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Stroffolini T, Stroffolini G. A Historical Overview on the Role of Hepatitis B and C Viruses as Aetiological Factors for Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:cancers15082388. [PMID: 37190317 DOI: 10.3390/cancers15082388] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 04/14/2023] [Accepted: 04/19/2023] [Indexed: 05/17/2023] Open
Abstract
Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the leading cause of hepatocellular carcinoma (HCC) worldwide. Currently, HBV-related HCC predominates in Sub-Saharan Africa and South-East-Asia, while HCV-related HCC predominates in northern Africa and in the western world. Liver cirrhosis is the underlying condition in most HBV cases and in nearly all HCV cases. Several cofactors, viral and non-viral, play a role in the progression toward HCC: dual HBV/HCV infection, HDV, HIV, alcohol intake, smoking, diabetes mellitus, obesity, and NAFLD/NASH. HBV vaccine is effective in preventing both infection and HCC; antiviral drugs may suppress HBV replication and eradicate HCV infection, halting progression to HCC. Inequalities exist between high- and low-income countries with respect to vaccine availability and access to antivirals. These factors represent barriers to the control of HCC incidence. Lack of an effective vaccine against HCV is also a serious barrier to HCV elimination and HCC prevention. The most crucial steps and knowledge that have arisen over time on the association between the two major hepatotropic viruses and HCC are discussed in this historical review.
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Affiliation(s)
- Tommaso Stroffolini
- Department of Tropical and Infectious Diseases, Policlinico Umberto I, 00161 Rome, Italy
| | - Giacomo Stroffolini
- Department of Infectious-Tropical Diseases and Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, Via Don A. Sempreboni, 5, Negrar, 37024 Verona, Italy
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Risk Factors for Liver Decompensation and HCC in HCV-Cirrhotic Patients after DAAs: A Multicenter Prospective Study. Cancers (Basel) 2021; 13:cancers13153810. [PMID: 34359711 PMCID: PMC8345116 DOI: 10.3390/cancers13153810] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 07/09/2021] [Accepted: 07/25/2021] [Indexed: 01/06/2023] Open
Abstract
Simple Summary The present study explored the predictors of the development of liver-related events in HCV cirrhotic subjects achieving SVR following antiviral therapy with direct-acting antiviral agents (DAAs) during a follow-up of 24 months after SVR confirmation. Patients had a liver stiffness measurement (LSM) of ≥14 kPa at baseline. We found that baseline liver stiffness ≥ 20 kPa and HCV genotype different from 1 were both independent predictors of liver decompensation, while only LSM ≥ 20 kPa was an independent predictor of HCC. Abstract Background: Prospective studies on predictors of liver-related events in cirrhotic subjects achieving SVR after DAAs are lacking. Methods: We prospectively enrolled HCV cirrhotic patients in four Italian centers between November 2015 and October 2017. SVR and no-SVR cases were compared according to the presence or absence of liver-related events during a 24-month follow-up. Independent predictors of liver-related events were evaluated by Cox regression analysis. Results: A total of 706 subjects started DAAs therapy. SVR was confirmed in 687 (97.3%). A total of 61 subjects (8.9%) in the SVR group and 5 (26.3%) in the no-SVR group had liver-related events (p < 0.03). The incidence rate x 100 p/y was 1.6 for HCC, 1.7 for any liver decompensation, and 0.5 for hepatic death. Baseline liver stiffness (LSM) ≥ 20 kPa (HR 4.0; 95% CI 1.1–14.1) and genotype different from 1 (HR 7.5; 95% CI 2.1–27.3) were both independent predictors of liver decompensation. Baseline LSM > 20 KPa (HR 7.2; 95% CI 1.9–26.7) was the sole independent predictor of HCC. A decrease in liver stiffness (Delta LSM) by at least 20% at the end of follow-up was not associated with a decreased risk of liver-related events. Conclusion: Baseline LSM ≥ 20 kPa identifies HCV cirrhotic subjects at higher risk of liver-related events after SVR.
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Cossiga V, Guarino M, Morisco F, Caporaso N. Risk stratification of HCC occurrence after HCV eradication: a complicate plot of risk factors related and unrelated to the previous viral disease. Hepatobiliary Surg Nutr 2020; 9:511-513. [PMID: 32832506 DOI: 10.21037/hbsn.2019.11.27] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Valentina Cossiga
- Gastroenterology Unit, Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy
| | - Maria Guarino
- Gastroenterology Unit, Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy
| | - Filomena Morisco
- Gastroenterology Unit, Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy
| | - Nicola Caporaso
- Gastroenterology Unit, Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy
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Cento V, Nguyen THT, Di Carlo D, Biliotti E, Gianserra L, Lenci I, Di Paolo D, Calvaruso V, Teti E, Cerrone M, Romagnoli D, Melis M, Danieli E, Menzaghi B, Polilli E, Siciliano M, Nicolini LA, Di Biagio A, Magni CF, Bolis M, Antonucci FP, Di Maio VC, Alfieri R, Sarmati L, Casalino P, Bernardini S, Micheli V, Rizzardini G, Parruti G, Quirino T, Puoti M, Babudieri S, D’Arminio Monforte A, Andreoni M, Craxì A, Angelico M, Pasquazzi C, Taliani G, Guedj J, Perno CF, Ceccherini-Silberstein F. Improvement of ALT decay kinetics by all-oral HCV treatment: Role of NS5A inhibitors and differences with IFN-based regimens. PLoS One 2017; 12:e0177352. [PMID: 28545127 PMCID: PMC5436665 DOI: 10.1371/journal.pone.0177352] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Accepted: 04/26/2017] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Intracellular HCV-RNA reduction is a proposed mechanism of action of direct-acting antivirals (DAAs), alternative to hepatocytes elimination by pegylated-interferon plus ribavirin (PR). We modeled ALT and HCV-RNA kinetics in cirrhotic patients treated with currently-used all-DAA combinations to evaluate their mode of action and cytotoxicity compared with telaprevir (TVR)+PR. STUDY DESIGN Mathematical modeling of ALT and HCV-RNA kinetics was performed in 111 HCV-1 cirrhotic patients, 81 treated with all-DAA regimens and 30 with TVR+PR. Kinetic-models and Cox-analysis were used to assess determinants of ALT-decay and normalization. RESULTS HCV-RNA kinetics was biphasic, reflecting a mean effectiveness in blocking viral production >99.8%. The first-phase of viral-decline was faster in patients receiving NS5A-inhibitors compared to TVR+PR or sofosbuvir+simeprevir (p<0.001), reflecting higher efficacy in blocking assembly/secretion. The second-phase, noted δ and attributed to infected-cell loss, was faster in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.27 vs 0.21 d-1, respectively, p = 0.0012). In contrast the rate of ALT-normalization, noted λ, was slower in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.17 vs 0.27 d-1, respectively, p<0.001). There was no significant association between the second-phase of viral-decline and ALT normalization rate and, for a given level of viral reduction, ALT-normalization was more profound in patients receiving DAA, and NS5A in particular, than TVR+PR. CONCLUSIONS Our data support a process of HCV-clearance by all-DAA regimens potentiated by NS5A-inhibitor, and less relying upon hepatocyte death than IFN-containing regimens. This may underline a process of "cell-cure" by DAAs, leading to a fast improvement of liver homeostasis.
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Affiliation(s)
- Valeria Cento
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy
| | - Thi Huyen Tram Nguyen
- INSERM, Université Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, Paris, France
| | - Domenico Di Carlo
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy
| | - Elisa Biliotti
- Tropical Diseases, Umberto I Hospital – “Sapienza” University, Rome, Italy
| | - Laura Gianserra
- Infectious Diseases, Sant’Andrea Hospital – “Sapienza” University, Rome, Italy
| | - Ilaria Lenci
- Hepatology Unit, Polyclinic of Rome Tor Vergata, Rome, Italy
| | | | | | - Elisabetta Teti
- Infectious Diseases, Polyclinic of Rome Tor Vergata, Rome, Italy
| | - Maddalena Cerrone
- Clinic of Infectious Disease, Department of Health Sciences, San Paolo University Hospital, University of Milan, Milan, Italy
| | - Dante Romagnoli
- Department of Biomedical, Metabolic and Neural Sciences, NOCSAE Baggiovara, Baggiovara, Modena, Italy
| | - Michela Melis
- Infectious Diseases Unit, Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy
| | - Elena Danieli
- Infectious Diseases, AO Ospedale Niguarda Cà Granda, Milan, Italy
| | - Barbara Menzaghi
- Infectious Diseases, Ospedale di circolo di Busto Arsizio, Busto Arsizio, Varese, Italy
| | - Ennio Polilli
- Infectious Disease Unit, “Spirito Santo” General Hospital, Pescara, Italy
| | | | - Laura Ambra Nicolini
- University of Genoa (DISSAL) Infectious Diseases Unit/AOU IRCCS San Martino-IST, Genoa, Italy
| | - Antonio Di Biagio
- University of Genoa (DISSAL) Infectious Diseases Unit/AOU IRCCS San Martino-IST, Genoa, Italy
| | | | - Matteo Bolis
- 1 Division of Infectious Diseases, ASST Fatebenefratelli Sacco, Milan, Italy
| | | | - Velia Chiara Di Maio
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy
| | - Roberta Alfieri
- Istituto Nazionale di Genetica Molecolare (INGM) "Romeo ed Enrica Invernizzi", Milan, Italy
| | - Loredana Sarmati
- Infectious Diseases, Polyclinic of Rome Tor Vergata, Rome, Italy
| | - Paolo Casalino
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy
| | - Sergio Bernardini
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy
| | - Valeria Micheli
- Clinical Microbiology, Virology and Bioemergencies, ASST Fatebenefratelli Sacco, Milan, Italy
| | - Giuliano Rizzardini
- 1 Division of Infectious Diseases, ASST Fatebenefratelli Sacco, Milan, Italy
- School of Clinical Medicine, Faculty of Health Science, University of the Witwatersrand, Johannesburg, South Africa
| | - Giustino Parruti
- Infectious Disease Unit, “Spirito Santo” General Hospital, Pescara, Italy
| | - Tiziana Quirino
- Infectious Diseases, Ospedale di circolo di Busto Arsizio, Busto Arsizio, Varese, Italy
| | - Massimo Puoti
- Infectious Diseases, AO Ospedale Niguarda Cà Granda, Milan, Italy
| | - Sergio Babudieri
- Infectious Diseases Unit, Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy
| | - Antonella D’Arminio Monforte
- Clinic of Infectious Disease, Department of Health Sciences, San Paolo University Hospital, University of Milan, Milan, Italy
| | - Massimo Andreoni
- Infectious Diseases, Polyclinic of Rome Tor Vergata, Rome, Italy
| | - Antonio Craxì
- Gastroenterology, “P. Giaccone” University Hospital, Palermo, Italy
| | - Mario Angelico
- Hepatology Unit, Polyclinic of Rome Tor Vergata, Rome, Italy
| | - Caterina Pasquazzi
- Infectious Diseases, Sant’Andrea Hospital – “Sapienza” University, Rome, Italy
| | - Gloria Taliani
- Tropical Diseases, Umberto I Hospital – “Sapienza” University, Rome, Italy
| | - Jeremie Guedj
- INSERM, Université Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, Paris, France
| | - Carlo Federico Perno
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy
- * E-mail:
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Abstract
Consensus interferon (CIFN) is an artificially engineered interferon that reflects most of the human genotype 1 interferons and shows a higher biological and antiviral capacity in vitro. It has been used internationally to treat patients with chronic hepatitis C (HCV) infection before pegylated IFN became available. To mimic the half-life of PEG-IFN it has to be administered on a daily basis. The gold standard in the treatment of hepatitis C is well established and recommended. Today patients are being treated with a combination therapy of pegylated IFN and ribavirin. Length and dosage of therapy depends on the genotype of the virus. Patients with genotype 1 and 4 and high viral load should be treated for 48 weeks; for patients with these genotypes along with either low viral load or early virological response, therapy for 24 weeks is sufficient. Patients with genotype 2 and 3 should be treated for up to 24 weeks. However, daily dosing of IFN-α, eg, CIFN, resulting in a higher cumulative dosage, might be beneficial and more efficacious in some chronic HCV-infected patients. Patients with genotype 1, having initially high viral load (>800,000 IU/mL) and showing advanced liver disease with progressive fibrosis or even cirrhosis comprise the difficult-to-treat in order to overcome the infection. This review summarizes and critically discusses the published data on the treatment of HCV with CIFN.
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Affiliation(s)
- Th Witthöft
- University Hospital Schleswig Holstein, Campus Lübeck, Dept of Medicine I, Division of Gastroenterology, Lübeck, Germany
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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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7
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Pockros PJ, Hamzeh FM, Martin P, Lentz E, Zhou X, Govindarajan S, Lok AS. Histologic outcomes in hepatitis C-infected patients with varying degrees of virologic response to interferon-based treatments. Hepatology 2010; 52:1193-200. [PMID: 20658462 DOI: 10.1002/hep.23809] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
UNLABELLED Patients with chronic hepatitis C with partial virologic response or nonresponse to interferon-based therapies can experience treatment-related improvements in liver histology. This retrospective analysis assessed the histologic response to treatment in patients with varying degrees of virologic response (sustained virologic response [SVR], breakthrough, relapse, or nonresponse), time to hepatitis C virus (HCV) RNA undetectability, and duration of viral suppression. Patients (HCV genotypes 1-6) with baseline and follow-up liver biopsies from eight phase 2 to phase 4 interferon-based trials were analyzed. Blinded biopsies were evaluated by a single pathologist. Improvements or worsening of METAVIR necroinflammatory activity and fibrosis were defined as increase or decrease of ≥1 grading category from baseline to 24 weeks after end of treatment. A majority of the 1571 patients with paired biopsy data were white, male, with HCV genotype 1/4, baseline HCV RNA levels >800,000 IU/mL, and baseline alanine aminotransferase levels ≤3 × upper limit of the normal range; mean baseline activity and fibrosis scores were 1.8 and 1.7, respectively. Overall, 80% of patients received peginterferon alfa-2a monotherapy or peginterferon alfa-2a/ribavirin combination therapy. Mean treatment duration was 46 weeks. There was a positive correlation between the degree of virologic response and improvements in METAVIR activity and fibrosis, and an inverse correlation with worsening activity and fibrosis (all comparisons, P < 0.0001). Patients with SVR had the greatest histologic benefit. As a combined group, relapsers and patients with breakthrough had significantly greater benefits than nonresponders (activity, P = 0.0001; fibrosis, P = 0.003). Consistent with these results, a better histologic response was correlated with a shorter time to undetectable HCV RNA and a longer duration of viral suppression (all comparisons, P < 0.0001). CONCLUSION In patients with chronic hepatitis C who were treated with interferon-based therapies, histologic benefits may be observed even in the absence of an SVR.
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Affiliation(s)
- Paul J Pockros
- Division of Gastroenterology/Hepatology, Scripps Clinic, La Jolla, CA 92037, USA.
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Denzer UW, Lüth S. Non-invasive diagnosis and monitoring of liver fibrosis and cirrhosis. Best Pract Res Clin Gastroenterol 2009; 23:453-60. [PMID: 19505671 DOI: 10.1016/j.bpg.2009.03.002] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The accurate staging of liver fibrosis in chronic liver diseases, especially the early diagnosis of liver cirrhosis, is crucial for prognostic assessment of the course of the disease. The histological evaluation of a liver biopsy cylinder is still the gold standard in assessing the stage of liver fibrosis. However, liver biopsy is an invasive procedure and carries the risk of complications. This has to be balanced against the information benefit of liver histology. To overcome this, non-invasive tests were developed assessing liver fibrosis based on combinations of laboratory markers or techniques measuring liver elasticity. In this review the current impact of the non invasive methods is discussed and weighted against liver biopsy.
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Affiliation(s)
- Ulrike W Denzer
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, D-24046 Hamburg, Germany.
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Narciso-Schiavon JL, Freire FCF, Suarez MM, Ferrari MVO, Scanhola GQ, Schiavon LDL, Carvalho Filho RJD, Ferraz MLG, Silva AEB. Antinuclear antibody positivity in patients with chronic hepatitis C: clinically relevant or an epiphenomenon? Eur J Gastroenterol Hepatol 2009; 21:350-356. [PMID: 20611005 DOI: 10.1097/meg.0b013e3283089392] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND Serum autoantibodies such as antinuclear antibody (ANA) are frequently detected in patients with chronic hepatitis C virus (HCV) infection, but its relevance is a matter of discussion. AIM To assess the association of ANA positivity with clinical and histological features, and with the outcome of antiviral therapy in patients with HCV infection. METHODS Baseline samples from patients with hepatitis C treated with interferon and ribavirin were tested for ANA positivity by indirect immunofluorescence. RESULTS The mean age was 48.3+/-11.1 years and 56% were men. Among 234 included patients, 22 patients (9.4%) were positive for ANA. These patients showed significantly higher median alanine aminotransferase level (3.52 vs. 2.39 x upper limit of normal, P=0.009) when compared with ANA-negative patients. Fibrosis stage and necroinflammatory grading were not influenced by ANA positivity. Sustained virological response (SVR) rates were similar between ANA-positive and ANA-negative patients (27 vs. 29%, P=0.882). Alanine aminotransferase flares (> or = 1.5-fold the baseline) during treatment were observed in 28 patients (12%), irrespective of the presence of ANA and without any clinical significance. CONCLUSION Among HCV patients, ANA positivity seems to represent an immunological epiphenomenon. It neither influences clinical, biochemical, and histological features of chronic hepatitis C nor predicts response to antiviral treatment.
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Feld JJ, Nanda S, Huang Y, Chen W, Cam M, Pusek SN, Schweigler LM, Theodore D, Zacks SL, Liang TJ, Fried MW. Hepatic gene expression during treatment with peginterferon and ribavirin: Identifying molecular pathways for treatment response. Hepatology 2007; 46:1548-63. [PMID: 17929300 PMCID: PMC2808168 DOI: 10.1002/hep.21853] [Citation(s) in RCA: 217] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
UNLABELLED The reasons for hepatitis C treatment failure remain unknown but may be related to different host responses to therapy. In this study, we compared hepatic gene expression in patients prior to and during peginterferon and ribavirin therapy. In the on-treatment group, patients received either ribavirin for 72 hours prior to peginterferon alpha-2a injection or peginterferon alpha-2a for 24 hours, prior to biopsy. The patients were grouped into rapid responders (RRs) with a greater than 2-log drop and slow responders (SRs) with a less than 2-log drop in hepatitis C virus RNA by week 4. Pretreatment biopsy specimens were obtained from a matched control group. The pretreatment patients were grouped as RRs or SRs on the basis of the subsequent treatment response. Gene expression profiling was performed with Affymetrix microarray technology. Known interferon-stimulated genes (ISGs) were induced in treated patients. In the pretreatment group, future SRs had higher pretreatment ISG expression than RRs. On treatment, RRs and SRs had similar absolute ISG expression, but when it was corrected for the baseline expression with the pretreatment group, RRs showed a greater fold change in ISGs, whereas SRs showed a greater change in interferon (IFN)-inhibitory pathways. The patients pretreated with ribavirin had heightened induction of IFN-related genes and down-regulation of genes involved in IFN inhibition and hepatic stellate cell activation. CONCLUSION These data suggest that ISG inducibility is important for the treatment response and that ribavirin may improve outcomes by enhancing hepatic gene responses to peginterferon. Collectively, these mechanisms may provide a molecular basis for the improved efficacy of combination therapy.
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Affiliation(s)
- Jordan J. Feld
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Santosh Nanda
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Ying Huang
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Weiping Chen
- Microarray Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Maggie Cam
- Microarray Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | | | | | | | | | - T. Jake Liang
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
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11
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Jeong S, Aikata H, Katamura Y, Azakami T, Kawaoka T, Saneto H, Uka K, Mori N, Takaki S, Kodama H, Waki K, Imamura M, Shirakawa H, Kawakami Y, Takahashi S, Chayama K. Low-dose intermittent interferon-alpha therapy for HCV-related liver cirrhosis after curative treatment of hepatocellular carcinoma. World J Gastroenterol 2007; 13:5188-95. [PMID: 17876889 PMCID: PMC4171300 DOI: 10.3748/wjg.v13.i39.5188] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the efficacy of low-dose intermittent interferon (IFN) therapy in patients with hepatitis C virus (HCV)-related compensated cirrhosis who had received curative treatment for primary hepatocellular carcinoma (HCC).
METHODS: We performed a prospective case controlled study. Sixteen patients received 3 MIU of natural IFN-alpha intramuscularly 3 times weekly for at least 48 wk (IFN group). They were compared with 16 matched historical controls (non-IFN group).
RESULTS: The cumulative rate of first recurrence of HCC was not significantly different between the IFN group and the non-IFN group (0% vs 6.7% and 68.6% vs 80% at 1- and 3-year, P = 0.157, respectively). The cumulative rate of second recurrence was not also significantly different between the IFN group and the non-IFN group (0% vs 6.7% and 35.9% vs 67% at 1- and 3-year, P = 0.056, respectively). Although the difference in the Child-Pugh classification score between the groups at initial treatment of HCC was not significant, the score was significantly worse at the time of data analysis in the non-IFN group than IFN group (7.19 ± 1.42 vs 5.81 ± 0.75, P = 0.0008). The cumulative rate of deviation from objects of any treatment for recurrent HCC was also higher in the non-IFN group than IFN group (6.7% and 27% vs 0 and 0% at 1- and 3-year, P = 0.048, respectively).
CONCLUSION: Low-dose intermittent IFN-alpha therapy for patients with HCV-related compensated cirrhosis after curative HCC treatment was effective by making patients tolerant to medical or surgical treatment for recurrent HCC in the later period of observation.
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Affiliation(s)
- Soocheol Jeong
- Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3, Kasumi, Hiroshima, Japan
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12
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Teixeira R, Marcos LA, Friedman SL. Immunopathogenesis of hepatitis C virus infection and hepatic fibrosis: New insights into antifibrotic therapy in chronic hepatitis C. Hepatol Res 2007; 37:579-95. [PMID: 17517074 DOI: 10.1111/j.1872-034x.2007.00085.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Fibrosis and cirrhosis represent the consequences of a sustained wound-healing response to chronic liver injury of any cause. Chronic hepatitis C virus (HCV) has emerged as a leading cause of cirrhosis in the USA and throughout the world. HCV may induce fibrogenesis directly by hepatic stellate cell activation or indirectly by promoting oxidative stress and apoptosis of infected cells. The ultimate result of chronic HCV injury is the accumulation of extracellular matrix with high density type I collagen within the subendothelial space of Disse, culminating in cirrhosis with hepatocellular dysfunction. The treatment of hepatitis C with the combination of pegylated interferon and ribavirin is still both problematic and costly, has suboptimal efficacy, serious side effects and a high level of intolerance, and is contraindicated in many patients. Hence, new approaches have assumed greater importance, for which there is an urgent need. The sustained progress in understanding the pathophysiology of hepatic fibrosis in the past two decades has increased the possibility of developing drugs specifically targeting the fibrogenic process. Future efforts should identify genetic markers associated with fibrosis risk in order to tailor the treatment of HCV infection based on genetically regulated pathways of injury and/or fibrosis. Such advances will expand the arsenal to overcome liver fibrosis, particularly in patients with hepatic diseases who have limited treatment options, such as those patients with chronic hepatitis C who have a high risk of fibrosis progression and recurrent HCV disease after liver transplantation.
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Affiliation(s)
- Rosângela Teixeira
- School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
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13
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Ghorbani M, Nass T, Azizi A, Soare C, Aucoin S, Giulivi A, Anderson DE, Diaz-Mitoma F. Comparison of antibody- and cell-mediated immune responses after intramuscular hepatitis C immunizations of BALB/c mice. Viral Immunol 2006; 18:637-48. [PMID: 16359230 DOI: 10.1089/vim.2005.18.637] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Current treatments for hepatitis C infection have limited efficacy, and there is no vaccine available. The goal of this study was to compare the immune response to several immunization combinations against hepatitis C virus (HCV). Six groups of mice were immunized at weeks 0, 4, and 8 with different combinations of a candidate HCV vaccine consisting of 100 microg recombinant HCV core/E1/E2 (rHCV) DNA plasmid and/or 25 microg rHCV polyprotein and 50 microL Montanide ISA- 51. Four weeks after the last injection, all groups of mice were sacrificed and blood samples and spleens were collected for measuring the levels of specific HCV antibodies (total IgG, IgG1, and IgG2a). Cell proliferation and intracellular interferon-gamma were also measured. Among the groups of immunized mice, only the mice immunized with rHCV DNA plasmid, rHCV polyprotein, and montanide (group D) and mice immunized with rHCV polyprotein and montanide (group F) demonstrated a significant increase in the total IgG titer after immunization. IgG1 was the predominant antibody detected in both groups D and F. No IgG2a was detected in any of the groups. Proliferation assays demonstrated that splenocytes from group D and group C (rHCV DNA primed/rHCV polyprotein boost) developed significant anti-HCV proliferative responses. The combination of an rHCV DNA plasmid, rHCV polyprotein, and montanide induced a high antibody titer with a predominance of IgG1 antibodies and recognized the major neutralization epitopes in HVR1. In contrast, group C did not show an increase in anti-HCV antibodies, but did show a proliferative response.
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Affiliation(s)
- M Ghorbani
- Division of Virology, Children's Hospital of Eastern Ontario and University of Ottawa, Ottawa, Ontario, Canada
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14
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Cholongitas E, Senzolo M, Standish R, Marelli L, Quaglia A, Patch D, Dhillon AP, Burroughs AK. A systematic review of the quality of liver biopsy specimens. Am J Clin Pathol 2006. [PMID: 16707372 DOI: 10.1309/w3xcnt4hkfbn2g0b] [Citation(s) in RCA: 149] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Characteristics for an optimal liver biopsy specimen were recently defined as 20 to 25 mm long and/or containing more than 11 complete portal tracts (CPTs). A systematic review of percutaneous liver biopsy (PLB) and transjugular liver biopsy (TJLB) series yielded only 32 PLB studies in which these characteristics were evaluated: mean +/- SD length, 17.7 +/- 5.8 mm and number of CPTs, 7.5 +/- 3.4; and 15 TJLB studies: mean +/- SD length, 13.5 +/- 4.5 mm and number of CPTs, 6.8 +/- 2.3. Studies of sampling heterogeneity and intraobserver and interobserver variability also used inadequate specimens by present standards. Only 11 (5.3%) of 207 therapeutic studies for chronic hepatitis B and C documented length and/or number of CPTs. Of the current 12 studies evaluating noninvasive fibrosis tests, only 8 documented length or number of CPTs, and only 1 documented length and number of CPTs. New studies are needed based on adequate liver biopsy samples to provide reliable estimation of grading and staging in chronic liver disease.
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15
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Radaeva S, Sun R, Jaruga B, Nguyen VT, Tian Z, Gao B. Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners. Gastroenterology 2006; 130:435-52. [PMID: 16472598 DOI: 10.1053/j.gastro.2005.10.055] [Citation(s) in RCA: 471] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2005] [Accepted: 10/19/2005] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Viral hepatitis infection, which is a major cause of liver fibrosis, is associated with activation of innate immunity. However, the role of innate immunity in liver fibrosis remains obscure. METHODS Liver fibrosis was induced either by feeding mice with the 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet or by injecting them with carbon tetrachloride. The Toll-like receptor 3 ligand, polyinosinic-polycytidylic acid, was used to activate innate immunity cells and mediators, including natural killer cells and interferon gamma. RESULTS In the mouse model of DDC-induced liver fibrosis, natural killer cell activation by polyinosinic-polycytidylic acid induced cell death to activated hepatic stellate cells and attenuated the severity of liver fibrosis. Polyinosinic-polycytidylic acid treatment also ameliorated liver fibrosis induced by carbon tetrachloride. The observed protective effect of polyinosinic-polycytidylic acid on liver fibrosis was diminished through either depletion of natural killer cells or by disruption of the interferon gamma gene. Expression of retinoic acid early inducible 1, the NKG2D ligand, was undetectable on quiescent hepatic stellate cells, whereas high levels were found on activated hepatic stellate cells, which correlated with the resistance and susceptibility of quiescent hepatic stellate cells and activated hepatic stellate cells to natural killer cell lysis, respectively. Moreover, treatment with polyinosinic-polycytidylic acid or interferon gamma enhanced the cytotoxicity of natural killer cells against activated hepatic stellate cells and increased the expression of NKG2D and tumor necrosis factor-related apoptosis-inducing ligand on liver natural killer cells. Blocking NKG2D or tumor necrosis factor-related apoptosis-inducing ligand with neutralizing antibodies markedly diminished the cytotoxicity of polyinosinic-polycytidylic acid-activated natural killer cells against activated hepatic stellate cells. CONCLUSIONS Our findings suggest that natural killer cells kill activated hepatic stellate cells via retinoic acid early inducible 1/NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent mechanisms, thereby ameliorating liver fibrosis.
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MESH Headings
- Animals
- Apoptosis/immunology
- DNA Primers
- Disease Models, Animal
- Flow Cytometry
- Hepatitis, Viral, Animal/immunology
- Killer Cells, Natural/immunology
- Ligands
- Liver Cirrhosis, Experimental/immunology
- Male
- Membrane Glycoproteins/deficiency
- Membrane Glycoproteins/genetics
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- NK Cell Lectin-Like Receptor Subfamily K
- Perforin
- Pore Forming Cytotoxic Proteins
- Receptors, Immunologic/genetics
- Receptors, Immunologic/physiology
- Receptors, Natural Killer Cell
- Reverse Transcriptase Polymerase Chain Reaction
- Tretinoin/physiology
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Affiliation(s)
- Svetlana Radaeva
- Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892, USA
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16
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Tinè F, Attanasio M, Russo F, Pagliaro L. A decade of trials of interferon-alpha for chronic hepatitis C. A meta-regression analysis. Contemp Clin Trials 2005; 26:179-210. [PMID: 15837440 DOI: 10.1016/j.cct.2004.12.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2003] [Revised: 12/23/2004] [Accepted: 12/23/2004] [Indexed: 01/22/2023]
Abstract
The most relevant randomized controlled trials of interferon-alpha (IFN) for naive patients with chronic hepatitis C (CHC) published in a decade, just before appearance of pegylated IFN trials in 2000, were included in this paper. Its purpose is to review the relationship between sustained biochemical response in active versus control group versus usual clinical variables as IFN regimens, cirrhosis, genotype and versus less frequently addressed variables as funding, methodological quality or location of principal author. Meta-analysis estimates of global treatment effect varied according to trial design: group 1=IFN versus placebo/no treatment, 32 RCTs, 2499 pts, OR 9.5 (6.3-14.2); group 2a=comparison of IFN schedules, 43 RCTs, 7454 pts, OR 1.6 (1.4-1.9); group 2b=IFN+other drugs versus standard IFN, 30 RCTs, 4737 pts, OR 2.0 (1.6-2.6). Fixed effects (arm-level) meta-regression on the complete data set (171 arms, 10,580 pts) revealed that sustained response was most likely in experimental arms of IFN+ribavirin or other drugs (OR 2.4), arms using yearly schedule (OR 2.0), trial principal author from Asia (OR 1.7), trial sample size >200 (OR 1.4) and arms enrolling less than 50% of cirrhotics (OR 1.3). Moreover, focus was on some significant interactions too, as the effect of trial's quality interacting to the recorded funding (more benefit if no-profit, less if for-profit) and the effect of trial funding interacting to the location of first author (more benefit if from Asia). Three main effects (experimental arm, cirrhosis, funding) and one interaction (funding*location of principal author) explained 31% of between study variability in a random-effect meta-regression. In a subgroup analysis on a data set including available information on HCV genotype (93 arms, around 7000 pts), meta-regression revealed that genotype 1 or 4 less than 50% per arm and specialistic journal were significant predictors of either biochemical (transaminases) or virological (HCV-RNA) sustained response, in a model including the same main effects identified in the complete data set analysis. Finally, although mostly captured by different IFN regimens along time, heterogeneity of effect in a large set of (not-pegylated) IFN trials was also explained by HCV genotype and variables of quality and reporting, such as trial's principal author from Asia.
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Affiliation(s)
- Fabio Tinè
- Divisione di Medicina Interna e Gastroenterologia, Ospedale V. Cervello, Palermo, Italy.
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17
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Lebray P, Nalpas B, Vallet-Pichard A, Broissand C, Sobesky R, Serpaggi J, Fontaine H, Pol S. The Impact of Haematopoietic Growth Factors on the Management and Efficacy of Antiviral Treatment in Patients with Hepatitis C Virus. Antivir Ther 2005. [DOI: 10.1177/135965350501000605] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Aim To evaluate the benefits of haematopoietic growth factors (HGFs) during the treatment of chronic hepatitis C virus (HCV) infection with severe haematotoxicity. Methods This was a 1-year retrospective study of HCV-positive patients receiving pegylated interferon and ribavirin. Patients received different HGFs, depending on certain criteria: they received erythropoietin (EPO) when their haemoglobin (Hb) levels were less than 10 g/dl and granulocyte colony-stimulating factor (G-CSF) when their neutrophil count was less than 750 cells/mm3. Haematological data, adherence and virological response were analysed and compared according to HGF use. Results In total, 132 patients were studied and 31 (23.5%) required HGF. Under multivariate analysis, baseline Hb levels of less than 13g/dl or a drop in Hb levels of over 2% per week predicted severe anaemia, and a base-line neutrophil count under 2900/mm3 predicted severe neutropaenia. HGF administration restored Hb values and the neutrophil count to above 10 g/dl and 1500 cells/mm3, respectively, in all 31 patients. Adherence to antiviral treatment was achieved in 25% of patients versus 58% of controls without severe haematotoxicity. The primary and sustained virological response did not differ statistically between HGF support and the control group (61% versus 57% and 32% versus 39%, respectively). Conclusion HGF administration counteracts the severe haematological adverse effects which occur during antiviral therapy and maintains the rate of sustained response.
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Affiliation(s)
- Pascal Lebray
- Unité d'Hépatologie, Hôpital Necker, Paris, France
- Inserm, U370, Paris, France
| | - Bertrand Nalpas
- Unité d'Hépatologie, Hôpital Necker, Paris, France
- Inserm, U370, Paris, France
| | | | | | - Rodolphe Sobesky
- Unité d'Hépatologie, Hôpital Necker, Paris, France
- Inserm, U370, Paris, France
| | - Jeanne Serpaggi
- Unité d'Hépatologie, Hôpital Necker, Paris, France
- Inserm, U370, Paris, France
| | - Hélèn Fontaine
- Unité d'Hépatologie, Hôpital Necker, Paris, France
- Inserm, U370, Paris, France
| | - Stanislas Pol
- Unité d'Hépatologie, Hôpital Necker, Paris, France
- Inserm, U370, Paris, France
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18
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Abstract
Hepatitis C is found in approximately a third of patients infected with HIV. Therapy of hepatitis C in HIV patients is very important from several view points. First, hepatitis C in the setting of immunosuppression may progress faster, although recent data show that mortality from liver disease was decreased in highly active antiretroviral therapy. HIV/hepatitis C coinfection is associated with more frequent elevation in liver tests (drug-induced liver injury) during highly active antiretroviral therapy, and in some studies, hepatitis C has been associated with lower CD4+ recoveries. The therapeutic standard of care is a combination of peginterferon and ribavirin at a fixed dose, 800 mg/day, although higher ribavirin doses may further improve virologic outcomes. In patients that do not respond virologically, maintenance therapy with peginterferon monotherapy is a potential avenue to stem the advance of liver fibrosis, although controlled data in coinfected patients are needed to issue formal recommendations.
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Affiliation(s)
- Tami Daugherty
- California Pacific Medical Center, 2340 Clay Street, 2nd Floor, San Francisco, CA 94115, USA.
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19
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20
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Ribeiro RM, Layden-Almer J, Powers KA, Layden TJ, Perelson AS. Dynamics of alanine aminotransferase during hepatitis C virus treatment. Hepatology 2003; 38:509-17. [PMID: 12883496 DOI: 10.1053/jhep.2003.50344] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Studies of the kinetics of hepatitis C virus (HCV) decline during interferon (IFN)-based therapy have led to insights into treatment efficacy. However, the kinetics of serum alanine aminotransferase (ALT), an enzyme used as a surrogate of liver damage, have not been closely monitored, and it is not known if they correlate with those of HCV RNA. Here we describe the associations between ALT and HCV dynamics. We analyzed 35 patients treated daily with 10 mIU IFN-alpha 2b with or without ribavarin for 28 days followed by standard IFN/ribavirin therapy. Patients exhibited 4 patterns of ALT change: (1) exponential decay of ALT, (2) transient increase in ALT followed by a decrease to pretreatment or normal levels, (3) increase in ALT to a new level, and (4) no significant change. By simultaneously modeling HCV and ALT dynamics, we successfully fit the observed changes. We found ALT decays with t(1/2) = 12.7 hours. The transient increase in ALT observed in some patients suggested a mild hepatotoxic effect of IFN. However, patients with a smaller initial ALT increase achieved higher rates of viral negativity by week 72 (P =.02). The week-4 ALT decline correlated with the HCV log drop (P =.006) and the efficacy of therapy (P =.025). In conclusion, our results suggest the use of ALT as a surrogate marker for treatment effect in patients with elevated ALT.
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Affiliation(s)
- Ruy M Ribeiro
- Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545, USA
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21
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Cacoub P, Benhamou Y. [Role of interferons in the treatment of hepatitis B and hepatitis C virus infections]. Rev Med Interne 2002; 23 Suppl 4:459s-474s. [PMID: 12481401 DOI: 10.1016/s0248-8663(02)00660-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Since the discovery of hepatitis C (HCV), the efficacy of treatment has significantly progressed using standard mono-therapy: with Interferon alpha (IFN) during six months we obtained approximately 10% sustained response and currently with the association of pegylated IFN and Ribavirin a 55% sustained response was achieved. CURRENT POSITION AND MAJOR POINTS HCV infection continues to present therapeutic problems which have not entirely been solved, mainly related to clinical and biological tolerance, and non-responders. Moreover, the care of patients with extra-hepatic localization, cirrhotic patients, as well as therapeutic problems of co-infected HIV-HCV patients. As regards hepatitis B (HBV) new effective treatments against this virus have appeared, IFN then nucleoside analogs, some of which are available in France (i.e. lamivudine, adefovir, dipovoxil). The main objective of chronic hepatitis B treatment is to obtain the complete inhibition of the HBV virus by Hbe-antigen antibody seroconversion which would therefore significantly increase patient survival. In this article the advantages and disadvantages of the different treatments are assessed. FUTURE PERSPECTIVES Despite the considerable and rapid progress obtained in the therapeutic treatment of infection due to HCV and HBV a number of unknown factors remain, which warrants further trials, in particular to evaluate the efficacy as well as the tolerance of the antiviral agent association.
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Affiliation(s)
- P Cacoub
- Service de médecine interne, hôpital La Pitié-Salpêtrière, 83, boulevard de l'Hôpital, 75651 Paris, France.
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22
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Sánchez-Quijano A, Leal M, Lissen E. [Chronic hepatitis C in patients coinfected by human immunodeficiency virus]. GASTROENTEROLOGIA Y HEPATOLOGIA 2002; 25:423-31. [PMID: 12069706 DOI: 10.1016/s0210-5705(02)70277-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- A Sánchez-Quijano
- Grupo Estudio Hepatitis Vírica y SIDA, Hospital Universitario Virgen del Rocío, Sevilla, Spain.
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23
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Renou C, Harafa A, Bouabdallah R, Dematteï C, Cummins C, Rifflet H, Muller P, Ville E, Bertrand J, Benderitter T, Halfon P. Severe neutropenia and post-hepatitis C cirrhosis treatment: is interferon dose adaptation at once necessary? Am J Gastroenterol 2002; 97:1260-3. [PMID: 12014740 DOI: 10.1111/j.1572-0241.2002.05716.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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24
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Melian EB, Plosker GL. Interferon alfacon-1: a review of its pharmacology and therapeutic efficacy in the treatment of chronic hepatitis C. Drugs 2002; 61:1661-91. [PMID: 11577799 DOI: 10.2165/00003495-200161110-00009] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
UNLABELLED Interferon alfacon-1 (consensus interferon) is a non-naturally occurring, synthetic, type 1 interferon (IFN)alpha that is used for the treatment of patients with chronic hepatitis C. The efficacy of subcutaneously administered interferon alfacon-1 has been demonstrated in clinical trials during the treatment of LFN-naive patients (interferon alfacon-1 9microg 3 times a week for 24 weeks) and retreatment of nonresponders and relapsers to previous interferon therapy (interferon alfacon1 15 microg 3 times a week for up to 48 weeks). Higher and more frequent interferon alfacon-1 dosages have also been investigated. Results from a pivotal double-blind randomised trial in 704 patients with chronic hepatitis C showed that interferon alfacon-19 microg 3 times a week achieved virological and biochemical response rates of 34.9 and 42.2%, respectively, at treatment end-point (week 24). Sustained virological and biochemical responses (week 48) were reported in 12.1 and 20.3% of the patients, respectively. In general, response rates in recipients of interferon alfacon-1 9 microg 3 times a week were similar to those achieved with IFN-alpha2b 3 MIU 3 times a week. However, interferon alfacon-1 was more effective in the subgroup of patients infected with hepatitis C virus (HCV) genotype 1 at end-point (virological response, 24 vs 15%; p < 0.05) and post-treatment observation period (8 vs 4%) although the difference between treatment groups was statistically significant only at treatment end-point. The sustained virological response rate achieved in patients with high baseline levels of serum HCV RNA receiving interferon alfacon-1 was statistically superior to that exhibited in the IFN-alpha2b treatment group (7 vs 0%; p < Interferon alfacon-1 also showed efficacy during the retreatment of non-responders and relapsers to previous IFN therapy in a large nonblind multicentre trial. Sustained virological response (week 72) was observed among 13 and 58% of nonresponders and relapsers, respectively, after 48 weeks of treatment with interferon alfacon-1 15 microg 3 times a week. Interferon alfacon-1 has been generally well tolerated in clinical trials. As with other IFNs, adverse events were reported frequently but were usually considered of mild to moderate severity, decreased with time and caused a small percentage of patients to withdraw from the treatment. Fever, fatigue, arthralgia, myalgia, headache and rigors were the most frequently reported adverse events. Psychiatric adverse events appeared to be dose-related and caused the majority of treatment withdrawals. CONCLUSION Interferon alfacon-1 is generally well tolerated and is an effective agent in the treatment of patients with chronic hepatitis C. Comparative data from a pivotal randomised trial indicate that the drug has at least equivalent efficacy to IFNalpha-2b, and a statistically significant advantage was demonstrated at treatment end-point in patients infected with HCV genotype 1. A number of ongoing trials with interferon alfacon-1 are evaluating issues such as the optimal dosage regimen and duration of therapy in an effort to improve sustained virological response to therapy, a goal for IFNs in general.
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Affiliation(s)
- E B Melian
- Adis International Limited, Mairangi Bay, Auckland, New Zealand.
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25
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Fanning L, Loane J, Kenny-Walsh E, Sheehan M, Whelton M, Kirwan W, Collins JK, Shanahan F. Tissue viral load variability in chronic hepatitis C. Am J Gastroenterol 2001; 96:3384-9. [PMID: 11774953 DOI: 10.1111/j.1572-0241.2001.05271.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Liver biopsy is regarded as the gold standard for assessing disease activity in chronic hepatitis C, but sampling error is a potential limitation. Whether sampling variability applies equally to viral load assessment as it does to histology is uncertain. To examine this, we compared viral load between right- and left-lobe biopsy specimens from patients infected with hepatitis C virus (HCV). METHODS Bilobe biopsies were taken from 16 patients who were serum positive for HCV RNA by reverse transcription-polymerase chain reaction. Genotype was identified by reverse line probe hybridization. There was an absence of competing risk factors for infectious and other liver diseases in this patient group. Histology and hepatic viral load were assessed blindly. None of the patients had received antiviral therapy at the time of study. RESULTS Detection of HCV in right and left lobes was concordant with serum positivity in all cases. The viral load between lobes was highly correlated (p = 0.0003, r = 0.79). In contrast, the histological activity indices of inflammation and fibrosis/cirrhosis were poorly correlated between lobes (p = 0.038, r = 0.60, and p = 0.098, r = 0.50, respectively). CONCLUSION Hepatic viral load variability does not suffer from the same degree of heterogeneity of sampling variability as does histology.
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Affiliation(s)
- L Fanning
- Department of Medicine, Cork University Hospital, National University of Ireland
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26
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Rajan S, Liebman HA. Treatment of hepatitis C related thrombocytopenia with interferon alpha. Am J Hematol 2001; 68:202-9. [PMID: 11754404 DOI: 10.1002/ajh.1180] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Thrombocytopenia is a common extrahepatic manifestation of hepatitis C (HCV) infection. Treatment with steroids may be effective, but can exacerbate the viral infection. Interferon alpha (INF) has documented efficacy in the treatment of HCV, but its use in the treatment of HCV thrombocytopenia is controversial. We treated eight patients with HCV-related thrombocytopenia, who had platelet counts of fewer than 50 x 10(9)/l (range: 16 to 46 x 10(9)/L) with INF 3 MU SQ three times a week. Planned duration of treatment was 24 weeks. Five patients had no evidence of hepatic cirrhosis, three had cirrhosis, and two had palpable splenomegaly. Only three patients tolerated the full course of treatment, and all three had improvement in their platelet counts to greater than 50 x 10(9)/l. Two other patients had improvement in platelet counts to more than 50 x 10(9)/l with shorter duration of treatment (six and 16 weeks, respectively). The mean increase in platelet count in the five responders was 44 x 10(9)/lL (range: 28 to 90 x 10(9)/l). The average peak platelet count in the responders was 81 x 10(9)/l (range: 62 to 136 x 10(9)/l). Duration of response ranged from four to 18+ months, with the shortest responses observed in the two patients treated with a shorter course of INF. Response was independent of the presence of cirrhosis. Responding patients had improvement in hepatic transaminases, reduction in cryoglobulin and anticardiolipin antibodies, and HCV plasma RNA when tested. Relapse was associated with an increase in these laboratory markers of HCV infection. We conclude that INF can be an effective treatment in patients with HCV-related thrombocytopenia.
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Affiliation(s)
- S Rajan
- Division of Hematology, Department of Medicine, University of Southern California-Keck School of Medicine, Los Angeles, California, USA
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27
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28
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Abstract
Until recently, interferon monotherapy has been the only available therapeutic option for patients with chronic hepatitis B and hepatitis C. Lamivudine has emerged as another effective first-line therapy for chronic hepatitis B as well as a beneficial treatment option for patients with decompensated hepatitis B cirrhosis. Viral resistance with long-term lamivudine therapy remains a major concern but new data continue to show benefits despite the development of YMDD mutations. Combination therapy with ribavirin and pegylated interferon-alpha has revolutionized the treatment of chronic hepatitis C. The rate of sustained virological response can now be expected to be as high as nearly 50% for genotype 1 and 80% for non-1 genotypes of hepatitis C.
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Affiliation(s)
- M H Nguyen
- Department of Gastroenterology and Hepatology, Stanford University, Palo Alto, USA
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30
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Tang ZY. Hepatocellular carcinoma--cause, treatment and metastasis. World J Gastroenterol 2001; 7:445-54. [PMID: 11819809 PMCID: PMC4688653 DOI: 10.3748/wjg.v7.i4.445] [Citation(s) in RCA: 302] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2001] [Revised: 07/20/2001] [Accepted: 07/27/2001] [Indexed: 02/06/2023] Open
Abstract
In the recent decades, the incidence of hepatocellular carcinoma (HCC) has been found to be increasing in males in some countries. In China, HCC ranked second of cancer mortality since 1990s. Hepatitis B and C viruses (HBV and HCV) and dietary aflatoxin intake remain the major causative factors of HCC. Surgery plays a major role in the treatment of HCC, particularly for small HCC. Down-staging unresectable huge HCC to smaller HCC and followed by resection will probably be a new approach for further study. Liver transplantation is indicated for small HCC, however, some issues remain to be solved. Different modes of regional cancer therapy for HCC have been tried. Systemic chemotherapy has been disappointing in the past but the future can be promising. Biotherapy, such as cytokines, differentiation inducers, anti-angiogenic agents, gene therapy and tumor vaccine will probably play a role, particularly in the prevention of tumor recurrence. HCC invasiveness is currently the major target of study. Tremendous works have been done at the molecular level, which will provide clues for biomarker of HCC progression as well as targets for intervention.
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Affiliation(s)
- Z Y Tang
- Liver Cancer Institute of Fudan University, 136 Yixueyuan Road, Zhongshan Hospital, Shanghai 200032, China.
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31
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Abstract
Significant advances have been made in the treatment of both hepatitis B and C. Cure for the majority is becoming reality. Combination regimens are now established therapy in hepatitis C and the near future will see the adoption of a similar approach to hepatitis B. Interferon alpha therapy remains important, with the development of more efficacious pegylated forms. In this article we review current therapy and discuss future strategies of the therapy for chronic viral hepatitis.
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Affiliation(s)
- M Wright
- Imperial College School of Medicine at St Mary's Hospital, London, UK.
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32
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Aguilar C, Lucia JF, Simón MA. An emerging role for interferon in haemophiliacs with chronic hepatitis C? Haemophilia 2001; 7:6-8. [PMID: 11136373 DOI: 10.1046/j.1365-2516.2001.00462.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The combination of interferon (IFN) and ribavirin is the current gold standard for treatment of chronic hepatitis C virus (HCV) infection with sustained remission rates of 35--40% being achieved in haemophilic patients. A similar beneficial effect of this combined therapy has been suggested even for patients with compensated liver cirrhosis and some authors have reported a possible role for IFN and ribavirin in the prevention or delay in the development of hepatocellular carcinoma (HCC), a well known complication of HCV infection in haemophiliacs. The absence, due to design difficulties, of definite randomized controlled clinical trials remains a handicap for the routine use of specific therapy of HCV infected patients with the aim of preventing HCC. A discussion of these important issues has been performed in this paper.
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Affiliation(s)
- C Aguilar
- Department of Haematology, Hospital General del Insalud, Soria, Spain.
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Hu KQ, Vierling JM, Redeker AG. Viral, host and interferon-related factors modulating the effect of interferon therapy for hepatitis C virus infection. J Viral Hepat 2001; 8:1-18. [PMID: 11155147 DOI: 10.1046/j.1365-2893.2001.00253.x] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The estimated prevalence of hepatitis C virus infection in the US is approximately 1.8%. Although interferon monotherapy and combination therapy of interferon with ribavirin represent mainstay for treating HCV infection, the rate of sustained virologic response remains suboptimal. The growing evidence suggested that the clinical sequence and treatment response of chronic hepatitis C are determined by a dynamic, complex tripartite relationship among HCV infection, the host immune response, and the effect of different interferon regimens. The treatment response is associated with various viral factors including the pretreatment viral level, dynamic change of viral level during treatment, viral genotype quasispecies and nucleotide mutation in nonstructural protein 5A of hepatitis C virus. Host factors that may affect treatment response include age, gender, race, HLA alleles and the host immune responses. Interferon regimens, including type, dose, frequency and duration of treatment and combination of interferon with other anti-HCV agents also alter the therapeutic response. Understanding these complicated interaction may provide better insights into the mechanism(s) of interferon response, leading to more effective clinical application of interferon therapy.
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Affiliation(s)
- K Q Hu
- Department of Medicine and Transplantation Institute, Loma Linda University Medical Canter and Jerry L. Pettis Memorial Veterans' Affairs Medical Center, Loma Linda, CA 92354, USA
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Heathcote EJ, Shiffman ML, Cooksley WG, Dusheiko GM, Lee SS, Balart L, Reindollar R, Reddy RK, Wright TL, Lin A, Hoffman J, De Pamphilis J. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med 2000; 343:1673-80. [PMID: 11106716 DOI: 10.1056/nejm200012073432302] [Citation(s) in RCA: 668] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Chronic hepatitis C virus (HCV) infection in patients with cirrhosis is difficult to treat. In patients with chronic hepatitis C but without cirrhosis, once-weekly administration of interferon modified by the attachment of a 40-kd branched-chain polyethylene glycol moiety (peginterferon alfa-2a) is more efficacious than a regimen of unmodified interferon. We examined the efficacy and safety of peginterferon alfa-2a in patients with HCV-related cirrhosis or bridging fibrosis. METHODS We randomly assigned 271 patients with cirrhosis or bridging fibrosis to receive subcutaneous treatment with 3 million units of interferon alfa-2a three times weekly (88 patients), 90 microg of peginterferon alfa-2a once weekly (96), or 180 microg of peginterferon alfa-2a once weekly (87). Treatment lasted 48 weeks and was followed by a 24-week follow-up period. We assessed efficacy by measuring HCV RNA and alanine aminotransferase and by evaluating liver-biopsy specimens. A histologic response was defined as a decrease of at least 2 points on the 22-point Histological Activity Index. RESULTS In an intention-to-treat analysis, HCV RNA was undetectable at week 72 in 8 percent, 15 percent, and 30 percent of the patients treated with interferon alfa-2a and with 90 microg and 180 microg of peginterferon alfa-2a, respectively (P=0.001 for the comparison between 180 microg of peginterferon alfa-2a and interferon alfa-2a). At week 72, alanine aminotransferase concentrations had normalized in 15 percent, 20 percent, and 34 percent of patients, respectively (P=0.004 for the comparison between 180 microg of peginterferon alfa-2a and interferon alfa-2a). In the subgroup of 184 patients with paired liver-biopsy specimens, the rates of histologic response at week 72 were 31 percent, 44 percent, and 54 percent, respectively (P=0.02 for the comparison between 180 microg of peginterferon alfa-2a and interferon alfa-2a). All three treatments were similarly tolerated. CONCLUSIONS In patients with chronic hepatitis C and cirrhosis or bridging fibrosis, 180 microg of peginterferon alfa-2a administered once weekly is significantly more effective than 3 million units of standard interferon alfa-2a administered three times weekly.
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Affiliation(s)
- E J Heathcote
- Department of Medicine, University Health Network, Toronto Western Hospital, ON, Canada
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Wright M, Main J. The prevention and management of viral hepatitis. Curr Opin Infect Dis 2000; 13:489-494. [PMID: 11964819 DOI: 10.1097/00001432-200010000-00010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
In this review we will discuss advances in the primary and secondary prevention of viral hepatitis and the treatment for chronic viral hepatitis.
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Affiliation(s)
- Mark Wright
- Imperial College Medical School, St Mary's Hospital, London, UK
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Malnick SD, Beergabel M, Lurie Y. Treatment of chronic hepatitis C virus infection. Ann Pharmacother 2000; 34:1156-1164. [PMID: 11054985 DOI: 10.1345/aph.10017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
OBJECTIVE To review the literature on the treatment of chronic hepatitis C virus (HCV) infection. DATA SOURCES MEDLINE search (1986-December 1999) using key words such as HCV, hepatitis, non-A and non-B hepatitis, as well as terms regarding treatment during that time period. DATA SYNTHESIS HCV infection was initially treated with interferon monotherapy, but only a minority of patients responded to long-term therapy. A higher rate of response in both interferon-naïve patients and interferon-relapsers has been achieved by using the combination of interferon and ribavarin. Other treatment regimens including high-dose interferon protocols, ursodeoxycholic acid, amantadine, and nonsteroidal antiinflammatory drugs have been less promising. Many alternative therapies are being investigated. CONCLUSIONS HCV infection is a major public health problem. It is now possible to achieve a cure in nearly 50% of the patients with this infection. Many additional therapies are being evaluated in order to achieve a higher cure rate.
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Affiliation(s)
- S D Malnick
- Department of Internal Medicine C, Kaplan Medical Center, Rehovot Israel.
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Imperiale TF, Said AT, Cummings OW, Born LJ. Need for validation of clinical decision aids: use of the AST/ALT ratio in predicting cirrhosis in chronic hepatitis C. Am J Gastroenterol 2000; 95:2328-32. [PMID: 11007237 DOI: 10.1111/j.1572-0241.2000.02322.x] [Citation(s) in RCA: 78] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE A value of > or = 1 for the ratio of aspartate amino-transferase to alanine aminotransferase (the AST/ALT ratio or AAR) has been shown to have a positive predictive value of 100% for the diagnosis of cirrhosis in patients with chronic hepatitis C. If validated on separate cohorts, an AAR > or = 1 might obviate the need for liver biopsy in some patients with hepatitis C. METHODS We attempted to validate the AAR by abstracting demographic and clinical data from a database of consecutive patients with hepatitis C who had a liver biopsy between 1993 and 1998. We used definitions, methods of data collection, and analyses comparable to those of the published study. A hepatopathologist blindly reviewed 49 liver biopsies for histological grade and stage. RESULTS The current cohort of 177 patients and the previous cohort of 139 patients were comparable in mean age (42.3 vs 43.8 yr), percentage of men (63 vs 67), percentage with an AAR > or =1 (20 vs 17), and Child-Pugh distribution, but differed in substantial use of ethanol (11% vs 3.6%; p = 0.01) and in the prevalence of cirrhosis (23% vs 34%, p = 0.06). Respective sensitivities of the AAR were 56% and 53%. An AAR > or =1 had a positive predictive value of 64% (95% confidence interval 48-78%) for the current cohort. Thirteen of 36 patients (36%) with an AAR > or =1 were incorrectly identified as having cirrhosis. Of these 13 patients, 6 had a normal AST and ALT, 5 had a minimally elevated AST or ALT, and 1 had advanced fibrosis without cirrhosis. CONCLUSIONS These results suggest that an AAR > or =1 may not be as useful for predicting cirrhosis in chronic hepatitis C as previously thought, and emphasizes the need for validation of clinical decision aids on independent patient cohorts.
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Affiliation(s)
- T F Imperiale
- Department of Medicine, Indiana University School of Medicine and the Roudebush VA Medical Center, Indianapolis, USA
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Mallat D, Schiff E. Viral hepatitis. Curr Opin Gastroenterol 2000; 16:255-61. [PMID: 17023883 DOI: 10.1097/00001574-200005000-00008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
Viral hepatitis accounts for most liver diseases seen in hepatology practice. In the past year studies have been focused on uncovering the basic mechanisms of viral-cellular interactions, the knowledge of which will contribute to more effective treatment. Hepatitis A virus outbreaks still occur, even in the most developed countries, which points to the need for more comprehensive vaccination measures. Lessons learned from the treatment of HIV with combination antiviral therapies are being applied to both chronic hepatitis B and C. Progress has been made toward better understanding of viral kinetics and the quasi-species of hepatitis C virus with new and more sensitive diagnostic methods. Several therapeutic protocols are emerging to identify and tailor the management approach in various subsets of the population. Although posttransplantation hepatitis B has been more effectively managed with lamivudine therapy, no major advances have been accomplished in the treatment of recurrent hepatitis C among transplant recipients. Major advances in the field of viral hepatitis including A to E and TT viruses during the past year are highlighted.
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Affiliation(s)
- D Mallat
- Center for Liver Diseases, University of Miami, Miami, Florida 33136, USA
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Abstract
Hepatocellular carcinoma (HCC) is increasing in many countries as a result of an increase in hepatitis C virus (HCV) infection since World War II. The epidemiology of HCC varies with the global region. There have been conflicting observations from different parts of the world concerning the frequency of HCC in patients who in the distant past had post-transfusion non-A, non-B hepatitis. The genetic basis of hepatocarcinogenesis is still poorly understood. In hepatitis B virus (HVB) associated HCC, codon 249 mutation in the p 53 gene seems more related to exposure to aflatoxin B1 than to hepatocarcinogenesis itself. HCC that occurs in children in high HBV endemic regions could be associated with germ-line mutations, but little information is available; not much is known about chemical hepatocarcinogens in the environment other than aflatoxins. The X gene of HBV seems to play an important role in HBV-associated hepatocarcinogenesis. There are preliminary observations on the molecular mechanism of HCV-associated HCC, such as HCV core protein inducing HCC in transgenic mice and the NS3 genome transforming NIH 3T3 cells. Pathological distinction between preneoplastic and very early transformed lesions still depends on classical morphology, and a more genetically oriented differential diagnosis is required. Clinical diagnosis based on modern imaging has improved greatly, but is still unsatisfactory in the differential diagnosis of preneoplastic and early transformed nodules, because the vasculature changes that occur within the nodule are not accurately discerned with the current imaging. Use of sensitive des-gamma-carboxy prothrombin (PIVKA II) assay, and lectin affinity chromatography separating HCC specific subspecies of AFP molecules with a more practical biochemical technique will further improve diagnosis. Early diagnosis and transplantation are the best treatment at the moment, but transplantation is not widely available because of the donor shortage. Despite successful resection, the remnant cirrhotic liver frequently develops new HCC lesions, seriously curtailing long-term survival. All-out efforts should be directed to the prevention of HCC, through prevention of viral hepatitis, prevention of acute hepatitis from becoming chronic, prevention of chronic hepatitis from progressing to cirrhosis, and prevention of the cirrhotic liver from developing HCC (chemoprevention). At the moment, very few such studies exist.
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Affiliation(s)
- K Okuda
- Department of Medicine, Chiba University School of Medicine, Japan
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Abstract
Antiviral therapy is generally indicated in patients who have histologic evidence of chronic hepatitis and ongoing viral replication. The aim of treatment is to normalize alanine aminotransferase levels and to eliminate virus replication. Interferon-alfa (IFN-alpha) is the most used agent. The standard treatment regimen for hepatitis B e antigen (HBeAg)-positive cirrhosis is based on IFN-alpha given alone, but the efficacy of new antivirals (famciclovir, lamivudine) with or without IFN-alpha is currently under investigation. Conversely, the therapy of antiHBe-positive cirrhosis is far from being satisfactory. The results of treatment of patients affected by type C cirrhosis with IFN-alpha alone have been disappointing, as 10-15% of treated patients shows a sustained virologic response. Although current evidence suggests that the combination of ribavirin and IFN-alpha might be more efficacious than IFN alone in increasing the response rate in patients in the advanced fibrotic stage, the efficacy of this regimen for patients with well-compensated HCV-related cirrhosis is still unknown and prospective well-designed studies are urgently needed. Patients with decompensated cirrhosis are not generally treated unless they are included in liver transplantation programs. Prospective long-term trials with large sample sizes are needed to determine if responders to IFN-alpha have a low incidence of liver-related complications and hepatocellular carcinoma.
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Affiliation(s)
- C Zavaglia
- Divisione di Medicina Generale Crespi, Ospedale Niguarda, Milano, Italy
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