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Affeldt P, Di Cristanziano V, Grundmann F, Wirtz M, Kaiser R, Benzing T, Stippel D, Kann M, Kurschat C. Monitoring of hepatitis E virus RNA during treatment for chronic hepatitis E virus infection after renal transplantation. IMMUNITY INFLAMMATION AND DISEASE 2021; 9:513-520. [PMID: 33559399 PMCID: PMC8127542 DOI: 10.1002/iid3.411] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 01/06/2021] [Accepted: 01/22/2021] [Indexed: 12/26/2022]
Abstract
Background Recently, chronic hepatitis E virus (HEV) infections gained increasing attention as a possible cause for elevated liver enzymes of unknown origin and liver cirrhosis in solid organ transplant recipients. Reduction of immunosuppressive therapy and/or use of antiviral drug ribavirin have been established as possible treatment strategies. Methods The efficacy of dose reduction of mycophenolic acid (MPA) and ribavirin therapy was retrospectively analyzed in eight renal transplant patients of our outpatient clinic who were diagnosed with HEV infection by detection of specific antibodies (immunoglobulin M and immunoglobulin G) and/or positive RNA in blood and stool. In four patients serial HEV viral loads in blood were measured. Results Only one patient reached HEV clearance after reduction of immunosuppressive therapy (predominantly reduction of MPA daily dose) alone, whereas six patients were treated with ribavirin after reduction of immunosuppressive therapy due to persistent virus replication. Four of six patients reached HEV clearance after 3 months of ribavirin therapy. HEV clearance was observed after 34–42 days. Two patients, both treated with rituximab within the last 12 months before diagnosis of HEV infection, needed prolonged ribavirin therapy due to persistent viral replication. Conclusion Reduction of daily dose of MPA therapy alone in transplant patients with chronic HEV infection may not be sufficient to control viral replication. HEV clearance under ribavirin therapy shows interindividual variability. Therefore, serial viral monitoring may be useful to personalize treatment duration. Rituximab therapy is a risk factor for complicated‐to‐treat chronic HEV infection.
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Affiliation(s)
- Patrick Affeldt
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Veronica Di Cristanziano
- Faculty of Medicine, University Hospital of Cologne, Institute of Virology, University of Cologne, Cologne, Germany
| | - Franziska Grundmann
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Maike Wirtz
- Faculty of Medicine, University Hospital of Cologne, Institute of Virology, University of Cologne, Cologne, Germany
| | - Rolf Kaiser
- Faculty of Medicine, University Hospital of Cologne, Institute of Virology, University of Cologne, Cologne, Germany
| | - Thomas Benzing
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Dirk Stippel
- Department of General, Visceral and Cancer Surgery, University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Martin Kann
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Christine Kurschat
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
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Loustaud-Ratti V, Debette-Gratien M, Jacques J, Alain S, Marquet P, Sautereau D, Rousseau A, Carrier P. Ribavirin: Past, present and future. World J Hepatol 2016; 8:123-130. [PMID: 26807208 PMCID: PMC4716528 DOI: 10.4254/wjh.v8.i2.123] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Revised: 11/06/2015] [Accepted: 12/29/2015] [Indexed: 02/06/2023] Open
Abstract
Before the advent of direct acting antiviral agents (DAAs) ribavirin, associated to pegylated-interferon played a crucial role in the treatment of chronic hepatitis C, preventing relapses and breakthroughs. In the present era of new potent DAAs, a place is still devoted to the drug. Ribavirin associated with sofosbuvir alone is efficient in the treatment of most cases of G2 infected patients. All options currently available for the last difficult-to-treat cirrhotic G3 patients contain ribavirin. Reducing treatment duration to 12 wk in G1 or G4 cirrhotic compensated patients is feasible thanks to ribavirin. Retreating patients with acquired anti NS5A resistance-associated variants using ribavirin-based strategies could be useful. The addition of ribavirin with DAAs combinations however, leads to more frequent but mild adverse events especially in cirrhotic patients. Preliminary data with interferon-free second generation DAAs combinations without ribavirin suggest that future of the drug is jeopardized even in difficult-to-treat patients: The optimization of ribavirin dosage according to an early monitoring of blood levels has been suggested to be relevant in double therapy with peginterferon or sofosbuvir but not with very potent combinations of more than two DAAs.
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Affiliation(s)
- Véronique Loustaud-Ratti
- Véronique Loustaud-Ratti, Marilyne Debette-Gratien, Jérémie Jacques, Denis Sautereau, Paul Carrier, Fédération Hépatologie, Service d'Hépato-gastroentérologie, CHU Limoges, 87042 Limoges, France
| | - Marilyne Debette-Gratien
- Véronique Loustaud-Ratti, Marilyne Debette-Gratien, Jérémie Jacques, Denis Sautereau, Paul Carrier, Fédération Hépatologie, Service d'Hépato-gastroentérologie, CHU Limoges, 87042 Limoges, France
| | - Jérémie Jacques
- Véronique Loustaud-Ratti, Marilyne Debette-Gratien, Jérémie Jacques, Denis Sautereau, Paul Carrier, Fédération Hépatologie, Service d'Hépato-gastroentérologie, CHU Limoges, 87042 Limoges, France
| | - Sophie Alain
- Véronique Loustaud-Ratti, Marilyne Debette-Gratien, Jérémie Jacques, Denis Sautereau, Paul Carrier, Fédération Hépatologie, Service d'Hépato-gastroentérologie, CHU Limoges, 87042 Limoges, France
| | - Pierre Marquet
- Véronique Loustaud-Ratti, Marilyne Debette-Gratien, Jérémie Jacques, Denis Sautereau, Paul Carrier, Fédération Hépatologie, Service d'Hépato-gastroentérologie, CHU Limoges, 87042 Limoges, France
| | - Denis Sautereau
- Véronique Loustaud-Ratti, Marilyne Debette-Gratien, Jérémie Jacques, Denis Sautereau, Paul Carrier, Fédération Hépatologie, Service d'Hépato-gastroentérologie, CHU Limoges, 87042 Limoges, France
| | - Annick Rousseau
- Véronique Loustaud-Ratti, Marilyne Debette-Gratien, Jérémie Jacques, Denis Sautereau, Paul Carrier, Fédération Hépatologie, Service d'Hépato-gastroentérologie, CHU Limoges, 87042 Limoges, France
| | - Paul Carrier
- Véronique Loustaud-Ratti, Marilyne Debette-Gratien, Jérémie Jacques, Denis Sautereau, Paul Carrier, Fédération Hépatologie, Service d'Hépato-gastroentérologie, CHU Limoges, 87042 Limoges, France
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Pineda-Tenor D, García-Álvarez M, Jiménez-Sousa MA, Vázquez-Morón S, Resino S. Relationship between ITPA polymorphisms and hemolytic anemia in HCV-infected patients after ribavirin-based therapy: a meta-analysis. J Transl Med 2015; 13:320. [PMID: 26438033 PMCID: PMC4595047 DOI: 10.1186/s12967-015-0682-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2015] [Accepted: 09/25/2015] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND There is growing evidence that variations in the gene encoding inosine triphosphate pyrophosphohydrolase (ITPase), known as inosine triphosphatase (ITPA), are related to hemolytic anemia, which is frequently observed among hepatitis C virus (HCV)-infected patients receiving ribavirin (RBV)-based therapy. We performed a meta-analysis of all eligible studies assessing ITPA gene polymorphisms related to RBV-induced hemolytic anemia in HCV-infected patients published in PubMed, Embase and the Cochrane library prior to the end of 2014. METHODS Three outcomes were evaluated: (1) hemoglobin decline, (2) severe anemia, and (3) RBV dose reduction or treatment discontinuation. Pooled odds ratio (OR) and 95 % confidence interval (95 % CI) were estimated by either fixed or random effects models. RESULTS Twenty-nine studies were selected from the literature search: 20 references involving 6533 individuals for hemoglobin decline, 13 references on 3764 patients for severe anemia, and 16 references on 3918 patients for RBV dose reduction or discontinuation. Significant associations with hemoglobin decline were found for rs1127354 CC [OR = 12.84 (95 % CI 7.44; 22.17)], rs7270101 AA [OR = 3.41 (95 % CI 2.08; 5.59)] and rs6051702 AA [OR = 4.43 (95 % CI 2.80; 7.00)] genotypes. Moreover, significant associations with hemoglobin decline were also found for absent [OR = 6.01 (95 % CI 4.84; 7.46)] and mild [OR = 4.68 (95 % CI 2.83; 7.74)] ITPase deficiency haplotypes. The ITPA rs1127354 CC genotype and absent ITPase deficiency haplotype were also associated with severe anemia {[OR = 7.77 (95 % CI 5.03; 12.00)] and [OR = 4.79 (95 % CI 1.69; 13.56)], respectively}. Additionally, the rs1127354 CC genotype showed significant association with RBV dose reduction or stopping treatment (OR = 2.24; 95 % CI 1.79; 2.81). CONCLUSIONS ITPA polymorphisms increase the likelihood of developing hemolytic anemia for HCV-infected patients on RBV-based therapy, particularly rs1127354 CC and rs7270101 AA genotypes, suggesting the utility of screening for ITPA polymorphisms to avoid hematological toxicity and increase adherence to RBV-based therapy.
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Affiliation(s)
- Daniel Pineda-Tenor
- Servicio de Laboratorio Clínico, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, Spain.
| | - Mónica García-Álvarez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda-Pozuelo, km 2.2, Majadahonda, 28220, Madrid, Spain.
| | - María A Jiménez-Sousa
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda-Pozuelo, km 2.2, Majadahonda, 28220, Madrid, Spain.
| | - Sonia Vázquez-Morón
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda-Pozuelo, km 2.2, Majadahonda, 28220, Madrid, Spain.
| | - Salvador Resino
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda-Pozuelo, km 2.2, Majadahonda, 28220, Madrid, Spain.
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Gurusamy KS, Tsochatzis E, Toon CD, Davidson BR, Burroughs AK, Cochrane Hepato‐Biliary Group. Antiviral prophylaxis for the prevention of chronic hepatitis C virus in patients undergoing liver transplantation. Cochrane Database Syst Rev 2013; 2013:CD006573. [PMID: 24297303 PMCID: PMC6599865 DOI: 10.1002/14651858.cd006573.pub3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND It is not clear whether prophylactic antiviral therapy is indicated to improve patient and graft survival in patients undergoing liver transplantation for chronic decompensated hepatitis C virus (HCV) infection. OBJECTIVES To compare the benefits and harms of different prophylactic antiviral therapies for patients undergoing liver transplantation for chronic HCV infection. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 1, 2013), MEDLINE, EMBASE, and Science Citation Index Expanded to February 2013. SELECTION CRITERIA Only randomised clinical trials irrespective of language, blinding, or publication status and comparing various prophylactic antiviral therapies (alone or in combination) in the prophylactic treatment of patients undergoing liver transplantation for chronic HCV infection. DATA COLLECTION AND ANALYSIS Two authors collected the data independently. We calculated the risk ratio (RR) or mean difference (MD) or hazard ratio (HR) with 95% confidence intervals (CI) using the fixed-effect and the random-effects models based on available case analysis. MAIN RESULTS A total of 501 liver transplant recipients undergoing liver transplantation for chronic HCV infection were randomised in 12 trials to various experimental interventions and control interventions. The proportion of genotype I varied between 49% and 100% in the seven trials that reported the genotype. Only one or two trials were included under each comparison. All the trials were of high risk of bias. Ten trials including 441 liver transplant recipients provided data for this review.There were no significant differences in the 90-day mortality (1 trial; 81 participants; 5/35 (adjusted proportion: 14.2%) in interferon group versus 5/46 (10.9%) in control group; RR 1.31; 95% CI 0.41 to 4.19); mortality at maximal follow-up (2 trials; 105 participants; 7/47 (adjusted proportion: 14.8%) in interferon group versus 10/58 (17.2%) in control group; RR 0.86; 95% CI 0.36 to 2.08); long-term mortality (1 trial; 81 participants; HR 0.45; 95% CI 0.13 to 1.56); mortality at maximal follow-up (1 trial; 54 participants; 1/26 (3.9%) in pegylated interferon group versus 2/28 (7.1%) in control group; RR 0.54; 95% CI 0.05 to 5.59); 90-day mortality (1 trial; 115 participants; 5/55 (9.1%) in pegylated interferon plus ribavirin group versus 3/60 (5.0%) in control group; RR 1.82; 95% 0.46 to 7.25); 90-day mortality (3 trials; 53 participants; 3/37 (adjusted proportion: 4.3%) in HCV antibody group versus 1/16 (6.3%) in placebo group; RR 0.69; 95% CI 0.15 to 3.11); or 90-day mortality (2 trials; 31 participants; 2/14 (adjusted proportion: 16.2%) in HCV antibody high-dose group versus 1/17 (5.9%) in HCV antibody low-dose group; RR 2.75; 95% CI; 0.30 to 25.35). There were no significant differences in the retransplantation at maximal follow-up (2 trials; 105 participants; 2/47 (adjusted proportion: 4.0%) in interferon group versus 2/58 (3.4%) in control group; RR 1.17; 95% CI 0.22 to 6.2); 90-day retransplantation (1 trial; 18 participants; 1/12 (8.3%) in HCV antibody group versus 0/6 (0%) in control group; RR 1.71; 95% CI 0.09 to 32.93); or 90-day retransplantation (1 trial; 12 participants; 1/6 (17.7%) in HCV antibody high-dose group versus 0/6 (0%) in HCV antibody low-dose group; RR 3.00; 95% CI 0.15 to 61.74). There were no significant differences in serious adverse events, graft rejection, worsening of fibrosis, or HCV recurrence between intervention and control groups in any of the comparisons that reported these outcomes. None of the trials reported quality of life, liver decompensation, intensive therapy unit stay, or hospital stay. Life-threatening adverse events were not reported in either group in any of the comparisons. AUTHORS' CONCLUSIONS There is currently no evidence to recommend prophylactic antiviral treatment to prevent recurrence of HCV infection either in primary liver transplantation or retransplantation. Further randomised clinical trials with adequate trial methodology and adequate duration of follow-up are necessary.
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Affiliation(s)
- Kurinchi Selvan Gurusamy
- Royal Free Campus, UCL Medical SchoolDepartment of SurgeryRoyal Free Hospital,Rowland Hill StreetLondonUKNW3 2PF
| | - Emmanuel Tsochatzis
- Royal Free Hampstead NHS Foundation Trust and UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetHampsteadLondonUKNW3 2QG
| | - Clare D Toon
- West Sussex County CouncilPublic Health1st Floor, The GrangeTower StreetChichesterWest SussexUKPO19 1QT
| | - Brian R Davidson
- Royal Free Campus, UCL Medical SchoolDepartment of SurgeryRoyal Free Hospital,Rowland Hill StreetLondonUKNW3 2PF
| | - Andrew K Burroughs
- Royal Free Hampstead NHS Foundation TrustSheila Sherlock Liver CentrePond StreetHampsteadLondonUKNW3 2QG
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Barcaui HS, Tavares GC, May SB, Brandão-Mello CE, Amendola Pires MM, Barroso PF. Low rates of sustained virologic response with peginterferon plus ribavirin for chronic hepatitis C virus infection in HIV infected patients in Rio de Janeiro, Brazil. PLoS One 2013; 8:e67734. [PMID: 23874441 PMCID: PMC3706550 DOI: 10.1371/journal.pone.0067734] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Accepted: 05/22/2013] [Indexed: 02/06/2023] Open
Abstract
Background The standard treatment for chronic hepatitis C virus (HCV) infection in HIV-infected subjects is the combination of alfapeginterferon (PEG-IFN) plus ribavirin. We designed this study to evaluate the rate of SVR and predictors of SVR in a public health setting in Rio de Janeiro, Brazil. Methods Retrospective cohort study of HCV/HIV co-infected patients treated with PEG-IFN plus ribavirin from 2004 to 2011 in 3 outpatient units in Rio de Janeiro. Exposure variables included age, sex, CD4+ cell count, HCV genotype, HCV and HIV viral loads, liver histology (METAVIR fibrosis scoring system) and previous treatment. The main outcome measurement was SVR. Results 100 patients were included in this analysis. Median age was 47 years and 68% were male. 80%, 4%, 14% and 2% were infected with HCV genotypes 1, 2, 3 and 4, respectively. At baseline, 77% had HCV viral load greater than 800,000 IU/ml, 99% had CD4+ greater than 200 cells/mm3 and 10% had a diagnosis of cirrhosis. The treatment was withdrawn in 9% of the subjects (5% with adverse effects and 4% dropped out). SVR was observed in 27 (27%) of the 100 patients included. 13 (13%) subjects were classified as null-responders, 33(33%) as non-responders, 9 (9%) as breakthrough and 9(9%) as relapsers. In the multivariate model only being infected with genotype 2 or 3 (p<0.01) and having low levels of gamma glutamyl transferase (GGT) at baseline (p = 0.04), were predictive of SVR. Conclusion SVR in HCV/HIV co-infected subjects in a public health setting is similar to that observed in clinical trials, albeit very low. A delay in therapy initiation should be considered until new therapies as direct acting antiviral drugs (DAA) become widely available and tested in coinfected subjects.
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Affiliation(s)
- Halime Silva Barcaui
- Infectious Diseases Service, Department of Preventive Medicine, Hospital Universitário Clementino Fraga Filho, School of Medicine, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
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Pure red cell aplasia caused by ribavirin and interferon treatment. Clin J Gastroenterol 2011; 4:313-317. [PMID: 26189631 DOI: 10.1007/s12328-011-0235-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2010] [Accepted: 05/12/2011] [Indexed: 10/17/2022]
Abstract
Anemia is a common complication of hepatitis C (HCV), and antiviral treatment can further increase this risk. We present the case of a 59-year-old man with HCV treated with ribavirin and pegylated interferon alpha (INF-α) who presented with severe anemia. Two months after initiating treatment his hemoglobin dropped from 14.2 to 5.0 g/dL. There was no evidence of bleeding or hemolysis, and a bone marrow biopsy revealed pure red cell aplasia (PRCA). Evaluations for acute cytomegalovirus and parvovirus B19 were negative. There was no evidence of malignancy or thymoma. The INF-α and ribavirin treatment were determined to have caused the PRCA, and withdrawal of the medications led to PRCA remission. INF-α and ribavirin have become the standard treatment for HCV. While these medications offer a potential cure, they are often poorly tolerated due to frequent side effects including anemia. Patients who are receiving treatment with ribavirin and INF-α warrant close monitoring for development of anemia, and PRCA should be considered in all patients in whom reticulocytopenic anemia develops.
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Chayama K, Hayes CN, Abe H, Miki D, Ochi H, Karino Y, Toyota J, Nakamura Y, Kamatani N, Sezaki H, Kobayashi M, Akuta N, Suzuki F, Kumada H. IL28B but not ITPA polymorphism is predictive of response to pegylated interferon, ribavirin, and telaprevir triple therapy in patients with genotype 1 hepatitis C. J Infect Dis 2011; 204:84-93. [PMID: 21628662 PMCID: PMC3307155 DOI: 10.1093/infdis/jir210] [Citation(s) in RCA: 111] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2010] [Accepted: 02/11/2011] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Pegylated interferon, ribavirin, and telaprevir triple therapy is a new strategy expected to eradicate the hepatitis C virus (HCV) even in patients infected with difficult-to-treat genotype 1 strains, although adverse effects, such as anemia and rash, are frequent. METHODS We assessed efficacy and predictive factors for sustained virological response (SVR) for triple therapy in 94 Japanese patients with HCV genotype 1. We included recently identified predictive factors, such as IL28B and ITPA polymorphism, and substitutions in the HCV core and NS5A proteins. RESULTS Patients treated with triple therapy achieved comparatively high SVR rates (73%), especially among treatment-naive patients (80%). Of note, however, patients who experienced relapse during prior pegylated interferon plus ribavirin combination therapy were highly likely to achieve SVR while receiving triple therapy (93%); conversely, prior nonresponders were much less likely to respond to triple therapy (32%). In addition to prior treatment response, IL28B SNP genotype and rapid viral response were significant independent predictors for SVR. Patients with the anemia-susceptible ITPA SNP rs1127354 genotype typically required ribavirin dose reduction earlier than did patients with other genotypes. CONCLUSIONS Analysis of predictive factors identified IL28B SNP, rapid viral response, and transient response to previous therapy as significant independent predictors of SVR after triple therapy.
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Affiliation(s)
- Kazuaki Chayama
- Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Japan.
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Krishnan SM, Dixit NM. Ribavirin-induced anemia in hepatitis C virus patients undergoing combination therapy. PLoS Comput Biol 2011; 7:e1001072. [PMID: 21304937 PMCID: PMC3033369 DOI: 10.1371/journal.pcbi.1001072] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2010] [Accepted: 12/29/2010] [Indexed: 01/11/2023] Open
Abstract
The current standard of care for hepatitis C virus (HCV) infection – combination therapy with pegylated interferon and ribavirin – elicits sustained responses in only ∼50% of the patients treated. No alternatives exist for patients who do not respond to combination therapy. Addition of ribavirin substantially improves response rates to interferon and lowers relapse rates following the cessation of therapy, suggesting that increasing ribavirin exposure may further improve treatment response. A key limitation, however, is the toxic side-effect of ribavirin, hemolytic anemia, which often necessitates a reduction of ribavirin dosage and compromises treatment response. Maximizing treatment response thus requires striking a balance between the antiviral and hemolytic activities of ribavirin. Current models of viral kinetics describe the enhancement of treatment response due to ribavirin. Ribavirin-induced anemia, however, remains poorly understood and precludes rational optimization of combination therapy. Here, we develop a new mathematical model of the population dynamics of erythrocytes that quantitatively describes ribavirin-induced anemia in HCV patients. Based on the assumption that ribavirin accumulation decreases erythrocyte lifespan in a dose-dependent manner, model predictions capture several independent experimental observations of the accumulation of ribavirin in erythrocytes and the resulting decline of hemoglobin in HCV patients undergoing combination therapy, estimate the reduced erythrocyte lifespan during therapy, and describe inter-patient variations in the severity of ribavirin-induced anemia. Further, model predictions estimate the threshold ribavirin exposure beyond which anemia becomes intolerable and suggest guidelines for the usage of growth hormones, such as erythropoietin, that stimulate erythrocyte production and avert the reduction of ribavirin dosage, thereby improving treatment response. Our model thus facilitates, in conjunction with models of viral kinetics, the rational identification of treatment protocols that maximize treatment response while curtailing side effects. The treatment of HCV infection poses a major global health-care challenge today. The current standard of care, combination therapy with interferon and ribavirin, works in only about half of the patients treated. Because no alternatives are available yet for patients in whom combination therapy fails, identifying ways to improve response to combination therapy is critical. Increasing exposure to ribavirin does improve response but is associated with the severe side-effect, anemia. One way to maximize treatment response therefore is to increase ribavirin exposure to levels just below where anemia becomes intolerable. A second way is to supplement combination therapy with growth hormones, such as erythropoietin, that increase the production of red blood cells (erythrocytes) and compensate for ribavirin-induced anemia. Rational optimization of combination therapy thus relies on a quantitative description of ribavirin-induced anemia, which is currently lacking. Here, we develop a model of the population dynamics of erythrocytes in individuals exposed to ribavirin that quantitatively describes ribavirin-induced anemia. Model predictions capture several independent observations of ribavirin-induced anemia in HCV patients undergoing combination therapy, estimate the threshold ribavirin exposure beyond which anemia becomes intolerable, suggest guidelines for the usage of growth hormones, and facilitate rational optimization of therapy.
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Affiliation(s)
- Sheeja M. Krishnan
- Department of Chemical Engineering, Indian Institute of Science, Bangalore, India
| | - Narendra M. Dixit
- Department of Chemical Engineering, Indian Institute of Science, Bangalore, India
- Bioinformatics Centre, Indian Institute of Science, Bangalore, India
- * E-mail:
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Tsubota A, Fujise K, Namiki Y, Tada N. Peginterferon and ribavirin treatment for hepatitis C virus infection. World J Gastroenterol 2011; 17:419-32. [PMID: 21274371 PMCID: PMC3027008 DOI: 10.3748/wjg.v17.i4.419] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2010] [Revised: 08/02/2010] [Accepted: 08/09/2010] [Indexed: 02/06/2023] Open
Abstract
Pegylated interferon α (IFNα) in combination with ribavirin is currently recommended as a standard-of-care treatment for chronic hepatitis C virus (HCV) infection. This combination therapy has drastically improved the rate of sustained virological response, specifically in difficult-to-treat patients. Recently, individualized treatment, such as response-guided therapy, is being developed based on host-, HCV- and treatment-related factors. Furthermore, modified regimens with currently available medications, novel modified IFNα and ribavirin or combinations with specifically targeted antiviral therapy for HCV agents, are currently being investigated. The purpose of this review is to address some issues and epoch-making topics in the treatment of chronic HCV infection, and to discuss more optimal and highly individualized therapeutic strategies for HCV-infected patients.
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Bertino G, Ardiri A, Boemi PM, Calvagno GS, Ruggeri IM, Speranza A, Santonocito MM, Ierna D, Bruno CM, Valenti M, Boemi R, Naimo S, Neri S. Epoetin alpha improves the response to antiviral treatment in HCV-related chronic hepatitis. Eur J Clin Pharmacol 2010; 66:1055-63. [PMID: 20652232 DOI: 10.1007/s00228-010-0868-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2010] [Accepted: 07/06/2010] [Indexed: 12/20/2022]
Abstract
BACKGROUND The conventional antiviral treatment of chronic hepatitis related to hepatitis C virus (HCV) often leads to anemia. In this case, it is necessary to reduce ribavirin dose or stop treatment, thus reducing the rate of sustained virological response. AIM We investigated whether epoetin alpha administration improves treatment adherence and leads to higher percentage of response at the end of therapy and sustained virological response. METHODS Two hundred and fourteen individuals with genotype 1b HCV-related chronic hepatitis underwent treatment with pegylated (peg)-interferon alpha-2A 180 μg once weekly and ribavirin 1,000-1,200 mg/day; 174 were responders. Forty individuals completed treatment with no hemoglobin reduction; 134 developed anemia during therapy. Anemic responders were distributed randomly into two groups: group 1 continued therapy with epoetin alpha addiction; group 2 continued antiviral therapy with ribavirin reduction only. RESULTS Patients in group 1 achieved better control of hemoglobin levels (13.8 ± 1.2 g/dl at the end of therapy) than those in group 2 (11.5 ± 0.8 g/dl). Sustained virological response was 59.7% in group 1 compared with 34.4% in group 2 (p<0.01). CONCLUSIONS In patients with 1b HCV-related chronic hepatitis who develop anemia during antiviral treatment, administration of epoetin alpha increases hemoglobin levels and the end-of-treatment rate and sustains virological response by improving treatment adherence.
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Affiliation(s)
- Gaetano Bertino
- Hepatology Unit, Department of Internal Medicine and Systemic Diseases, University of Catania, S. Marta Hospital, Via Gesualdo Clementi, 36, 95124 Catania, Italy.
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11
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Jafferbhoy H, Gashau W, Dillon J. Cost effectiveness and quality of life considerations in the treatment of hepatitis C infection. CLINICOECONOMICS AND OUTCOMES RESEARCH 2010; 2:87-96. [PMID: 21935317 PMCID: PMC3169967 DOI: 10.2147/ceor.s7283] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2010] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis C1 is a common cause of liver disease worldwide. It is a slow and progressive condition which can lead to decompensated cirrhosis and hepatocellular carcinoma. Hepatitis C virus1 impairs quality of life (QOL) even in the absence of chronic liver disease, but its relative silent nature can lead to a delay in diagnosis. The current standard of care of treatment is pegylated interferon and ribavarin. This achieves a sustained virological response (SVR), which is a cure of infection, in up to 80% of patients depending on viral genotype. The attainment of SVR improves survival, avoids long-term complications, and improves QOL. But treatment is not only expensive; there are issues of tolerability and adverse effects. This has led to a multitude of cost effective analysis and health technology assessment on HCV treatment. This overview discusses the natural history of the virus infection and its effect on the patients’ QOL. It focuses on the treatment options available, their efficacy, and cost effectiveness. It reviews the evaluations that suggest combination therapy is cost effective and explores the assumptions and limitations of these studies in real world treatment arenas.
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Affiliation(s)
- H Jafferbhoy
- Gut Group, Biomedical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK
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12
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El-Zayadi AR. Hepatitis C comorbidities affecting the course and response to therapy. World J Gastroenterol 2009; 15:4993-9. [PMID: 19859990 PMCID: PMC2768876 DOI: 10.3748/wjg.15.4993] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2009] [Revised: 09/05/2009] [Accepted: 09/12/2009] [Indexed: 02/06/2023] Open
Abstract
Several studies have demonstrated that the outcome of chronic hepatitis C (CHC) infection is profoundly influenced by a variety of comorbidities. Many of these comorbidities have a significant influence on the response to antiviral therapy. These comorbidities negatively affect the course and outcome of liver disease, often reducing the chance of achieving a sustained virological response with PEGylated interferon and ribavirin treatments. Comorbidities affecting response to antiviral therapy reduce compliance and adherence to inadequate doses of therapy. The most important comorbidities affecting the course of CHC include hepatitis B virus coinfection, metabolic syndrome, and intestinal bacterial overgrowth. Comorbidities affecting the course and response to therapy include schistosomiasis, iron overload, alcohol abuse, and excessive smoking. Comorbidities affecting response to antiviral therapy include depression, anemia, cardiovascular disease, and renal failure.
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Moreno López R, Sicilia Aladrén B, Gomollón García F. Use of agents stimulating erythropoiesis in digestive diseases. World J Gastroenterol 2009; 15:4675-85. [PMID: 19787831 PMCID: PMC2754516 DOI: 10.3748/wjg.15.4675] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Anemia is the most common complication of inflammatory bowel disease (IBD). Control and inadequate treatment leads to a worse quality of life and increased morbidity and hospitalization. Blood loss, and to a lesser extent, malabsorption of iron are the main causes of iron deficiency in IBD. There is also a variable component of anemia related to chronic inflammation. The anemia of chronic renal failure has been treated for many years with recombinant human erythropoietin (rHuEPO), which significantly improves quality of life and survival. Subsequently, rHuEPO has been used progressively in other conditions that occur with anemia of chronic processes such as cancer, rheumatoid arthritis or IBD, and anemia associated with the treatment of hepatitis C virus. Erythropoietic agents complete the range of available therapeutic options for treatment of anemia associated with IBD, which begins by treating the basis of the inflammatory disease, along with intravenous iron therapy as first choice. In cases of resistance to treatment with iron, combined therapy with erythropoietic agents aims to achieve near-normal levels of hemoglobin/hematocrit (11-12 g/dL). New formulations of intravenous iron (iron carboxymaltose) and the new generation of erythropoietic agents (darbepoetin and continuous erythropoietin receptor activator) will allow better dosing with the same efficacy and safety.
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Rituximab therapy for pure red cell aplasia due to anti-epoetin antibodies in a woman treated with epoetin-alfa: a case report. J Med Case Rep 2009; 3:7335. [PMID: 19830190 PMCID: PMC2737792 DOI: 10.4076/1752-1947-3-7335] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2008] [Accepted: 01/22/2009] [Indexed: 12/01/2022] Open
Abstract
Introduction Pure red cell aplasia due to anti-epoetin antibodies is a known complication of epoetin therapy for anemia due to chronic kidney disease. This disease has not previously been well described in the setting of therapy for chronic hepatitis C virus infection. While treatment for pure red cell aplasia due to anti-epoetin antibodies is usually with immunosuppressive therapy such as calcineurin inhibition, the safety of this treatment in chronic hepatitis C virus infection is unknown. To date, little has been published on the efficacy of rituximab on pure red cell aplasia due to anti-epoetin antibodies. Case presentation This report describes a 65-year-old Asian-American woman who developed pure red cell aplasia from high titer neutralizing anti-epoetin antibodies after epoetin-alfa therapy during ribavirin and peg-interferon treatment for chronic hepatitis C virus infection. We describe the outcome of her treatment with rituximab. The reticulocyte count increased, and anti-epoetin antibody titer decreased with a loss of neutralizing activity in vitro, leading to a reduction in blood transfusions, and eventual resolution of anemia, without reactivation of hepatitis C virus. Conclusion The diagnosis of pure red cell aplasia from anti-epoetin antibodies should be considered in patients undergoing therapy for chronic hepatitis C virus infection who develop severe anemia after administration of erythropoietin or darbepoetin. Though it is currently an off-label indication, rituximab is a therapeutic option for patients with pure red cell aplasia due to anti-epoetin antibodies.
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Mindikoglu AL, Miller RR. Hepatitis C in the elderly: epidemiology, natural history, and treatment. Clin Gastroenterol Hepatol 2009; 7:128-34; quiz 124. [PMID: 19084480 PMCID: PMC2950699 DOI: 10.1016/j.cgh.2008.07.017] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2008] [Revised: 07/05/2008] [Accepted: 07/16/2008] [Indexed: 12/16/2022]
Abstract
Hepatitis C continues to be a major public health problem affecting approximately 3% of the global population. According to the World Health Organization, an estimated 170 million people have chronic hepatitis C. Ten percent to 20% of those who are chronically infected with hepatitis C will progress to cirrhosis and 5% will develop hepatocellular carcinoma. Although the safety and efficacy of hepatitis C therapies have been studied extensively in patients between the ages of 18 and 65, patients who are older than 65 still remain an understudied and difficult-to-treat population. This review discusses the epidemiology, natural history, and treatment of chronic hepatitis C in older adults.
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Affiliation(s)
- Ayse L Mindikoglu
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, Maryland 21201-1595, USA.
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16
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Maru DSR, Bruce RD, Basu S, Altice FL. Clinical outcomes of hepatitis C treatment in a prison setting: feasibility and effectiveness for challenging treatment populations. Clin Infect Dis 2008; 47:952-61. [PMID: 18715156 PMCID: PMC4847716 DOI: 10.1086/591707] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND More than one-third of people in the United States with hepatic C virus (HCV) infection pass through the correctional system annually. Data are lacking on outcomes of treatment with pegylated interferon plus ribavirin (PEG-RBV) in correctional settings. METHODS During 2002-2006, we analyzed patients in the Connecticut Department of Correction who received PEG-RBV. We assessed the rates of sustained virological response, hospitalization, and use of medications to treat psychiatric disorders and anemia. RESULTS Of 138 treatment-naive patients referred for treatment, 68 (49%) were approved. Overall, sustained virological response occurred in 47.1% of patients (for HCV genotype 1, 43.1%; for HCV genotypes 2 and 3, 58.8%). Only 9 patients (13%) discontinued treatment because of adverse effects. Multiple regression analysis revealed that not achieving a sustained virological response was correlated with HCV genotype 1 infection plus cirrhosis (adjusted odds ratio, 12.9; 95% confidence interval, 1.1-148) and baseline major depression (adjusted odds ratio, 3.4; 95% confidence interval, 1.01-11.6), but not with HIV infection, a baseline HCV RNA level >or=400,000 IU/mL, or black race. Compared with baseline, the rate of prescription of a new mood stabilizer (2.2 vs. 0.8 prescriptions per person-year) or an opioid (1.8 vs. 0.5 prescriptions per person-year) was higher during treatment, whereas there was no change in the rate of prescription of benzodiazepines and antipsychotic medications. CONCLUSIONS These results support the feasibility and clinical effectiveness of PEG-RBV for the treatment of chronic HCV infection in correctional facilities.
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Affiliation(s)
- Duncan Smith-Rohrberg Maru
- Yale AIDS Program, Yale University School of Medicine, New Haven, Connecticut
- Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut
| | | | - Sanjay Basu
- Yale AIDS Program, Yale University School of Medicine, New Haven, Connecticut
- Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut
| | - Frederick L. Altice
- Yale AIDS Program, Yale University School of Medicine, New Haven, Connecticut
- Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut
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Larsson G, Janson ET. Anemia in patients with midgut carcinoid, treated with alpha interferon: effects by erythropoietin treatment on the perceived quality of life. Eur J Cancer Care (Engl) 2008; 17:200-4. [PMID: 18302658 DOI: 10.1111/j.1365-2354.2007.00844.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
One important side effect from alpha interferon is depression of bone marrow function and studies have shown that patients with carcinoid tumours treated with alpha interferon suffers from fatigue and impaired physical functions. The aim of this pilot study was to investigate if treatment with erythropoietin (EPO) could have a positive effect on self-rated quality of life (QoL). Eighteen patients with midgut carcinoid treated with alpha interferon were included in the study. There were statistical significant increases in haemoglobin (Hb) levels between baseline and 4 months, between baseline and 8 months as well as between baseline and 2-year follow-up. No EPO related side effects were reported. There were improvements of more than 10 points in self-rated QoL-issues related to anaemia. Even though the analysis did not reveal any statistically significant relation between the observed increase in Hb levels and self-rated QoL, this pilot study has increased the knowledge about benefits, doses and frequency of EPO treatment in patients with midgut carcinoid suffering from interferon related anaemia.
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Affiliation(s)
- G Larsson
- Department of Endocrine Oncology, University Hospital, Uppsala, Sweden.
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18
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Danish FA, Koul SS, Subhani FR, Rabbani AE, Yasmin S. Role of hematopoietic growth factors as adjuncts in the treatment of chronic hepatitis C patients. Saudi J Gastroenterol 2008; 14:151-7. [PMID: 19568529 PMCID: PMC2702921 DOI: 10.4103/1319-3767.41739] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2008] [Accepted: 05/07/2008] [Indexed: 12/23/2022] Open
Abstract
Drug-induced hematotoxicity is the most common reason for reducing the dose or withdrawing ribavirin (RBV) and interferon (IFN) therapy in chronic hepatitis C, which leads to the elimination of a possible cure for the patient. Traditionally, severe anemia and neutropenia have been considered as absolute contraindications to start antiviral therapy. This has not however, been the case since the advent of adjunct therapy with hematopoietic growth factors (erythropoietin (EPO) and granulocyte-colony stimulating factor (G-CSF)). Some recent landmark studies have used this adjunct therapy to help avoid antiviral dose reductions. Although the addition of this adjunct therapy has been shown to significantly increase the overall cost of the treatment, this extra cost is worth bearing if the infection is cured at the end of the day. Although more studies are needed to refine the true indications of this adjunct therapy, determine the best dose regimen, quantify the average extra cost and determine whether or not the addition of this therapy increases the sustained virological response rates achieved, the initial reports are encouraging. Therefore, although not recommended on a routine basis, some selected patients may be given the benefits of these factors. This article reviews the current literature on this subject and makes a few recommendations to help develop local guidelines.
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Affiliation(s)
- Fazal A. Danish
- Human Genetics Division, MP 808, Southampton General Hospital, Southampton, United Kingdom
| | - Salman S. Koul
- Department of Medicine (Unit-I), Pakistan Institute of Medical Sciences (PIMS), Islamabad, Pakistan
| | - Fazal R. Subhani
- Department of Pediatrics, Holy Family Hospital, Rawalpindi, Pakistan
| | - Ahemd E. Rabbani
- Foundation University Medical College (FUMC), Rawalpindi, Pakistan
| | - Saeeda Yasmin
- Department of Surgery (Unit-II), Rawalpindi General Hospital, Rawalpindi, Pakistan,Address: Dr. Saeeda Yasmin 1156 57, Lyton Street, Adam-Jee Road, Rawalpindi, Pakistan. E-mail:
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19
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Abstract
BACKGROUND AND AIM Current practice guidelines recommend that individuals chronically infected with the hepatitis C virus (HCV) be treated with pegylated interferon plus ribavirin. Ribavirin, however, is associated with serious adverse events (AE), especially anemia. We review its mechanism of action, its importance in treating chronic hepatitis C (CHC) patients, the AE associated with its use, and techniques used to lessen these AE. METHODS Medline searches were performed using the keywords ribavirin and hepatitis, together with the keywords mechanism, anemia, liver transplant, renal function, pharmacokinetics, and dose reduction. Searches of abstracts of recent Digestive Diseases Week, American Association for the Study of Liver Diseases, and European Association for the Study of Liver Diseases meetings were also performed. RESULTS Ribavirin may be effective in treating CHC by affecting the virus or the host; for example by inducing viral mutations, blocking cellular enzymes, or affecting the host immune response. Although the pegylated interferons are the primary drugs used to treat CHC, a combination with ribavirin is more effective than pegylated interferon alone. Ribavirin-associated AE may be lessened by ribavirin dose reductions and by maintenance of the hematocrit. CONCLUSIONS Treatments of ribavirin toxicities, especially anemia, can allow patients to continue full-dose combination therapy with peginterferon and ribavirin, enhancing their probability of attaining a sustained virologic response (SVR). Treatment of CHC should be tailored to individual patients, especially those with renal dysfunction, and should include agents that treat the side-effects of CHC treatment. Monitoring of plasma ribavirin concentrations during treatment may help in the future.
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Kagawa T, Shiozawa H, Kojima SI, Takashimizu S, Nagata N, Numata M, Morino F, Nishizaki Y, Mochizuki K, Watanabe N, Watanabe T, Matsuzaki S, Mine T. Eight-week oral administration of meloxicam, a non-steroidal anti-inflammatory drug, prevents dose reduction of pegylated interferon alpha-2a in the treatment of chronic hepatitis C. Hepatol Res 2008; 38:259-266. [PMID: 17825059 DOI: 10.1111/j.1872-034x.2007.00260.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM We conducted a trial to evaluate whether eight-week oral administration of meloxicam, a non-steroidal anti-inflammatory drug, would decrease the rate of the patients who required dose reduction of pegylated interferon alpha-2a in the treatment of chronic hepatitis C. METHODS Sixty patients given weekly subcutaneous administration of pegylated interferon alpha-2a at a dose of 180 mug for 48 weeks were allocated into the meloxicam group (n = 22) and the control group (n = 38) before interferon treatment. Meloxicam was given orally at a dose of 10 mg once a day for eight weeks from the start of interferon treatment. RESULTS The cumulative rate of dose-reduction-free patients was significantly higher in the meloxicam group (P < 0.05). Until week eight, 44.7% of the control group and 9.1% of the meloxicam group required dose reduction. Dose was modified by neutropenia in 31.6% and 18.2% of the control and meloxicam groups, respectively. Meloxicam relieved a declineof neutrophil count within the first eight weeks from 54.2% to 44.2% (P < 0.05). Multivariate analysis revealed that greater pretreatment neutrophil count and the use of meloxicam were independent factors associated with avoiding dose reduction. Sustained virological response was obtained in 52.6% of the patients. The multivariate logistic analysis revealed that viral serotype and viral load were the only independent factors associated with sustained virological response. CONCLUSION Eight-week administration of meloxicam prevented dose reduction of pegylated interferon by relieving a decline of neutrophil count in the treatment of chronic hepatitis C.
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Affiliation(s)
- Tatehiro Kagawa
- Department of Gastroenterology, Tokai University School of Medicine, Kanagawa, Japan
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Abstract
Chronic hepatitis C affects >170 million people worldwide, causing cirrhosis and liver cancer in a sizeable proportion of patients. Substantial progress has been made in the treatment of chronic hepatitis C. More than 50% of patients can achieve sustained virological response after 24-48 weeks of interferon and ribavirin combination therapy, making chronic hepatitis C a potentially curable disease. However, a large proportion of patients with chronic hepatitis C do not clear the virus after current standard therapy. Hepatitis C virus develops two pathways to counteract the antiviral effect of interferon. Some chronic hepatitis C patients may have a virus that is more resistant to interferon therapy, while other patients appear to have defective immune responses or poor tolerance or compliance to interferon-based antiviral therapy. The possible strategies to improve antiviral efficiency in these nonresponders are to increase the dosage, prolong the duration of treatment and improve the compliance of patients. A total of 6-15% of prior nonresponders to standard interferon plus ribavirin therapy will respond to re-treatment with peginterferon plus ribavirin, while 32-50% of patients who have relapsed will respond to re-treatment. New small molecules are under development to treat chronic hepatitis C and may be important particularly in the treatment of prior nonresponders to current standard therapy.
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Affiliation(s)
- He-Jun Yuan
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical School, Dallas, Texas 75390-8887, USA
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Hiramatsu N, Kurashige N, Oze T, Takehara T, Tamura S, Kasahara A, Oshita M, Katayama K, Yoshihara H, Imai Y, Kato M, Kawata S, Tsubouchi H, Kumada H, Okanoue T, Kakumu S, Hayashi N. Early decline of hemoglobin can predict progression of hemolytic anemia during pegylated interferon and ribavirin combination therapy in patients with chronic hepatitis C. Hepatol Res 2008; 38:52-9. [PMID: 17714473 DOI: 10.1111/j.1872-034x.2007.00205.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM Ribavirin, used to treat chronic hepatitis C, can induce hemolytic anemia, forcing the discontinuance of treatment. To establish a predictive measure to help circumvent this, we evaluated the relationship of hemoglobin (Hb) decline with the discontinuance of treatment during the progression of ribavirin-induced anemia. METHODS One hundred and sixteen patients (71% male) with genotype 1 chronic hepatitis C were treated with pegylated interferon (PegIFN) alpha-2b and ribavirin. The mean age was 50.6 years and 55% were IFN naïve. A decline of Hb concentration by 2 g/dL at two weeks from the start of the treatment ("2 by 2" standard) was adopted as the predictive factor for the progression of anemia. RESULTS By applying the "2 by 2" standard, with DeltaHb >/= 2 g/dL (34%, n = 39), treatment was discontinued in 12 cases (31%), three of which (8%) because of severe anemia. ForDeltaHb < 2 g/dL (64%, n = 76), treatment was discontinued in 11 (14%) cases; none due to severe anemia. Ten percent (4/39) of patients showed the minimum Hb </= 8.5 g/dL in the DeltaHb >/= 2 g/dL group, with none in the DeltaHb < 2 g/dL group (P = 0.001). Furthermore, the patients with minimum Hb </= 8.5 g/dL were found only in the "2 by 2" standard-positive and low CL/F (<15) group (4/29, 14%). CONCLUSION Monitoring the Hb decline using the "2 by 2" standard can identify patients who are prone to developing severe anemia. Further prospective studies are needed using ribavirin reduction based on the "2 by 2" standard.
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Affiliation(s)
- Naoki Hiramatsu
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
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McHutchison JG, Manns MP, Brown RS, Reddy KR, Shiffman ML, Wong JB. Strategies for managing anemia in hepatitis C patients undergoing antiviral therapy. Am J Gastroenterol 2007; 102:880-9. [PMID: 17397412 DOI: 10.1111/j.1572-0241.2007.01139.x] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Anemia is a common side effect that begins soon after the initiation of peginterferon/ribavirin in the treatment of hepatitis C virus (HCV) infection. It can cause symptoms that negatively impact quality of life (QOL) and is the most common reason for reducing the dose and temporarily or permanently discontinuing ribavirin. Such dose modifications have been shown to reduce the efficacy of treatment. Administering erythropoietin can improve anemia caused by peginterferon and ribavirin therapy and is more effective than dose reduction at improving QOL during treatment. However, erythropoietin, which is not approved by the U.S. Food and Drug Administration (FDA) for use in patients with HCV infection, adds another parenteral drug to the patient's treatment regimen, and is associated with additional costs, inconvenience, and potential side effects. A new ribavirin analog, viramidine, is expected to be associated with a lower incidence of anemia and, if proven effective, may eventually be substituted for ribavirin in combination with peginterferon to treat chronic hepatitis C. In the meantime, physicians must make the best possible use of the available options for managing anemia, especially in select patient groups who are most at risk for anemia and its complications.
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Affiliation(s)
- John G McHutchison
- Duke Clinical Research Institute, Division of Gastroenterology Duke University, Durham, North Carolina 27705, USA
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Vilar Gomez E, Gra Oramas B, Soler E, Llanio Navarro R, Ruenes Domech C. Viusid, a nutritional supplement, in combination with interferon alpha-2b and ribavirin in patients with chronic hepatitis C. Liver Int 2007; 27:247-59. [PMID: 17311621 DOI: 10.1111/j.1478-3231.2006.01411.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
BACKGROUND The pathogenesis of chronic hepatitis C (CHC) is associated to severe oxidative stress that leads to necro-inflammation and progression of fibrosis. Previous trials suggested that antioxidative therapy may have a beneficial effect. We evaluated the efficacy and safety of Viusid in combination with interferon alpha-2b (IFN alpha-2b) and ribavirin in patients with CHC. METHODS We randomly assigned 100 patients, between October 2002 and December 2004, in two arms: IFN alpha-2b (5 MU on alternate days), ribavirin at a dose of 13 mg/kg daily and Viusid (three sachets daily) vs. IFN alpha-2b (5 MU on alternate days) and ribavirin at a dose of 13 mg/kg daily. Subjects were treated for 48 weeks and then followed for an additional 24 weeks. The primary end point was the histologic response (reduction of at least two points without fibrosis worsening in the total score on the Histological Activity Index). RESULTS A significantly high proportion of patients who received combined therapy plus Viusid had a histologic response better than those patients who received IFN alpha-2b and ribavirin (57% vs. 37%, P=0.03). The patients with virologic response achieved the highest percentages of histologic response, irrespective of assigned treatment. Among non-responders, the highest reduction in the mean change from baseline score for necro-inflammatory activity (NA) and fibrosis (F) was reported in patients treated with Viusid [NA, -1.50 (Viusid), -1.20 (without Viusid); F, -0.31 (Viusid), 0.00 (without Viusid)]. Sustained normalization of serum alanine aminotransferase concentration was highest in the Viusid group compared with standard therapy (67% vs. 41%, P=0.009). The overall safety profile was similar in both groups, but interestingly, the anemia was less intense in the group with Viusid (P=0.04). CONCLUSIONS Our results suggest that triple therapy with Viusid, IFN alpha-2b and ribavirin was well tolerated and may have a beneficial effect on histologic and biochemical variables. The intensity of anemia is reduced in patients treated with Viusid.
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Affiliation(s)
- Eduardo Vilar Gomez
- Department of Hepatology, National Institute of Gastroenterology, Havana, Cuba.
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Watt KDS, Burak K, Deschênes M, Lilly L, Marleau D, Marotta P, Mason A, Peltekian KM, Renner EL, Yoshida EM. Recurrent hepatitis C post-transplantation: where are we now and where do we go from here? A report from the Canadian transplant hepatology workshop. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2007; 20:725-34. [PMID: 17111055 PMCID: PMC2660828 DOI: 10.1155/2006/238218] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Approximately 400 liver transplants are performed in Canada every year and close to 6000 per year in the United States. Forty per cent to 45% of all liver transplants are performed for patients with underlying hepatitis C virus (HCV)-related liver disease. These patients have a different natural history, new complication risks and different treatment efficacy than nontransplant HCV patients. Every effort must be made to identify those patients at highest risk for progressive liver disease post-transplant. Recurrent HCV is an Achilles' heel to transplant hepatology. The true natural history of this disease is only starting to unravel and many questions remain unanswered on the optimal management of these patients after liver transplantation. The present report summarizes the literature and ongoing research needs that are specific to HCV-related liver transplantation.
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Yoshida EM, Dar Santos A, Partovi N, Ford JAE. Erythropoietin and hepatitis C therapy: useful adjuvant therapy but remember to treat the patient and not just a number. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2006; 20:519-20. [PMID: 16967572 PMCID: PMC2659933 DOI: 10.1155/2006/793589] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Sherman M, Cohen L, Cooper MA, Elkashab M, Feinman V, Fletcher D, Girgrah N, Heathcote J, Levstik M, McNaull WB, Wong D, Wong F, Yim C. Clinical recommendations for the use of recombinant human erythropoietin in patients with hepatitis C virus being treated with ribavirin. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2006; 20:479-85. [PMID: 16858501 PMCID: PMC2659916 DOI: 10.1155/2006/497059] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Today, combination antiviral therapy with pegylated interferon-alpha and ribavirin (RBV) allows many patients infected with hepatitis C virus (HCV) to achieve a sustained virological response, which is equivalent to cure. Data also support the clinical benefit of combination antiviral therapy in patients coinfected with HCV and HIV, and in patients who have received a liver transplant. Antiviral therapy with pegylated interferon-alpha and RBV is, however, associated with a high incidence and significant magnitude of anemia. This anemia may have several mechanisms, including bone marrow suppression and hemolysis. In addition, patients coinfected with HIV may have both pre-existing and RBV-associated anemia. Management of anemia in patients with HCV through RBV dose reduction or treatment discontinuation may compromise the effectiveness of treatment, because studies have demonstrated that treatment adherence or maintenance of antiviral therapy dose is an important predictor of sustained virological response. Anemia associated with combination antiviral therapy in patients with HCV is frequently associated with an inadequate or blunted endogenous erythropoietin response. Accumulating evidence now supports the use of recombinant human erythropoietin (rHuEpo) to manage anemia in these patients, with the objective of maintaining the RBV dose, but clinical standards are lacking. The present article reviews the data relevant to the use of rHuEpo in this patient population and proposes a set of clinical practice standards to assist clinicians in selecting patients for rHuEpo and in implementing rHuEpo therapy effectively.
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Affiliation(s)
- Morris Sherman
- Toronto General Hospital, University of Toronto, Toronto, Canada.
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Pol S, Bourlière M. Optimizing Treatment Outcomes in Chronic Hepatitis C: Management of Non-Response. Antivir Ther 2006. [DOI: 10.1177/135965350601100815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The overarching goal in treating chronic hepatitis C (CHC) is the prevention of serious hepatic complications such as cirrhosis, end-stage liver disease and hepatocellular carcinoma. Successful eradication of the hepatitis C virus has been shown to prevent liver disease progression and even promote regression of fibrosis. The treatment of CHC has improved significantly over the past decade with the introduction of interferons (IFNs), and more recently, pegylated IFNs. Up to two-thirds of all patients treated with a pegylated IFN combined with ribavirin can now achieve viral eradication if treated according to current guidelines. Despite this success rate, limited treatment options currently exist for the growing number of patients who do not respond to this combination, and those who have previously failed treatment with conventional IFN-based regimens. There are numerous host-and viral-related factors that can contribute to these outcomes. In addition, treatment insufficiency, whether due to treatment type, side effects or non-compliance, can result in inadequate antiviral pressure and a reduced likelihood of response. This review explores putative management strategies for patients who have previously failed to achieve a response to IFN-based therapy, and summarises retreatment options that have been, and are currently being evaluated.
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Affiliation(s)
- Stanislas Pol
- Unité d'Hépatologie, Inserm U-567 Hôpital Cochin, Paris, France
| | - Marc Bourlière
- Service Hépato-gastroentérologie, Hôpital Saint Joseph, Marseille, France
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Alvarez D, Dieterich DT, Brau N, Moorehead L, Ball L, Sulkowski MS. Zidovudine use but not weight-based ribavirin dosing impacts anaemia during HCV treatment in HIV-infected persons. J Viral Hepat 2006; 13:683-9. [PMID: 16970600 DOI: 10.1111/j.1365-2893.2006.00749.x] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Anaemia during peginterferon (PEG-IFN) and ribavirin (RBV) therapy is common in human immunodeficiency virus/hepatitis C virus (HIV/HCV)-coinfected patients despite the use of lower doses of RBV than are recommended for HIV-seronegative persons. In addition, concurrent zidovudine (ZDV) may exacerbate the anaemia caused by PEG-IFN and RBV. We retrospectively analysed the incidence of anaemia, RBV dose reduction and epoetin-alpha (EPO) use among coinfected patients treated with PEG-IFN and weight-based RBV (800-1400 mg/day) who enrolled in two clinical trials and had haemoglobin (Hb) levels assessed at baseline and after 4 and/or 12 weeks of HCV treatment. Overall, 217 patients were included; pre-treatment Hb levels (mean 14.7 g/dL) were similar in all patients, including ZDV users (29% of patients). After 4 weeks of therapy, the mean Hb decline was greater among ZDV recipients (3.13 g/dL) compared with those on other anti-retroviral treatment (ART) (2.13 g/dL) or on no ART (1.47 g/dL) (P < 0.0001). RBV dose reduction and EPO use were more common in patients taking ZDV compared with those not taking ZDV (P < 0.0001). RBV dose was not associated with Hb reduction, RBV dose reduction or EPO use. Virologic response after 12 weeks of therapy and the treatment discontinuation rate did not differ by ZDV use. The use of ZDV but not weight-based RBV dosing was associated with an increased risk of anaemia, RBV dose reduction or EPO use in coinfected patients treated with PEG-IFN/RBV. However, ZDV use was not associated with higher rates of treatment discontinuation or lower early virologic response rates. HIV and hepatitis C care providers should be cognizant of these data.
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Affiliation(s)
- D Alvarez
- Drexel University College of Medicine, Philadelphia, PA, USA
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Homoncik M, Sieghart W, Formann E, Schmid M, Ferenci P, Gangl A, Jilma B, Peck-Radosavljevic M. Erythropoietin treatment is associated with more severe thrombocytopenia in patients with chronic hepatitis C undergoing antiviral therapy. Am J Gastroenterol 2006; 101:2275-2282. [PMID: 17032193 DOI: 10.1111/j.1572-0241.2006.00774.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Erythropoietin (EPO) not only stimulates erythropoiesis but also thrombopoiesis. As pegylated-interferon-alpha(PEG-IFN-alpha)-induced thrombocytopenia may become a limiting factor for continuation of therapy, the present study investigated if EPO can alleviate PEG-IFN-alpha induced thrombocytopenia. Further, we hypothesize that EPO increases platelet reactivity and protease activated receptor 1 (PAR-1) expression during combination antiviral therapy. METHODS Forty patients with chronic hepatitis C received either 10,000 IU EPO 3 x/week or placebo in a randomized, placebo-controlled, double-blinded fashion for 4 wk and combination antiviral therapy with PEG-IFN-2a and ribavirin. RESULTS EPO alleviated the decrease in hemoglobin during combination antiviral therapy with ribavirin (10%vs 20%, p < 0.0001). Platelet counts decreased stronger in EPO than in placebo group on day 28 (p= 0.007). EPO induced a 40% increase in PAR-1 (p < 0.0001), which was accompanied by 100% increase in platelet reactivity (p < 0.0001). PFA-100 platelet plug formation time and PEG-IFN-alpha-induced vWF-increase were not different between study groups. CONCLUSIONS Treatment with EPO alleviated the decrease in hemoglobin but worsened PEG-IFN-alpha induced thrombocytopenia after the first 4 wk of combination therapy. EPO caused PAR-1 receptor upregulation on platelets, which promoted an increase in platelet reactivity without affecting PFA-100 platelet plug formation time. EPO is not a useful option for short-term support of platelet production during antiviral therapy.
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Affiliation(s)
- Monika Homoncik
- Department of Internal Medicine IV, Division of Gastroenterology, Medical University Vienna, Vienna, Austria
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Abstract
BACKGROUND Although the current standard of care for controlling anaemia and neutropenia during anti-viral therapy for hepatitis C is to use dose reduction of ribavirin and pegylated interferon, respectively, erythropoietin and granulocyte colony-stimulating factor are now being advocated as alternatives to dose reduction. AIM To determine the cost-effectiveness of erythropoietin and granulocyte colony-stimulating factor as an alternative to anti-viral dose reduction during antihepatitis C therapy. METHODS Decision analysis was used to assess cost-effectiveness by estimating the cost of using a growth factor per quality-adjusted life-year gained. RESULTS Under baseline assumptions, the cost per quality-adjusted life-year of using growth factors ranged from 16,247 US dollars for genotype 1 with neutropenia to 145,468 US dollars for genotype 2/3 patients with anaemia. These findings are sensitive to the relationship between dose reduction and sustained virological response. CONCLUSIONS Based upon our findings and the varying strength of the evidence for a relationship between dose reduction and sustained virological response: granulocyte colony-stimulating factor may be cost-effective for genotype 1 patients; erythropoietin is probably not cost-effective for genotype 2/3 patients; no conclusion can be reached regarding the cost-effectiveness of erythropoietin for genotype 1 patients or granulocyte colony-stimulating factor for genotype 2/3 patients. Randomized trials are needed to firmly establish the relationship between dose reduction and sustained virological response.
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Affiliation(s)
- M K Chapko
- Northwest Hepatitis C Resource Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA.
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Abstract
Chronic infection with hepatitis C virus (HCV) can progress to cirrhosis, hepatocellular carcinoma, and end-stage liver disease. The current best treatment for HCV infection is combination therapy with pegylated interferon and ribavirin. Although this regimen produces sustained virologic responses (SVRs) in approximately 50% of patients, it can be associated with a potentially dose-limiting hemolytic anemia. Hemoglobin concentrations decrease mainly as a result of ribavirin-induced hemolysis, and this anemia can be problematic in patients with HCV infection, especially those who have comorbid renal or cardiovascular disorders. In general, anemia can increase the risk of morbidity and mortality, and may have negative effects on cerebral function and quality of life. Although ribavirin-associated anemia can be reversed by dose reduction or discontinuation, this approach compromises outcomes by significantly decreasing SVR rates. Recombinant human erythropoietin has been used to manage ribavirin-associated anemia but has other potential disadvantages. Viramidine, a liver-targeting prodrug of ribavirin, has the potential to maintain the virologic efficacy of ribavirin while decreasing the risk of hemolytic anemia in patients with chronic hepatitis C.
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Abstract
In patients with liver disease, thrombocytopenia is a clinical feature that may represent an obstacle to invasive diagnostic or therapeutic procedures, chemotherapy, and anti-viral treatment. Stimulation of the bone marrow is the most promising therapeutic intervention for thrombocytopenia in patients with chronic liver disease. The description of thrombopoietin and its (de)regulation in patients with chronic liver disease have disclosed new treatment opportunities. Indeed, pharmacologic treatment options for thrombocytopenia can be divided into treatments targeted at the thrombopoietin receptor (synthetic thrombopoietins and thrombopoietin-mimetic agents), and use of cytokines with general thrombopoietic potential. Unfortunately, use of synthetic thrombopoietin was hampered by the development of neutralizing antibodies, and thrombopoietin mimetic agents have not yet entered clinical studies. Interleukin-11 proved to be useful in increasing platelet count in patients with chronic liver disease, although its use is limited by side-effects. Erythropoietin has shown promising results in improving thrombocytopenia in cirrhotic patients. In patients with chronic liver disease, safe and well-tolerated treatments aimed at improving thrombocytopenia are still lacking. Larger studies are needed to evaluate and better characterize the thrombopoietic potential of erythropoietin. Human studies with thrombopoietin-mimetic agents are eagerly awaited in order to assess both effectiveness and safety of these drugs.
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Affiliation(s)
- E G Giannini
- Department of Internal Medicine, Gastroenterology Unit, University of Genoa, Genoa, Italy.
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Fuster D, Huertas JA, Gómez G, Solà R, García JG, Vilaró J, Pedrol E, Force L, Tor J, Sirera G, Videla S, Planas R, Clotet B, Tural C, Fuster D, Tor J, Sirera G, Videla S, Planas R, Clotet B, Tural C, Huertas JA, Gómez G, Solà R, García JG, Vilaró J, Pedrol E, Force L, Cervantes M, García I, Roget M. Baseline Factors associated with Haematological Toxicity that Leads to a Dosage Reduction of Pegylated Interferon-α2a and Ribavirin in HIV- and HCV-Coinfected Patients on HCV Antiviral Therapy. Antivir Ther 2005. [DOI: 10.1177/135965350501000710] [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
Objective To assess the baseline factors associated with haematological toxicity that lead to ribavirin or pegylated interferon (peginterferon) dosage reductions in hepatitis C and human immunodeficiency virus (HCV/HIV)-coinfected patients. Design Multicentre, prospective, observational study. Setting Eleven hospitals in Spain during the period 2002–2003. Subjects and methods One-hundred and forty-two HIV/HCV-coinfected patients received peginterferon-α2a plus ribavirin. Baseline characteristics and haematological parameters were recorded at baseline, week 4, 8, 12, 24 and 48. Cox's regression model was used to study the factors associated with the appearance of a haemoglobin level below 10g/dl (haemoglobin-endpoint), a neutrophil count below 750/mm3 (neutrophil-endpoint) and a platelet count below 50,000/mm3 (platelet-endpoint). Results Nineteen patients (13.4%) reached the haemoglobin-endpoint, 22.5% the neutrophil-endpoint and 7% the platelet-endpoint. Mean time of follow-up was 8 months (±3.5). A baseline haemoglobin level below 14g/dl [hazard ratio (HR): 3.65; 95% confidence interval (CI): 1.46–9.06] and treatment with zidovudine (HR: 3.25; 95% CI: 1.31–8.11) were the independent factors associated with the appearance of the haemoglobin-endpoint. A baseline neutrophil below 2050/mm3 (HR: 3.59; 95% CI: 1.77–7.28) and baseline weight <60 kg (HR: 2.21; 95% CI: 1.04–4.56) were independently associated with the appearance of the neutrophil-endpoint. Baseline platelet count (x1000/mm3 decrease) (HR: 1.074; 95% CI: 1.04-1.11) was independently associated with the appearance of the platelet-endpoint. Conclusions Baseline factors allow the identification of a subset of HIV/HCV-coinfected patients who are prone to experience haematological toxicity during HCV antiviral therapy.
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Affiliation(s)
- Daniel Fuster
- HIV Clinical Unit/Fundació de la Lluita contra la SIDA/Internal Medicine Service and Hepatology Unit, University Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Barcelona, Spain
| | - Jaime A Huertas
- Statistics and Operations Research Department, Universitat Politècnica de Catalunya, Barcelona, Spain
| | - Guadalupe Gómez
- Statistics and Operations Research Department, Universitat Politècnica de Catalunya, Barcelona, Spain
| | - Ricard Solà
- Hepatology Unit, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain
| | | | | | | | | | - Jordi Tor
- HIV Clinical Unit/Fundació de la Lluita contra la SIDA/Internal Medicine Service and Hepatology Unit, University Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Barcelona, Spain
| | - Guillem Sirera
- HIV Clinical Unit/Fundació de la Lluita contra la SIDA/Internal Medicine Service and Hepatology Unit, University Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Barcelona, Spain
| | - Sebastiá Videla
- HIV Clinical Unit/Fundació de la Lluita contra la SIDA/Internal Medicine Service and Hepatology Unit, University Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Barcelona, Spain
| | - Ramon Planas
- HIV Clinical Unit/Fundació de la Lluita contra la SIDA/Internal Medicine Service and Hepatology Unit, University Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Barcelona, Spain
| | - Bonaventura Clotet
- HIV Clinical Unit/Fundació de la Lluita contra la SIDA/Internal Medicine Service and Hepatology Unit, University Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Barcelona, Spain
| | - Cristina Tural
- HIV Clinical Unit/Fundació de la Lluita contra la SIDA/Internal Medicine Service and Hepatology Unit, University Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Barcelona, Spain
| | | | | | | | - Sebastiá Videla
- (HIV Clinical Unit, Fundació de la Lluita contra la SIDA/Internal Medicine Service and Hepatology Unit. University Hospital Germans Trias i Pujol. Universitat Autónoma de Barcelona. Badalona, Barcelona, Spain)
| | - Ramon Planas
- (HIV Clinical Unit, Fundació de la Lluita contra la SIDA/Internal Medicine Service and Hepatology Unit. University Hospital Germans Trias i Pujol. Universitat Autónoma de Barcelona. Badalona, Barcelona, Spain)
| | - Bonaventura Clotet
- (HIV Clinical Unit, Fundació de la Lluita contra la SIDA/Internal Medicine Service and Hepatology Unit. University Hospital Germans Trias i Pujol. Universitat Autónoma de Barcelona. Badalona, Barcelona, Spain)
| | - Cristina Tural
- (HIV Clinical Unit, Fundació de la Lluita contra la SIDA/Internal Medicine Service and Hepatology Unit. University Hospital Germans Trias i Pujol. Universitat Autónoma de Barcelona. Badalona, Barcelona, Spain)
| | - Jaime A Huertas
- (Statistics and Operations Research Department, Universitat Politècnica de Catalunya, Barcelona, Spain)
| | - Guadalupe Gómez
- (Statistics and Operations Research Department, Universitat Politècnica de Catalunya, Barcelona, Spain)
| | - Ricard Solà
- (Hepatology Unit, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain)
| | | | | | | | | | | | | | - Mercè Roget
- (Consorci Sanitari de Terrassa, Barcelona, Spain)
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Tien PC. Management and treatment of hepatitis C virus infection in HIV-infected adults: recommendations from the Veterans Affairs Hepatitis C Resource Center Program and National Hepatitis C Program Office. Am J Gastroenterol 2005; 100:2338-54. [PMID: 16181388 DOI: 10.1111/j.1572-0241.2005.00222.x] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Nearly 40% of human immunodeficiency virus- (HIV-) infected veterans on highly active antiretroviral therapy (HAART) in the United States are coinfected with hepatitis C virus (HCV). With the increased survival due to declining opportunistic infections as a result of HAART, HCV-associated liver disease has become a leading cause of death in HIV-infected individuals. HCV infection has been shown to lead to rapid progression of HCV-related liver disease in HIV infection. Results from recent clinical trials in HIV/HCV-coinfected patients show improved response rates using pegylated formulations of interferon plus ribavirin when compared to standard interferon plus ribavirin. However, the treatment of HCV in HIV/HCV-coinfected patients can be complicated by the hepatotoxic and myelosuppressive effects of HIV therapy and HIV infection itself. Prior to initiating HCV therapy, HIV therapy should be optimized by improving immune suppression and avoiding specific antiretroviral drugs that may cause hepatotoxicity and myelosuppression. In the event of treatment-related neutropenia or anemia during HCV therapy, the use of growth factors should be considered to maximize sustained virologic response to HCV therapy. In HIV/HCV-coinfected patients with end-stage liver disease, liver transplantation is being investigated and shows promise as a potential therapeutic option. With the recent advances in the treatment of HCV in HIV/HCV-coinfected individuals, all HIV/HCV-coinfected patients eligible for HCV treatment should be evaluated for HCV combination therapy with careful consideration of their HIV disease.
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Affiliation(s)
- Pyllis C Tien
- VAMC Infectious Disease Section, San Francisco, CA 94121, USA
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36
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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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Inati A, Taher A, Ghorra S, Koussa S, Taha M, Aoun E, Sharara AI. Efficacy and tolerability of peginterferon alpha-2a with or without ribavirin in thalassaemia major patients with chronic hepatitis C virus infection. Br J Haematol 2005; 130:644-646. [PMID: 16098081 DOI: 10.1111/j.1365-2141.2005.05645.x] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Thalassaemia patients with genotype 1 or 4 chronic hepatitis C virus (HCV) infection were randomised to receive peginterferon alpha-2a 180 mg/week ribavirin for 48 weeks. Primary efficacy variable was sustained viral response (SVR) at 72 weeks. Thirty-two patients were evaluated; 20 enrolled. Baseline characteristics were comparable. SVR occurred in four of 12 and five of eight patients in the monotherapy and combination groups (30% and 62.5%; P=0.19), respectively. Undetectable RNA at 12 weeks and age <18 years were associated with improved SVR (P<0.05). Transfusion requirements rose by 34% in the combination arm (P=0.08). Peginterferon/ribavirin was effective in thalassaemics with HCV and moderate iron overload.
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Affiliation(s)
- Adlette Inati
- Chronic Care Center, American University of Beirut Medical Center, Beirut, Lebanon
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38
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Schmid M, Kreil A, Jessner W, Homoncik M, Datz C, Gangl A, Ferenci P, Peck-Radosavljevic M. Suppression of haematopoiesis during therapy of chronic hepatitis C with different interferon alpha mono and combination therapy regimens. Gut 2005; 54:1014-1020. [PMID: 15951552 PMCID: PMC1774617 DOI: 10.1136/gut.2004.057893] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Revised: 02/08/2005] [Accepted: 03/09/2005] [Indexed: 12/08/2022]
Abstract
BACKGROUND Treatment of chronic hepatitis C with interferon (IFN)-alpha and ribavirin has haematotoxic effects. We evaluated the effects of four different IFN/IFN-ribavirin treatment regimens on haematopoiesis. METHODS Haematopoiesis was studied in 133 patients with chronic hepatitis C receiving IFN-alpha2b alone (group A) or in combination with ribavirin (group B), pegylated IFN-alpha2a (group C), or pegylated IFN-alpha2b (group D) in combination with ribavirin. RESULTS At week 4, haemoglobin levels were diminished in all groups receiving combination therapy. In the monotherapy group, haemoglobin decreased slightly after eight weeks. In all groups, haemoglobin remained diminished throughout therapy. In all patients, leucocytes (while blood cells) decreased after four weeks and remained low during treatment. Platelets (peripheral platelet count (PPC)) were decreased in all groups after four weeks and remained below baseline levels during therapy in group A, C, and D whereas in group B PPC recovered early and reached baseline levels at week 16 of therapy. Concomitantly with the decreases in haemoglobin and PPC, erythropoietin increased in all groups receiving combination therapy and thrombopoietin in all groups. Patients treated with pegylated IFN-alpha2a and those who received pegylated IFN-alpha2b combination therapy differed only in leucopoiesis, whereas erythropoiesis and thrombopoiesis were comparable. CONCLUSION IFN-alpha based therapies are associated with a decrease in all three haematopoietic lineages, irrespective of the type of therapy used. The stronger suppressive effect of pegylated IFN-alpha2a on leucopoiesis could be due to a dose effect. Overall, concentrations of endogenous haematopoietic growth factors are increased but can only partially alleviate haematotoxicity. Potential uses of exogenous haematopoietic growth factors and their impact on the virological response need to be explored.
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Affiliation(s)
- M Schmid
- Department of Internal Medicine IV, Division of Gastroenterology and Hepatology, University of Vienna, Währingergürtel 18-20, A-1090 Vienna, Austria
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Abstract
Coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV) is common in patients with HIV infection. HIV infection and immunosuppression alter the natural history of chronic viral hepatitis, and some patients experience accelerated progression to clinically significant liver disease. Therapies used in the treatment of HBV or HCV monoinfection have been applied to the treatment of HIV-coinfected patients. However, development of viral resistance and lack of virologic response remain significant areas of concern. Timely diagnosis and clinical staging of chronic hepatitis infection are critical in the management of HIV-coinfected patients.
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Affiliation(s)
- Patrick Yachimski
- GRJ 825, GI Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
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40
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Stravitz RT, Chung H, Sterling RK, Luketic VA, Sanyal AJ, Price AS, Purrington A, Shiffman ML. Antibody-mediated pure red cell aplasia due to epoetin alfa during antiviral therapy of chronic hepatitis C. Am J Gastroenterol 2005; 100:1415-9. [PMID: 15929778 DOI: 10.1111/j.1572-0241.2005.41910.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Anemia frequently complicates the treatment of chronic hepatitis C with interferon and ribavirin (RVN), requiring dose reduction and jeopardizing sustained virologic response. Increasingly, epoetin alfa is used to prevent anemia in this setting. Below, we report the first case of pure red cell aplasia (PRCA) in a patient with chronic hepatitis C who received epoetin alfa (Procrit) to manage anti-viral treatment-induced anemia. Red blood cell transfusion-dependence developed 16 wk after the patient was started on peginterferon alfa-2b and RVN for chronic hepatitis C despite the simultaneous administration of epoetin alfa and subsequent discontinuation of the antiviral medications. Bone marrow biopsy was consistent with PRCA. High-titer erythropoietin antibodies, assayed by two methods, appeared shortly after epoetin alfa was administered, and were associated with a decline in serum erythropoietin to undetectable levels. Erythropoietin antibodies directed toward epoetin alfa were shown to cross react with darbepoetin alfa (Aranesp), and a neutralization assay confirmed that they inhibited cell growth in the presence of erythropoietin. Transfusion-dependence resolved approximately 16 wk after discontinuing epoetin alfa, and 6 wk after starting danazol. PRCA caused by the development of erythropoietin antibodies is a potentially life-threatening complication of administering epoetin alfa to prevent the anemia associated with antiviral therapy in patients with chronic hepatitis C.
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Affiliation(s)
- R Todd Stravitz
- Section of Hepatology, Division of Gastroenterology and the Division of Hematology/Oncology, Virginia Commonwealth University Medical Center, Richmond, Virginia 23298-0341, USA
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Lee SD, Yu ML, Cheng PN, Lai MY, Chao YC, Hwang SJ, Chang WY, Chang TT, Hsieh TY, Liu CJ, Chen DS. Comparison of a 6-month course peginterferon alpha-2b plus ribavirin and interferon alpha-2b plus ribavirin in treating Chinese patients with chronic hepatitis C in Taiwan. J Viral Hepat 2005; 12:283-291. [PMID: 15850469 DOI: 10.1111/j.1365-2893.2005.00590.x] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Previous studies in Caucasian patients showed treatment of chronic hepatitis C with pegylated interferon/ribavirin was well tolerated, and produced a higher response rate especially in genotype 1 infections. However, it is unknown whether this conclusion can be extrapolated to patients with Chinese ethnic origin. A total of 153 patients with biopsy-proven chronic hepatitis C were randomly assigned to receive either weekly injection of peginterferon alpha-2b 1.5 mcg/kg plus oral ribavirin (1000 or 1200 mg/day, depending on body weight) (PEG group, n = 76) or 3 MU of interferon alpha-2b t.i.w. plus ribavirin (IFN group, n = 77) for 24 weeks. Sustained virological response (SVR) was defined as the sustained disappearance of serum hepatitis C virus (HCV) RNA at 24 weeks after the end of treatment by polymerase chain reaction assay. Baseline demographic, viral and histological characteristics were comparable between the two groups. Using an intent-to-treat analysis, HCV genotype 1 patients showed a significantly higher SVR in patients receiving PEG-IFN rather than IFN (65.8%vs 41.0%, P = 0.019), but no difference was found in genotype non-1 patients (PEG vs IFN: 68.4%vs 86.8%, P = 0.060). Genotype 1 patients (28.6%) in the PEG-IFN group relapsed, as compared with 52.9% in the IFN group (P = 0.040). Multivariate analyses showed early virological response at week 12 of therapy and genotype non-1 were significant predictors to SVR. As compared with the IFN group, patients receiving PEG-IFN had a significantly higher rate of discontinuation, dose reduction, fever, headache, insomnia, leucopenia and thrombocytopenia. In genotype 1 chronic hepatitis C Chinese patient, PEG-IFNalpha2b ribavirin had significantly better SVR and lower relapse rate when compared to IFN/ribavirin. Both regimens can be recommended for genotype non-1 chronic hepatitis C Chinese patients. However, a higher rate of adverse events and discontinuance of therapy were noted in patients treated with PEG-IFNalpha2b ribavirin.
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Affiliation(s)
- S-D Lee
- Department of Medicine, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taipei 100, Taiwan
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Balan V, Schwartz D, Wu GY, Muir AJ, Ghalib R, Jackson J, Keeffe EB, Rossaro L, Burnett A, Goon BL, Bowers PJ, Leitz GJ. Erythropoietic response to anemia in chronic hepatitis C patients receiving combination pegylated interferon/ribavirin. Am J Gastroenterol 2005; 100:299-307. [PMID: 15667486 DOI: 10.1111/j.1572-0241.2005.40757.x] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES In hepatitis C virus (HCV)-infected patients receiving pegylated interferon (PEG-IFN)/ribavirin (RBV) combination therapy, anemia is a well-known side effect. The purpose of this study was to describe the time course and extent of hemoglobin (Hb) changes and the erythropoietic response to PEG-IFN/RBV-induced anemia. METHODS In this multicenter, observational, 8-wk study, laboratory parameters were measured weekly for 8 wk or until early withdrawal. Primary endpoints included changes in Hb and serum erythropoietin (sEPO) from baseline to week 8; other measures were changes in reticulocytes and RBV dose. The predictive value of baseline factors for maximum Hb decline was assessed. RESULTS In the 97 evaluable patients, mean Hb decreased from 14.4 +/- 1.4 g/dl (baseline) to 11.9 +/- 1.3 g/dl (week 8). Twenty-one percent of patients withdrew before week 8. The estimated erythropoietic response was lower than that seen in two historic control populations of iron deficiency anemia patients. Mean RBV dose decreased from 986 +/- 190 mg/day (baseline) to 913 +/- 228 mg/day (week 8). Fifty-seven out of 77 (74%) patients who completed the study maintained their initial prescribed RBV dose. Patients maintained on the initial dose of RBV who had a higher baseline Hb and viral load showed a trend toward larger Hb declines. Platelets and white blood cells (WBCs) also declined during the study. CONCLUSIONS HCV-infected patients receiving PEG-IFN/RBV therapy have reductions in Hb, platelets, and WBCs, possibly due to bone marrow suppression. They also have diminished endogenous sEPO production for their degree of anemia.
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Affiliation(s)
- Vijayan Balan
- Division of Transplantation Medicine, Mayo Clinic Hospital, 5777 E. Mayo Boulevard, Phoenix, AZ 85054, USA
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Pang KR, Wu JJ, Huang DB, Tyring SK, Baron S. Biological and clinical basis for molecular studies of interferons. METHODS IN MOLECULAR MEDICINE 2005; 116:1-23. [PMID: 16007741 PMCID: PMC7121562 DOI: 10.1385/1-59259-939-7:001] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The cytokine family of interferons (IFNs) has multiple functions, including antiviral, anti-tumor, and immunomodulatory effects and regulation of cell differentiation. The multiple functions of the IFN system are thought to be an innate defense against microbes and foreign substances. The IFN system consists first of cells that produce IFNs in response to viral infection or other foreign stimuli and second of cells that establish the antiviral state in response to IFNs. This process of innate immunity involves multiple signaling mechanisms and activation of various host genes. Viruses have evolved to develop mechanisms that circumvent this system. IFNs have also been used clinically in the treatment of viral diseases. Improved treatments will be possible with better understanding of the IFN system and its interactions with viral factors. In addition, IFNs have direct and indirect effects on tumor cell proliferation, effector leukocytes and on apoptosis and have been used in the treatment of some cancers. Improved knowledge of how IFNs affect tumors and the mechanism that lead to a lack of response to IFNs would help the development of better IFN treatments for malignancies.
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Shergill AK, Khalili M, Straley S, Bollinger K, Roberts JP, Ascher NA, Terrault NA. Applicability, tolerability and efficacy of preemptive antiviral therapy in hepatitis C-infected patients undergoing liver transplantation. Am J Transplant 2005; 5:118-24. [PMID: 15636619 DOI: 10.1111/j.1600-6143.2004.00648.x] [Citation(s) in RCA: 131] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Preliminary studies suggest preemptive anti-HCV therapy in liver transplant recipients may enhance the rates of viral clearance, but the applicability and tolerability of preemptive therapy has not been evaluated in a contemporary cohort. In this randomized study, the safety and tolerability of preemptive standard (IFN) or pegylated (peg-IFN) interferon alfa-2b (3 MU thrice weekly or 1.5 microg/kg weekly), or IFN/peg-IFN plus ribavirin (600 mg increased to 1.0-1.2 g daily) was initiated 2-6 weeks post-transplantation and continued for a total of 48 weeks. Only 51 (41%) of 124 transplant recipients were eligible for preemptive treatment; eligible patients had lower model for end-stage liver disease (MELD) and Childs-Pugh scores pre-transplantation and were more frequently live donor transplant recipients than ineligible patients. Dose reductions and discontinuations were required in 85% and 37% of patients, respectively, and 27% experienced serious adverse events. Growth factor (GF) use (erythropoietin and GCSF) in the latter half of the study did not significantly affect the frequency of dose reductions. Only 15% of patients were able to achieve full-dose treatment during treatment. End-of-treatment and sustained virological responses were 13.6% and 9.1%, respectively, with most responders in the combination therapy group. We conclude that preemptive antiviral therapy is applicable to only a portion of transplant recipients, with 'sicker' patients less likely to be managed by this approach. Living donor liver transplant recipients were more frequently eligible for treatment than deceased donor recipients. Virological response rates are low, likely related to the poor tolerability of therapy and the lack of achievement of target drug doses. Future studies should focus on alternative dosing schedules with more aggressive use of adjuvant therapies, including GFs.
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Affiliation(s)
- Amandeep K Shergill
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
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45
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Sherman M, Bain V, Villeneuve JP, Myers RP, Cooper C, Martin S, Lowe C. The management of chronic viral hepatitis: A Canadian consensus conference 2004. THE CANADIAN JOURNAL OF INFECTIOUS DISEASES & MEDICAL MICROBIOLOGY = JOURNAL CANADIEN DES MALADIES INFECTIEUSES ET DE LA MICROBIOLOGIE MEDICALE 2004; 15:313-26. [PMID: 18159509 PMCID: PMC2094989 DOI: 10.1155/2004/326964] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2004] [Accepted: 09/09/2004] [Indexed: 12/11/2022]
Abstract
Several government and nongovernment organizations held a consensus conference on the management of acute and chronic viral hepatitis to update previous management recommendations. The conference became necessary because of the introduction of new forms of therapy for both hepatitis B and hepatitis C. The conference issued recommendations on the investigation and management of chronic hepatitis B, including the use of lamivudine, adefovir and interferon. The treatment of hepatitis B in several special situations was also discussed. There were also recommendations on the investigation and treatment of chronic hepatitis C and hepatitis C-HIV coinfection. In addition, the document makes some recommendations about the provision of services by provincial governments to facilitate the delivery of care to patients with hepatitis virus infection. The present document is meant to be used by practitioners and other health care providers, including public health staff and others not directly involved in patient care.
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Heathcote J, Ramji A. When to treat patients with chronic hepatitis C. Curr Gastroenterol Rep 2004; 6:261-3. [PMID: 15245691 DOI: 10.1007/s11894-004-0074-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Jenny Heathcote
- Department of Medicine, Toronto Western Hospital, University Health Network/University of Toronto, 399 Bathurst Street, Fell Pavilion, 6th floor, Room 170, Toronto, ON M5T 2S8, Canada.
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Sulkowski MS, Wasserman R, Brooks L, Ball L, Gish R. Changes in haemoglobin during interferon alpha-2b plus ribavirin combination therapy for chronic hepatitis C virus infection. J Viral Hepat 2004; 11:243-50. [PMID: 15117326 DOI: 10.1111/j.1365-2893.2004.00490.x] [Citation(s) in RCA: 117] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Interferon alpha and ribavirin (RBV) combination therapy is associated with decreases in haemoglobin (Hb) concentrations and anaemia. The aim of this analysis was to better characterize the magnitude and frequency of Hb changes and risk factors. This retrospective analysis evaluated treatment-related changes in Hb in 677 patients who participated in either of two interferon alpha-2b plus RBV studies for chronic hepatitis C virus (HCV) infection. Study 1 included 192 interferon alpha-naïve patients randomized to receive RBV 1000-1200 mg/day plus interferon alpha-2b 3 million IU daily or three times weekly for 48 weeks. Study 2 included 485 interferon alpha-experienced patients randomized to receive RBV 1000-1200 mg daily plus interferon alpha-2b 3 million IU daily or three times weekly for 4 weeks, followed by three times weekly dosing for 44 weeks. More than 50% of all patients experienced a decrease in Hb > or =30 g/L. Women were 4.4 times as likely as men to experience a Hb level of <100 g/L; however, men were at a 40% higher risk to experience a Hb decline of >30 g/L from baseline. Daily use of interferon alpha-2b did not impact the magnitude of Hb decrease. In this pooled analysis, RBV dose reduction resulted in increases in Hb concentration of approximately 10 g/L. Lower baseline creatinine clearance, higher baseline Hb levels and increased age were independently associated with increased risk of Hb decreases of >27.7%. Lower baseline weight was not associated with increased risk of Hb decrease. Substantial Hb decreases occur frequently with interferon alpha/RBV combination therapy. Sex, the magnitude of the Hb decline and renal function are potentially important factors to consider in patients receiving RBV. Further research is needed to determine the impact on virological response and to develop strategies to manage the medical consequences.
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Affiliation(s)
- M S Sulkowski
- Viral Hepatitis Center, Johns Hopkins University, Baltimore, MD 21205, USA.
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Bräu N. Epoetin alfa treatment for acute anaemia during interferon plus ribavirin combination therapy for chronic hepatitis C. J Viral Hepat 2004; 11:191-7. [PMID: 15117320 DOI: 10.1111/j.1365-2893.2004.00506.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Infection with the hepatitis C virus (HCV) remains chronic in 75% of infected individuals, in whom it can cause liver inflammation and progressive fibrosis leading to cirrhosis in 20% of patients. A sustained viral response (SVR) to HCV therapy, i.e. undetectable plasma HCV RNA 6 months after the end of treatment, leads to permanent eradication of the virus in 98.3% of patients. The current treatment of choice is combination therapy with pegylated interferon alfa (PEG-IFN alfa), 2a or 2b, and ribavirin (RBV), which achieves an SVR in 54-56% of patients. In patients with HCV genotype 1, RBV doses of 1000-1200 mg/day are associated with a higher SVR than 800 mg/day (51 vs 40%). However, RBV also causes dose-dependent reversible haemolytic anaemia that, in combination with the myelosuppressive effects of PEG-IFN, results in a mean drop in haemoglobin (Hb) level of 3.7 g/dL within 4 weeks. Conventionally, this acute anaemia has been managed with RBV dose reductions. However, this may result in a decreased SVR rate. Alternatively, this anaemia can be managed with administration of epoetin alfa at 40 000 IU once weekly. In a randomized placebo-controlled trial, treatment with epoetin alfa has been shown to raise Hb levels and maintain RBV doses. Furthermore, the increase in Hb level was associated with improved quality of life. Anaemia in patients treated with interferon plus RBV combination therapy can be managed effectively and safely with once weekly epoetin alfa without sacrificing optimal dosing of RBV.
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Affiliation(s)
- N Bräu
- Department of Medicine, Division of Infectious Diseases, Veterans Affairs Medical Center, Bronx, and Mount Sinai School of Medicine, New York, NY, USA.
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