, depends on the presence of cirrhosis, and a significant increase in the incidence of cirrhosis-related events, including mortality, is likely in the following years. All-oral therapy with direct-acting antivirals (DAAs) offers a safe and short treatment, with cure rates over 90% in compensated cirrhosis. Cirrhotic patients should be given high priority for treatment because viral clearance has a significant impact on the natural history of HCV infection, halting the progression of the disease and inducing the regression of fibrosis, as well as reducing the need for liver transplantation and improving survival. The benefit of DAAs is great in patients with decompensated cirrhosis, up until recently a population for whom no alternative therapy was available. The efficacy of all-oral therapy has been reported to improve liver function in about 50% of Child-Pugh class C patients. The regression of cirrhosis observed in more than half of patients achieving viral eradication on prior interferon-based regimens still has to be demonstrated in patients treated with DAAs, although there is reason to believe that this will happen. Advanced cirrhosis will eventually become the last boundary of antiviral therapy that will soon be conquered with new drugs currently pending approval.
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Affiliation(s)
- José Velosa
- Hospital de Santa Maria - Gastroenterology and Hepatology, Lisbon, Portugal
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Evidence-based clinical practice guidelines for liver cirrhosis 2015. J Gastroenterol 2016; 51:629-50. [PMID: 27246107 DOI: 10.1007/s00535-016-1216-y] [Citation(s) in RCA: 231] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 04/12/2016] [Indexed: 02/04/2023]
Abstract
The Japanese Society of Gastroenterology revised the evidence-based clinical practice guidelines for liver cirrhosis in 2015. Eighty-three clinical questions were selected, and a literature search was performed for the clinical questions with use of the MEDLINE, Cochrane, and Igaku Chuo Zasshi databases for the period between 1983 and June 2012. Manual searching of the latest important literature was added until August 2015. The guidelines were developed with use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. This digest version in English introduces selected clinical questions and statements related to the management of liver cirrhosis and its complications. Branched-chain amino acids relieve hypoalbuminemia and hepatic encephalopathy and improve quality of life. Nucleoside analogues and peginterferon plus ribavirin combination therapy improve the prognosis of patients with hepatitis B virus related liver cirrhosis and hepatitis C related compensated liver cirrhosis, respectively, although the latter therapy may be replaced by direct-acting antivirals. For liver cirrhosis caused by primary biliary cirrhosis and active autoimmune hepatitis, urosodeoxycholic acid and steroid are recommended, respectively. The most adequate modalities for the management of variceal bleeding are the endoscopic injection sclerotherapy for esophageal varices and the balloon-occluded retrograde transvenous obliteration following endoscopic obturation with cyanoacrylate for gastric varices. Beta-blockers are useful for primary prophylaxis of esophageal variceal bleeding. The V2 receptor antagonist tolvaptan is a useful add-on therapy in careful diuretic therapy for ascites. Albumin infusion is useful for the prevention of paracentesis-induced circulatory disturbance and renal failure. In addition to disaccharides, the nonabsorbable antibiotic rifaximin is useful for the management of encephalopathy. Anticoagulation therapy is proposed for patients with acute-onset or progressive portal vein thrombosis.
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Di Marco V, Calvaruso V, Ferraro D, Bavetta MG, Cabibbo G, Conte E, Cammà C, Grimaudo S, Pipitone RM, Simone F, Peralta S, Arini A, Craxì A. Effects of Eradicating Hepatitis C Virus Infection in Patients With Cirrhosis Differ With Stage of Portal Hypertension. Gastroenterology 2016; 151:130-139.e2. [PMID: 27039970 DOI: 10.1053/j.gastro.2016.03.036] [Citation(s) in RCA: 111] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2015] [Revised: 02/22/2016] [Accepted: 03/15/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Clearance of hepatitis C virus (HCV) via antiviral treatment changes the course of liver disease. We evaluated the benefit of sustained virologic response (SVR) in patients with HCV and cirrhosis without (stage 1) and with (stage 2) esophageal varices (EV). METHODS We performed a prospective cohort study of 444 patients with HCV and compensated cirrhosis (218 with stage 1 and 226 with stage 2 disease) treated with peg-interferon and ribavirin from June 2001 through December 2009 at the University of Palermo, Italy and followed for a median of 7.6 years (range, 1-12.6 years). We used Cox regression analysis to identify variables associated with appearance or progression of EVs, development of hepatocellular carcinoma (HCC), liver decompensation, and overall survival. RESULTS In the intention-to-treat analysis, 67 patients with stage 1 disease (30.7%) and 41 patients with stage 2 disease (18.1%) achieved an SVR (P = .003). Patients with stage 1 disease and an SVR were less likely to develop EVs than stage 1 patients without an SVR (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.11-0.48; P < .001). However, SVR did not affect whether patients with stage 2 disease developed further EVs (HR, 1.58; 95% CI, 0.33-1.03; P = .07, by log-rank test). An SVR was associated with lower risk for HCC (HR, 0.25; 95% CI, 0.12-0.55; P < .001). Patients with stage 2 disease, regardless of SVR, were at greater risk than patients with stage 1 disease for liver decompensation (HR, 2.82; 95% CI, 1.73-4.59; P < .001) or death (HR, 1.77; 95% CI, 1.12-2.80; P = .015). A lower proportion of patients with stage 1 disease and an SVR died from HCC (2.9%), compared with those without an SVR (11.9%) (P = .03) or developed liver decompensation (none vs 7.1% without an SVR; P = .009). A lower proportion of patients with stage 2 disease and an SVR died from causes secondary to HCC (2.0%) compared with those without an SVR (18.4%) (P = .003). Death from causes secondary to liver decompensation did not differ significantly between patients with stage 2 disease with or without an SVR (12.1% vs 25.4%; P = .15). CONCLUSIONS In a prospective study of 444 patients with HCV and compensated cirrhosis, HCV eradication reduced risk for liver decompensation, HCC, and death, regardless of whether the patients had EVs.
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Affiliation(s)
- Vito Di Marco
- Sezione di Gastroenterologia e Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Italy.
| | - Vincenza Calvaruso
- Sezione di Gastroenterologia e Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Italy
| | - Donatella Ferraro
- Sezione di Microbiologia, Dipartimento di Scienze per la Promozione della Salute e Materno-Infantile G. D'Alessandro, University of Palermo, Italy
| | - Maria Grazia Bavetta
- Sezione di Gastroenterologia e Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Italy
| | - Giuseppe Cabibbo
- Sezione di Gastroenterologia e Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Italy
| | - Elisabetta Conte
- Sezione di Gastroenterologia e Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Italy
| | - Calogero Cammà
- Sezione di Gastroenterologia e Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Italy
| | - Stefania Grimaudo
- Sezione di Gastroenterologia e Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Italy
| | - Rosaria Maria Pipitone
- Sezione di Gastroenterologia e Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Italy
| | - Fabio Simone
- Sezione di Gastroenterologia e Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Italy
| | - Sergio Peralta
- Sezione di Gastroenterologia e Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Italy
| | - Andrea Arini
- Sezione di Gastroenterologia e Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Italy
| | - Antonio Craxì
- Sezione di Gastroenterologia e Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Italy
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Dresch KFN, Mattos AAD, Tovo CV, Onofrio FQD, Casagrande L, Feltrin AA, Barros ICD, Almeida PRLD. IMPACT OF THE PEGYLATED-INTERFERON AND RIBAVIRIN THERAPY ON THE TREATMENT-RELATED MORTALITY OF PATIENTS WITH CIRRHOSIS DUE TO HEPATITIS C VIRUS. Rev Inst Med Trop Sao Paulo 2016; 58:37. [PMID: 27253739 PMCID: PMC4879994 DOI: 10.1590/s1678-9946201658037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2015] [Accepted: 11/17/2015] [Indexed: 12/15/2022] Open
Abstract
UNLABELLED Although the protease inhibitors have revolutionized the therapy of chronic hepatitis C (CHC), the concomitant use of pegylated-interferon (PEG-IFN) and ribavirin (RBV) is associated to a high rate of adverse effects. In this study, we evaluated the consequences of PEG-IFN and RBV and their relationship with mortality in patients with cirrhosis. METHODS Medical records of CHC who underwent treatment with PEG-IFN and RBV in a public hospital in Brazil were evaluated. All the patients with cirrhosis were selected, and their clinical and laboratory characteristics, response to treatment, side effects and mortality were evaluated. RESULTS From the 1,059 patients with CHC, 257 cirrhotic patients were evaluated. Of these, 45 (17.5%) achieved sustained viral response (SVR). Early discontinuation of therapy occurred in 105 (40.8%) patients, of which 39 (15.2%) were due to serious adverse effects. The mortality rate among the 257 cirrhotic patients was 4.3%, occurring in 06/242 (2.4%) of the Child-A, and in 05/15 (33.3%) of the Child-B patients. In conclusion, the treatment of patients with cirrhosis due to HCV with PEG-IFN and RBV shows a low SVR rate and a high mortality, especially in patients with liver dysfunction.
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Affiliation(s)
| | | | | | | | - Leandro Casagrande
- Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brasil
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Mandorfer M, Kozbial K, Freissmuth C, Schwabl P, Stättermayer AF, Reiberger T, Beinhardt S, Schwarzer R, Trauner M, Ferlitsch A, Hofer H, Peck-Radosavljevic M, Ferenci P. Interferon-free regimens for chronic hepatitis C overcome the effects of portal hypertension on virological responses. Aliment Pharmacol Ther 2015; 42:707-718. [PMID: 26179884 DOI: 10.1111/apt.13315] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Revised: 03/14/2015] [Accepted: 06/22/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Portal hypertension is the strongest predictor of virological response to pegylated interferon (IFN)/ribavirin in patients with chronic hepatitis C (CHC)-related cirrhosis. AIM To investigate the effects of portal pressure assessed by hepatic venous pressure gradient (HVPG) measurement on virological responses in patients treated with IFN-free regimens outside of clinical trials. METHODS Fifty-six patients with CHC and cirrhosis who underwent HVPG measurement before starting an IFN-free therapy were retrospectively studied. Patients were treated with sofosbuvir in combination with daclatasvir (n = 32), ribavirin (n = 12) or simeprevir (n = 11), or the combination of simeprevir/daclatasvir (n = 1), for 12-24 weeks. RESULTS Hepatic venous pressure gradient values ≥10 mmHg and ≥16 mmHg were observed in 41 (73%) and 31 (55%) patients respectively. The distributions of treatment regimens and durations were comparable between patients with or without portal hypertension. Patients with portal hypertension had lower platelet counts and albumin levels, while bilirubin levels, INR, MELD and Child-Pugh scores were higher than in patients without portal hypertension. Importantly, rates of on-treatment virological response and viral kinetics, as well as the rates of sustained virological response 12 weeks after the end of therapy [96% (54/56)] were not affected by portal hypertension. Anti-viral therapy improved liver stiffness, platelet count, serum albumin and bilirubin levels, as well as prothrombin time. CONCLUSIONS This is the first study to demonstrate that IFN-free regimens overcome the negative effect of portal hypertension on virological responses and viral kinetics. Improvements in liver stiffness and platelet count might reflect an anti-portal hypertensive effect of IFN-free treatments.
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Affiliation(s)
- M Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - K Kozbial
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - C Freissmuth
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - P Schwabl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - A F Stättermayer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - T Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - S Beinhardt
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - R Schwarzer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - M Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - A Ferlitsch
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - H Hofer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - M Peck-Radosavljevic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - P Ferenci
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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Understanding the Complexities of Cirrhosis. Clin Ther 2015; 37:1822-36. [DOI: 10.1016/j.clinthera.2015.05.507] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2015] [Revised: 03/25/2015] [Accepted: 05/08/2015] [Indexed: 12/13/2022]
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van der Meer AJ. Achieving sustained virological response: what's the impact on further hepatitis C virus-related disease? Expert Rev Gastroenterol Hepatol 2015; 9:559-66. [PMID: 25579804 DOI: 10.1586/17474124.2015.1001366] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Continuous hepatic inflammation as a result of chronic infection with the hepatitis C virus may lead to the development of fibrosis and eventually cirrhosis. At the stage of cirrhosis, patients are at elevated risk of liver failure and hepatocellular carcinoma, two complications that shorten their life expectancy. Survival may be further impaired by the extra-hepatic manifestations of chronic hepatitis C virus infection, such as diabetes mellitus and lymphoma. Sustained virological response (SVR) following antiviral therapy has been associated with regression of hepatic fibrosis as well as with a reduction in portal pressure, both important markers of liver disease severity. Long-term follow-up studies indicated that SVR was related not only to a reduced occurrence of solid clinical end points, including liver failure and hepatocellular carcinoma, but also cardiovascular events and malignant lymphomas. Together, these findings may explain the recently observed improved overall survival among patients who attained SVR, even in the case of advanced liver disease.
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Affiliation(s)
- Adriaan J van der Meer
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, 's Gravendijkwal 230, Room Ha 206, 3015 CE Rotterdam, The Netherlands
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Gentile I, Buonomo AR, Zappulo E, Borgia G. Interferon-free therapies for chronic hepatitis C: toward a hepatitis C virus-free world? Expert Rev Anti Infect Ther 2015; 12:763-73. [PMID: 24918116 DOI: 10.1586/14787210.2014.929497] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
About 2% of the world's population is estimated to be chronically infected with hepatitis C virus (HCV). These chronic carriers are at risk of developing liver cirrhosis and its complications. Successful treatment of HCV infection is associated with improved quality of life and increased survival. Antiviral approaches were formerly based on interferon and therefore all patients with a contraindication to interferon were excluded from treatment (e.g., patients with decompensated disease, severe impairment of other organs). Very recently, interferon-free combinations have become available for genotypes 2 and 3. This review focuses on the most recently reported data on the various interferon-free combinations used (namely, sofosbuvir-based combinations, the ABT-450/ombitasvir/dasabuvir/ribavirin combination, the daclatasvir/asunaprevir combination, and the MK-5172/MK-8742 combination). All these combinations yielded amazing results in terms of efficacy (90-100%), tolerability and safety. If the problem of the high cost is overcome, interferon-free therapies will lead to what has long been a chimera, namely, an HCV-free world.
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Affiliation(s)
- Ivan Gentile
- Department of Clinical Medicine and Surgery, University of Naples "Federico II", via S. Pansini 5, I-80131 Naples, Italy
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Kumari R, Nguyen MH. Fixed-dose combination of sofosbuvir and ledipasvir for the treatment of chronic hepatitis C genotype 1. Expert Opin Pharmacother 2015; 16:739-48. [PMID: 25676581 DOI: 10.1517/14656566.2015.1013938] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
INTRODUCTION The recent October 2014 approval of the fixed dose combination (FDC) of the NS5B polymerase inhibitor sofosbuvir (SOF) and the NS5A inhibitor ledipasvir (LDV) for the treatment of treatment-naive and -experienced HCV genotype 1a/1b (HCV-1) has marked a new era of IFN and ribavirin free treatment for chronic hepatitis C. SOF/LDV combination is approved for 12 weeks in treatment-naive patients with and without cirrhosis. For treatment-experienced patients, it is approved for 12 weeks in patients without cirrhosis but for 24 weeks in patients with cirrhosis. A shorter 8-week course of treatment can be considered for treatment-naive patients who have pretreatment HCV RNA of < 6 million IU/ml and do not have cirrhosis. AREAS COVERED The purpose of this synopsis is to review the pharmacotherapy and results of pivotal clinical trials for SOF/LDV as the current standard-of-care for HCV-1 patients. We also briefly discuss emerging data with SOF/LDV for certain special populations. Preliminary data is also emerging for HCV genotypes non-1, but their discussion is beyond the scope of this synopsis. The review was done based on data from Phase I, II and III published studies as well as data presented at major national and international meetings. EXPERT OPINION The FDC of LDV (90 mg) and SOF (400 mg) has a sustained virologic response of approximately 96% when given as a once-a-day pill for 3 months to both treatment-naive and -experienced HCV-1 patients with the exception of prior null responders with cirrhosis. The latter group of patients also achieves high sustained virologic response of 95% but with therapy for 24 weeks. In addition, emerging data suggest that this FDC regimen may be effective in the treatment of HCV-1 co-infected patients with HIV, HCV-1 and -4, patients with cirrhosis and hepatic decompensation and those with post-liver transplant HCV recurrence.
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Affiliation(s)
- Radhika Kumari
- Stanford University Medical Center, Division of Gastroenterology and Hepatology , 750 Welch Road, Suite 210, Palo Alto, CA 94304 , USA
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Lee HJ, Yeon JE, Yoon EL, Suh SJ, Kang K, Kim HR, Kang SH, Yoo YJ, Je J, Kim JH, Seo YS, Yim HJ, Byun KS. Long-term follow-up of chronic hepatitis C patients treated with interferon-alpha: risk of cirrhosis and hepatocellular carcinoma in a single center over 10 years. Intervirology 2015; 58:14-21. [PMID: 25592614 DOI: 10.1159/000369206] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Accepted: 10/18/2014] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVES Interferon (IFN)-based therapy for chronic hepatitis C (CHC) is cost-effective and is associated with reduced risk of disease progression. We aimed to assess the incidence of cirrhosis and hepatocellular carcinoma (HCC) and to identify risk factors associated with disease progression. METHODS We retrospectively reviewed 280 CHC patients who were registered at our hospital between 2001 and 2010. RESULTS About 80% of patients received antiviral treatment. The 10-year cumulative incidence of cirrhosis was significantly lower among patients who received antiviral therapy than among those who did not (8.3 vs. 44.0%; p = 0.001). Among them, patients with sustained virological response (SVR) had a significantly lower incidence of cirrhosis than those without SVR (0.6 vs. 33.9%; p < 0.001). Cox proportional hazards regression showed that SVR was the significant independent factor for reducing the risk of cirrhosis (hazard ratio, HR = 0.03; p = 0.034). The 10-year cumulative incidence of HCC was higher among patients who did not receive antiviral therapy than among those who did (43.9 vs. 6.1%; p < 0.001). Multivariate analysis showed that underlying cirrhosis was the only independent risk factor associated with HCC development (HR = 7.70; p = 0.010). CONCLUSIONS SVR secondary to IFN-based therapy could reduce cirrhosis development in CHC patients. Underlying cirrhosis was the strongest predictor of HCC development.
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Affiliation(s)
- Hyun Jung Lee
- Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea
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13
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Atsukawa M, Tsubota A, Shimada N, Kondo C, Itokawa N, Nakagawa A, Hashimoto S, Fukuda T, Matsushita Y, Narahara Y, Iwakiri K, Nakatsuka K, Kawamoto C, Sakamoto C. Serum 25-hydroxyvitamin D3 levels affect treatment outcome in pegylated interferon/ribavirin combination therapy for compensated cirrhotic patients with hepatitis C virus genotype 1b and high viral load. Hepatol Res 2014; 44:1277-85. [PMID: 24417888 DOI: 10.1111/hepr.12298] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Revised: 12/11/2013] [Accepted: 01/07/2014] [Indexed: 02/08/2023]
Abstract
AIM Much is unknown about the effect of 25-hydroxyvitamin D3 levels on the outcome of pegylated interferon/ribavirin (PEG IFN/RBV) therapy for hepatitis C virus-related cirrhosis. The purpose of the present study was to analyze and elucidate factors, including 25-hydroxyvitamin D3 , that contribute to a sustained virological response (SVR) in patients with cirrhosis. METHODS We analyzed whether 25-hydroxyvitamin D3 contributes to the response to PEG IFN/RBV therapy among 134 cirrhotic patients. RESULTS SVR was achieved in 43 patients. The median 25-hydroxyvitamin D3 level was 20 ng/mL. Univariate analysis showed that the following factors contributed to SVR: low-density lipoprotein cholesterol, albumin, 25-hydroxyvitamin D3 , core a.a.70 (a.a.70) substitutions, the number of mutations at the interferon sensitivity-determining region and IL28B genotype. Multivariate analysis identified IL28B genotype and 25-hydroxyvitamin D3 as independent factors contributing to SVR. Subsequently, SVR rate was examined by using 25-hydroxyvitamin D3 and other important factors. The SVR rate was 51.8% in patients with core a.a.70 wild and ≥15 ng/mL of 25-hydroxyvitamin D3 , whereas the SVR rate was 7.1% in patients with core a.a.70 wild and <15 ng/mL of 25-hydroxyvitamin D3 . The SVR rate was 56.9% in patients with IL28B major genotype and ≥15 ng/mL of 25-hydroxyvitamin D3 . Surprisingly, the SVR rate was 0% in patients with IL28B minor genotype and <15 ng/mL of 25-hydroxyvitamin D3 . CONCLUSION IL28B genotype and 25-hydroxyvitamin D3 were identified as independent factors contributing to SVR. Stratified analyses according to core a.a.70 substitution and IL28B genotype suggested that 25-hydroxyvitamin D3 influences the outcome of PEG IFN/RBV therapy for cirrhosis.
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Affiliation(s)
- Masanori Atsukawa
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan
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14
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Gentile I, Buonomo AR, Zappulo E, Coppola N, Borgia G. GS-9669: a novel non-nucleoside inhibitor of viral polymerase for the treatment of hepatitis C virus infection. Expert Rev Anti Infect Ther 2014; 12:1179-86. [PMID: 25096404 DOI: 10.1586/14787210.2014.945432] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hepatitis C virus (HCV) is an RNA virus that chronically infects 2-3% of the world's population. About 25% of these chronic carriers evolve towards liver cirrhosis, a disease that is significantly associated with reduced survival and quality of life. Antiviral therapy can eradicate the infection - a process that is associated with a reduced disease progression rate. Several oral direct agents have been developed and tested for the treatment of HCV infection. This review focuses on the mechanism of action, pharmacokinetics, efficacy, safety and resistance of GS-9669, a non-nucleoside inhibitor of viral polymerase, active against HCV genotype 1. In combination with other oral antivirals, GS-9669 results: in very high rates of viral eradication (90-100%) in patients with HCV genotype 1 infection, with a good tolerability and safety profile. In conclusion, GS-9669 is a good candidate to be used in interferon-free combinations for the treatment of chronic HCV infection.
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Affiliation(s)
- Ivan Gentile
- Department of Clinical Medicine and Surgery, University of Naples 'Federico II', via S. Pansini 5,I-80131 Naples, Italy
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15
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Gentile I, Buonomo AR, Borgia G. Ombitasvir: a potent pan-genotypic inhibitor of NS5A for the treatment of hepatitis C virus infection. Expert Rev Anti Infect Ther 2014; 12:1033-43. [PMID: 25074011 DOI: 10.1586/14787210.2014.940898] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hepatitis C virus (HCV) chronically infects about 150,000,000 people worldwide and is a relevant cause of liver cirrhosis, hepatocellular carcinoma and death. Antiviral treatment is rapidly moving from interferon (IFN)-based therapy to IFN-free approaches. This review focuses on the mechanism of action, pharmacokinetics, efficacy, tolerability, safety and resistance of ombitasvir, which is an inhibitor of the HCV nonstructural protein 5A. The pharmacokinetics of ombitasvir enables its once daily administration. In vivo, in combinations with other oral direct acting antivirals, ombitasvir achieves very high rates of sustained virological response (about 95%) in patients with HCV genotype 1 infection with a good tolerability. Resistance profiling revealed a low barrier to resistance when given as monotherapy. However, coadministration of ombitasvir and other antivirals enhances its barrier to resistance. In conclusion, ombitasvir is a good drug to be used in IFN-free combinations for the treatment of chronic hepatitis C.
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Affiliation(s)
- Ivan Gentile
- Department of Clinical Medicine and Surgery, University of Naples "Federico II", via S. Pansini 5, I-80131 Naples, Italy
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16
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Gentile I, Buonomo AR, Zappulo E, Minei G, Morisco F, Borrelli F, Coppola N, Borgia G. Asunaprevir, a protease inhibitor for the treatment of hepatitis C infection. Ther Clin Risk Manag 2014; 10:493-504. [PMID: 25061308 PMCID: PMC4079632 DOI: 10.2147/tcrm.s66731] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
According to the World Health Organization, approximately 150 million people worldwide are chronic carriers of hepatitis C virus (HCV). HCV infection can evolve into cirrhosis of the liver and its complications, which are ultimately responsible for more than 350,000 deaths every year. Antiviral therapy, when successful, is able to decrease the rate of progression and increase survival. Two types of therapies are currently available, ie, interferon-based therapies and interferon-free ones. The latter have several advantages in terms of safety and tolerability, and could be used even in the most advanced stages of the disease. However, their use is restricted to some viral genotypes (genotype 2 and 3) and they are expensive. Several molecules are in an advanced phase of development. This review deals with the pharmacokinetics, pharmacodynamics, tolerability, and safety of asunaprevir, an inhibitor of HCV nonstructural 3 protease. Asunaprevir exerts optimal in vitro activity particularly against HCV genotypes 1 and 4, and its pharmacokinetic profile enables twice daily administration. The drawback of asunaprevir, and of all protease inhibitors, is its low barrier to resistance. Consequently, it is used in association with other drugs to prevent resistance. Specifically, when combined with daclatasvir, an NS5A inhibitor, asunaprevir results in a very high rate of viral eradication in both treatment-naïve and treatment-experienced patients, with a sustained virological response rate of 80%-90%. Tolerability is fair; in fact, asunaprevir is associated with a transient increase in aminotransferase levels, which is mild in most cases. In conclusion, asunaprevir is a good candidate component of interferon-free combinations and may revolutionize the treatment of chronic HCV infection in the near future.
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Affiliation(s)
- Ivan Gentile
- Section of Infectious Diseases, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Antonio Riccardo Buonomo
- Section of Infectious Diseases, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Emanuela Zappulo
- Section of Infectious Diseases, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Giuseppina Minei
- Section of Infectious Diseases, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Filomena Morisco
- Section of Gastroenterology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Francesco Borrelli
- Section of Infectious Diseases, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Nicola Coppola
- Section of Infectious Diseases, Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy
| | - Guglielmo Borgia
- Section of Infectious Diseases, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
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17
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Gentile I, Coppola N, Buonomo AR, Zappulo E, Borgia G. Investigational nucleoside and nucleotide polymerase inhibitors and their use in treating hepatitis C virus. Expert Opin Investig Drugs 2014; 23:1211-23. [PMID: 24848437 DOI: 10.1517/13543784.2014.921680] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION About 150 million people worldwide are estimated to be chronically infected with the hepatitis C virus (HCV). Successful antiviral treatment can stop the progression of the disease toward liver cirrhosis, hepatocellular carcinoma and death. IFN has been the drug of choice and the backbone of all combinations in the past two decades. However, an IFN-free combination (sofosbuvir and ribavirin) has been recently approved for genotypes 2 and 3 patients with many other drugs in preclinical and clinical development. AREAS COVERED This review focuses on investigational nucleoside or nucleotide inhibitors of viral polymerase that are potential treatments of HCV. The article reviews drugs that are currently under investigational status. EXPERT OPINION Currently, mericitabine has the most robust data but its efficacy appears to be less than optimal. Other drugs such as ALS-2200 (and its diastereomer VX-135) and BMS-986094 are promising but the data in humans are too scanty to draw conclusions about their future role at this current point in time. Other promising molecules are LG-7501, ACH-3422 and EP-NI266, although no clinical studies have been performed thus far, so this must be rectified. Another drug of promise GS-6620 has displayed a high degree of pharmacokinetic and pharmacodynamic variability, which makes further development unlikely.
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Affiliation(s)
- Ivan Gentile
- University of Naples "Federico II", Department of Clinical Medicine and Surgery , via S. Pansini 5, I-80131 Naples , Italy +39 0 81 7463083 ; +39 0 81 7463190 ;
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18
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Gentile I, Buonomo AR, Borgia F, Zappulo E, Castaldo G, Borgia G. MK-5172 : a second-generation protease inhibitor for the treatment of hepatitis C virus infection. Expert Opin Investig Drugs 2014; 23:719-28. [PMID: 24666106 DOI: 10.1517/13543784.2014.902049] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Approximately 170 million people worldwide are chronic carriers of the hepatitis C virus (HCV). Twenty-five percent of them develop liver cirrhosis and hepatocellular carcinoma during their life. Successful antiviral treatment dramatically reduces the risk of disease progression. HCV infection is treated with pegylated interferon and ribavirin; the addition of a protease inhibitor (boceprevir or telaprevir) can also be considered for patients with genotype 1. AREAS COVERED This review summarizes the data about the pharmacokinetics, pharmacodynamics, efficacy and safety of MK-5172 , a second-generation inhibitor of HCV NS3/4A protease. EXPERT OPINION The pharmacokinetic profile allows for once-a-day administration. Combined with pegylated interferon and ribavirin, MK-5172 results in a high rate of HCV eradication (in about 90% of cases) and a better outcome than boceprevir-based triple therapy. Also in interferon-free combinations, MK-5172-associated eradication rates are very high (89 - 100%). MK-5172 has a higher barrier to resistance than first-generation protease inhibitors and is active against most variants associated with resistance to first-generation protease inhibitors. Tolerability and safety profile are good. Although data are limited, MK-5172 appears to overcome most of the drawbacks of the first-generation protease inhibitors and is thus a very promising agent to be used in combination with other antivirals to eradicate HCV infection.
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Affiliation(s)
- Ivan Gentile
- University of Naples "Federico II", Department of Clinical Medicine and Surgery (Ed. 18) , via S. Pansini 5, I-80131 Naples , Italy +39 0 81 7463178 ; +39 0 81 7463190 ;
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19
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Toshikuni N, Arisawa T, Tsutsumi M. Hepatitis C-related liver cirrhosis - strategies for the prevention of hepatic decompensation, hepatocarcinogenesis, and mortality. World J Gastroenterol 2014; 20:2876-2887. [PMID: 24659879 PMCID: PMC3961980 DOI: 10.3748/wjg.v20.i11.2876] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2013] [Revised: 01/13/2014] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis (LC) is a critical stage of chronic liver disease, including that caused by hepatitis C virus (HCV). In the absence of antiviral therapy, 67%-91% of patients with HCV-related LC patients die of liver-related causes, including hepatocellular carcinoma (HCC) and liver failure. Among the therapeutic strategies used to prevent liver-related complications in these patients is standard therapy with pegylated interferon and ribavirin, which induces a sustained virological response (SVR) in 25% of HCV genotype 1-infected patients and in 69% of patients infected with genotypes 2 and 3. SVR in patients with HCV-related LC has been associated with reduced rates of hepatic decompensation, HCC, and mortality. More recently developed direct-acting antiviral agents have shown excellent antiviral efficacy, with preliminary data demonstrating that an interferon-free regimen that includes these direct-acting antiviral agents achieved SVR in more than 50% of patients with HCV genotype 1 LC. Branched-chain amino acid supplementation, improvement of insulin resistance, and the use of β-blockers for portal hypertension may also reduce liver-related complications. Here, we review advances in antiviral and adjunctive therapies for improved outcomes in patients with HCV-associated LC.
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20
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Gentile I, Buonomo AR, Borgia F, Castaldo G, Borgia G. Ledipasvir: a novel synthetic antiviral for the treatment of HCV infection. Expert Opin Investig Drugs 2014; 23:561-71. [DOI: 10.1517/13543784.2014.892581] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Inagaki Y, Sugimoto K, Shiraki K, Tameda M, Kusagawa S, Nojiri K, Ogura S, Yamamoto N, Takei Y, Ito M, Mizuno S, Usui M, Sakurai H, Isaji S. The long-term effects of splenectomy and subsequent interferon therapy in patients with HCV-related liver cirrhosis. Mol Med Rep 2014; 9:487-492. [PMID: 24336960 DOI: 10.3892/mmr.2013.1856] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Accepted: 11/11/2013] [Indexed: 12/14/2022] Open
Abstract
Partial splenic embolization (PSE) or splenectomy is widely performed to increase platelet counts for interferon (IFN) therapy. The aim of the present study was to evaluate the long-term effects of splenectomy and subsequent IFN therapy in patients with hepatitis C virus (HCV)-related liver cirrhosis (LC). The present study included 19 patients with HCV-related LC who underwent splenectomy for thrombo-cytopenia caused by hypersplenism. IFN therapy was performed in all 19 patients. The effects of splenectomy and subsequent IFN therapy on peripheral blood counts, liver function, carcinogenesis and survival rates were evaluated. Splenectomy was safely performed in all patients without major complications with the exception of portal thrombosis, which, however, it did not affect liver function when treated appropriately. Thrombocytopenia improved and IFN therapy could be performed in all the patients. A sustained virological response (SVR) was not observed in patients with genotype 1 although it was observed in 75% of patients with genotype 2. Due to severe side effects, five patients did not undergo scheduled IFN therapy. Over 5 years, the mean platelet number increased from 5.2 x 10(4) to 16.8 x 10(4)/mm3 (P<0.01) and liver function improved following splenectomy (albumin, Alb: 3.5‑3.8 g/dl; total bilirubin, T-Bil: 1.0‑0.7 mg/dl; prothrombin time, PT: 74.1‑97.7%; total cholesterol; T-cho: 140‑168 mg/dl; P<0.05). Hepatocellular carcinoma (HCC) occurred in only one patient during long‑term observation and follow‑up of the patients not presenting with HCC at entry. The results of the present study demonstrate that splenectomy followed by interferon therapy could be beneficial in patients with HCV-related LC.
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Affiliation(s)
- Yuji Inagaki
- Department of Internal Medicine, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Kazushi Sugimoto
- Department of Internal Medicine, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Katsuya Shiraki
- Department of Internal Medicine, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Masahiko Tameda
- Department of Internal Medicine, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Satoko Kusagawa
- Department of Internal Medicine, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Keiichiro Nojiri
- Department of Internal Medicine, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Suguru Ogura
- Department of Internal Medicine, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Norihiko Yamamoto
- Department of Internal Medicine, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Yoshiyuki Takei
- Department of Internal Medicine, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Masaaki Ito
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Shugo Mizuno
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Masanobu Usui
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Hiroyuki Sakurai
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Shuji Isaji
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
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Agarwal K, Barnabas A. Treatment of chronic hepatitis C virus infection after liver transplantation. Dig Liver Dis 2013; 45 Suppl 5:S349-54. [PMID: 24091115 DOI: 10.1016/j.dld.2013.07.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Accepted: 07/01/2013] [Indexed: 12/11/2022]
Abstract
Chronic hepatitis C virus infection is a leading cause of end stage liver disease and one of the leading indications for liver transplantation. Furthermore, hepatitis C virus recurrence is universal post-transplant leading to decreased graft and patient survival. Recurrent disease related to hepatitis C virus can lead to between 20 and 30% of patients developing recurrent cirrhosis within 5 years. Treatment options with antiviral therapy are limited and are associated with a significant side-effect profile, suboptimal tolerability and inferior response rates. Attention has therefore turned to strategies that can reduce hepatitis C virus recurrence rates post-transplant. Approximately only 30% of patients will achieve a sustained virologic response with current therapy with pegylated interferon and ribavirin. Successful hepatitis C virus eradication is the only factor associated with improved graft and patient survival post liver transplantation. Here we provide an overview of antiviral treatment in patients in the transplant arena and the potential opportunities and challenges with the introduction of new directly acting antivirals in G1 patients.
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Affiliation(s)
- Kosh Agarwal
- Institute of Liver Studies, King's College Hospital, London, UK.
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Hatzakis A, Van Damme P, Alcorn K, Gore C, Benazzouz M, Berkane S, Buti M, Carballo M, Cortes Martins H, Deuffic-Burban S, Dominguez A, Donoghoe M, Elzouki AN, Ben-Alaya Bouafif N, Esmat G, Esteban R, Fabri M, Fenton K, Goldberg D, Goulis I, Hadjichristodoulou C, Hatzigeorgiou T, Hamouda O, Hasurdjiev S, Hughes S, Kautz A, Malik M, Manolakopoulos S, Matičič M, Papatheodoridis G, Peck R, Peterle A, Potamitis G, Prati D, Roudot-Thoraval F, Reic T, Sharara A, Shennak M, Shiha G, Shouval D, Sočan M, Thomas H, Thursz M, Tosti M, Trépo C, Vince A, Vounou E, Wiessing L, Manns M. The state of hepatitis B and C in the Mediterranean and Balkan countries: report from a summit conference. J Viral Hepat 2013; 20 Suppl 2:1-20. [PMID: 23827008 DOI: 10.1111/jvh.12120] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The burden of disease due to chronic viral hepatitis constitutes a global threat. In many Balkan and Mediterranean countries, the disease burden due to viral hepatitis remains largely unrecognized, including in high-risk groups and migrants, because of a lack of reliable epidemiological data, suggesting the need for better and targeted surveillance for public health gains. In many countries, the burden of chronic liver disease due to hepatitis B and C is increasing due to ageing of unvaccinated populations and migration, and a probable increase in drug injecting. Targeted vaccination strategies for hepatitis B virus (HBV) among risk groups and harm reduction interventions at adequate scale and coverage for injecting drug users are needed. Transmission of HBV and hepatitis C virus (HCV) in healthcare settings and a higher prevalence of HBV and HCV among recipients of blood and blood products in the Balkan and North African countries highlight the need to implement and monitor universal precautions in these settings and use voluntary, nonremunerated, repeat donors. Progress in drug discovery has improved outcomes of treatment for both HBV and HCV, although access is limited by the high costs of these drugs and resources available for health care. Egypt, with the highest burden of hepatitis C in the world, provides treatment through its National Control Strategy. Addressing the burden of viral hepatitis in the Balkan and Mediterranean regions will require national commitments in the form of strategic plans, financial and human resources, normative guidance and technical support from regional agencies and research.
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MESH Headings
- Antiviral Agents/economics
- Antiviral Agents/therapeutic use
- Balkan Peninsula/epidemiology
- Carcinoma, Hepatocellular/epidemiology
- Carcinoma, Hepatocellular/etiology
- Cross Infection/epidemiology
- Cross Infection/prevention & control
- Cross Infection/transmission
- Disease Transmission, Infectious/prevention & control
- Epidemiological Monitoring
- Hepatitis B Vaccines/administration & dosage
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/diagnosis
- Hepatitis B, Chronic/epidemiology
- Hepatitis B, Chronic/prevention & control
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/diagnosis
- Hepatitis C, Chronic/epidemiology
- Hepatitis C, Chronic/prevention & control
- Humans
- Liver Neoplasms/epidemiology
- Liver Neoplasms/etiology
- Mediterranean Region/epidemiology
- Treatment Outcome
- Vaccination/statistics & numerical data
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Affiliation(s)
- A Hatzakis
- National Retrovirus Reference Center, Department of Hygiene, Epidemiology and Medical Statistics, Athens University Medical School, Athens, Greece.
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Ciria R, Pleguezuelo M, Khorsandi SE, Davila D, Suddle A, Vilca-Melendez H, Rufian S, de la Mata M, Briceño J, Cillero PL, Heaton N. Strategies to reduce hepatitis C virus recurrence after liver transplantation. World J Hepatol 2013; 5:237-50. [PMID: 23717735 PMCID: PMC3664282 DOI: 10.4254/wjh.v5.i5.237] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2012] [Revised: 11/16/2012] [Accepted: 12/01/2012] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is a major health problem that leads to chronic hepatitis, cirrhosis and hepatocellular carcinoma, being the most frequent indication for liver transplantation in several countries. Unfortunately, HCV re-infects the liver graft almost invariably following reperfusion, with an accelerated history of recurrence, leading to 10%-30% of patients progressing to cirrhosis within 5 years of transplantation. In this sense, some groups have even advocated for not re-transplanting this patients, as lower patient and graft outcomes have been reported. However, the management of HCV recurrence is being optimized and several strategies to reduce post-transplant recurrence could improve outcomes, decrease the rate of re-transplantation and optimize the use of available grafts. Three moments may be the focus of potential actions in order to decrease the impact of viral recurrence: the pre-transplant moment, the transplant environment and the post-transplant management. In the pre-transplant setting, it is not well established if reducing the pre transplant viral load affects the risk for HCV progression after transplant. Obviously, antiviral treatment can render the patient HCV RNA negative post transplant but the long-term benefit has not yet been fully established to justify the cost and clinical risk. In the transplant moment, factors as donor age, cold ischemia time, graft steatosis and ischemia/reperfusion injury may lead to a higher and more aggressive viral recurrence. After the transplant, discussion about immunosuppression and the moment to start the treatment (prophylactic, pre-emptive or once-confirmed) together with new antiviral drugs are of interest. This review aims to help clinicians have a global overview of post-transplant HCV recurrence and strategies to reduce its impact on our patients.
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Affiliation(s)
- Ruben Ciria
- Ruben Ciria, Shirin Elizabeth Khorsandi, Diego Davila, Abid Suddle, Hector Vilca-Melendez, Nigel Heaton, Institute of Liver Studies, King's College Hospital, London SE5 9RS, United Kingdom
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Hepatitis C virus treatment and liver transplantation in the era of new antiviral therapies. Curr Opin Organ Transplant 2013; 17:216-24. [PMID: 22476221 DOI: 10.1097/mot.0b013e3283534d64] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW The new standard-of-care treatment for genotype 1 hepatitis C virus infection is a combination of PEG-interferon (PEG-IFN), ribavirin (RBV) and a protease inhibitor - telaprevir or boceprevir. As triple therapy is not yet approved for use in decompensated cirrhotics and liver transplant recipients, we examine the efficacy and safety of PEG-IFN, RBV and protease inhibitors in nontransplant populations to inform the current and future treatment paradigms for transplant candidates and recipients. RECENT FINDINGS Protease inhibitor-based triple therapy is more efficacious than PEG-IFN and RBV in nontransplant genotype 1 patients, so sustained virologic response rates are predicted to be higher in waitlisted candidates and transplant recipients treated with protease inhibitor-triple therapy. Because of the need to use a backbone of PEG-IFN and RBV, tolerability of therapy will remain a major challenge. Anemia, a well recognized side-effect with PEG-IFN and RBV, will be especially common with protease inhibitor-triple therapy. Both protease inhibitors can modify the levels of drugs metabolized by the CYP3A/4 pathway, and in posttransplant patients, the protease inhibitors increase the levels of cyclosporine and tacrolimus, with the magnitude of the drug-drug interactions varying with protease inhibitor and type of calcineurin inhibitor (CNI). SUMMARY Given the complexities of treatment, it is best undertaken by experienced clinicians and only after a detailed discussion of risks-benefits with the patient. To maximize the benefit while minimizing risk, only Child-Turcott-Pugh A (CPT-A) cirrhotics should be considered for pretransplant protease inhibitor-triple therapy. For transplant recipients, very close monitoring and adjustment of CNI levels is critical during protease inhibitor-triple therapy. Cytopenias, especially anemia, will require aggressive management.
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Joshi D, Carey I, Agarwal K. Review article: the treatment of genotype 1 chronic hepatitis C virus infection in liver transplant candidates and recipients. Aliment Pharmacol Ther 2013; 37:659-71. [PMID: 23432320 DOI: 10.1111/apt.12260] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Revised: 12/20/2012] [Accepted: 02/03/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND Recently, the therapeutic landscape with regard to anti-HCV therapy has changed dramatically. The new directly acting anti-virals (DAAs) have demonstrated improved sustained virological response (SVR) compared with pegylated-interferon and ribavirin. AIM To examine and present the latest data with regard to anti-viral therapy in genotype 1 HCV-positive transplant candidates and recipients. METHODS An electronic search using Medline was performed. Search terms included 'HCV, DAA and protease inhibitor' in combination with 'treatment pre-transplantation' and 'treatment post-transplantation'. RESULTS Patients with advanced fibrosis and cirrhosis have inferior SVR rates compared with patients with minimal fibrosis. A low accelerating dose regimen (LADR) of pegylated interferon and ribavirin (PR) appears to be a safe therapeutic option. Side effects also appear to be more pronounced in patients with advanced disease. Data from the large registration studies with triple therapy (boceprevir or telaprevir plus PR) demonstrated improved SVR rates even in patients with advanced disease, although virological relapse rates were highest amongst these patients. In transplant recipients, initial data are being reported on the use of triple therapy, and although no SVR data are available, promising results are accruing. The drug-drug interactions appear to be manageable. Side effects in particular anaemia appear to be markedly increased in the posttransplant setting. CONCLUSIONS The use of the new DAAs in patients with advanced fibrosis/cirrhosis pretransplant and posttransplant appears possible, with manageable side effects and drug-drug interactions, and improved early virological response rates. We recommend that these patients are managed in centres with the appropriate expertise.
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Affiliation(s)
- D Joshi
- Institute of Liver Studies, King's College Hospital, London, UK.
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Bota S, Sporea I, Sirli R, Popescu A, Neghină AM, Dănilă M, Străin M. Severe adverse events during antiviral therapy in hepatitis C virus cirrhotic patients: A systematic review. World J Hepatol 2013; 5:120-126. [PMID: 23556044 PMCID: PMC3612570 DOI: 10.4254/wjh.v5.i3.120] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2012] [Revised: 11/26/2012] [Accepted: 01/17/2013] [Indexed: 02/06/2023] Open
Abstract
AIM To identify severe adverse events (SAEs) leading to treatment discontinuation that occur during antiviral therapy in hepatitis C virus (HCV)-infected cirrhotic patients. METHODS We identified all the articles published prior to December 2011 in the PubMed, Medline, Lilacs, Scopus, Ovid, EMBASE, Cochrane and Medscape databases that presented these data in cirrhotic patients. These studies evaluated the rate of SAEs leading to discontinuation of standard care treatment: Pegylated interferon (PegIFN) alpha 2a (135-180 μg/wk) or PegIFN alpha 2b (1 or 1.5 μg/kg per week) and ribavirin (800-1200 mg/d). Patients with genotype 1 + 4 underwent treatment for 48 wk, whereas those with genotypes 2 + 3 were treated for 24 wk. RESULTS We included 17 papers in this review, comprising of 1133 patients. Treatment was discontinued due to SAEs in 14.5% of the patients. The most common SAEs were: severe thrombocytopenia and/or neutropenia (23.2%), psychiatric disorders (15.5%), decompensation of liver cirrhosis (12.1%) and severe anemia (11.2%). The proportion of patients who needed to discontinue their therapy due to SAEs was significantly higher in patients with Child-Pugh class B and C vs those with Child-Pugh class A: 22% vs 11.4% (P = 0.003). A similar discontinuation rate was found in cirrhotic patients treated with PegIFN alpha 2a and those treated with PegIFN alpha 2b, in combination with ribavirin: 14.2% vs 13.7% (P = 0.96). The overall sustained virological response rate in cirrhotic patients was 37% (95%CI: 33.5-43.1) but was significantly lower in patients with genotype 1 + 4 than in those with genotype 2 + 3: 20.5% (95%CI: 17.9-24.8) vs 56.5% (95%CI: 51.5-63.2), (P < 0.0001). CONCLUSION Fourteen point five percent of HCV cirrhotic patients treated with PegIFN and ribavirin needed early discontinuation of therapy due to SAEs, the most common cause being hematological disorders.
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Affiliation(s)
- Simona Bota
- Simona Bota, Ioan Sporea, Roxana Şirli, Alina Popescu, Mirela Dănilă, Mihnea Străin, Department of Gastroenterology and Hepatology, University of Medicine and Pharmacy, 300736 Timişoara, Romania
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Efficacy and safety of boceprevir plus peginterferon-ribavirin in patients with HCV G1 infection and advanced fibrosis/cirrhosis. J Hepatol 2013. [PMID: 23183529 DOI: 10.1016/j.jhep.2012.11.020] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS We assessed the safety and efficacy of boceprevir (BOC) plus peginterferon-ribavirin (PR) in patients with HCV-G1 infection and advanced fibrosis/cirrhosis (Metavir F3/F4). METHODS In two randomized controlled studies of previously untreated and previous treatment failures, patients received a 4-week lead-in of PR followed by PR plus placebo for 44 weeks (PR48); PR plus BOC using response guided therapy (BOC/RGT); or PR plus BOC for 44 weeks (BOC/PR48). RESULTS The trials enrolled 178 patients with F3/4. HCV RNA levels at week 4 and 8 were highly predictive of response. No patient with F3/4 in the PR48 arm with a <1 log(10) decline in HCV RNA at week 4 achieved SVR, whereas those randomized to BOC/RGT or BOC/PR48 had SVR rates of 11-33% (F3) and 10-14% (F4). In these latter groups, patients with high baseline viral load (>2 × 10(6)IU/ml) had an overall SVR rate of 6% (2/33). For patients with a ≥1 log(10) decline at week 4, SVR rates in the BOC/PR48 arm of SPRINT-2 and RESPOND-2, respectively, were 77% and 87% vs. 18% and 50% for PR48; SVR rates in early responders (undetectable HCV RNA at week 8) were 90-93% in the BOC/PR48 arm. Neutropenia and thrombocytopenia were more common in cirrhotics than non-cirrhotics. CONCLUSIONS BOC improves SVR rates in patients with F3/4, and longer treatment duration provides the most benefit. With triple therapy, SVR rates are modest in F4 patients with a <1 log(10) decline at week 4, thus the 4-week PR lead-in aids in the assessment of early futility.
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Di Marco V, Calvaruso V, Grimaudo S, Ferraro D, Pipitone RM, Di Stefano R, Craxì A. Role of IL-28B and inosine triphosphatase polymorphisms in efficacy and safety of Peg-Interferon and ribavirin in chronic hepatitis C compensated cirrhosis with and without oesophageal varices. J Viral Hepat 2013; 20:113-21. [PMID: 23301546 DOI: 10.1111/j.1365-2893.2012.01637.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Genetic factors can influence the outcome of antiviral therapy in chronic hepatitis C (HCV). We evaluated the role of interleukin-28B single nucleotide polymorphisms (SNPs) and inosine triphosphatase (ITPA) gene variants in HCV cirrhosis treated with Peg-Interferon and ribavirin. A prospective cohort of 233 patients with compensated cirrhosis received 1-1.5 μg/kg/week of Peg-Interferon alpha-2b plus 1000-1200 mg/day of RBV for 48 weeks. A sustained virologic response (SVR) was achieved in 27% of patients. On multivariate logistic analysis, the absence of oesophageal varices (OR 3.64 CI 95% 1.27-10.44 P = 0.016), infection with genotype 2 or 3 (OR 4.06, CI 95% 1.08-15.26, P = 0.038), C/C alleles of rs12979860 SNP (OR 7.04, CI 95% 2.40-20.72, P < 0.001) and rapid virologic response (RVR) (OR 78.29, CI 95% 16.07-381.29, P < 0.001) were independently associated with SVR. Patients who experienced post-treatment relapse received lower total doses of Peg-Interferon (52.0 ± 15.8 μg/kg vs 65.7 ± 13.3 μg/kg, P < 0.001) and lower total dose of RBV (3829 ± 1210 mg vs 4709 ± 954 mg, P < 0.001) than patients who achieved an SVR. ITPA variants predictive of high ITPase activity were associated with reduction of haemoglobin ≥3 g/dL in the first 4 weeks (P < 0.001), and with reduction of haemoglobin <10 g/dL (P = 0.03) on treatment. In conclusion, combination therapy with Peg-Interferon and RBV in patients with HCV cirrhosis must be guided by virus genotype, severity of portal hypertension, favourable IL-28B polymorphisms and ITPA variants, and RVR on treatment.
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Affiliation(s)
- V Di Marco
- Sezione di Gastroenterologia & Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy.
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Guidelines for the Management of Hepatitis C Virus Infection: First edition, May 2012, The Japan Society of Hepatology. Hepatol Res 2013; 43:1-34. [PMID: 23332085 DOI: 10.1111/hepr.12020] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
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- Department of Gastroenterology and Hepatology, Faculty of Medicine, Tokyo Medical and Dental University
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31
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Beckebaum S, Kabar I, Cicinnati VR. Hepatitis B and C in liver transplantation: new strategies to combat the enemies. Rev Med Virol 2012; 23:172-93. [PMID: 23239274 DOI: 10.1002/rmv.1734] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2012] [Revised: 10/29/2012] [Accepted: 11/01/2012] [Indexed: 12/16/2022]
Abstract
Hepatitis B immune globulin-free therapeutic regimens with a nucleos(t)ide analogue (NUC) or NUC combinations after liver transplantation (LT) are currently being investigated for their efficacy and safety as HBV re-infection prophylaxis in clinical studies. Recurrence rates differ among these studies as most of them are limited by a non-randomised study design, small sample size, lack of long-term data and varying time intervals for the switch from combined to purely virostatic prophylaxis. Post-transplant pre-emptive antiviral therapy with pegylated IFN and ribavirin is associated with low sustained virological response rates and was found to have no advantage over treatment of manifest HCV re-infection. Safety and efficacy of triple antiviral therapy including boceprevir or telaprevir in patients with manifest HCV re-infection are currently under investigation in clinical trials. Relevant drug interactions have been shown to occur during calcineurin inhibitor (CNI) and concomitant triple antiviral therapy, which vary with type of CNI and choice of HCV protease inhibitor. Newer direct-acting antivirals with lower or minimal toxicity, when used in combination with immunosuppressives, are worthy of further study in LT patients. This review focuses on hot topics in the management of hepatitis B and C patients before and after LT and offers a critical summarised selection of the corresponding relevant studies published in the current literature or presented at recent liver congresses.
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Affiliation(s)
- Susanne Beckebaum
- Department of Transplant Medicine, University Hospital Münster, Münster, Germany.
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32
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33
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Afdhal NH. Hepatitis C viral infection in difficult-to-treat populations: An overview. Clin Liver Dis (Hoboken) 2012; 1:63-64. [PMID: 31186850 PMCID: PMC6499269 DOI: 10.1002/cld.57] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2012] [Revised: 06/06/2012] [Indexed: 02/04/2023] Open
Affiliation(s)
- Nezam H. Afdhal
- Liver Center, Beth Israel Deaconess Medical Center, Boston, MA
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D'Ambrosio R, Aghemo A. Treatment of patients with HCV related cirrhosis: many rewards with very few risks. HEPATITIS MONTHLY 2012; 12:361-8. [PMID: 22879824 PMCID: PMC3412551 DOI: 10.5812/hepatmon.6095] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/01/2012] [Revised: 01/18/2012] [Accepted: 06/01/2012] [Indexed: 12/11/2022]
Abstract
Antiviral treatment of chronic hepatitis C virus (HCV) is aimed at the persistent eradication of the virus, the so-called sustained virological response (SVR), with the aim ultimately being to prevent the development of liver-related complications and improve patients' survival. Patients with HCV-related compensated cirrhosis are the group most likely to benefit from viral clearance, as several retrospective studies have shown liver complications rates to be positively modified by the achievement of a SVR. Whether these benefits rely on viral clearance or on the histological improvements seen following successful interferon (IFn)-based therapies has recently been a matter for debate, as studies have shown cirrhosis to regress in some patients with a SVR. Whatever the mechanisms, cirrhosis has the uncanny ability to be both a dominant indication for therapy, as well as one of the strongest baseline factors associated with reduced efficacy of any IFn-based regimen. This has led to the development of alternative treatment strategies, such as low dose pegylated IFn (PegIFn) monotherapy, that unfortunately has proven to be of limited efficacy. For this reason regimens able to clear the virus without relying on the broad antiviral effect of IFN are eagerly awaited.
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Affiliation(s)
- Roberta D'Ambrosio
- First Division of Gastroenterology, Cà Granda Hospital Foundation IRCCS Maggiore Policlinico, University of Milan, Milan, Italy
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35
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Kim KH, Jang BK, Chung WJ, Hwang JS, Kweon YO, Tak WY, Lee HJ, Lee CH, Suh JI. Peginterferon alpha and ribavirin combination therapy in patients with hepatitis C virus-related liver cirrhosis. THE KOREAN JOURNAL OF HEPATOLOGY 2012; 17:220-5. [PMID: 22102389 PMCID: PMC3304650 DOI: 10.3350/kjhep.2011.17.3.220] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND/AIMS Pegylated interferon (peginterferon) and ribavirin combination therapy is less effective and associated with a higher frequency of serious complications in chronic hepatitis C patients with cirrhosis than in noncirrhotic patients. This study evaluated the efficacy and tolerability of peginterferon and ribavirin treatment in patients with hepatitis C virus (HCV)-related cirrhosis. METHODS Eighty-six patients with clinically diagnosed liver cirrhosis were treated with either peginterferon alpha-2a (n=51) or peginterferon alpha-2b (n=35) plus ribavirin. The sustained virologic response (SVR) and adverse effects were analyzed retrospectively. RESULTS Of the 86 patients (55 males), 48 patients (55.8%) had HCV genotype 1 infection and 38 (44.2%) had genotype non-1 infection. The overall SVR rate was 34.9% (30/86), and the rates of SVR in the genotype 1 and non-1 patients were 20.8% (10/48) and 52.6% (20/38), respectively. The multivariate analysis revealed that having HCV genotype 1 (P=0.003) and high baseline viral load (<8.0×10(5) IU/mL, P=0.012) were the independent predictive factors for SVR failure. In 20.9% (18/86) of the patients, treatment was not completed due to adverse events (27.8%), loss to follow-up (50.0%), and other reasons (22.2%). CONCLUSIONS Peginterferon and ribavirin combination therapy was relatively effective and feasible for clinically diagnosed HCV patients, especially in those with genotype non-1 infection and low baseline viral load.
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Affiliation(s)
- Kyung Hoon Kim
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
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36
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Bourlière M, Khaloun A, Wartelle-Bladou C, Oules V, Portal I, Benali S, Adhoute X, Castellani P. Future treatment of patients with HCV cirrhosis. Liver Int 2012; 32 Suppl 1:113-9. [PMID: 22212581 DOI: 10.1111/j.1478-3231.2011.02702.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
Of all hepatitis C virus (HCV) patients, those with cirrhosis are most in need of treatment because of increased morbidity and mortality. Treatment with pegylated-interferon (PEG-IFN) and ribavirin (RBV) (PR) has definitely shown the benefits of successful treatment by improving fibrosis, causing the regression of cirrhosis and reducing and preventing cirrhosis-related complications. However, the sustained virological response (SVR) is lower in patients with cirrhosis. First generation protease inhibitors (boceprevir and telaprevir) in combination with PR are a major advancement in the treatment of both naïve and treatment-experienced genotype 1 patients. In naïve patients, the SVR rate with the triple regimen with boceprevir was increased by 14% in patients with severe fibrosis or cirrhosis compared with PR. This benefit was lower than that observed in patients with mild or moderate fibrosis (30%). The SVR rate of the triple regimen with telaprevir was increased by 10-30% compared with PR in patients with severe fibrosis or cirrhosis compared with nearly 30% in patients with mild or moderate fibrosis. In treatment-experienced patients, previous relapsers have the highest increase in SVR with the triple regimen compared with PR, whatever the status of fibrosis. Previous partial or non-responder patients with cirrhosis had lower SVR rates than those without cirrhosis. However, the benefits of telaprevir and boceprevir vs PR was maintained. Previous non-responder patients with cirrhosis benefited the least from treatment. The relapse rate was always higher and side effects were more frequent in patients with cirrhosis compared with those without. First generation protease inhibitors plus PR appear to be a new step forward in the management of HCV genotype 1 patients with cirrhosis.
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Affiliation(s)
- Marc Bourlière
- Department of Hepato-Gastroenterology, Hospital Saint Joseph, Marseille, France.
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37
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Asahina Y, Izumi N, Oketani M, Kumada H, Koike K, Suzuki F, Takikawa H, Tanaka A, Tsubouchi H, Hayashi N, Hiramatsu N, Yotsuyanagi H. Treatment Guidelines of Hepatitis C. ACTA ACUST UNITED AC 2012. [DOI: 10.2957/kanzo.53.355] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Persico M, Bruno S, Costantino A, Mazza M, Almasio PL. The impact of antiviral therapy and the influence of metabolic cofactors on the outcome of chronic HCV infection. Int J Hepatol 2011; 2011:314301. [PMID: 22164334 PMCID: PMC3230116 DOI: 10.4061/2011/314301] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2010] [Revised: 08/09/2011] [Accepted: 08/18/2011] [Indexed: 12/20/2022] Open
Abstract
NATURAL HISTORY OF HCV RELATED CHRONIC HEPATITIS IS INFLUENCED AND MODIFIED BY MANY FACTORS: virus features, coinfections and host characteristics. In particular, a peculiar genetic background of the host by conditioning the occurrence of intracellular metabolic derangements (i.e., insulin resistance) might contribute to accelerate the rate of progression to cirrhosis and eventually the occurrence of hepatocellular carcinoma (HCC) and death. Likely, direct interplays between virus genotype and host genetic background might be hypothesized at this level. Morbidity and mortality in cirrhosis is primarily associated with complications of liver cirrhosis (ascites, hepatic encephalopathy, jaundice, and gastroesophageal bleeding) and HCC occurrence. Therefore the main goal of therapy is to clear viral infection and decrease liver necro-inflammation that directly relates to development of cirrhosis and HCC. Among patients treated with Interferon-based therapy, those with sustained viral response showed a significant reduction of progression to cirrhosis and development of HCC. However, a residual risk of hepatocellular carcinoma still remains indicating the need for careful follow-up using ultrasonography every six months in cirrhotic patients, even in those showing persistently normal ALT and undetectable HCV RNA levels after antiviral therapy.
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Affiliation(s)
- Marcello Persico
- Internal Medicine and Hepatology Division, Second University of Naples, Via Del Parco Carelli 36, 80123 Naples, Italy
| | - Savino Bruno
- Department of Internal Medicine, AO Fatebenefratelli e Oftalmico, Corso di Porta Nuova 23, 20121 Milano, Italy
| | - Andrea Costantino
- Gastroenterology & Hepatology Unit, Di.Bi.M.I.S., University of Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy
| | - Marta Mazza
- Gastroenterology & Hepatology Unit, Di.Bi.M.I.S., University of Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy
| | - Piero Luigi Almasio
- Gastroenterology & Hepatology Unit, Di.Bi.M.I.S., University of Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy
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Masarone M, Persico M. Antiviral therapy: why does it fail in HCV-related chronic hepatitis? Expert Rev Anti Infect Ther 2011; 9:535-43. [PMID: 21609265 DOI: 10.1586/eri.11.10] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
HCV infection is a very common cause of chronic viral hepatitis. It is a worldwide health problem with approximately 170 million persons infected and areas of high endemicity in which the percentage of the population infected reaches 30%. It is a progressive disease that can lead to complications such as severe liver fibrosis and cirrhosis, ascites, esophageal varices, gastrointestinal bleeding and, in 30-50% of patients with cirrhosis, hepatocellular carcinoma. Extrahepatic pathologies such as mixed cryoglobulinemia, non-Hodgkin lymphoma and membrano-proliferative glomerulonephritis have been associated with HCV infection. Effective treatment exists, and is based on IFN-α. Sustained disappearance of the virus (sustained virological response) radically changes the natural history of chronic hepatitis C, with reduced or no disease progression and complications. Interferon-based treatment has improved over the years owing to the association with ribavirin and subsequently with 'pegylation' of interferon molecules. The present standard of care results in a response rate of up to 80% in some subpopulations. Nevertheless, some patients do not respond to this therapy. Several factors predicting nonresponse to interferon therapy have been investigated since it became available. These factors include the characteristics of the virus and of the subject infected, and the therapy used. The aim of this article is to provide an overview of these factors, and insights into the newly recognized causes of nonresponse to help clinicians select the most appropriate therapy for HCV viral hepatitis.
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Affiliation(s)
- Mario Masarone
- Internal Medicine and Hepatology Division, Second University of Naples, Italy
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40
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Pearlman BL, Traub N. Sustained virologic response to antiviral therapy for chronic hepatitis C virus infection: a cure and so much more. Clin Infect Dis 2011; 52:889-900. [PMID: 21427396 DOI: 10.1093/cid/cir076] [Citation(s) in RCA: 190] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Sustained virologic response (SVR) is defined as aviremia 24 weeks after completion of antiviral therapy for chronic hepatitis C virus (HCV) infection. In analyses of SVR durability, the incidence of late relapse is extremely low (<1%). Histologic regression of both necroinflammation and fibrosis has been demonstrated in paired liver biopsy samples in SVR-achieving patients. More noteworthy is the sustained responder's favorable prognosis even with baseline cirrhosis; despite mostly retrospective analyses, relative to nonresponders or to those untreated, patients with SVR have significantly fewer liver-related complications, less hepatocellular carcinoma, and fewer liver-related deaths. Although HCV is associated with insulin resistance, successful eradication of HCV appears to reduce the risk of impaired fasting glucose and diabetes development. In summary, chronic HCV infection is curable with SVR attainment, and with cure comes improved liver histology and more favorable clinical outcomes, in comparison with patients who do not achieve the same therapeutic milestone.
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Affiliation(s)
- Brian L Pearlman
- Center for Hepatitis C, Atlanta Medical Center, Atlanta, Georgia 30312, USA.
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Vezali E, Aghemo A, Colombo M. A review of the treatment of chronic hepatitis C virus infection in cirrhosis. Clin Ther 2011; 32:2117-38. [PMID: 21316532 DOI: 10.1016/s0149-2918(11)00022-1] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/26/2010] [Indexed: 02/06/2023]
Abstract
BACKGROUND Cirrhosis developing during chronic infection with the hepatitis C virus (HCV) poses a risk of anticipated liver-related death, therefore representing a dominant indication to anti-HCV therapy. OBJECTIVE This review highlights the efficacy and safety of treatment of HCV infection in cirrhotic patients with respect to the clinical stage of the disease. METHODS The PubMed, MEDLINE, EMBASE, and Cochrane databases, as well as the conference proceedings from the annual meetings of the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, and the Asian Pacific Association for the Study of the Liver, were searched for articles published in English from January 1990 through May 2010, fulfilling the following criteria: (1) randomized, prospective observational, retrospective, or meta-analysis; (2) involving adult patients with chronic HCV infection; and (3) data (fibrosis stage, treatment regimen, efficacy, safety) available for cirrhotics. Reviews were excluded. Search terms included chronic hepatitis C, fibrosis, cirrhosis, interferon alfa, ribavirin, hepatocellular carcinoma, and liver decompensation. RESULTS Forty-five studies were identified. The rates of sustained virologic response to pegylated interferon in combination with ribavirin ranged from 10% to 44% for HCV genotypes 1/4 to 33% to 72% for genotypes 2/3 in compensated cirrhosis, while falling to 0% to 16% and 44% to 57%, respectively, in the decompensated stage, compared with 29% to 55% for genotypes 1/4 and 70% to 80% for genotypes 2/3 in noncirrhotic patients (compensated cirrhosis vs no cirrhosis: P < 0.001 for genotypes 1/4 and P = 0.002 for genotypes 2/3; decompensated cirrhosis vs no cirrhosis: P < 0.001 for all genotypes). HCV clearance was associated with a reduced risk of liver decompensation, hepatocellular carcinoma development, liver-related mortality, and hepatitis recurrence after liver transplantation. Treatment during compensated cirrhosis proved to be most cost-effective versus treatment after decompensation or a no-treatment strategy. Headache (54%), irritability (38%), fatigue (34%), and nausea (30%) were the most common adverse events in compensated patients, while anorexia (100%), fatigue (59%), neutropenia (53%), and thrombocytopenia (50%) were most common in decompensated patients. CONCLUSIONS Anti-HCV treatment in cirrhotic patients was less effective than in noncirrhotic patients. Viral eradication reduced the risk of liver complications and improved survival in noncirrhotics. Based on effectiveness and tolerability data, therapy has a significant effect in patients with compensated cirrhosis, while decompensated patients need to weigh the risks versus benefits of treatment.
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Affiliation(s)
- Elena Vezali
- Centro A.M. e A. Migliavacca, Unità Operativa di Gastroenterologia 1, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
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Managing patients with hepatitis‑B-related or hepatitis‑C-related decompensated cirrhosis. Nat Rev Gastroenterol Hepatol 2011; 8:285-95. [PMID: 21695841 DOI: 10.1038/nrgastro.2011.57] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Treatment of patients with hepatitis-B-related or hepatitis-C-related decompensated cirrhosis should focus on controlling the complications of cirrhosis, surveillance for hepatocellular carcinoma and, if applicable, preparation for orthotopic liver transplant. Interferon-based regimens for the treatment of hepatitis C have been somewhat successful in patients with cirrhosis, although treatment of patients with decompensated cirrhosis should be approached with caution. Given the potential for exacerbation of decompensation and poor tolerance of adverse effects, treatment should be reserved for those patients awaiting liver transplantation. Eradication of HCV before liver transplantation reduces the chances of recurrent hepatitis C infection after transplant. HBV can be treated with few adverse effects in patients with decompensated cirrhosis. This treatment is associated with improvement in decompensation in some patients. Hepatocellular carcinoma remains a significant risk in all patients with cirrhosis, and control of or eradication of HBV or HCV does not remove this risk.
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43
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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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Shin SR, Paik SW, Gwak GY, Choi MS, Lee JH, Koh KC, Yoo BC. Antiviral therapy in patients after treatment for hepatitis C-related hepatocellular carcinoma. Gut Liver 2011; 5:77-81. [PMID: 21461077 DOI: 10.5009/gnl.2011.5.1.77] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2010] [Accepted: 12/06/2010] [Indexed: 12/09/2022] Open
Abstract
BACKGROUND/AIMS Despite great progress, antiviral treatment for chronic hepatitis C in patients with prior hepatocellular carcinoma (HCC) has been rarely investigated. We evaluated the efficacy and safety of antiviral therapy following treatment for hepatitis C-related HCC. METHODS Thirteen patients (age 34 to 60 years) who were treated with peginterferon plus ribavirin after treatment for HCC were reviewed. RESULTS There were 6 patients with genotype 1 and 7 patients with genotype 2. All patients showed advanced fibrosis (≥F3) but belonged to the Child-Pugh class A. Treatment was stopped in 2 patients because of recurrent HCC and in 1 patient due to a lack of early virologic response. Seven patients achieved sustained virologic response and three patients relapsed. The sustained virologic response rate was 54% overall, 17% in genotype 1, and 86% in genotype 2. No significant adverse events were reported. CONCLUSIONS Antiviral therapy should not be excluded in patients who were previously treated with HCC with genotype 2 chronic hepatitis C, in which an efficacious antiviral treatment for chronic hepatitis C was feasible. Additional study is needed to prove the validity of antiviral therapy in patients with genotype 1 hepatitis C-related HCC.
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Affiliation(s)
- Su Rin Shin
- Department of Medicine, Kangnam Sacred Heart Hospital, College of Medicine, Hallym University, Seoul, Korea
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Iacobellis A, Perri F, Valvano MR, Caruso N, Niro GA, Andriulli A. Long-term outcome after antiviral therapy of patients with hepatitis C virus infection and decompensated cirrhosis. Clin Gastroenterol Hepatol 2011; 9:249-53. [PMID: 21092761 DOI: 10.1016/j.cgh.2010.10.036] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2010] [Revised: 10/19/2010] [Accepted: 10/22/2010] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS We evaluated the long-term outcomes after antiviral therapy of patients with decompensated cirrhosis and hepatitis C virus (HCV) infection. METHODS Seventy-five patients with HCV infection and decompensated cirrhosis received therapy with peginterferon alfa-2b and ribavirin. We compared adverse-event profiles and mortality rates between patients with or without sustained virologic responses (SVRs). The mean follow-up time off therapy was 51 ± 18 months (range, 3-78 months). RESULTS Seven patients with HCV genotypes 1 or 4 (16%) and 17 patients with genotypes 2 or 3 (55%) achieved SVRs. The mean survival times were 53 months among patients who did not achieve SVRs (95% confidence interval [CI], 48-59 months) and 73 months among those who did achieve SVRs (95% CI, 67-80 months) (P = .004). During the study, 25 patients died (2 with and 23 without SVRs). During the follow-up period, 8 of 24 patients with SVRs (33.3%) and 49 of 51 without SVRs (96.1%) experienced further events of decompensation (P < .0001). The hospital readmission rates for patients with and without SVRs were 7.4 and 56 per 1000 person-months, respectively (ratio of 7.5 without/with SVR; 95% CI, 4.0-16.0; P < .0001). At the end of the follow-up period, the incidence of hepatocellular carcinoma was not associated with clearance of HCV. CONCLUSIONS Among patients with cirrhosis that is a result of HCV infection and who have progressed to a stage of liver decompensation, an SVR after antiviral therapy is a positive prognostic factor.
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Affiliation(s)
- Angelo Iacobellis
- Division of Gastroenterology and Digestive Endoscopy, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy
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Huang JF, Yu ML, Huang CF, Chiu CF, Dai CY, Huang CI, Yeh ML, Yang JF, Hsieh MY, Hou NJ, Lin ZY, Chen SC, Wang LY, Chuang WL. The efficacy and safety of pegylated interferon plus ribavirin combination therapy in chronic hepatitis c patients with hepatocellular carcinoma post curative therapies - a multicenter prospective trial. J Hepatol 2011; 54:219-226. [PMID: 21056500 DOI: 10.1016/j.jhep.2010.07.011] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2010] [Revised: 05/14/2010] [Accepted: 07/01/2010] [Indexed: 01/19/2023]
Abstract
BACKGROUND & AIMS Evidence on the efficacy of antiviral treatment in chronic hepatitis C (CHC) patients with hepatocellular carcinoma (HCC) after curative treatment is scarce. We aimed to evaluate the efficacy and safety of pegylated interferon-alpha plus ribavirin (pegIFN/RBV) combination therapy in these patients, compared to cirrhotic patients. METHODS This prospective, multicenter, case-control study recruited 82 consecutive CHC patients with HCC after curative management and 87 sex/age-matched cirrhotic patients. All patients received pegIFN-alpha-2a and weight-based RBV according to current treatment recommendations. The primary outcome measurement was sustained virological response (SVR, seronegative of hepatitis C virus RNA throughout the 6-month post-treatment follow-up period). RESULTS The SVR rate was significantly lower in the HCC group compared to the cirrhosis group (48.8% vs 64.4%, p=0.04). However, the significantly lower rate of SVR in the HCC group was observed among genotype-1 patients (33.3% vs 60.7%, p=0.005) but not among genotype-2/3 patients (70.6% vs 71.0%, p=0.88). In patients who achieved 80/80/80 adherence, there was no significant difference of SVR rate between groups (50.7% vs 64.2%, p=0.12) Multivariate logistic regression analysis demonstrated that rapid virological response (viral clearance during the first 4 weeks of treatment, odds ratio=22.1, p<0.001) and adherence (odds ratio=3.1, p=0.05) were predictive factors associated with SVR, whilst previous occurrence of HCC was not associated with SVR (Odds ratio=0.4, p=0.09). The incidence of severe adverse events did not differ between the two groups. CONCLUSIONS The study proved the feasibility of pegIFN/RBV therapy with current treatment guidelines in CHC patients after successful eradication of HCC, with careful monitoring.
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Affiliation(s)
- Jee-Fu Huang
- Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
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Noureddin M, Ghany MG. Editorial: Treatment of patients with HCV-related cirrhosis with peginterferon and ribavirin: Swinging the pendulum toward treatment. Am J Gastroenterol 2010; 105:2174-6. [PMID: 20927065 PMCID: PMC7725429 DOI: 10.1038/ajg.2010.288] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Patients with hepatitis C virus-related cirrhosis are at increased risk for hepatic decompensation and hepatocellular carcinoma (HCC). They also responded less well to standard therapy compared with those without cirrhosis. Several recent studies have demonstrated that patients with cirrhosis can be safely treated and those who achieve a sustained virological response have better clinical outcomes compared with nonresponders. These results support treatment for patients with compensated cirrhosis. In addition, cirrhotic patients should be monitored after a sustained virological response is obtained, because some patients remain at risk for complications of liver disease, particularly HCC. Newer, more effective therapy is needed for patients with cirrhosis.
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Fernández-Rodríguez CM, Alonso S, Martinez SM, Forns X, Sanchez-Tapias JM, Rincón D, Rodriguez-Caravaca G, Bárcena R, Serra MA, Romero-Gómez M, Fernandez I, Garcia-Samaniego J, Fuente J, Solá R, Moreno-Otero R, Planas R. Peginterferon plus ribavirin and sustained virological response in HCV-related cirrhosis: outcomes and factors predicting response. Am J Gastroenterol 2010; 105:2164-2173. [PMID: 20700116 DOI: 10.1038/ajg.2010.294] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Patients with hepatitis C virus (HCV) cirrhosis are difficult to treat and have a high risk of liver decompensation or hepatocellular carcinoma. We sought to identify factors that could predict treatment response. METHODS Collaborating centers (n=26) provided data for patients (n=568) with HCV cirrhosis undergoing treatment with peginterferon-α plus ribavirin (RBV). Univariate and multivariate analyses were used to evaluate factors predicting treatment outcomes. RESULTS Sustained viral response (SVR) in naive patients was 30.7%, with no significant differences between centers. Median follow-up was 35 months (range: 1-81). Factors predicting SVR were: non-genotype 1 (odds ratio (OR)=4.183; 95% confidence interval (CI): 2.353-7.438) overall dose and ≥80% of the scheduled time of treatment (OR=3.177; 95% CI: 1.752-5.760); serum γ-glutamyl transpeptidase (GGT) <76 IU per ml (OR=4.092; 95% CI: 2.418-6.927); baseline viral load <6 × 10(5) (OR=2.597; 95% CI: 1.583-4.262); absence of ultrasound signs of portal hypertension (OR=2.067; 95% CI: 1.26-3.39). No patient with a HCV-RNA decline <1 log(10) at week 4 achieved SVR. Event-free survival at 5 years was 91% in patients with SVR vs. 59% in non-responders (P<0.001). Overall survival in patients with SVR was 98% vs. 86% in non-responders (P=0.005). Independent factors predicting events were absence of SVR (hazard ratio (HR)=2.66; 95% CI: 1.32-5.54), baseline serum albumin <3.9 g per 100 ml (HR=3.06; 95% CI: 1.81-5.15), presence of esophageal varices on endoscopy (HR=2.489; 95% CI: 1.546-4). Improved outcome was more evident in responders with less advanced disease at baseline. CONCLUSIONS SVR can be achieved in approximately one-third of patients with HCV-related cirrhosis. SVR independently reduces the likelihood of clinical decompensation and improves survival.
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Danish FA, Koul SS, Subhani FR, Rabbani AE, Yasmin S. Antiviral therapy in HCV-infected decompensated cirrhotics. Saudi J Gastroenterol 2010; 16:310-4. [PMID: 20871208 PMCID: PMC2995112 DOI: 10.4103/1319-3767.70632] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2009] [Accepted: 03/05/2010] [Indexed: 01/15/2023] Open
Abstract
Decompensated cirrhosis has traditionally been considered a contraindication to interferon and ribavirin therapy. Whereas, the same may be true for advanced cirrhosis, which is only successfully amenable to liver transplantation (LT), there are reports in the literature in which antiviral therapy was given successfully in selected cases of early hepatic decompensation with an aim to attain sustained viral clearance, halt disease progression, and expect potential (though, often, partial) recovery of hepatic metabolic activity. Antiviral therapy may also be instituted to prevent hepatitis C recurrence after LT (it has even caused removal of some patients from the waiting list for LT). Thus, decompensation per se is no more an absolute contraindication to antiviral therapy. Nonetheless, considering that a large proportion of such patients have pre-existing hematological cytopenias, modifications in antiviral dose regimens and close monitoring is required in order to prevent worsening of the same. Although the final sustained virological response rates attained in these patients are relatively low, successful antiviral therapy is potentially lifesaving which explains the need to go for it. In this article, the pros and cons of antiviral therapy in decompensated liver cirrhosis are reviewed with special emphasis on how to avoid antiviral dose reductions/withdrawals secondary to the development of hematologic side effects by using hematopoietic growth factors.
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Yang JF, Kao YH, Dai CY, Huang JF, Hsieh MY, Lin ZY, Chen SC, Hsieh MY, Wang LY, Chuang WL, Yu ML. Comparison of adverse effects related to pegylated interferon-based therapy for patients with chronic hepatitis B and chronic hepatitis C in Taiwan. Hepatol Int 2010; 4:732-740. [PMID: 21286344 PMCID: PMC2994613 DOI: 10.1007/s12072-010-9208-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2009] [Accepted: 07/21/2010] [Indexed: 02/07/2023]
Abstract
PURPOSE Pegylated interferon (Peg-IFN)-based therapy is effective in treating chronic hepatitis B (CHB) and C (CHC) but frequently induces adverse events (AEs). This study was conducted to compare the incidence of Peg-IFN-based therapy-associated AEs in Taiwanese patients with CHB and CHC. METHODS Fifty-six patients with CHB and 103 age-, sex- and treatment duration-matched patients with CHC were enrolled. Patients with CHB were treated with Peg-IFN-α-2a 180 μg/week for 24 weeks (HBeAg(+), n = 31) or 48 weeks (HBeAg(-), n = 25); patients with CHC were treated with Peg-IFN-α-2a 180 μg/week plus ribavirin 1,000-1,200 mg/day for 24 weeks (genotype 2/3, n = 57) or 48 weeks (genotype 1, n = 46). RESULTS Significantly higher incidences of Peg-IFN-related AEs, especially neuropsychiatric symptoms, and ribavirin-associated skin manifestations were observed in patients with CHC compared with those with CHB, with either the 24- or 48-week regimen. Frequencies of laboratory abnormalities, except for anemia, were comparable in both groups. Neither group showed overt hepatic decompensation. Frequency of dose reduction was similar between the groups. Substantially higher rates of early termination and severe AEs were observed in patients with CHC. CONCLUSIONS Patients with CHB treated with Peg-IFN had fewer AEs than patients with CHC treated with Peg-IFN/ribavirin. All patients were treated safely.
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Affiliation(s)
- Jeng-Fu Yang
- Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Hepatobiliary and Pancreatic Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Yi-Hui Kao
- School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Division of Hepatobiliary and Pancreatic Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan
| | - Ming-Yen Hsieh
- Division of Hepatobiliary and Pancreatic Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Zu-Yau Lin
- Division of Hepatobiliary and Pancreatic Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shinn-Cherng Chen
- Division of Hepatobiliary and Pancreatic Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Yuh Hsieh
- Division of Hepatobiliary and Pancreatic Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Liang-Yen Wang
- Division of Hepatobiliary and Pancreatic Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Division of Hepatobiliary and Pancreatic Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Division of Hepatobiliary and Pancreatic Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
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