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Ma Z, de Man RA, Kamar N, Pan Q. Chronic hepatitis E: Advancing research and patient care. J Hepatol 2022; 77:1109-1123. [PMID: 35605741 DOI: 10.1016/j.jhep.2022.05.006] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 05/08/2022] [Accepted: 05/10/2022] [Indexed: 12/15/2022]
Abstract
The hepatitis E virus (HEV) was initially thought to exclusively cause acute hepatitis. However, the first diagnosis of chronic hepatitis E in transplant recipients in 2008 profoundly changed our understanding of this pathogen. We have now begun to understand that specific HEV genotypes can cause chronic infection in certain immunocompromised populations. Over the past decade, dedicated clinical and experimental research has substantiated knowledge on the epidemiology, transmission routes, pathophysiological mechanisms, diagnosis, clinical features and treatment of chronic HEV infection. Nevertheless, many gaps and major challenges remain, particularly regarding the translation of knowledge into disease prevention and improvement of clinical outcomes. This article aims to highlight the latest developments in the understanding and management of chronic hepatitis E. More importantly, we attempt to identify major knowledge gaps and discuss strategies for further advancing both research and patient care.
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Affiliation(s)
- Zhongren Ma
- Biomedical Research Center, Northwest Minzu University, Lanzhou, China
| | - Robert A de Man
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Nassim Kamar
- Department of Nephrology, Dialysis and Organ Transplantation, CHU Rangueil, INSERM UMR 1291, Toulouse Institute for Infectious and Inflammatory Disease (Infinity), University Paul Sabatier, Toulouse, France
| | - Qiuwei Pan
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
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Correia AL, Pimenta AC, Carias E, Guedes Marques M, Leal R, Rodrigues L, Santos L, Romãozinho C, Leitão J, Alves R, Figueiredo A. A Less Common Cause of Acute Hepatitis in Kidney Transplant Recipients: A Case Series. Transplant Proc 2022; 54:1278-1281. [PMID: 35768296 DOI: 10.1016/j.transproceed.2022.03.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 03/13/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatitis E virus (HEV) is a cause of significant morbidity and mortality, representing an important global public health problem. Immunocompetent patients with acute hepatitis E can clear the infection spontaneously; however, in approximately two thirds of cases, immunosuppressed patients, such as kidney transplant (KT) recipients, fail to clear the HEV infection and develop chronic hepatitis. PATIENTS AND METHODS We report 3 cases of HEV infection in KT patients. Two presented only with laboratory abnormalities and elevated liver enzymes, and 1 presented with symptomatic disease motivating hospital admission. None was able to clear the infection spontaneously, and they were all treated with ribavirin, accompanied with reduction of immunosuppressive drugs. Adverse effects of the treatment were reported in 2 patients, and in 1 case, a dose reduction was necessary. All patients responded to the treatment and have no current evidence of active disease. No alterations of basal kidney function during or related to the treatment were registered. DISCUSSION HEV screening in KT patients presenting with abnormal liver function of undetermined cause is fundamental, as it might have poorer outcomes in this specific population. The treatment with ribavirin seems to be safe and effective, although we must always be alert to potential side effects, maintaining a close follow-up of these patients.
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Affiliation(s)
- Ana Luísa Correia
- Nephrology Department, Coimbra Hospital and University Centre, Coimbra, Portugal.
| | - Ana Carolina Pimenta
- Nephrology Department, Coimbra Hospital and University Centre, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Eduarda Carias
- Nephrology Department, University Hospital Center of Algarve, Algarve, Portugal
| | - Maria Guedes Marques
- Nephrology Department, Coimbra Hospital and University Centre, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Rita Leal
- Nephrology Department, Coimbra Hospital and University Centre, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Luís Rodrigues
- Nephrology Department, Coimbra Hospital and University Centre, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Lídia Santos
- Nephrology Department, Coimbra Hospital and University Centre, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Catarina Romãozinho
- Nephrology Department, Coimbra Hospital and University Centre, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Jorge Leitão
- Internal Medicine Department, Coimbra Hospital and University Centre, Coimbra, Portugal
| | - Rui Alves
- Nephrology Department, Coimbra Hospital and University Centre, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Arnaldo Figueiredo
- Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Urology and Renal Transplant Department, Coimbra Hospital and University Centre, Coimbra, Portugal
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Aslan AT, Balaban HY. Hepatitis E virus: Epidemiology, diagnosis, clinical manifestations, and treatment. World J Gastroenterol 2020; 26:5543-5560. [PMID: 33071523 PMCID: PMC7545399 DOI: 10.3748/wjg.v26.i37.5543] [Citation(s) in RCA: 107] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 08/11/2020] [Accepted: 09/09/2020] [Indexed: 02/06/2023] Open
Abstract
The hepatitis E virus (HEV) is the fifth known form of viral hepatitis and was first recognized as the cause of an epidemic of unexplained acute hepatitis in the early 1980s. Globally, it is one of the most frequent causes of acute viral hepatitis. The majority of HEV infections are asymptomatic and lead to the spontaneous clearance of the virus. Among the eight different genotypes identified to date, HEV genotype 1 (HEV1), HEV2, HEV3, and HEV4 are the most frequent genotypes causing infections in humans. HEV1 and HEV2 are prevalent in developing regions and able to result in large-scale outbreaks originating from contaminated water supplies. They are also responsible for severe hepatitis in pregnant patients and infants. In contrast, HEV3 and HEV4 are zoonotic, and the transmission of these genotypes to humans occurs mainly through the fecal contamination of water and consumption of contaminated meat from infected animals. Their main reservoir is the pig, and they are mostly encountered in developed countries. The major risk groups for HEV infection and its ensuing adverse consequences are pregnant women, infants, older people, immunocompromised individuals, patients with underlying chronic liver diseases, and workers that come into close contact with HEV-infected animals. In the clinical perspective, HEV infections have diverse clinical manifestations including acute and self-limiting hepatitis, acute-on-chronic liver disease, chronic hepatitis, cirrhosis, and liver failure. Although HEV mainly results in acute self-limiting infection, chronic HEV infection may occur among immunocompromised patients (e.g., solid-organ transplant recipients). Additionally, HEV-associated extrahepatic manifestations involving various organs have been reported in the last decade, although the causal link for many of them still needs to be proven. Ribavirin and interferon-alpha are the most widely used agents for the treatment of HEV infections with a certain level of success. However, ribavirin is contraindicated in pregnant patients, and interferon-alpha cannot be used in most transplant recipients. Therefore, there is an urgent need for novel antiviral compounds that are safe and effective particularly for patients having contraindications for ribavirin or interferon-alpha and infected by the ribavirin-resistant HEV. In this review article, a literature search using PubMed and MEDLINE databases was performed, up to March 2020. Only the articles published in English were reviewed.
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Affiliation(s)
| | - Hatice Yasemin Balaban
- Department of Gastroenterology, Hacettepe University Faculty of Medicine, Ankara 06100, Turkey
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Kar P, Karna R. A Review of the Diagnosis and Management of Hepatitis E. CURRENT TREATMENT OPTIONS IN INFECTIOUS DISEASES 2020; 12:310-320. [PMID: 32837339 PMCID: PMC7366488 DOI: 10.1007/s40506-020-00235-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Purpose of review We aim to provide the readers an up-to-date knowledge of the structure, epidemiology, and transmission followed by a detailed discussion on testing, diagnostics and management of hepatitis E virus infection. We have also included a comprehensive review of hepatitis E in pregnancy. Recent findings European Association for the Study of the Liver established clinical practice guidelines for testing and treatment of suspected hepatitis E virus infections in 2018. Evidence suggests chronic hepatitis E may follow a course similar to hepatitis B/C with progression to cirrhosis and possibly hepatocellular carcinoma in immunocompromised patients. Summary Hepatitis E virus is the most common cause of acute viral hepatitis worldwide. A combination of serology and nucleic acid amplification testing is the recommended strategy for suspected patients. Ribavirin therapy for a period of 3 months is the drug of choice for severe acute hepatitis, acute-on chronic liver failure, and chronic infections from hepatitis E virus in immunocompromised patients who are unresponsive to decreased immunosuppression. PEGylated interferon α can be used for ribavirin-resistant liver transplant patients with chronic hepatitis E. Further research in therapeutic options is essential considering the stormy course of hepatitis E infection during pregnancy and teratogenicity of all available options.
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Affiliation(s)
- P. Kar
- Department of Gastroenterology and Hepatology, Max Super Specialty Hospital,Ghaziabad, Delhi, New Delhi 110017 India
| | - R. Karna
- Maulana Azad Medical College & Lok Nayak Hospital, Bahadurshah Zafar Road, New Delhi, India
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Yoshida T, Takamura M, Goto R, Takeuchi S, Tsuchiya A, Kamimura K, Tasaki M, Nakagawa Y, Saito K, Tomita Y, Terai S. Efficacy and safety of ribavirin therapy for chronic hepatitis E after kidney transplantation. Hepatol Res 2019; 49:1244-1248. [PMID: 31077507 DOI: 10.1111/hepr.13363] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 04/28/2019] [Accepted: 05/04/2019] [Indexed: 12/16/2022]
Abstract
Hepatitis E virus (HEV) infection has been recognized as an acute condition. However, recent reports have shown that immunocompromised patients, such as those receiving solid-organ transplantation, can develop chronic hepatitis with HEV infection. We report two cases of chronic hepatitis E after kidney transplantation (KT) who were successfully treated with ribavirin monotherapy. Several years after KT, both patients had sustained elevations in the levels of liver enzymes for a period of more than 6 months. Both patients had HEV infection, genotype 3a. Histological studies showed infiltration of inflammatory cells without fibrosis. Treatment included ribavirin monotherapy at a dosage of 600 mg daily for 3 months. One month after therapy initiation, HEV-RNA turned to negative, and remained negative at 24 weeks after ribavirin therapy without severe complications. Although the treatment of chronic hepatitis E is not fully established, ribavirin therapy can be a safe and effective treatment for chronic hepatitis E.
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Affiliation(s)
- Tomoaki Yoshida
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, Niigata City, Japan
| | - Masaaki Takamura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, Niigata City, Japan
| | - Ryo Goto
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, Niigata City, Japan
| | - Suguru Takeuchi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, Niigata City, Japan
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, Niigata City, Japan
| | - Kenya Kamimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, Niigata City, Japan
| | - Masayuki Tasaki
- Division of Urology, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yuki Nakagawa
- Division of Urology, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Kazuhide Saito
- Division of Urology, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yoshihiko Tomita
- Division of Urology, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, Niigata City, Japan
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Lhomme S, DebRoy S, Kamar N, Abravanel F, Metsu D, Marion O, Dimeglio C, Cotler SJ, Izopet J, Dahari H. Plasma Hepatitis E Virus Kinetics in Solid Organ Transplant Patients Receiving Ribavirin. Viruses 2019; 11:E630. [PMID: 31323954 PMCID: PMC6669701 DOI: 10.3390/v11070630] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 07/06/2019] [Accepted: 07/08/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatitis E virus (HEV) infection causes chronic hepatitis in solid organ transplant (SOT) recipients. Antiviral therapy consists of three months of ribavirin, although response rates are not optimal. We characterized plasma HEV kinetic patterns in 41 SOT patients during ribavirin therapy. After a median pharmacological delay of three (range: 0-21) days, plasma HEV declined from a median baseline level of 6.12 (3.53-7.45) log copies/mL in four viral kinetic patterns: (i) monophasic (n = 18), (ii) biphasic (n = 13), (iii) triphasic (n = 8), and (iv) flat-partial response (n = 2). The mean plasma HEV half-life was estimated to be 2.0 ± 0.96 days. Twenty-five patients (61%) had a sustained virological response (SVR) 24 weeks after completion of therapy. Viral kinetic patterns (i)-(iii) were not associated with baseline characteristics or outcome of therapy. A flat-partial response was associated with treatment failure. All patients with a log concentration decrease of plasma HEV at day seven of >15% from baseline achieved SVR. In conclusion, viral kinetic modeling of plasma HEV under ribavirin therapy showed, for the first time, four distinct kinetic profiles, a median pharmacologic delay of three days, and an estimated HEV half-life of two days. Viral kinetic patterns were not associated with response to therapy, with the exception of a flat-partial response.
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Affiliation(s)
- Sebastien Lhomme
- National Reference Center for Hepatitis E, Department of Virology, Federative Institute of Biology, CHU Purpan, INSERM U1043, University Toulouse III-Paul Sabatier, 31300 Toulouse, France.
| | - Swati DebRoy
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Loyola University Medical Center, Maywood, IL 60153, USA
- Department of Mathematics and Computational Science, University of South Carolina-Beaufort, Bluffton, SC 29909, USA
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, CHU Rangueil, INSERM U1043, University Toulouse III-Paul Sabatier, 31300 Toulouse, France
| | - Florence Abravanel
- National Reference Center for Hepatitis E, Department of Virology, Federative Institute of Biology, CHU Purpan, INSERM U1043, University Toulouse III-Paul Sabatier, 31300 Toulouse, France
| | - David Metsu
- Department of Pharmacokinetics and Toxicology, Federative Institute of Biology, CHU Purpan, INTHERES, INRA, ENVT, University Toulouse III-Paul Sabatier, 31300 Toulouse, France
| | - Olivier Marion
- Department of Nephrology and Organ Transplantation, CHU Rangueil, INSERM U1043, University Toulouse III-Paul Sabatier, 31300 Toulouse, France
| | - Chloé Dimeglio
- National Reference Center for Hepatitis E, Department of Virology, Federative Institute of Biology, CHU Purpan, INSERM U1043, University Toulouse III-Paul Sabatier, 31300 Toulouse, France
| | - Scott J Cotler
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Loyola University Medical Center, Maywood, IL 60153, USA
| | - Jacques Izopet
- National Reference Center for Hepatitis E, Department of Virology, Federative Institute of Biology, CHU Purpan, INSERM U1043, University Toulouse III-Paul Sabatier, 31300 Toulouse, France
| | - Harel Dahari
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Loyola University Medical Center, Maywood, IL 60153, USA.
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Dalton HR, Kamar N, Baylis SA, Moradpour D, Wedemeyer H, Negro F. EASL Clinical Practice Guidelines on hepatitis E virus infection. J Hepatol 2018; 68:1256-1271. [PMID: 29609832 DOI: 10.1016/j.jhep.2018.03.005] [Citation(s) in RCA: 434] [Impact Index Per Article: 62.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 03/09/2018] [Indexed: 02/08/2023]
Abstract
Infection with hepatitis E virus (HEV) is a significant cause of morbidity and mortality, representing an important global health problem. Our understanding of HEV has changed completely over the past decade. Previously, HEV was thought to be limited to certain developing countries. We now know that HEV is endemic in most high-income countries and is largely a zoonotic infection. Given the paradigm shift in our understanding of zoonotic HEV and that locally acquired HEV is now the commonest cause of acute viral hepatitis in many European countries, the focus of these Clinical Practice Guidelines will be on HEV genotype 3 (and 4).
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De Winter BCM, Hesselink DA, Kamar N. Dosing ribavirin in hepatitis E-infected solid organ transplant recipients. Pharmacol Res 2018; 130:308-315. [PMID: 29499270 DOI: 10.1016/j.phrs.2018.02.030] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Revised: 02/06/2018] [Accepted: 02/26/2018] [Indexed: 12/22/2022]
Abstract
Hepatitis E virus (HEV) is the most common cause of viral hepatitis worldwide. Genotypes 1 and 2 (GT1 and GT2) are mainly present in developing countries, while GT3 and GT4 are prevalent in developed and high-income countries. In the majority of cases, HEV causes a self-limiting hepatitis. GT3 and GT4 can be responsible for a chronic hepatitis that can lead to cirrhosis in immunocompromized patients, i.e. solid-organ- and stem-cell-transplant-patients, human immunodeficiency virus-infected patients, and patients receiving chemotherapy or immunotherapy. HEV has also been associated with extra-hepatic manifestations such as neurologic disorders (Guillain-Barré Syndrome and neuralgic amyotrophy) and kidney disease. In patients with chronic hepatitis, reduction of immunosuppression, when possible, is the first therapeutic option. In the remaining patients, ribavirin therapy has been shown to very efficient for treating HEV infection leading to a sustained virological response in nearly 80-85% of patients. However, the mechanism of action of ribavirin in this setting is still unknown, as is the impact of HEV RNA polymerase mutations. There are unmet needs with regard to the treatment of chronic HEV with ribavirin. These include the optimal dosing and duration of treatment, and the potential beneficial effects of therapeutic drug monitoring on the virological response and the incidence of side effects. In the present review, we will provide an overview of HEV epidemiology, its mode of transmission and clinical manifestations, as well as its treatment by ribavirin with a focus on the drug's pharmacokinetics and dosing.
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Affiliation(s)
- Brenda C M De Winter
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Dennis A Hesselink
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, The Netherlands; Rotterdam Transplant Group, Division of Nephrology and Organ Transplantation, CHU Rangueil, INSERM U1043, IFR-BMT, Université Paul Sabatier, Toulouse, France
| | - Nassim Kamar
- Department of Internal Medicine, Division of Nephrology and Organ Transplantation, CHU Rangueil, INSERM U1043, IFR-BMT, Université Paul Sabatier, Toulouse, France.
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Choi M, Hofmann J, Köhler A, Wang B, Bock CT, Schott E, Reinke P, Nickel P. Prevalence and Clinical Correlates of Chronic Hepatitis E Infection in German Renal Transplant Recipients With Elevated Liver Enzymes. Transplant Direct 2018; 4:e341. [PMID: 29464202 PMCID: PMC5811270 DOI: 10.1097/txd.0000000000000758] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 10/04/2017] [Accepted: 10/24/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Elevated liver enzymes are frequently observed in renal transplant recipients and warrant further exploration. In immunosuppressed patients, hepatitis E virus (HEV) infection may cause chronic hepatitis, cirrhosis, and extrahepatic manifestations such as renal injury. METHODS We performed a retrospective cross-sectional study investigating the prevalence, clinical correlates, and outcome of chronic HEV infection in a cohort of renal transplant recipients with elevated liver enzymes. RESULTS Over a period of 30 months, 140 of 1469 renal transplant recipients had elevated liver enzymes, of which serum samples from 98 patients were available to determine HEV status. Seventeen patients were detected with HEV infection, of which 16 developed chronic HEV infection, while 1 patient controlled viremia (prevalence of chronic infection of 16.3%, with a minimum prevalence of 1.1% in the whole cohort). Increased liver stiffness was indicated by an average FibroScan result of 11.2 kPa in these patients. All 16 patients with chronic HEV infection were treated with ribavirin for a mean duration of 3 months. Five patients developed a viral rebound and received a second treatment course, of which 2 controlled HEV replication. Six months after the end of therapy, HEV clearance was achieved in 81.3% of the patients. One patient developed ribavirin resistance. Hemolytic anemia after ribavirin treatment was frequent, requiring blood transfusion in 3 patients. Four patients developed de novo glomerulonephritis, of which 2 were possibly associated with HEV infection. CONCLUSIONS This retrospective study showed that prevalence of chronic HEV infection was high in our renal transplant patient cohort and was associated with significant liver impairment and the occurrence of renal injury. Ribavirin treatment was effective and should be initiated early to avoid complications, but the risk of severe hemolytic anemia makes strict monitoring essential.
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Affiliation(s)
- Mira Choi
- Department of Nephrology and Intensive Care, Charité Universitätsmedizin Berlin, Germany
| | | | - Anja Köhler
- Labor Berlin, Charité-Vivantes GmbH, Berlin, Germany
| | - Bo Wang
- Department of Infectious Diseases, Robert Koch-Institute, Berlin, Germany
| | - Claus-Thomas Bock
- Department of Infectious Diseases, Robert Koch-Institute, Berlin, Germany
| | - Eckart Schott
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Germany
| | - Petra Reinke
- Department of Nephrology and Intensive Care, Charité Universitätsmedizin Berlin, Germany
| | - Peter Nickel
- Department of Nephrology and Intensive Care, Charité Universitätsmedizin Berlin, Germany
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10
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Treatment of HEV Infection in Patients with a Solid-Organ Transplant and Chronic Hepatitis. Viruses 2016; 8:v8080222. [PMID: 27537905 PMCID: PMC4997584 DOI: 10.3390/v8080222] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 07/30/2016] [Accepted: 08/09/2016] [Indexed: 12/19/2022] Open
Abstract
Hepatitis E virus (HEV) infection can cause hepatic and extra-hepatic manifestations. Treatment of HEV infection has been thoroughly studied in solid-organ-transplant patients who have developed a chronic HEV infection. In this review, we report on our current knowledge regarding treatment of HEV infection.
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Kamar N, Marion O, Rostaing L, Cointault O, Ribes D, Lavayssière L, Esposito L, Del Bello A, Métivier S, Barange K, Izopet J, Alric L. Efficacy and Safety of Sofosbuvir-Based Antiviral Therapy to Treat Hepatitis C Virus Infection After Kidney Transplantation. Am J Transplant 2016; 16:1474-9. [PMID: 26587971 DOI: 10.1111/ajt.13518] [Citation(s) in RCA: 165] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Revised: 08/11/2015] [Accepted: 08/30/2015] [Indexed: 01/25/2023]
Abstract
There is no approved therapy for hepatitis C virus (HCV) infection after kidney transplantation, and no data regarding the use of new-generation direct antiviral agents (DAAs) have been published so far. The aims of this pilot study were to assess the efficacy and safety of an interferon-free sofosbuvir-based regimen to treat chronic HCV infection in kidney transplant recipients. Twenty-five kidney transplant recipients with chronic HCV infection were given, for 12 (n = 19) or 24 weeks (n = 6), sofosbuvir plus ribavirin (n = 3); sofosbuvir plus daclatasvir (n = 4); sofosbuvir plus simeprevir, with (n = 1) or without ribavirin (n = 6); sofosbuvir plus ledipasvir, with (n = 1) or without ribavirin (n = 9); and sofosbuvir plus pegylated-interferon plus ribavirin (n = 1). A rapid virological response, defined by undetectable viremia at week 4 after starting DAA therapy, was observed in 22 of the 25 patients (88%). At the end of therapy, HCV RNA was undetectable in all patients. At 4 and 12 weeks after completing DAA therapy, all had a sustained virological response. The tolerance to anti-HCV therapy was excellent and no adverse event was observed. A significant decrease in calcineurin inhibitor levels was observed after HCV clearance. New-generation oral DAAs are efficient and safe to treat HCV infection after kidney transplantation.
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Affiliation(s)
- N Kamar
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France.,INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France.,Université Paul Sabatier, Toulouse, France
| | - O Marion
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - L Rostaing
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France.,INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France.,Université Paul Sabatier, Toulouse, France
| | - O Cointault
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - D Ribes
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - L Lavayssière
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - L Esposito
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - A Del Bello
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - S Métivier
- Department of Hepatology and Gastroenterology, Toulouse, France
| | - K Barange
- Department of Hepatology and Gastroenterology, Toulouse, France
| | - J Izopet
- INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France.,Université Paul Sabatier, Toulouse, France.,Laboratory of Virology, CHU Purpan, Toulouse, France
| | - L Alric
- Université Paul Sabatier, Toulouse, France.,MR 152 IRD-Toulouse 3 University, Toulouse, France.,Internal Medicine-Digestive Department, CHU Purpan, Toulouse, France
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Kamar N, Lhomme S, Abravanel F, Cointault O, Esposito L, Cardeau-Desangles I, Del Bello A, Dörr G, Lavayssière L, Nogier MB, Guitard J, Ribes D, Goin AL, Broué P, Metsu D, Sauné K, Rostaing L, Izopet J. An Early Viral Response Predicts the Virological Response to Ribavirin in Hepatitis E Virus Organ Transplant Patients. Transplantation 2016. [PMID: 26214817 DOI: 10.1097/tp.0000000000000850] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND Ribavirin is efficient at treating chronic hepatitis E virus infection in solid-organ transplant patients. However, the early kinetics of viral replication under therapy and the impact of immunosuppressant regimens on viral replication are unknown: thus, determining the aim of our study. METHODS Thirty-five patients with a solid-organ transplant and chronic hepatitis E virus infection were given ribavirin for 3 months. The hepatitis E virus (HEV) RNA concentrations were determined before treatment, at days 7, 15, and 21 and at months 1, 2, and 3 during therapy and after ribavirin cessation. RESULTS A sustained virological response (SVR) occurred in 63%. Decreased viral concentration within the first week post-ribavirin therapy was an independent predictive factor for SVR, and a decreased HEV concentration of 0.5 log copies/mL or greater had an 88% positive predictive value. No correlation between ribavirin trough level on day 7 or at month 2 with a virological response or an SVR was observed. Before therapy, HEV RNA concentration was significantly greater in patients receiving mechanistic target of rapamycin inhibitor-based immunosuppression compared to patients given calcineurin inhibitors. The use of mycophenolic acid did not impact on the response to ribavirin. CONCLUSION An early response to ribavirin can be used to define the optimal duration of therapy in the setting of HEV infection.
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Affiliation(s)
- Nassim Kamar
- 1 Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France. 2 INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France. 3 Université Paul Sabatier, Toulouse, France. 4 Laboratory of Virology, CHU Purpan, Toulouse, France. 5 Department of Thoracic Surgery and Lung Transplantation, CHU Rangueil-Larrey, Toulouse, France. 6 Pediatric Hepatology, Hôpital des enfants, Toulouse, France. 7 Laboratory of Toxicology, CHU Purpan, Toulouse, France
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Nemr N, Kishk R, Mandour M. Role of ITPA gene polymorphism in ribavirin-induced anemia and thrombocytopenia in Egyptian patients with chronic hepatitis C. Indian J Gastroenterol 2016; 35:7-13. [PMID: 26880169 DOI: 10.1007/s12664-016-0618-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Accepted: 01/10/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND Ribavirin (RBV)-induced anemia is one of the major causes of dose reduction and discontinuation of therapy for chronic hepatitis C (CHC) patients. We investigated the role of inosine triphosphate pyrophosphatase (ITPA) single nucleotide polymorphism (SNP) (rs1127354) in predicting RBV-induced anemia and thrombocytopenia among Egyptian patients with CHC genotype 4 infection. METHODS One hundred and twenty Egyptian patients with CHC genotype 4 who had received standard of care combination therapy were enrolled in this study. Single nucleotide polymorphism at ITPA (rs1127354) was genotyped by real-time detection polymerase chain reaction. RESULTS Hb levels between CC and non-CC groups were significantly different at weeks 4, 8, and 12. Hemoglobin decline was significantly higher among CC patient than non-CC patients at week 4 and week 8 of treatment. The RBV dose reduction was higher in CC than non-CC group. Platelet decline was significantly lower in CC patients than non-CC patients at baseline, 4, 12 weeks only. CONCLUSION Rs1127354 ITPA polymorphism was associated with RBV-induced anemia and thrombocytopenia in Egyptian patients with hepatitis C virus genotype 4 infection.
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Affiliation(s)
- Nader Nemr
- Department of Endemic and Infectious Diseases, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Rania Kishk
- Department of Microbiology and Immunology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
| | - Mohamed Mandour
- Department of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
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Hepatitis C virus infection in nonliver solid organ transplant candidates and recipients. Curr Opin Organ Transplant 2015; 20:259-66. [PMID: 25944237 DOI: 10.1097/mot.0000000000000195] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
PURPOSE OF REVIEW Transplantation is the best treatment for many patients with end-stage organ failure. Hepatitis C infection is prevalent among solid organ candidates and recipients and continues to represent a major source of morbidity and mortality. Prior interferon (IFN)-based therapies have been associated with limited efficacy and high rates of adverse events. Furthermore, prior IFN-based regimens are associated with high rates of allograft rejection limiting their use post-transplant. This review will outline the limited experience with current treatment regimens and how to incorporate the new hepatitis C virus (HCV) treatment regimens. RECENT FINDINGS The introduction of new direct-acting antiviral (DAA) agents against HCV has dramatically altered the landscape of treatment for HCV. Different all-oral regimens are currently available and are rapidly becoming the standard for treating patients with chronic hepatitis C. Excluding patients with liver disease or those who received liver transplant, those regimens have not been studied in patients awaiting solid organ transplant, or those transplanted. SUMMARY The safety and efficacy of DAAs in patients awaiting liver transplant and liver transplant recipients provide us with some insight and guidance on how to use those all-oral IFN-free regimens to allow effective treatment for patients who received or are awaiting nonliver solid organ transplants.
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15
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Balk JM, Haenen GR, Koc ÖM, Peters R, Bast A, van der Vijgh WJ, Koek GH. Once-daily dose regimen of ribavirin is interchangeable with a twice-daily dose regimen: randomized open clinical trial. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2015; 8:137-44. [PMID: 26445557 PMCID: PMC4593207 DOI: 10.2147/pgpm.s82782] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Background The combination of ribavirin (RBV) and pegylated interferon (PEG-IFN) is effective in the treatment of chronic hepatitis C infection. Reducing the frequency of RBV intake from twice to once a day will improve compliance and opens up the opportunity to combine RBV with new and more specific direct-acting agents in one pill. Therefore, the purpose of this study was to evaluate the pharmacokinetic profile of RBV in a once-daily to twice-daily regimen. The secondary aim was to determine tolerability as well as the severity and differences in side effects of both treatment regimens. Methods In this randomized open-label crossover study, twelve patients with chronic type 1 hepatitis C infection and weighing more than 75 kg were treated with 180 µg of PEG-IFN weekly and 1,200 mg RBV daily for 24 weeks. The patients received RBV dosed as 1,200 mg once-daily for 12 weeks followed by RBV dosed as 600 mg twice-daily for 12 weeks, or vice versa. In addition to the pharmacokinetic profile, the hematological profile and side effects were recorded. The RBV concentrations in plasma were determined using liquid chromatography-tandem mass spectrometry. Results Eight of twelve patients completed the study. Neither the time taken for RBV to reach peak plasma concentration nor the AUC0-last (adjusted for difference in dose) was significantly different between the two groups (P>0.05). Furthermore, the once-daily regimen did not give more side effects than the twice-daily regimen (P>0.05). No significant differences in the hematological profile were observed (P>0.05). Conclusion The standard twice-daily RBV regimen is interchangeable with the once-daily regimen. The once-daily regimen will improve compliance and opens the opportunity to combine RBV with other drugs dosed once a day, in a single pill.
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Affiliation(s)
- Jiska M Balk
- Department of Toxicology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Guido Rmm Haenen
- Department of Toxicology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Özgür M Koc
- Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands
| | | | - Aalt Bast
- Department of Toxicology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Wim Jf van der Vijgh
- Department of Toxicology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Ger H Koek
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, the Netherlands
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Boceprevir-Based Triple Antiviral Therapy for Chronic Hepatitis C Virus Infection in Kidney-Transplant Candidates. J Transplant 2015; 2015:159795. [PMID: 26257919 PMCID: PMC4519545 DOI: 10.1155/2015/159795] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Revised: 07/05/2015] [Accepted: 07/06/2015] [Indexed: 12/28/2022] Open
Abstract
Background. There are few data on the combination of (pegylated-) interferon- (Peg-IFN-) α, ribavirin, and first-generation direct-acting antiviral agents (DAAs). Our aim was to describe the efficacy and safety of Peg-IFN-α, ribavirin, and boceprevir in hemodialysis patients. Patients. Six hemodialysis patients, chronically infected by genotype-1 HCV, were given Peg-IFN-α (135 µg/week), ribavirin (200 mg/d), and boceprevir (2400 mg/d) for 48 weeks. Results. At initiation of antiviral therapy, median viral concentration was 5.68 (3.78–6.55) log IU/mL. HCV RNA was undetectable in four of the six patients at week 4 and in all patients at week 24. A breakthrough was observed in two patients between weeks 24 and 48, and a third patient stopped antiviral therapy between weeks 24 and 48 because of severe peripheral neuropathy. At week 48, HCV RNA was undetectable in three patients. Of these, two patients relapsed within a month after antiviral therapy was stopped. Hence, only one patient had a sustained virological response; he was a previous partial responder. Overall, anemia was the main side effect. Conclusion. A triple antiviral therapy based on Peg-IFN-α, ribavirin, and boceprevir is not optimal at treating hemodialysis patients with chronic HCV infection. Studies using new-generation drugs are required in this setting.
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Rower JE, Meissner EG, Jimmerson LC, Osinusi A, Sims Z, Petersen T, Bushman LR, Wolfe P, McHutchison JG, Kottilil S, Kiser JJ. Serum and cellular ribavirin pharmacokinetic and concentration-effect analysis in HCV patients receiving sofosbuvir plus ribavirin. J Antimicrob Chemother 2015; 70:2322-9. [PMID: 25971261 DOI: 10.1093/jac/dkv122] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Accepted: 04/10/2015] [Indexed: 12/25/2022] Open
Abstract
OBJECTIVES Ribavirin concentrations may impact hepatitis C virus (HCV) treatment outcome. We modelled ribavirin serum and intracellular ribavirin monophosphate (RBV-MP) and ribavirin triphosphate (RBV-TP) pharmacokinetics in red blood cells (RBC) using samples collected during the NIAID SPARE trial to explore associations with treatment outcome and the development of anaemia. PATIENTS AND METHODS Individuals infected with HCV genotype 1 (GT1) received 400 mg of sofosbuvir and either low-dose or weight-based ribavirin as part of the NIAID SPARE trial. Concentrations were modelled using NONMEM and associated with treatment outcomes using unpaired t-tests or Pearson's rho correlations. RESULTS Average day 14 RBV-MP concentrations were higher in subjects with haemoglobin nadir <10 g/dL relative to patients with haemoglobin nadir ≥10 g/dL (6.54 versus 4.48 pmol/10(6) cells; P = 0.02). Additionally, day 14 RBV-MP average concentrations trended towards being higher in subjects that achieved sustained virological response (SVR) as compared with patients who relapsed (4.97 versus 4.09 pmol/10(6) cells; P = 0.07). Receiver operating characteristic curves suggested day 14 RBV-MP concentration thresholds of 4.4 pmol/10(6) cells for SVR (P = 0.06) and 6.1 pmol/10(6) cells for haemoglobin nadir <10 versus ≥10 g/dL (P = 0.02), with sensitivity and specificity ≥60%. Dosing simulations showed that 800 mg of ribavirin once daily produced day 14 RBV-MP concentrations within the 4.4-6.1 pmol/10(6) cells range. CONCLUSIONS RBV-MP concentrations in RBC at day 14 were related to anaemia and SVR. A therapeutic range was identified for RBV-MP in persons with HCV GT1 disease receiving 24 weeks of sofosbuvir plus ribavirin, suggesting a potential pharmacological basis for individualized ribavirin dosing in IFN-free regimens.
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Affiliation(s)
- Joseph E Rower
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA
| | - Eric G Meissner
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, NIAID, Bethesda, MD, USA
| | - Leah C Jimmerson
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA
| | - Anu Osinusi
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, NIAID, Bethesda, MD, USA Gilead Sciences Inc., Foster City, CA, USA
| | - Zayani Sims
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, NIAID, Bethesda, MD, USA
| | - Tess Petersen
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, NIAID, Bethesda, MD, USA
| | - Lane R Bushman
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA
| | - Pamela Wolfe
- School of Public Health, University of Colorado, Aurora, CO, USA
| | | | - Shyamasundaran Kottilil
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, NIAID, Bethesda, MD, USA
| | - Jennifer J Kiser
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA
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Ahn SB, Jun DW, Kim SG, Lee SH, Shin HP, Choe WH, Kim JK, Jung KS, Kim DY, Shim JJ, Park SY, Seo YS, Kim W, Chung JI. Efficacy and safety of pegylated interferon base treatment in patients with chronic hepatitis C on dialysis. Eur J Intern Med 2015; 26:292-6. [PMID: 25877760 DOI: 10.1016/j.ejim.2015.03.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Revised: 03/07/2015] [Accepted: 03/28/2015] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Patients with chronic hepatitis C (CHC) and end-stage renal disease (ESRD) on dialysis are difficult to treat and show higher dropout rates during treatment. The aim of this study was to analyze the treatment outcomes in patients with CHC and underlying end-stage renal disease on dialysis in Korea. METHODS A retrospective multi-center study of 35 patients with CHC and underlying ESRD on regular dialysis from 13 centers were analyzed. We investigated the tolerability and efficacy of pegylated interferon therapy with or without ribavirin on dialysis patients. RESULTS Twenty patients (57%) were genotype 1. Sixteen patients (46%) were treated with pegylated interferon monotherapy. Nineteen patients (54%) were treated with pegylated interferon and ribavirin. The overall sustained virological response (SVR) rate was 65.7% in all subjects. Thirteen patients (37%) dropped out before completion of treatment, and six patients (46.2%) showed SVR despite premature termination of treatment. Twenty patients (90.9%) achieved SVR among the 22 patients who completed the scheduled course. The most common side effects were anemia and neutropenia. The patients receiving ribavirin treatment showed a higher dropout rate (52.6% vs. 18.8%, p=0.04) and higher SVR rate (68.4% vs. 62.5%, p=0.07) compared to the pegylated interferon mono-treatment group. CONCLUSIONS The difficulty in treating HCV patients with ESRD was attributed to higher dropout rate. However, despite the high dropout rate (37%), the SVR rate in genotype 1 was 65% and in genotypes 2 and 3 was 66%. Patients who completed the treatment showed a high SVR rate of 89.5%.
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Affiliation(s)
- Sang Bong Ahn
- Department of Internal Medicine, Eulji University College of Medicine, Republic of Korea
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University College of Medicine, Republic of Korea.
| | - Sang Gyune Kim
- Department of Internal Medicine, Soonchunhyang University, Bucheon Hospital, Republic of Korea
| | - Sae Hwan Lee
- Department of Internal Medicine, Soonchunhyang University, Bucheon Hospital, Republic of Korea
| | - Hyun Phil Shin
- Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Republic of Korea
| | - Won Hyeok Choe
- Department of Internal Medicine, Konkuk University School of Medicine, Republic of Korea
| | - Ja Kyung Kim
- Department of Internal Medicine, Yonsei University School of Medicine, Republic of Korea
| | - Kyu Sik Jung
- Department of Internal Medicine, Yonsei University School of Medicine, Republic of Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University School of Medicine, Republic of Korea
| | - Jae-Jun Shim
- Department of Internal Medicine, Kyung Hee University School of Medicine, Republic of Korea
| | - Soo Young Park
- Department of Internal Medicine, Kyungpook National University Hospital, Republic of Korea
| | - Yeon Seok Seo
- Department of Internal Medicine, Korea University School of Medicine, Republic of Korea
| | - Won Kim
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea
| | - Jae Il Chung
- Sahmyook Medical Center, Seoul, Republic of Korea
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Population pharmacokinetic modeling of plasma and intracellular ribavirin concentrations in patients with chronic hepatitis C virus infection. Antimicrob Agents Chemother 2015; 59:2179-88. [PMID: 25645847 DOI: 10.1128/aac.04618-14] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Ribavirin, a guanosine analog, is a broad-spectrum antiviral agent. Ribavirin has been a fundamental component of the treatment of hepatitis C virus (HCV) infection for decades, but there is a very limited understanding of the clinical pharmacology of this drug. Furthermore, it is associated with a major dose-limiting toxicity, hemolytic anemia. Ribavirin undergoes intracellular phosphorylation by host enzymes to ribavirin monophosphate (RMP), ribavirin diphosphate (RDP), and ribavirin triphosphate (RTP). The intracellular forms have been associated with antiviral and toxic effects in vitro, but the kinetics of these phosphorylated moieties have not been fully elucidated in vivo. We developed a model to characterize the plasma pharmacokinetics of ribavirin and the difference between intracellular phosphorylation kinetics in red cells (nonnucleated) and in peripheral blood mononuclear cells (nucleated). A time-independent two-compartment model with first-order absorption described the plasma data well. The cellular phosphorylation kinetics was described by a one-compartment model for RMP, with the formation rate driven by plasma concentrations and the first-order degradation rate. RDP and RTP rapidly reached equilibrium with RMP. Concomitant telaprevir use, inosine triphosphatase genetics, creatinine clearance, weight, and sex were significant covariates. The terminal ribavirin half-life in plasma and phosphorylated anabolites in cells was approximately 224 h. We found no evidence of time-dependent kinetics. These data provide a foundation for uncovering concentration-effect associations for ribavirin and determining the optimal dose and duration of this drug for use in combination with newer direct-acting HCV agents. (This study has been registered at ClinicalTrials.gov under registration no. NCT01097395.).
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Tamori A, Kioka K, Sakaguchi H, Enomoto M, Hai H, Kawamura E, Hagihara A, Fujii H, Uchida-Kobayashi S, Iwai S, Morikawa H, Murakami Y, Kawasaki Y, Tsuruta D, Kawada N. Effects on anemia of drug adjustment in patients with chronic hepatitis C during telaprevir-combined therapy. Ann Hepatol 2015; 14:28-35. [PMID: 25536639 DOI: 10.1016/s1665-2681(19)30798-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/29/2023]
Abstract
AIM Anemia is the most common adverse event in patients with chronic hepatitis C virus (HCV) treated with telaprevir (TVR) combined triple therapy. We examined the effects of drug dose adjustment on anemia and a sustained viral response (SVR) during combination therapy. MATERIAL AND METHODS This study enrolled 62 patients treated with TVR (2,250 mg) for 12 weeks plus pegylated interferon-alpha-2b and ribavirin for 24 weeks. The patients were assigned randomly to the TVR-standard or -reduced groups before treatment. At the occurrence of anemia (hemoglobin < 12 g/dL), the TVR-reduced group received 1500 mg TVR plus the standard dose of ribavirin, whereas the TVR-standard group received the standard TVR dose (2,250 mg) and a reduced dose of ribavirin (200 mg lower than prescribed originally). The safety and SVR at 24 weeks were compared between the TVR-standard (n = 28) and TVR-reduced (n = 25) groups. RESULTS No differences in the proportion of patients who became HCV RNA-negative were detected between the TVR-standard and -reduced groups (72 and 72% at week 4, 79 and 84% at the end of treatment, and 76 and 80% at SVR24, respectively). Two groups had comparable numbers of adverse events, which led to the discontinuation of TVR in 14 patients of TVR-standard group and in 14 of TVR-reduced group. A lower incidence of renal impairment was observed in the TVR-reduced group (6%) than the TVR-standard group (11%, not statistically significant). CONCLUSIONS TVR dose adjustment could prevent anemia progression without weakening the anti-viral effect during triple therapy in HCV-patients.
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Affiliation(s)
- Akihiro Tamori
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Kiyohide Kioka
- Department of Hepatology Osaka City General Hospital, Osaka Japan
| | | | - Masaru Enomoto
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hoang Hai
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Etsushi Kawamura
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Atsushi Hagihara
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hideki Fujii
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | | | - Shuji Iwai
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hiroyasu Morikawa
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yoshiki Murakami
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yasuko Kawasaki
- Department of Hepatology Osaka City General Hospital, Osaka Japan
| | - Daisuke Tsuruta
- Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Norifumi Kawada
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
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Abravanel F, Lhomme S, Rostaing L, Kamar N, Izopet J. Protracted fecal shedding of HEV during ribavirin therapy predicts treatment relapse. Clin Infect Dis 2014; 60:96-9. [PMID: 25249523 DOI: 10.1093/cid/ciu742] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Twenty-four solid-organ-transplant recipients with chronic hepatitis E virus (HEV) infections were given ribavirin therapy for 3 months. All the patients with protracted fecal HEV shedding during treatment suffered a relapse. Monitoring HEV fecal excretion could be used to determine the optimal duration of ribavirin therapy.
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Affiliation(s)
- Florence Abravanel
- INSERM, U1043, Centre de Physiopathologie de Toulouse Purpan CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, Centre National de Référence Hépatite E, Institut fédératif de biologie de Purpan
| | - Sébastien Lhomme
- INSERM, U1043, Centre de Physiopathologie de Toulouse Purpan CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, Centre National de Référence Hépatite E, Institut fédératif de biologie de Purpan
| | - Lionel Rostaing
- INSERM, U1043, Centre de Physiopathologie de Toulouse Purpan CHU Toulouse, Hôpital Rangueil, Service de Néphrologie, Dialyse et Transplantation multi-organe, France
| | - Nassim Kamar
- INSERM, U1043, Centre de Physiopathologie de Toulouse Purpan CHU Toulouse, Hôpital Rangueil, Service de Néphrologie, Dialyse et Transplantation multi-organe, France
| | - Jacques Izopet
- INSERM, U1043, Centre de Physiopathologie de Toulouse Purpan CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, Centre National de Référence Hépatite E, Institut fédératif de biologie de Purpan
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Karino Y, Ozeki I, Hige S, Kimura M, Arakawa T, Nakajima T, Kuwata Y, Sato T, Ohmura T, Toyota J. Telaprevir impairs renal function and increases blood ribavirin concentration during telaprevir/pegylated interferon/ribavirin therapy for chronic hepatitis C. J Viral Hepat 2014; 21:341-7. [PMID: 24001168 PMCID: PMC4282353 DOI: 10.1111/jvh.12162] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Accepted: 07/10/2013] [Indexed: 12/11/2022]
Abstract
We aimed to examine the relationship between renal dysfunction and anaemia that may develop during combination therapy involving pegylated interferon, ribavirin and telaprevir (PEG-IFN/RBV/TVR) for the treatment of chronic hepatitis C. Sixty-eight patients with genotype 1b high viral loads were treated with PEG-IFN/RBV/TVR. Peg-IFN and RBV doses were administered according to body weight. TVR was prescribed at 2250 mg/day for 44 patients and at 1500 mg/day for 24 patients who had low haemoglobin level (<12 g/dL). When anaemia had developed, the RBV dose was decreased. The serum TVR concentration at day 8 was measured, and the serum RBV concentration was measured serially. The estimated glomerular filtration rate (eGFR) was estimated to assess renal function. At week 1, serum TVR concentration was not correlated with a decrease in eGFR; however, the TVR dose, on a weight basis (mg/kg), and eGFR were correlated (r = 0.2691; P = 0.0265). Moreover, there was a negative correlation between eGFR and RBV serum concentration (r = −0.3694; P = 0.0025), and the serum RBV concentration and decrease in the haemoglobin were significantly correlated from week 1 to week 8. In triple therapy, the TVR dose per weight is correlated with a decline in renal function. Thus, the serum concentration of RBV increases, with a concomitant decrease in haemoglobin. It is important to adjust the doses of TVR and RBV to avoid excessive serum RBV levels and the development of severe anaemia, to achieve a good clinical effect.
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Affiliation(s)
- Y Karino
- Department of Hepatology, Sapporo Kosei General HospitalSapporo, Japan
| | - I Ozeki
- Department of Hepatology, Sapporo Kosei General HospitalSapporo, Japan
| | - S Hige
- Department of Hepatology, Sapporo Kosei General HospitalSapporo, Japan
| | - M Kimura
- Department of Hepatology, Sapporo Kosei General HospitalSapporo, Japan
| | - T Arakawa
- Department of Hepatology, Sapporo Kosei General HospitalSapporo, Japan
| | - T Nakajima
- Department of Hepatology, Sapporo Kosei General HospitalSapporo, Japan
| | - Y Kuwata
- Department of Hepatology, Sapporo Kosei General HospitalSapporo, Japan
| | - T Sato
- Department of Hepatology, Sapporo Kosei General HospitalSapporo, Japan
| | - T Ohmura
- Department of Hepatology, Sapporo Kosei General HospitalSapporo, Japan
| | - J Toyota
- Department of Hepatology, Sapporo Kosei General HospitalSapporo, Japan
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Kamar N, Izopet J, Tripon S, Bismuth M, Hillaire S, Dumortier J, Radenne S, Coilly A, Garrigue V, D'Alteroche L, Buchler M, Couzi L, Lebray P, Dharancy S, Minello A, Hourmant M, Roque-Afonso AM, Abravanel F, Pol S, Rostaing L, Mallet V. Ribavirin for chronic hepatitis E virus infection in transplant recipients. N Engl J Med 2014; 370:1111-20. [PMID: 24645943 DOI: 10.1056/nejmoa1215246] [Citation(s) in RCA: 366] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND There is no established therapy for hepatitis E virus (HEV) infection. The aim of this retrospective, multicenter case series was to assess the effects of ribavirin as monotherapy for solid-organ transplant recipients with prolonged HEV viremia. METHODS We examined the records of 59 patients who had received a solid-organ transplant (37 kidney-transplant recipients, 10 liver-transplant recipients, 5 heart-transplant recipients, 5 kidney and pancreas-transplant recipients, and 2 lung-transplant recipients). Ribavirin therapy was initiated a median of 9 months (range, 1 to 82) after the diagnosis of HEV infection at a median dose of 600 mg per day (range, 29 to 1200), which was equivalent to 8.1 mg per kilogram of body weight per day (range, 0.6 to 16.3). Patients received ribavirin for a median of 3 months (range, 1 to 18); 66% of the patients received ribavirin for 3 months or less. RESULTS All the patients had HEV viremia when ribavirin was initiated (all 54 in whom genotyping was performed had HEV genotype 3). At the end of therapy, HEV clearance was observed in 95% of the patients. A recurrence of HEV replication occurred in 10 patients after ribavirin was stopped. A sustained virologic response, defined as an undetectable serum HEV RNA level at least 6 months after cessation of ribavirin therapy, occurred in 46 of the 59 patients (78%). A sustained virologic response was also observed in 4 patients who had a recurrence and were re-treated for a longer period. A higher lymphocyte count when ribavirin therapy was initiated was associated with a greater likelihood of a sustained virologic response. Anemia was the main identified side effect and required a reduction in ribavirin dose in 29% of the patients, the use of erythropoietin in 54%, and blood transfusions in 12%. CONCLUSIONS This retrospective, multicenter study showed that ribavirin as monotherapy may be effective in the treatment of chronic HEV infection; a 3-month course seemed to be an appropriate duration of therapy for most patients.
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Affiliation(s)
- Nassim Kamar
- The authors' affiliations are listed in the Appendix
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Rostaing L, Izopet J, Kamar N. Hepatitis C virus infection in nephrology patients. J Nephropathol 2013; 2:217-33. [PMID: 24475454 PMCID: PMC3891131 DOI: 10.12860/jnp.2013.36] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2012] [Accepted: 12/29/2012] [Indexed: 12/19/2022] Open
Abstract
CONTEXT Hepatitis C virus (HCV) infection leads to chronic liver disease, but also to extra-hepatic manifestations. EVIDENCE ACQUISITIONS Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO) and Web of Science have been searched. RESULTS Herein, we provide an overview of renal diseases related to HCV and their therapies, as well as the treatment options available for HCV (+)/RNA (+) dialysis patients. We will not mention, however, HCV infection-related complications in the post-kidney transplantation setting. CONCLUSIONS Extra-hepatic manifestations of HCV infection include mixed cryoglobulinemia, lymphoproliferative disorders, and renal disease. HCV infection has been reported in association with distinct histological patterns of glomerulonephritis in native kidneys.
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Affiliation(s)
- Lionel Rostaing
- Department of Nephrology, Dialysis and Organ Transplantation, CHU Rangueil, Toulouse, France
- INSERM U1043, IFR–BMT, CHU Purpan, Toulouse, France
- Université Paul Sabatier, Toulouse, France
| | - Jacques Izopet
- INSERM U1043, IFR–BMT, CHU Purpan, Toulouse, France
- Université Paul Sabatier, Toulouse, France
- Department of Virology, CHU Purpan, Toulouse, France
| | - Nassim Kamar
- Department of Nephrology, Dialysis and Organ Transplantation, CHU Rangueil, Toulouse, France
- INSERM U1043, IFR–BMT, CHU Purpan, Toulouse, France
- Université Paul Sabatier, Toulouse, France
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Vallet-Pichard A, Pol S. Hepatitis C virus infection in hemodialysis patients. Clin Res Hepatol Gastroenterol 2013; 37:340-6. [PMID: 23933193 DOI: 10.1016/j.clinre.2013.03.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Revised: 02/27/2013] [Accepted: 03/13/2013] [Indexed: 02/04/2023]
Abstract
Hepatitis C virus (HCV) infection is observed in around 20% of dialysis patients and in allograft recipients and results in a significant morbidity and mortality, especially after transplantation. Its prevalence has markedly decreased in patients who are candidates for transplantation since the introduction of screening, hygiene and prevention measures, including systematic screening of blood and organ donations, use of erythropoietin, and compliance with universal hygiene rules. A liver biopsy is preferable to non-invasive biochemical and/or morphological tests of fibrosis to evaluate liver fibrosis before and even after transplantation. In HCV-infected dialyzed patients who are not candidates for renal transplantation, the indication for antiviral therapy is limited to significant fibrosis (fibrosis ≥ 2 on the METAVIR scale). Antiviral treatment should be proposed to any HCV-infected candidate for renal transplantation, whatever the baseline histopathology. The recommendation is to use standard interferon-α as monotherapy, but pegylated interferon can be used, resulting in sustained virological response, while low doses of combined ribavirin may enhance the antiviral efficacy. After transplantation, interferon-α is contra-indicated but may be used in patients for whom the benefits of antiviral treatment clearly outweigh the risks, especially that of allograft rejection. All cirrhotic patients should be screened for hepatocellular carcinoma, whose risk is enhanced by immunosuppressive regimens. Sustained suppression of necro-inflammation may result in the reversal of cirrhosis, which reduces liver-related morbidity and improves patient and allograft survival. Finally, due to the high mortality after renal transplantation, active cirrhosis must be considered to be a contraindication to kidney transplantation, but an indication to combined liver-kidney transplantation; on the contrary, inactive compensated cirrhosis may permit renal transplantation alone.
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Tsubota A, Shimada N, Abe H, Yoshizawa K, Agata R, Yumoto Y, Ika M, Namiki Y, Nagatsuma K, Matsudaira H, Fujise K, Tada N, Aizawa Y. Several factors including ITPA polymorphism influence ribavirin-induced anemia in chronic hepatitis C. World J Gastroenterol 2012; 18:5879-5888. [PMID: 23139603 PMCID: PMC3491594 DOI: 10.3748/wjg.v18.i41.5879] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2012] [Revised: 05/28/2012] [Accepted: 06/28/2012] [Indexed: 02/06/2023] Open
Abstract
AIM To construct formulae for predicting the likelihood of ribavirin-induced anemia in pegylated interferon α plus ribavirin for chronic hepatitis C. METHODS Five hundred and sixty-one Japanese patients with hepatitis C virus genotype 1b who had received combination treatment were enrolled and assigned randomly to the derivation and confirmatory groups. Single nucleotide polymorphisms at or nearby ITPA were genotyped by real-time detection polymerase chain reaction. Factors influencing significant anemia (hemoglobin concentration < 10.0 g/dL at week 4 of treatment) and significant hemoglobin decline (declining concentrations > 3.0 g/dL at week 4) were analyzed using multiple regression analyses. Prediction formulae were constructed by significantly independent factors. RESULTS Multivariate analysis for the derivation group identified four independent factors associated with significant hemoglobin decline: hemoglobin decline at week 2 [P = 3.29 × 10(-17), odds ratio (OR) = 7.54 (g/dL)], estimated glomerular filtration rate [P = 2.16 × 10(-4), OR = 0.962 (mL/min/1.73 m(2))], rs1127354 (P = 5.75 × 10(-4), OR = 10.94) and baseline hemoglobin [P = 7.86 × 10(-4), OR = 1.50 (g/dL)]. Using the model constructed by these factors, positive and negative predictive values and predictive accuracy were 79.8%, 88.8% and 86.2%, respectively. For the confirmatory group, they were 83.3%, 91.0% and 88.3%. These factors were closely correlated with significant anemia. However, the model could not be constructed, because no patients with rs1127354 minor genotype CA/AA had significant anemia. CONCLUSION Reliable formulae for predicting the likelihood of ribavirin-induced anemia were constructed. Such modeling may be useful in developing individual tailoring and optimization of ribavirin dosage.
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Jin R, Fossler MJ, McHutchison JG, Howell CD, Dowling TC. Population pharmacokinetics and pharmacodynamics of ribavirin in patients with chronic hepatitis C genotype 1 infection. AAPS JOURNAL 2012; 14:571-80. [PMID: 22639111 DOI: 10.1208/s12248-012-9368-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/06/2012] [Accepted: 05/04/2012] [Indexed: 12/13/2022]
Abstract
We report a population pharmacokinetic (PK) and pharmacodynamic (PD) model of orally administered ribavirin in patients with chronic hepatitis C virus (HCV) infection enrolled in a multicenter clinical trial, including the estimation of covariate effects on ribavirin PK parameters and sustained viral response (SVR). Ribavirin concentrations obtained from 144 patients, consisting of n = 71 African American (AA) and n = 73 Caucasian Americans (CA), during 24 weeks of therapy were best described by a two-compartment model with first-order absorption and elimination parameterized in terms of apparent oral clearance (CL/F), apparent central volume (Vc/F), apparent peripheral volume (Vp/F), and apparent intercompartmental clearance (Q/F). The typical population parameters were CL/F (19.0 L/h), Vc/F (1,130 L), Vp/F (4,020 L), and Q/F (38.6). The Vp/F was approximately 50% greater in AA compared to CA. Significant covariates in the SVR model included IL-28B genotype, homeostasis model assessment of insulin resistance, and ribavirin exposure during the first week (AUC(0-7)). The population PK and logistic regression models both described the observed ribavirin concentration data and SVR data well. These findings suggest that optimization of ribavirin plasma concentrations during the first week of ribavirin dosing is most critical in AA patients in order to increase the rate of SVR, especially those with the IL-28B TT genotype.
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Affiliation(s)
- Runyan Jin
- School of Pharmacy, University of Maryland, Baltimore, 21201, USA
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29
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Nicot F, Alric L, Barange K, Métivier S, Dramard JM, Combis JM, Castan B, Meurisse JJ, Payen JL, Garipuy D, Desmorat H, Peron JM, Thebault S, Morin T, Renou C, Barel P, Guerin B, Imbert Y, Sire S, Sauné K, Chatelut E, Izopet J. Influence of HCV genotype 1 subtypes on the virus response to PEG interferon alpha-2a plus ribavirin therapy. J Med Virol 2011; 83:437-44. [PMID: 21264864 DOI: 10.1002/jmv.21976] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
New factors that influence the viral response in HCV non-genotype 2/3 patients must be identified in order to optimize anti-HCV treatment. This multicenter prospective study evaluates the influence of HCV variability and pharmacological parameters on the virological response of these patients to pegylated interferon α2a (peg-IFN-α2a: 180 µg/week) and ribavirin (RBV; 800-1,200 mg/day) for 48 weeks. HCV subtypes were identified by sequencing the NS5B region. Serum RBV and peg-IFN-α2a concentrations were measured at weeks 4 and 12. The 115 patients (67 men; median age = 49, range 31-76) included 64 who had never been treated and 27 co-infected with HIV. The mean baseline HCV RNA was 6.30 ± 0.06 log IU/ml and the HCV genotypes were: G1 (n = 93) with 1a (n = 37) and 1b (n = 50), G4 (n = 20) and G5 (n = 2). Most patients (79/108; 73%) had an early virological response. Independent predictors of an early virological response were interferon naive patients (OR= 2.98, 95% CI: 1.15-7.72) and RBV of >2,200 ng/ml at week 12 (OR = 3.41, 95% CI: 1.31-8.90). Forty of 104 patients (38%) had a sustained virological response. The only independent predictors of a sustained virological response were subtype 1b (OR = 6.82, 95% CI: 1.7-26.8), and HCV RNA <15 IU/ml at week 12 (OR = 25, 95% CI: 6.4-97.6). Thus a serum RBV concentration of >2,200 ng/ml was associated with an early virological response and patients infected with HCV subtype 1b had a better chance of a sustained virological response than did those infected with subtype 1a.
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Affiliation(s)
- F Nicot
- CHU Toulouse, IFB Purpan, Laboratoire de Virologie, Toulouse, France
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Hiramatsu N, Kurosaki M, Sakamoto N, Iwasaki M, Sakamoto M, Suzuki Y, Sugauchi F, Tamori A, Kakinnuma S, Matsuura K, Izumi N. Pretreatment prediction of anemia progression by pegylated interferon alpha-2b plus ribavirin combination therapy in chronic hepatitis C infection: decision-tree analysis. J Gastroenterol 2011; 46:1111-1119. [PMID: 21681410 DOI: 10.1007/s00535-011-0412-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2011] [Accepted: 04/02/2011] [Indexed: 02/04/2023]
Abstract
BACKGROUND This study aimed to develop a model to predict the development of severe anemia during pegylated interferon alpha-2b plus ribavirin combination therapy. METHODS Data were collected from 1081 genotype 1b chronic hepatitis C patients who were treated at 6 hospitals in Japan. These patients were randomly assigned to a model-building group (n = 691) or an internal validation group (n = 390). Factors predictive of severe anemia (hemoglobin, Hb < 8.5 g/dl) were explored using data-mining analysis. RESULTS Hb values at baseline, creatinine clearance (Ccr), and an Hb concentration decline by 2 g/dl at week 2 were used to build a decision-tree model, in which the patients were divided into 5 subgroups based on variable rates of severe anemia ranging from 0.4 to 11.8%. The reproducibility of the model was confirmed by the internal validation group (r² = 0.96). The probability of severe anemia was high in patients whose Hb value was <14 g/dl before treatment (6.5%), especially (a) in those whose Ccr was <80 ml/min (11.8%) and (b) those whose Ccr was ≥ 80 ml/min but whose Hb concentration decline at week 2 was ≥ 2 g/dl (11.5%). The probability of severe anemia was low in the other patients (0.4-2.5%). CONCLUSIONS The decision-tree model that included Hb values at baseline, Ccr, and an Hb concentration decline by 2 g/dl at week 2 was useful for predicting the probability of severe anemia, and has the potential to support clinical decisions regarding early dose reduction of ribavirin.
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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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Vallet-Pichard A, Fontaine H, Mallet V, Pol S. Viral hepatitis in solid organ transplantation other than liver. J Hepatol 2011; 55:474-82. [PMID: 21241754 DOI: 10.1016/j.jhep.2011.01.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2010] [Revised: 12/27/2010] [Accepted: 01/05/2011] [Indexed: 12/15/2022]
Abstract
Transplantation is the best treatment for end-stage organ failure. Hepatitis virus infections, mainly hepatitis B virus (HBV) and hepatitis C virus (HCV) infections still constitute a major problem because they are common in allograft recipients and are a significant cause of morbidity and mortality after transplantation. Recently, hepatitis E virus infection has been added as an emergent cause of chronic hepatitis in organ transplantation. The prevalence of HBV and HCV infections has markedly decreased in patients who are candidates for transplantation since the introduction of screening, hygiene and prevention measures, including systematic screening of blood and organ donations, use of erythropoietin, compliance with universal hygiene rules, segregation of HBV-infected patients from non-infected patients and systematic vaccination against HBV. A liver biopsy is preferable to non-invasive biochemical and/or morphological tests of fibrosis to evaluate liver fibrosis before and even after transplantation. Treatment with entecavir or tenofovir is indicated in HBV-infected dialyzed patients who have moderate or severe disease (≥A2 or F2 on the Metavir scale) in preparation for renal transplantation. Due to the risks of severe reactivation, fibrosing cholestatic hepatitis or histological deterioration after transplantation, systematic use of nucleoside or nucleotide analogues shortly before or at the time of transplantation is recommended (tenofovir or entecavir are preferable to lamivudine) in all patients, whatever the baseline histological evaluation. In HCV-infected dialyzed patients who are not candidates for renal transplantation, the indication for antiviral therapy is limited to significant fibrosis (fibrosis ≥2 on the Metavir scale). Treatment must be proposed to all candidates for renal transplantation, whatever their baseline histopathology, and interferon-α should be used as monotherapy. After transplantation, interferon-α is contraindicated but may be used in patients for whom the benefits of antiviral treatment clearly outweigh the risks, especially that of allograft rejection. All cirrhotic patients, notably after solid organ transplantation, should be screened for hepatocellular carcinoma. Sustained suppression of necro-inflammation may result in regression of cirrhosis, which in turn may lead to decreased disease-related morbidity and improved survival. Finally, due to the high mortality after renal transplantation, active (namely without sustained viral suppression) cirrhosis should be considered a contraindication to kidney transplantation, but an indication to combined liver-kidney transplantation; on the contrary, inactive (namely with sustained viral suppression) compensated cirrhosis may permit renal transplantation alone. Organ transplantations other than kidney (cardiac or pulmonary transplantations) involve the same diagnosis and therapeutic issues.
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Melia MT, Muir AJ, McCone J, Shiffman ML, King JW, Herrine SK, Galler GW, Bloomer JR, Nunes FA, Brown KA, Mullen KD, Ravendhran N, Ghalib RH, Boparai N, Jiang R, Noviello S, Brass CA, Albrecht JK, McHutchison JG, Sulkowski MS. Racial differences in hepatitis C treatment eligibility. Hepatology 2011; 54:70-8. [PMID: 21488082 PMCID: PMC3736356 DOI: 10.1002/hep.24358] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
UNLABELLED Black Americans are disproportionally infected with hepatitis C virus (HCV) and are less likely than whites to respond to treatment with peginterferon (PEG-IFN) plus ribavirin (RBV). The impact of race on HCV treatment eligibility is unknown. We therefore performed a retrospective analysis of a phase 3B multicenter clinical trial conducted at 118 United States community and academic medical centers to evaluate the rates of and reasons for HCV treatment ineligibility according to self-reported race. In all, 4,469 patients were screened, of whom 1,038 (23.2%) were treatment ineligible. Although blacks represented 19% of treated patients, they were more likely not to be treated due to ineligibility and/or failure to complete required evaluations (40.2%) than were nonblack patients (28.5%; P < 0.001). After the exclusion of persons not treated due to undetectable HCV RNA or nongenotype 1 infection, blacks were 65% less likely than nonblacks to be eligible for treatment (28.1% > 17.0%; relative risk, 1.65; 95% confidence interval, 1.46-1.87; P < 0.001). Blacks were more likely to be ineligible due to neutropenia (14% versus 3%, P < 0.001), anemia (7% versus 4%, P = 0.02), elevated glucose (8% versus 3%, P < 0.001), and elevated creatinine (5% versus 1%, P < 0.001). CONCLUSION Largely due to a higher prevalence of neutropenia and uncontrolled medical conditions, blacks were significantly less likely to be eligible for HCV treatment. Increased access to treatment may be facilitated by less conservative neutrophil requirements and more effective care for chronic diseases, namely, diabetes and renal insufficiency.
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Affiliation(s)
- Michael T Melia
- Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
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Kohno H, Kouno H, Aimitsu S, Aisaka Y, Kitamoto M, Kawakami H, Chayama K. Impact of ribavirin dose reduction on the efficacy of pegylated interferon plus ribavirin combination therapy for elderly patients infected with genotype 1b and high viral loads. Hepatol Res 2011; 41:626-34. [PMID: 21711421 DOI: 10.1111/j.1872-034x.2011.00811.x] [Citation(s) in RCA: 2] [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 To examine the impact of ribavirin dose reduction on the efficacy of pegylated interferon (PEG IFN) plus ribavirin combination therapy for elderly patients infected with genotype 1b and high viral loads. METHODS A total of 72 patients, over 65 years old, were recruited for this study. Patients were divided into groups receiving either 600-800 mg of ribavirin according to bodyweight (Group 1, n = 36) or 400 mg of ribavirin (Group 2, n = 36) plus 1.5 µg/kg (range: 1.3-2.0 µg/kg) of PEG IFN-α-2b for 48 weeks. RESULTS Total ribavirin doses were administrated at 9.80 ± 2.39 mg/kg per day (3.29 ± 0.80 g/kg) for Group 1 and 5.87 ± 1.82 mg/kg per day (1.97 ± 0.61 g/kg) for Group 2 (P < 0.001). According to the total clearance (CL/F) of ribavirin, 34 of 36 patients in Group 1 received over-doses of ribavirin. In contrast, numbers of those receiving equivalent doses of ribavirin were two of 36 patients in Group 1 and 36 of 36 patients in Group 2, respectively (P < 0.001). End-of-treatment response (ETR) rates were observed in 23 of 36 patients (63.9%) in the standard ribavirin dose protocol and in 23 of 36 patients (63.9%) in the reduction ribavirin dose protocol (NS). Sustained virological response (SVR) rates were observed in 11 of 36 patients (30.6%) in the standard ribavirin dose protocol, and in 13 of 36 patients (36.1%) in the reduced ribavirin dose protocol (NS). CONCLUSION Reduction of ribavirin doses for elderly patients did not affect the outcome for the 48-week combination therapy.
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Affiliation(s)
- Hiroshi Kohno
- Department of Gastroenterology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure Department of Hepatology, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital Department of Gastroenterology, Hiroshima Prefectural Hospital Hiroshima IFN Study Group Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan
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Rostaing L, Kamar N. Hepatitis C virus infection in nephrology patients. ALEXANDRIA JOURNAL OF MEDICINE 2011. [DOI: 10.1016/j.ajme.2011.06.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/17/2022] Open
Affiliation(s)
- Lionel Rostaing
- Department of Nephrology Dialysis and Organ Transplantation CHU Rangueil Toulouse University Hospital France
| | - Nassim Kamar
- Department of Nephrology Dialysis and Organ Transplantation CHU Rangueil Toulouse University Hospital France
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Ponziani FR, Gasbarrini A, Pompili M, Burra P, Fagiuoli S. Management of hepatitis C virus infection recurrence after liver transplantation: an overview. Transplant Proc 2011; 43:291-5. [PMID: 21335208 DOI: 10.1016/j.transproceed.2010.09.102] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hepatitis C virus (HCV) infection is the major indication for liver transplantation worldwide. Its recurrence is virtually universal. Once reinfection is established, progression to cirrhosis occurs in 25%-30% of recipients within 5 years. Several studies have attempted to identify the ideal antiviral treatment for liver transplant recipients. At present, the management of recurrent HCV infection in liver transplant recipients is based on widely accepted indications, which represent a reliable guide to identify the "ideal" candidate for therapy, when therapy should be started, and what is to be expected in terms of side effects and response to treatment.
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Affiliation(s)
- F R Ponziani
- Department of Internal Medicine, Catholic University, Rome, Italy.
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36
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Brochot E, Castelain S, Duverlie G, Capron D, Nguyen-Khac E, François C. Ribavirin monitoring in chronic hepatitis C therapy: anaemia versus efficacy. Antivir Ther 2010; 15:687-95. [PMID: 20710050 DOI: 10.3851/imp1609] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The standard treatment of HCV infection with pegylated interferon-alpha2a or -alpha2b and ribavirin is effective in <50% of HCV genotype-1-infected patients. To improve this figure, it might be desirable to obtain optimal plasma concentrations of the drug by increasing the dose. Unfortunately, there is great interpatient variability in ribavirin pharmacokinetics. In the present review, we describe the mechanism of ribavirin-induced anaemia in detail, evaluate host predictive factors for this harmful side effect and assess the literature data on attempts to improve the sustained virological response rate by increasing the dose of ribavirin. We suggest an optimal steady-state concentration range for ribavirin in monoinfected and coinfected patients. Lastly, we propose that it would be of particular value to monitor ribavirin concentrations in HCV genotype-1-infected patients and (regardless of the genotype) coinfected patients, haemodialyzed patients and obese patients.
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Affiliation(s)
- Etienne Brochot
- Virology Department, Amiens University Medical Center, France
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37
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Kamar N, Rostaing L, Abravanel F, Garrouste C, Lhomme S, Esposito L, Basse G, Cointault O, Ribes D, Nogier MB, Alric L, Peron JM, Izopet J. Ribavirin therapy inhibits viral replication on patients with chronic hepatitis e virus infection. Gastroenterology 2010; 139:1612-8. [PMID: 20708006 DOI: 10.1053/j.gastro.2010.08.002] [Citation(s) in RCA: 225] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2010] [Revised: 07/27/2010] [Accepted: 08/04/2010] [Indexed: 12/27/2022]
Abstract
BACKGROUND & AIMS Hepatitis E virus (HEV) infection can evolve to chronic hepatitis in immunocompromised patients. Pegylated α-interferon can effectively treat chronic HEV infection after liver transplantation but is contraindicated for kidney transplantation. We assessed the antiviral effect of ribavirin monotherapy in patients with chronic HEV infection following kidney transplantation. METHODS In a pilot study performed at Toulouse University Hospital, 6 patients that received kidney transplants who were positive for HEV RNA (infected with HEV for 36.5 months; [range, 11-46 months]) were given ribavirin monotherapy for 3 months. Ribavirin was given at 600-800 mg/day in 2 separate doses, based on the patient's ability to clear creatinine. RESULTS Median serum concentration of HEV RNA at baseline was 5.77 log copies/mL (range, 4.35-7.35 log copies/mL). Three months after ribavirin therapy commenced, HEV RNA was undetectable in serum samples from all patients. A sustained virologic response was observed in 4 patients; the other 2 patients relapsed at 1 and 2 months after ribavirin therapy ended. At the end of the study, all patients had normal levels of alanine and aspartate aminotransferase. Anemia was the main side effect caused by ribavirin therapy. CONCLUSIONS Ribavirin monotherapy inhibits the replication of HEV in vivo and might induce a sustained virological response in patients with chronic HEV infections. Further studies are required to determine the optimal duration of ribavirin therapy.
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Affiliation(s)
- Nassim Kamar
- Department of Nephrology, Dialysis and Organ Transplantation, CHU Rangueil, Toulouse, France.
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Ishigami M, Hayashi K, Katano Y, Itoh A, Hirooka Y, Goto H. Impact of early elevation of serum bilirubin during treatment with pegylated interferon and ribavirin in patients with chronic hepatitis C. Hepatol Res 2010; 40:963-70. [PMID: 20887331 DOI: 10.1111/j.1872-034x.2010.00711.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM Hemolytic anemia is a well-known adverse effect of interferon and ribavirin combination treatment. Herein, we analyzed the impact of early elevation of serum bilirubin level as a marker for predicting severe anemia during treatment. METHODS We studied 245 chronic hepatitis C patients who received pegylated interferon and ribavirin combination treatment, and divided them using two different threshold levels: (i) elevation of total bilirubin of 0.5 mg/dL or more within 1 week of starting treatment; and (ii) drop of hemoglobin (Hb) by 3 g/dL or more within 4 weeks of starting treatment. We compared the dynamics in each group and then investigated independent factors for predicting a severe Hb drop (≥3 g/dL) at 4 weeks after beginning treatment and dose reduction of ribavirin. RESULTS Total bilirubin levels at 1 week were significantly higher in patients with a Hb drop of 3 g/dL or more as compared to those with a drop of less than 3 g/dL (P < 0.0001). Hb levels at 4 weeks were significantly lower in the group of 0.5 mg/dL or more increase of total bilirubin levels than in the group with a less than 0.5 mg/dL increase (P < 0.0001). Therefore, elevation of total bilirubin after 1 week of treatment was shown to be an independent factor for predicting severe Hb drop (≥3 g/dL) at 4 weeks (P < 0.0001), and dose reduction of ribavirin during treatment (P = 0.0321). CONCLUSION Early elevation of serum bilirubin level was found to be a possible predictive marker of both a severe drop of Hb in the early phase of treatment and dose reduction of ribavirin.
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Affiliation(s)
- Masatoshi Ishigami
- Department of Gastroenterology, Nagoya University School of Medicine, Nagoya, Japan
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Maintenance ribavirin monotherapy delays fibrosis progression in liver transplant recipients with recurrent hepatitis C at high risk of progression. Dig Liver Dis 2010; 42:297-303. [PMID: 19818696 DOI: 10.1016/j.dld.2009.08.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2009] [Revised: 08/26/2009] [Accepted: 08/31/2009] [Indexed: 12/11/2022]
Abstract
BACKGROUND Fibrosis in liver transplant recipients with recurrent HCV is fast, yet, different patterns of progression are recognized. AIMS To investigate histological findings associated with maintenance ribavirin monotherapy in patients with recurrent HCV transplanted > or =4 years earlier. METHODS 14 recipients at high risk of progression (fibrosis progression rate >0.33 units/year and/or persistently elevated ALT) were assigned to receive ribavirin for 3 years. 11 patients at lower risk of progression (FPR < or =0.33 units/year and normal ALT) as controls. Biopsies were obtained yearly since transplant and 7 consecutive biopsies were evaluated. RESULTS Improved necroinflammation (reduction > or =2 grading) was observed in 7 treated with ribavirin and 3 untreated patients, while 1 and 3 patients worsened respectively. Fibrosis improved (reduction >1 staging) in 2 ribavirin-treated patients, unchanged in 10 and worsened (increase > or =1 staging) in 2. Fibrosis progression decreased from 0.48+/-0.27 observed during the 3-year pre-treatment period to 0.04+/-0.31 units/year (p=0.003) during the 3 years of ribavirin. Among untreated fibrosis remained unchanged in 1 and worsened in 10 (p<0.001), yearly fibrosis progression rate increasing from 0.15+/-0.17 units/year to 0.42+/-0.39 units/year (p=0.10). CONCLUSIONS Maintenance ribavirin monotherapy delays fibrosis progression in high risk patients, offering an alternative strategy for those failing to respond to conventional treatment.
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40
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Notsumata K, Kanno M, Matsuda H, Sanada T, Shin K, Kosaka S, Watanabe H, Toya D, Tanaka N, Sudo Y, Miyayama S. The efficacy of ezetimibe add-on with combination peginterferon plus ribavirin therapy in patients with chronic hepatitis C. ACTA ACUST UNITED AC 2010. [DOI: 10.2957/kanzo.51.607] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Chan AHW, Partovi N, Ensom MHH. The utility of therapeutic drug monitoring for ribavirin in patients with chronic hepatitis C--a critical review. Ann Pharmacother 2009; 43:2044-63. [PMID: 19920162 DOI: 10.1345/aph.1m225] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE To evaluate the utility of therapeutic drug monitoring (TDM) for ribavirin in chronic hepatitis C. DATA SOURCES Literature searches were conducted through PubMed (1949-June 2009), EMBASE (1980-June 2009), BIOSIS Previews (1969-June 2009), International Pharmaceutical Abstracts (1970-June 2009), Google, and www.clinicaltrials.gov using the terms ribavirin, therapeutic monitoring, hepatitis C, and drug levels. In addition, pertinent reference citations from identified publications were reviewed. Studies were limited to English language, adult age, and human subjects. STUDY SELECTION AND DATA EXTRACTION All articles identified from the data sources were evaluated. Studies that measured ribavirin concentrations or dose and treatment response were included in the review. DATA SYNTHESIS While monitoring of ribavirin plasma concentrations to improve treatment response in patients with chronic hepatitis C has been described in the literature, the utility of TDM for ribavirin in this group of patients has not been systematically studied. Thus, a previously published 9-step decision-making algorithm was employed to help determine whether TDM is warranted, based on currently available evidence. Thirty articles involving patients with chronic hepatitis C mono-infection, 12 for hepatitis C-HIV coinfection, 5 for renal dysfunction, and 5 for post-liver transplant patients were reviewed. In all subpopulations, studies exist that either support or refute the usefulness of ribavirin TDM. Additionally, the majority of the included studies had methodologic limitations, such as small sample size, retrospective analyses, and lack of p value adjustment for multiple analyses. Large randomized controlled trials would help to definitively answer this question. CONCLUSIONS There is conflicting evidence about the existence of a correlation between ribavirin concentrations and virologic response or development of toxicity. This inconsistent evidence, coupled with the currently employed effective strategies that maximize sustained virologic response and minimize development of anemia, precludes the utility of TDM for ribavirin.
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Affiliation(s)
- Alice H W Chan
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada
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42
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Perico N, Cattaneo D, Bikbov B, Remuzzi G. Hepatitis C infection and chronic renal diseases. Clin J Am Soc Nephrol 2009; 4:207-20. [PMID: 19129320 DOI: 10.2215/cjn.03710708] [Citation(s) in RCA: 158] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
More than 170 million people worldwide are chronically infected with the hepatitis C virus (HCV), which is responsible for over 1 million deaths resulting from cirrhosis and liver cancers. Extrahepatic manifestations are also relevant and include mixed cryoglobulinemia, lymphoproliferative disorders, and kidney disease. HCV infection is both a cause and a complication of chronic kidney disease, occurring largely in the context of mixed cryoglobulinemia. This infection also represents a major medical and epidemiologic challenge in patients with end-stage renal disease on renal replacement therapy with dialysis or transplantation. In these settings the presence of HCV correlates with higher rates of patient mortality than in HCV-negative subjects on dialysis or undergoing kidney transplant. The major concern is the lack of safe and effective drugs to treat HCV-infected patients with chronic kidney disease. Unfortunately, there are no large-scale clinical trials in this population, especially those receiving renal replacement therapy, so that strong evidence for treatment recommendations is scant. This review article provides the readers with the most recent insights on HCV infection both as cause and complication of chronic kidney disease, discusses pitfalls and limitations of current therapies, and reports on preliminary experience with novel therapeutic agents, as well as directions for future research.
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Affiliation(s)
- Norberto Perico
- Department of Medicine and Transplantation Ospedali Riuniti di Bergamo-Mario Negri Institute for Pharmacological Research, Bergamo, Italy
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Moghaddam SMH, Alavian SM, Kermani NA. Hepatitis C and renal transplantation: a review on historical aspects and current issues. Rev Med Virol 2008; 18:375-86. [PMID: 18702126 DOI: 10.1002/rmv.590] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Chronic liver disease has a significant impact on the survival of renal transplant recipients with an incidence rate of 4-38%. Approximately, 8-28% of renal transplant recipients die due to chronic liver disease. Hepatitis C seems to be the leading cause of chronic liver disease in kidney recipients. Hepatitis C virus (HCV) infection has a wide range of prevalence (2.6-66%) among renal transplant recipients living in different countries with great genotype diversity in different parts of the world. Nowadays, antiviral drugs are used for the management of hepatitis C. Because of graft-threatening effects of some antiviral drugs used in HCV-infected renal transplant recipients, we specifically focused on HCV treatment after renal transplantation. Treatment of post-renal transplantation chronic liver disease with INF and ribavirin remains controversial. Anecdotal reports on post-renal transplantation hepatitis C demonstrate encouraging findings. This review summarises the most current information on diagnosis, treatment, prognosis, complications as well as the new aspects of treatment in HCV-infected renal transplant recipients. HCV belongs to the family of Flaviviridae, genus Hepacivirus.
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Nicot F, Legrand-Abravanel F, Lafont T, Dubois M, Sauné K, Pasquier C, Chatelut E, Izopet J. Serum concentrations of ribavirin and pegylated interferon and viral responses in patients infected with HIV and HCV. J Med Virol 2008; 80:1523-9. [PMID: 18649340 DOI: 10.1002/jmv.21227] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The hepatitis C virus (HCV) infects a substantial proportion of patients infected with human immunodeficiency virus (HIV). Patients infected with both HCV and HIV respond poorly to anti-HCV treatment with pegylated interferon alpha and ribavirin. But few data are available on the influence of ribavirin and interferon concentrations on treatment outcome for these patients. This study investigated the relationship between the serum pegylated interferon and ribavirin concentrations 3 and 6 months after treatment initiation, and treatment outcome in 35 HCV-HIV coinfected patients. The pegylated interferon and ribavirin concentrations at months 3 and 6 were similar. The pegylated interferon concentrations at 3 months in responders and nonresponders were similar. However, responders tended to have higher ribavirin concentrations (2,322 ng/ml) than nonresponders (1,833 ng/ml; P = 0.08). Responders infected with HCV genotype 1 or 4 had higher ribavirin concentrations (2,672 ng/ml) than did similarly infected nonresponders (1,758 ng/ml; P = 0.04). ROC curve analysis showed that a ribavirin concentration of 2,300 ng/ml was the best threshold for predicting a nonresponse (ROC area = 0.80 +/- 0.12). Thus ribavirin concentrations influence treatment outcome in HIV patients infected with HCV genotype 1 or 4. Monitoring ribavirin concentrations could help adapt ribavirin concentrations and improve the sustained virological response.
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45
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Toyoda H, Kumada T, Kiriyama S, Sone Y, Tanikawa M, Hisanaga Y, Kanamori A, Atsumi H, Nakano S, Arakawa T, Honda T, Hayashi K, Katano Y, Goto H. Correlation of serum ribavirin concentration with pretreatment renal function estimates in patients with chronic hepatitis C receiving combination antiviral therapy with peginterferon and ribavirin. J Viral Hepat 2008; 15:651-8. [PMID: 18637076 DOI: 10.1111/j.1365-2893.2008.01004.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Serum ribavirin concentration is an important factor in antiviral therapy in combination with peginterferon (PEG-IFN) and ribavirin for patients with chronic hepatitis C in terms of both beneficial and adverse effects. We evaluated whether the serum ribavirin concentration can be predicted on the basis of renal function estimates. Serum creatinine and cystatin C concentrations were measured at the start of treatment in a total of 148 patients with chronic hepatitis C who underwent combination PEG-IFN and ribavirin therapy. Creatinine clearance (CrCl) and total clearance of ribavirin (CL/F) were calculated on the basis of the serum creatinine level. The glomerular filtration rate was calculated with two different formulae on the basis of the serum cystatin C level. These values were compared with serum ribavirin concentrations 4 weeks after the start of therapy. The cystatin C level increased with the progression of liver fibrosis, whereas the creatinine level was constant regardless of the degree of liver fibrosis. Significant correlation was not observed between the serum ribavirin concentration and serum creatinine level, cystatin C level, or calculated renal function estimates. However, significant correlation was found between the serum ribavirin concentration and CrCl and CL/F in patients who were given ribavirin >800 mg/day. Overall, renal function estimates do not correlate with the serum ribavirin concentration in Japanese patients with chronic hepatitis C who undergo combination PEG-IFN and ribavirin therapy. Serum creatinine-based renal function estimates might be predictive for the serum ribavirin concentration only in patients with a daily ribavirin intake of 800 mg or more.
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Affiliation(s)
- H Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Gifu, Japan
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Effros RB, Fletcher CV, Gebo K, Halter JB, Hazzard WR, Horne FM, Huebner RE, Janoff EN, Justice AC, Kuritzkes D, Nayfield SG, Plaeger SF, Schmader KE, Ashworth JR, Campanelli C, Clayton CP, Rada B, Woolard NF, High KP. Aging and infectious diseases: workshop on HIV infection and aging: what is known and future research directions. Clin Infect Dis 2008; 47:542-53. [PMID: 18627268 PMCID: PMC3130308 DOI: 10.1086/590150] [Citation(s) in RCA: 404] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Highly active antiretroviral treatment has resulted in dramatically increased life expectancy among patients with HIV infection who are now aging while receiving treatment and are at risk of developing chronic diseases associated with advanced age. Similarities between aging and the courses of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome suggest that HIV infection compresses the aging process, perhaps accelerating comorbidities and frailty. In a workshop organized by the Association of Specialty Professors, the Infectious Diseases Society of America, the HIV Medical Association, the National Institute on Aging, and the National Institute on Allergy and Infectious Diseases, researchers in infectious diseases, geriatrics, immunology, and gerontology met to review what is known about HIV infection and aging, to identify research gaps, and to suggest high priority topics for future research. Answers to the questions posed are likely to help prioritize and balance strategies to slow the progression of HIV infection, to address comorbidities and drug toxicity, and to enhance understanding about both HIV infection and aging.
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Affiliation(s)
- Rita B. Effros
- David Geffen School of Medicine at the University of California, Los Angeles
| | | | - Kelly Gebo
- Johns Hopkins University School of Medicine, Baltimore
| | | | | | | | - Robin E. Huebner
- National Institute of Allergy and Infectious Diseases, Bethesda, Maryland
| | - Edward N. Janoff
- Mucosal and Vaccine Research Program Colorado, University of Colorado School of Medicine, Denver
| | | | - Daniel Kuritzkes
- Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts
| | | | - Susan F. Plaeger
- National Institute of Allergy and Infectious Diseases, Bethesda, Maryland
| | | | | | | | | | - Beth Rada
- Infectious Diseases Society of America, Arlington, Virginia
| | - Nancy F. Woolard
- Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Kevin P. High
- Wake Forest University School of Medicine, Winston-Salem, North Carolina
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47
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Effros R, Fletcher C, Gebo K, Halter J, Hazzard W, Horne F, Huebner R, Janoff E, Justice A, Kuritzkes D, Nayfield S, Plaeger S, Schmader K, Ashworth J, Campanelli C, Clayton C, Rada B, Woolard N, High K. Aging and Infectious Diseases: Workshop on HIV Infection and Aging: What Is Known and Future Research Directions. Clin Infect Dis 2008. [DOI: https:/doi.10.1086/590150] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
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Mallolas J, Laguno M. Pegylated IFN-alpha2b plus ribavirin for treatment-naive patients coinfected with HCV and HIV. Expert Rev Anti Infect Ther 2008; 6:281-9. [PMID: 18588492 DOI: 10.1586/14787210.6.3.281] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Since 1995, after the generalization of highly active antiretroviral therapy (HAART), HCV coinfection in patients with HIV has become a clinical problem of first magnitude. In fact, currently, HCV coinfection is the primary cause of morbi-mortality of AIDS patients in many hospitals. As a consequence, a significant number of clinical trials have been carried out during the past 8-10 years on HCV/HIV-coinfected patients, and have been coincident that the use of pegylated interferon (PEG-IFN) plus ribavirin should be now the gold standard for treating these patients. Various prospective, randomized studies have reached the conclusion that PEG-IFN-alpha(2b) plus ribavirin achieves HCV cure rates in approximately 50% of all patients, together with important clinical consequences, since hepatic illness progression stops or even reverts. Although adverse events are extremely common with this combined treatment, it is also true that their handling by experts means that only 10-15% of patients must abandon treatment.
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Affiliation(s)
- Josep Mallolas
- Servicio de Enfermedades Infecciosas, Hospital Clínic, Barcelona, Spain.
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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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50
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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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