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Hashem M, Medhat MA, Abdeltawab D, Makhlouf NA. Expanding the liver donor pool worldwide with hepatitis C infected livers, is it the time? World J Transplant 2024; 14:90382. [PMID: 38947961 PMCID: PMC11212581 DOI: 10.5500/wjt.v14.i2.90382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 02/29/2024] [Accepted: 04/12/2024] [Indexed: 06/13/2024] Open
Abstract
Liver transplantation (LT) provides a life-saving option for cirrhotic patients with complications and hepatocellular carcinoma. Despite the increasing number of liver transplants performed each year, the number of LT candidates on the waitlist remains unchanged due to an imbalance between donor organ supply and the demand which increases the waitlist time and mortality. Living donor liver transplant had a great role in increasing the donor pool and shortened waitlist time for LT candidates. Nevertheless, further strategies can be implemented to increase the pool of potential donors in deceased donor LT, such as reducing the rate of organ discards. Utilizing hepatitis C virus (HCV) seropositive liver grafts is one of the expanded donor organ criteria. A yearly increase of hundreds of transplants is anticipated as a result of maximizing the utilization of HCV-positive organs for HCV-negative recipients. Direct-acting antiviral therapy's efficacy has revolutionized the treatment of HCV infection and the use of HCV-seropositive donors in transplantation. The American Society of Transplantation advises against performing transplants from HCV-infected liver donors (D+) into HCV-negative recipient (R-) unless under Institutional Review Board-approved study rules and with full informed consent of the knowledge gaps associated with such transplants. Proper selection of patients to be transplanted with HCV-infected grafts and confirming their access to direct-acting antivirals if needed is important. National and international consensuses are needed to regulate this process to ensure the maximum benefit and the least adverse events.
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Affiliation(s)
- Mai Hashem
- Fellow of Tropical Medicine and Gastroenterology, Assiut University Hospital, Assiut 71515, Egypt
| | - Mohammed A Medhat
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | - Doaa Abdeltawab
- Department of Tropical Medicine and Gastroenterology, Al-Rajhi Liver Hospital, Assiut University, Assiut 71515, Egypt
| | - Nahed A Makhlouf
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
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Kurokawa K, Ohki T, Kato J, Fukumura Y, Imai M, Shibata C, Arai J, Kondo M, Takagi K, Kojima K, Seki M, Mori M, Toda N, Tagawa K. Hepatitis C virus relapse after successful treatment with direct-acting antivirals, followed by sarcomatous changes in hepatocellular carcinoma: a case report. J Med Case Rep 2020; 14:62. [PMID: 32456712 PMCID: PMC7251811 DOI: 10.1186/s13256-020-02392-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 04/28/2020] [Indexed: 12/16/2022] Open
Abstract
Background Combination therapy of interferon and ribavirin has traditionally been used to eradicate hepatitis C virus. The sustained virologic response achieved with interferon-related therapy is persistent, and late relapses after achieving sustained virologic response at 24 weeks using this therapy are reportedly rare (< 1%). In 2014, interferon-free therapy with direct-acting antivirals was developed, and the rate of sustained virologic response was improved. However, the persistence thereof remains uncertain, and the appropriate follow-up period for hepatitis C virus-positive patients is under discussion. Case presentation A 74-year-old Japanese man who had hepatitis C virus–related hepatocellular carcinoma and was successfully treated with radiofrequency ablation four times underwent direct-acting antiviral therapy with daclatasvir and asunaprevir; sustained virologic response at 24 weeks was confirmed. However, although he had no high risk factors for reinfection, hepatitis C virus ribonucleic acid was detected again 6 months after achieving sustained virologic response at 24 weeks. Moreover, he developed active hepatitis with an increased viral load. Five months after development of hepatitis, recurrent hepatocellular carcinoma emerged in segment II, where we had performed radiofrequency ablation 17 months previously. The recurrent hepatocellular carcinoma enlarged quite rapidly and induced multiple peritoneal disseminations and lung metastases. He died 3 months after the abrupt recurrence. A sarcomatous change in the hepatocellular carcinoma was identified during the autopsy. Conclusions Although sustained virologic response at 24 weeks has generally been regarded to denote complete eradication of hepatitis C virus, we present a patient in whom hepatitis C virus recurred 6 months after achieving sustained virologic response at 24 weeks with direct-acting antiviral therapy. In addition, a sarcomatous change in hepatocellular carcinoma emerged 5 months after active hepatitis developed due to late hepatitis C virus relapse in this case. The sarcomatous change in hepatocellular carcinoma is generally thought to be related to anticancer therapies, such as radiofrequency ablation. However, in this case, late viral relapse and active hepatitis in addition to the previous radiofrequency ablation could have been the trigger. There may be a need for follow-up of hepatitis C virus ribonucleic acid beyond sustained virologic response at 24 weeks with direct-acting antiviral therapy, owing to the possibility of late viral relapse and tumorigenesis.
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Affiliation(s)
- Ken Kurokawa
- Department of Gastroenterology, Mitsui Memorial Hospital, 1 Kandaizumi-cho Chiyoda-ku, Tokyo, 101-8643, Japan.
| | - Takamasa Ohki
- Department of Gastroenterology, Mitsui Memorial Hospital, 1 Kandaizumi-cho Chiyoda-ku, Tokyo, 101-8643, Japan
| | - Jun Kato
- Department of Gastroenterology, Mitsui Memorial Hospital, 1 Kandaizumi-cho Chiyoda-ku, Tokyo, 101-8643, Japan
| | - Yukiyo Fukumura
- Department of Gastroenterology, Mitsui Memorial Hospital, 1 Kandaizumi-cho Chiyoda-ku, Tokyo, 101-8643, Japan
| | - Makoto Imai
- Department of Gastroenterology, Mitsui Memorial Hospital, 1 Kandaizumi-cho Chiyoda-ku, Tokyo, 101-8643, Japan
| | - Chikako Shibata
- Department of Gastroenterology, Mitsui Memorial Hospital, 1 Kandaizumi-cho Chiyoda-ku, Tokyo, 101-8643, Japan
| | - Junya Arai
- Department of Gastroenterology, Mitsui Memorial Hospital, 1 Kandaizumi-cho Chiyoda-ku, Tokyo, 101-8643, Japan
| | - Mayuko Kondo
- Department of Gastroenterology, Mitsui Memorial Hospital, 1 Kandaizumi-cho Chiyoda-ku, Tokyo, 101-8643, Japan
| | - Kaoru Takagi
- Department of Gastroenterology, Mitsui Memorial Hospital, 1 Kandaizumi-cho Chiyoda-ku, Tokyo, 101-8643, Japan
| | - Kentaro Kojima
- Department of Gastroenterology, Mitsui Memorial Hospital, 1 Kandaizumi-cho Chiyoda-ku, Tokyo, 101-8643, Japan
| | - Michiharu Seki
- Department of Gastroenterology, Mitsui Memorial Hospital, 1 Kandaizumi-cho Chiyoda-ku, Tokyo, 101-8643, Japan
| | - Masaya Mori
- Department of Pathology, Mitsui Memorial Hospital, Tokyo, Japan
| | - Nobuo Toda
- Department of Gastroenterology, Mitsui Memorial Hospital, 1 Kandaizumi-cho Chiyoda-ku, Tokyo, 101-8643, Japan
| | - Kazumi Tagawa
- Department of Gastroenterology, Mitsui Memorial Hospital, 1 Kandaizumi-cho Chiyoda-ku, Tokyo, 101-8643, Japan
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Bonacini M, Kim Y, Pitney C, McKoin L, Tran M, Landis C. Wirelessly Observed Therapy to Optimize Adherence and Target Interventions for Oral Hepatitis C Treatment: Observational Pilot Study. J Med Internet Res 2020; 22:e15532. [PMID: 32352385 PMCID: PMC7226036 DOI: 10.2196/15532] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 10/07/2019] [Accepted: 10/20/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND A fixed-dose combination of ledipasvir/sofosbuvir (LDV/SOF) is efficacious in treating chronic hepatitis C virus (HCV) infection; however, objective adherence to prescribed regimens in real-world clinical settings has not been well studied. OBJECTIVE This study aimed to evaluate adherence and virologic outcomes in patients with chronic HCV infection treated with LDV/SOF using a novel digital medicine program that directly measures drug ingestion adherence. METHODS This prospective, observational, open-label, single-arm pilot study was conducted at 2 clinical research sites and followed patients with HCV infection who were prescribed LDV/SOF along with an ingestible sensor. Patients were treated for 8 or 12 weeks. The main outcomes were ingestion adherence, medical interventions, virologic response, safety, and patient satisfaction. RESULTS Of the 28 patients (mean 59 years, SD 7), 61% (17/28) were male, 61% (17/28) were non-Caucasian, and 93% (26/28) were treatment naïve. All 28 had genotype 1 HCV, and of these, 27 completed an 8- or 12-week treatment. Patients used the digital medicine program for 92% of the expected days; the overall mean ingestion adherence rate was 97%. Providers used the digital medicine program data for same-day medication therapy management in 39% (11/28) of patients. End-of-treatment response was achieved in all the available 21 of 28 patients. Sustained virologic response at 12 weeks or more was achieved in 26 of 28 patients; of the 2 patients who relapsed, one had less than 90% adherence and the other had greater than or equal to 95% adherence, lending insights into reasons for treatment failure. A total of 4 subjects reported nonserious adverse events, which were resolved. CONCLUSIONS Conclusions: The findings of this study suggest that digital medicines can be used for wirelessly observed therapy to support adherence to antiviral HCV therapy, reduce unnecessary medication wastage and retreatment costs, and potentially optimize sustained virologic response rates, especially in populations at high risk for nonadherence.
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Affiliation(s)
- Maurizio Bonacini
- Mission Gastroenterology and Hepatology, san francisco, CA, United States
| | - Yoona Kim
- Proteus Digital Health, Redwood City, CA, United States
| | - Caroline Pitney
- Paul G. Allen School of Computer Science and Engineering, University of Washington, Seattle, WA, United States
| | - Lee McKoin
- Paul G. Allen School of Computer Science and Engineering, University of Washington, Seattle, WA, United States
| | - Melody Tran
- Proteus Digital Health, Redwood City, CA, United States
| | - Charles Landis
- Paul G. Allen School of Computer Science and Engineering, University of Washington, Seattle, WA, United States
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Frías M, Rivero-Juárez A, Téllez F, Palacios R, Jiménez-Arranz Á, Pineda JA, Merino D, Gómez-Vidal MA, Pérez-Camacho I, Camacho Á, Rivero A. Evaluation of hepatitis C viral RNA persistence in HIV-infected patients with long-term sustained virological response by droplet digital PCR. Sci Rep 2019; 9:12507. [PMID: 31467339 PMCID: PMC6715682 DOI: 10.1038/s41598-019-48966-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 08/13/2019] [Indexed: 12/12/2022] Open
Abstract
Several studies have reported the persistence of HCV RNA in liver and/or peripheral blood mononuclear cells (PBMCs) in spite of undetectable viremia in patients who have achieved sustained virological response (SVR). This event, defined as occult HCV infection, remains controversial and low titers of persistent virus may be underestimated because it has not yet been analyzed by a highly sensitive test such as droplet digital PCR (ddPCR). This method provides an alternate ultra-sensitive detection technique for very low numbers of copies of viral RNA or DNA. The aim of this study was to evaluate the persistence of HCV in HIV-coinfected patients with long-term SVR using ddPCR. For each patient, the presence of HCV RNA in serum and PBMCs at baseline was determined by nested RT-ddPCR. Patients with HCV RNA in PBMCs at baseline were followed until the end of the study. One hundred and twenty-three patients were analyzed for persistence of HCV RNA in serum and PBMCs. Persistence of HCV was not found in serum in any patient. HCV RNA was detected in PBMCs in one patient (0.81%; 95% CI: 0.04–3.94) and resolved spontaneously during follow-up. Persistence of HCV RNA in PBMCs is not a common event in HIV/HCV co-infected patients with long-term SVR evaluated by RT-ddPCR.
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Affiliation(s)
- Mario Frías
- Unidad de Enfermedades Infecciosas. Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía de Córdoba, Universidad de Córdoba, Córdoba, Spain
| | - Antonio Rivero-Juárez
- Unidad de Enfermedades Infecciosas. Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía de Córdoba, Universidad de Córdoba, Córdoba, Spain.
| | - Francisco Téllez
- Unidad Gestión Clínica Enfermedades Infecciosas, Hospital La Línea, AGS Campo de Gibraltar, Cádiz, Spain
| | - Rosario Palacios
- Unidad de Enfermedades Infecciosas. Hospital Universitario Virgen de la Victoria, Complejo Hospitalario Provincial de Málaga, Málaga, Spain
| | - Álvaro Jiménez-Arranz
- Unidad de Genómica. Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Universidad de Córdoba, Córdoba, Spain
| | - Juan A Pineda
- Unidad de Enfermedades Infecciosas y Microbiología, Hospital Universitario de Valme, Instituto de Biomedicina de Sevilla (iBiS), Sevilla, Spain
| | - Dolores Merino
- Unidad de Enfermedades Infecciosas, Hospitales Juan Ramón Jiménez e Infanta Elena de Huelva, Huelva, Spain
| | | | - Inés Pérez-Camacho
- Unidad de Enfermedades Infecciosas, Hospital de Poniente, El Ejido, Spain
| | - Ángela Camacho
- Unidad de Enfermedades Infecciosas. Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía de Córdoba, Universidad de Córdoba, Córdoba, Spain
| | - Antonio Rivero
- Unidad de Enfermedades Infecciosas. Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía de Córdoba, Universidad de Córdoba, Córdoba, Spain
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Pisaturo M, Minichini C, Starace M, Caroprese M, Macera M, Brancaccio G, De Pascalis S, Santonicola A, Galeota Lanza A, Zampino R, Cotticelli G, Sagnelli E, Gaeta GB, Coppola N. Hepatitis C late relapse in patients with directly acting antiviral-related sustained virological response at week 12. Liver Int 2019; 39:844-853. [PMID: 30554459 DOI: 10.1111/liv.14025] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 11/21/2018] [Accepted: 12/02/2018] [Indexed: 12/15/2022]
Abstract
AIM The aim of the present study was to identify, among the patients with failure to DAA regimen, those with a late relapse (after the achievement of a sustained virological response at week 12) and to characterize the clinical, epidemiological and virological features of these patients. MATERIAL AND METHODS A total of 129 HCV patients with non-response to an IFN-free regimen were enrolled. Sanger sequencing of NS3, NS5A and NS5B was performed at failure by home-made protocols. RESULTS Of the 129 patients enrolled, 8 (6.2%) experienced a breakthrough, 15 (11.7%) non-response, 99 (76.7%) a relapse by week 12 after the end of DAA therapy, and 7 (5.4%) a late relapse (after week 12; median 24 weeks, range 24-72). For two of the seven patients with a late relapse, a serum sample collected before the start of the DAA regimen was available; phylogenetic analysis showed no change in sequences of NS3, NS5A and NS5B regions, suggesting a reactivation of the initial HCV strain; for the remaining five patients, no serum collected before the DAA regimen was available, and thus, a re-infection cannot be excluded. CONCLUSIONS Although a late relapse is infrequent, the study suggests a post-treatment follow-up of 72 weeks.
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Affiliation(s)
- Mariantonietta Pisaturo
- Laboratory for the Identification of Prognostic Factors of Response to the Treatment Against Infectious Diseases, University of Campania, Naples, Italy
| | - Carmine Minichini
- Laboratory for the Identification of Prognostic Factors of Response to the Treatment Against Infectious Diseases, University of Campania, Naples, Italy
| | - Mario Starace
- Laboratory for the Identification of Prognostic Factors of Response to the Treatment Against Infectious Diseases, University of Campania, Naples, Italy
| | - Mara Caroprese
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania, Naples, Italy
| | - Margherita Macera
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania, Naples, Italy
| | - Giuseppina Brancaccio
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania, Naples, Italy
| | - Stefania De Pascalis
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania, Naples, Italy
| | | | | | - Rosa Zampino
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, University of Campania "L. Vanvitelli", Naples, Italy
| | - Gaetano Cotticelli
- Internal Medicine and Hepatology, Department of Clinical and Experimental Medicine, University of Campania "L. Vanvitelli", Naples, Italy
| | - Evangelista Sagnelli
- Laboratory for the Identification of Prognostic Factors of Response to the Treatment Against Infectious Diseases, University of Campania, Naples, Italy
| | - Giovanni Battista Gaeta
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania, Naples, Italy
| | - Nicola Coppola
- Laboratory for the Identification of Prognostic Factors of Response to the Treatment Against Infectious Diseases, University of Campania, Naples, Italy
- Infectious Diseases Unit, AO Caserta, Caserta, Italy
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Use of Hepatitis C Virus Antibody-Positive Donor Livers in Hepatitis C Nonviremic Liver Transplant Recipients. J Am Coll Surg 2019; 228:560-567. [DOI: 10.1016/j.jamcollsurg.2018.12.004] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 12/10/2018] [Indexed: 01/28/2023]
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Brown KA, Hassan M. Utilizing Donors with Hepatitis C Antibody Positivity and Negative Nucleic Acid Testing. CURRENT TRANSPLANTATION REPORTS 2018. [DOI: 10.1007/s40472-018-0218-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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8
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Molecular characterization and clinical epidemiology of HCV in District Dir (Lower), Pakistan. Virusdisease 2018; 29:369-374. [PMID: 30159373 DOI: 10.1007/s13337-018-0457-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Accepted: 05/04/2018] [Indexed: 10/16/2022] Open
Abstract
With about 200 million infections globally, Hepatitis C virus (HCV) infection is a major global health threat. The relative prevalence of hepatitis and HCV genotypes/subtypes varies among different geographic regions. Therefore, the present study was conducted to determine the prevalence of hepatitis C and HCV genotypes/subtypes in District Dir (Lower), Pakistan. Blood samples from HCV positive patients were genotyped through multiplex PCR using specific primers for HCV core region. A structured questionnaire was used to obtain information from the patients and data was statistically analyzed for different epidemiological parameters. The molecular evaluation results suggested the prevalence of genotype 3 in this study. The frequency of hepatitis C was found higher in males (P < 0.01). Present study suggests injections received at local clinics as a highly significant mode of HCV transmission to these patients (P < 0.002). These findings might be helpful for clinicians and related health care personnel to assess status of this important disease and highlight the need for more detailed evaluation of this devastating disease in order to frame better treatment strategies.
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Bari K, Luckett K, Kaiser T, Diwan T, Cuffy M, Schoech MR, Safdar K, Blackard JT, Apewokin S, Paterno F, Sherman KE, Zucker SD, Anwar N, Shah SA. Hepatitis C transmission from seropositive, nonviremic donors to non-hepatitis C liver transplant recipients. Hepatology 2018; 67:1673-1682. [PMID: 29205441 DOI: 10.1002/hep.29704] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 11/09/2017] [Accepted: 11/28/2017] [Indexed: 12/11/2022]
Abstract
UNLABELLED Breakthroughs in hepatitis C virus (HCV) treatment and rising rates of intravenous drug use have led to an increase in the number of organ donors who are HCV antibody-positive but serum nucleic acid test (NAT)-negative. The risk of HCV transmission from the liver grafts of these donors to recipients is unknown. To estimate the incidence of HCV transmission, we prospectively followed 26 consecutive HCV antibody-negative (n = 25) or NAT-negative (n = 1) transplant recipients who received a liver graft from donors who were HCV antibody-positive but serum NAT-negative between March 2016 and March 2017. HCV transmission was considered to have occurred if recipients exhibited a positive HCV PCR test by 3 months following transplantation. Drug overdose was listed as the cause of death in 15 (60%) of the donors. One recipient died 18 days after transplantation from primary graft nonfunction and was excluded. Of the remaining 25 recipients, HCV transmission occurred in 4 (16%), at a median follow-up of 11 months, all from donors who died of drug overdose. Three of these patients were treated with direct-acting antiviral therapy, with two achieving a sustained virologic response and one an end-of-treatment response. One patient with HCV transmission died after a complicated postoperative course and did not receive antiviral therapy. CONCLUSION In this prospective cohort of non-HCV liver recipients receiving grafts from HCV antibody-positive/NAT-negative donors, the incidence of HCV transmission was 16%, with the highest risk conferred by donors who died of drug overdose; given the availability of safe and highly effective antiviral therapies, use of such organs could be considered to expand the donor pool. (Hepatology 2018;67:1673-1682).
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Affiliation(s)
- Khurram Bari
- Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH
| | - Keith Luckett
- Division of Infectious Diseases, Department of Medicine, University of Cincinnati, Cincinnati, OH
| | - Tiffany Kaiser
- Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH
| | - Tayyab Diwan
- Division of Transplant Surgery, Department of Surgery, University of Cincinnati, Cincinnati, OH
| | - Madison Cuffy
- Division of Transplant Surgery, Department of Surgery, University of Cincinnati, Cincinnati, OH
| | - Michael R Schoech
- Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH
| | - Kamran Safdar
- Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH
| | - Jason T Blackard
- Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH
| | - Senu Apewokin
- Division of Infectious Diseases, Department of Medicine, University of Cincinnati, Cincinnati, OH
| | - Flavio Paterno
- Division of Transplant Surgery, Department of Surgery, University of Cincinnati, Cincinnati, OH
| | - Kenneth E Sherman
- Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH
| | - Stephen D Zucker
- Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH.,Division of Gastroenterology, Hepatology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Nadeem Anwar
- Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH
| | - Shimul A Shah
- Division of Transplant Surgery, Department of Surgery, University of Cincinnati, Cincinnati, OH
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Akiyama MJ, Agyemang L, Arnsten JH, Heo M, Norton BL, Schackman BR, Linas BP, Litwin AH. Rationale, design, and methodology of a trial evaluating three models of care for HCV treatment among injection drug users on opioid agonist therapy. BMC Infect Dis 2018; 18:74. [PMID: 29426304 PMCID: PMC5807730 DOI: 10.1186/s12879-018-2964-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 01/16/2018] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND People who inject drugs (PWID) constitute 60% of the approximately 5 million people in the U.S. infected with hepatitis C virus (HCV). Treatment of PWID is complex due to addiction, mental illness, poverty, homelessness, lack of positive social support, poor adherence-related skills, low motivation and knowledge, and poor access to and trust in the health care system. New direct-acting antiviral medications are available for HCV with high cure rates and few side effects. The life expectancy and economic benefits of new HCV treatments will not be realized unless we determine optimal models of care for the majority of HCV-infected patients. The purpose of this study is to evaluate the effectiveness of directly observed therapy and group treatment compared with self-administered individual treatment in a large, urban opioid agonist therapy clinic setting in the Bronx, New York. METHODS/DESIGN In this randomized controlled trial 150 PWID with chronic HCV were recruited from opioid agonist treatment (OAT) clinics and randomized to one of three models of onsite HCV treatment in OAT: 1) modified directly observed therapy; 2) group treatment; or 3) control - self-administered individual treatment. Participants were age 18 or older, HCV genotype 1, English or Spanish speaking, treatment naïve (or treatment experienced after 12/3/14), willing to receive HCV treatment onsite, receiving methadone or buprenorphine at the medication window at least once per week, and able to provide informed consent. Outcomes of interest include adherence (as measured by self-report and electronic blister packs), HCV treatment completion, sustained virologic response, drug resistance, and cost-effectiveness. DISCUSSION This paper describes the design and rationale of a randomized controlled trial comparing three models of care for HCV therapy delivered in an opioid agonist treatment program. Our trial will be critical to rigorously identify models of care that result in high adherence and cure rates. Use of blister pack technology will help us determine the role of adherence in successful cure of HCV. Moreover, the trial methodology outlined here can serve as a template for the development of future programs and studies among HCV-infected drug users receiving opioid agonist therapy, as well as the cost-effectiveness of such programs. TRIAL REGISTRATION This trial was registered with ClinicalTrials.gov ( NCT01857245 ). Trial registration was obtained prospectively on May 20th, 2013.
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Affiliation(s)
- Matthew J. Akiyama
- Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY USA
| | - Linda Agyemang
- Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY USA
| | - Julia H. Arnsten
- Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY USA
| | - Moonseong Heo
- Department of Epidemiology and Population Health, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY USA
| | - Brianna L. Norton
- Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY USA
| | - Bruce R. Schackman
- Department of Healthcare Policy & Research, Weill Cornell Medical College, New York, NY USA
| | - Benjamin P. Linas
- Department of Epidemiology, Boston University School of Public Health, Boston, MA USA
| | - Alain H. Litwin
- Department of Medicine, University of South Carolina School of Medicine–Greenville, Greenville, South Carolina USA
- Department of Medicine, Greenville Health System, Greenville, South Carolina USA
- Department of Medicine, Clemson University School of Health Research, Clemson, South Carolina USA
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11
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KAHN JEFFREY, SAITO TAKESHI. Reply. Gastroenterology 2017; 153:328-329. [PMID: 28579275 PMCID: PMC8635450 DOI: 10.1053/j.gastro.2017.05.053] [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: 12/02/2022]
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12
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Hetta HF, Mekky MA, Khalil NK, Mohamed WA, El-Feky MA, Ahmed SH, Daef EA, Medhat A, Nassar MI, Sherman KE, Shata MTM. Extra-hepatic infection of hepatitis C virus in the colon tissue and its relationship with hepatitis C virus pathogenesis. J Med Microbiol 2016; 65:703-712. [PMID: 27166142 DOI: 10.1099/jmm.0.000272] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Extra-hepatic compartments might contribute to hepatitis C virus (HCV) persistence and extra-hepatic manifestations. Therefore, we investigated HCV infection in colonic tissue in patients with chronic hepatitis C (CHC) and its relationship with HCV pathogenesis. Colonic biopsies were collected from three groups with CHC infection: treatment naïve (TN; n=12), non-responders (NR; n=10) to anti-HCV therapy (pegylated interferon-α and ribavirin) and sustained virologic response (SVR; n=10) and from a fourth healthy control group (n=10). Liver biopsies were examined to assess inflammation and fibrosis. HCV infection and colonic T regulatory (Treg) frequency were detected by immunohistochemistry. HCV core and NS3 proteins were detected in B cells and macrophage/monocytes of 42 % and 25 % of TN and 50 % and 30 % of NR, respectively, but not in SVR or control group. The numbers of cells expressing HCV proteins were positively correlated with both HCV viral load and colonic Treg frequency. A significant negative correlation between HCV-expressing cells with both liver inflammation and fibrosis was identified. Our study provides evidence that HCV can infect B cells and macrophages of the colon. The correlations between HCV infection in colonic tissue and HCV viral load and liver pathology underline the significance of this extra-hepatic infection in HCV pathogenesis and response to therapy.
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Affiliation(s)
- Helal F Hetta
- Department of Internal Medicine, Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH, USA
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohamed A Mekky
- Department of Gastroenterology & Tropical Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Nasr K Khalil
- Assiut Liver Institute for Treatment of Hepatitis C, Assiut, Egypt
| | - Wegdan A Mohamed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohamed A El-Feky
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Shabaan H Ahmed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Enas A Daef
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Ahmed Medhat
- Department of Gastroenterology & Tropical Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mahmoud I Nassar
- Department of Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Kenneth E Sherman
- Department of Internal Medicine, Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH, USA
| | - Mohamed Tarek M Shata
- Department of Internal Medicine, Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH, USA
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Janahi EM, Al-Mannai M, Singh H, Jahromi MM. Distribution of Hepatitis C Virus Genotypes in Bahrain. HEPATITIS MONTHLY 2015; 15:e30300. [PMID: 26977163 PMCID: PMC4774338 DOI: 10.5812/hepatmon.30300] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Revised: 07/12/2015] [Accepted: 08/04/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Approximately 170 million people are infected with Hepatitis C virus (HCV) worldwide, making it one of the world's major infectious diseases. There are no published population based studies about the prevalence of HCV genotypes in Bahrain. OBJECTIVES Therefore, the aim of the present study was to investigate the prevalence and distribution of HCV genotypes and subtypes among a large sample of patients with chronic HCV infection in Bahrain. PATIENTS AND METHODS Serum samples were collected from 202 HCV positive patients; of them 128 had a viral load (> 500 IU/mL) suitable for the type-specific genotyping assay. Gender-wise and age-wise differences in the distribution of HCV genotypes were determined by Chi Square and Fisher's Exact tests. RESULTS The predominant genotype among Bahraini patients was type 1 (36.71%), followed by genotypes 3 and 4 (15.6% each) and the lowest frequency was found for genotype 2 (3.9%). Among genotype 1, subtype 1b had the highest frequency (21.09%), followed by subtype 1a (14.06%). Among genotype 3, subtype 3a had the highest frequency (11.72%), while among genotype 4, most of subtypes were undetermined. The frequency of all different HCV genotypes was higher in male patients compared to female patients. Genotype 1 was most common in the age group of 51 - 60 years (38.3%), genotype 2 in 21 - 30 years (60%) and genotype 3 in 51 - 60 years (30%), while genotype 4 was most frequent among the age group > 61 (40%). CONCLUSIONS The most common HCV genotype in Bahrain was subtype 1b followed by 1a and 3a. Further studies involving sources of transmission in Bahrain are required to enhance control measures for HCV infection.
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Affiliation(s)
- Essam M. Janahi
- Department of Biology, College of Science, University of Bahrain, Sakhir, Bahrain
- Corresponding Author: Essam M. Janahi, Department of Biology, College of Science, University of Bahrain, Zallaq, Bahrain. Tel: +973-1743742511, Fax: +973-17449662, E-mail:
| | - Mariam Al-Mannai
- Department of Mathematics, College of Science, University of Bahrain, Sakhir, Bahrain
| | - Hemlata Singh
- Department of Biology, College of Science, University of Bahrain, Sakhir, Bahrain
| | - Mohamed M. Jahromi
- Salmaniya Medical Complex, Ministry of Health, Manama, Bahrain and Dasman Diabetes Institute, Kuwait City, Kuwait
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Adherence during antiviral treatment regimens for chronic hepatitis C: a qualitative study of patient-reported facilitators and barriers. J Clin Gastroenterol 2015; 49:e41-50. [PMID: 24828358 PMCID: PMC4231022 DOI: 10.1097/mcg.0000000000000151] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
GOALS To understand patients' perceptions of factors which facilitate and hinder adherence to inform adherence-enhancing interventions. BACKGROUND Adherence to antiviral therapy for hepatitis C viral infection is critical to achieving a sustained virological response. However, persistence with and adherence to antiviral regimens can pose challenges for patients that interfere with sustained virological response. STUDY A qualitative analysis of 21 semistructured patient interviews using open-ended questions and specific follow-up probes was conducted. Interviews were audio-recorded, transcribed, and content-analyzed iteratively to determine frequent and salient themes. RESULTS Three broad themes emerged: (1) missing doses and dose-timing errors; (2) facilitators of adherence; and (3) barriers to adherence. Open-ended questioning revealed few dose-timing deviations, but more specific probes uncovered several more occurrences of delays in dosing. Facilitators of adherence fell into 2 broad categories: (a) patient knowledge and motivation; and (b) practical behavioral strategies and routines. Facilitators were noted post hoc to be consistent with the Information-Motivation-Behavioral Skills Model of Adherence. Barriers to adherence involved changes in daily routine, being preoccupied with family or work responsibilities, and sleeping through dosing times. A few patients reported skipping doses due to side effects. Patients with previous hepatitis C virus treatment experience may have fewer dose-timing errors. Finally, a high level of anxiety among some patients was discovered regarding dosing errors. Emotional and informational support from clinical and research staff was key to assuaging patient fears. CONCLUSION This qualitative study improves our understanding of patients' perspectives regarding adhering to hepatitis C treatment and can lead to the development of adherence-enhancing interventions.
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15
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Hetta HF, Mehta MJ, Shata MTM. Gut immune response in the presence of hepatitis C virus infection. World J Immunol 2014; 4:52-62. [DOI: 10.5411/wji.v4.i2.52] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Revised: 05/22/2014] [Accepted: 06/20/2014] [Indexed: 02/05/2023] Open
Abstract
Hepatitis C virus (HCV) is an important etiologic agent of hepatitis and a major cause of chronic liver infection that often leads to cirrhosis, fibrosis and hepatocellular carcinoma. Although, HCV is a hepatotropic virus, there is strong evidence that HCV could replicate extra-hepatic in the gastrointestinal tissue which could serve as a reservoir for HCV. The outcome of HCV infection depends mainly on the host innate and adaptive immune responses. Innate immunity against HCV includes mainly nuclear factor cells and activation of IFN-related genes. There is an immunologic link between the gut and the liver through a population of T-cells that are capable of homing to both the liver and gut via the portal circulation. However, little is known on the role of Gut immune response in HCV. In this review we discussed the immune regulation of Gut immune cells and its association with HCV pathogenesis, various outcomes of anti-HCV therapy, viral persistence and degree of liver inflammation. Additionally, we investigated the relationship between Gut immune responses to HCV and IL28B genotypes, which were identified as a strong predictor for HCV pathogenesis and treatment outcome after acute infection.
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16
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Veerapu NS, Park SH, Tully DC, Allen TM, Rehermann B. Trace amounts of sporadically reappearing HCV RNA can cause infection. J Clin Invest 2014; 124:3469-78. [PMID: 25003189 DOI: 10.1172/jci73104] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2013] [Accepted: 05/29/2014] [Indexed: 12/20/2022] Open
Abstract
Successful hepatitis C virus (HCV) treatment is defined as the absence of viremia 6 months after therapy cessation. We previously reported that trace amounts of HCV RNA, below the sensitivity of the standard clinical assay, can reappear sporadically in treatment responders. Here, we assessed the infectivity of this RNA and infused 3 chimpanzees sequentially at 9-week intervals with plasma or PBMCs from patients who tested positive for trace amounts of HCV RNA more than 6 months after completing pegylated IFN-α/ribavirin therapy. A fourth chimpanzee received HCV RNA-negative plasma and PBMCs from healthy blood donors. The 3 experimental chimpanzees, but not the control chimpanzee, generated HCV-specific T cell responses against nonstructural and structural HCV sequences 6-10 weeks after the first infusion of patient plasma and during subsequent infusions. In 1 chimpanzee, T cell responses declined, and this animal developed high-level viremia at week 27. Deep sequencing of HCV demonstrated transmission of a minor HCV variant from the first infusion donor that persisted in the chimpanzee for more than 6 months despite undetectable systemic viremia. Collectively, these results demonstrate that trace amounts of HCV RNA, which appear sporadically in successfully treated patients, can be infectious; furthermore, transmission can be masked in the recipient by an extended eclipse phase prior to establishing high-level viremia.
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17
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Hara K, Rivera MM, Koh C, Demino M, Page S, Nagabhyru PR, Rehermann B, Liang TJ, Hoofnagle JH, Heller T. Sequence analysis of hepatitis C virus from patients with relapse after a sustained virological response: relapse or reinfection? J Infect Dis 2013; 209:38-45. [PMID: 24127561 DOI: 10.1093/infdis/jit541] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND A sustained virological response (SVR) is the major end point of therapy for chronic hepatitis C virus (HCV) infection. Late relapse of infection is rare and poorly characterized. Three of 103 patients with a SVR treated at the National Institutes of Health had late relapse. We evaluated HCV RNA sequences in serum and liver tissue to distinguish relapse from reinfection. METHODS Per patient, 10-22 clones of amplified 5' untranslated region were evaluated in pretreatment and relapse serum specimens and in liver biopsy specimens obtained during SVR. Genotypes and sequence diversity were evaluated. Four patients whose infection relapsed before they reached a SVR (ie, the early relapse group) were used as a comparison. RESULTS Results of tests for detection of serum HCV RNA in all patients with late relapse were repeatedly negative during the first 24 weeks after therapy but became positive 8, 75, and 78 months after SVR. Reinfection risk factors were absent in 2 of 3 patients. In all patients with early or late relapse, apart from minor variations, the original HCV sequence was present before treatment and after relapse. All liver biopsy specimens from patients with late relapse were HCV RNA positive at SVR, with sequences nearly identical to those of specimens obtained at other time points. CONCLUSIONS Sequence comparisons suggest that reappearance of HCV RNA years after a SVR can be from relapse of the initial viral infection rather than reinfection from a different virus.
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Affiliation(s)
- Koji Hara
- Translational Hepatology Unit, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
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18
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Cruzado JM, Gil-Vernet S, Castellote J, Bestard O, Melilli E, Grinyó JM. Successful treatment of chronic HCV infection should not preclude kidney donation to an HCV negative recipient. Am J Transplant 2013; 13:2773-4. [PMID: 23919533 DOI: 10.1111/ajt.12400] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Affiliation(s)
- J M Cruzado
- Nephrology Department, Hospital Universitari de Bellvitge, University of Barcelona, L'Hospitalet de Llobregat, Spain
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19
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Colson P, Bregigeon S, Tourres C, Solas C, Poizot-Martin I, Tamalet C. Relapse of hepatitis C virus after 14 months of sustained virological response following pegylated-interferon alpha plus ribavirin therapy in a human immunodeficiency virus type 1 infected patient. J Clin Virol 2013; 58:309-14. [DOI: 10.1016/j.jcv.2013.05.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2013] [Revised: 05/13/2013] [Accepted: 05/14/2013] [Indexed: 01/29/2023]
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Uyanikoglu A, Kaymakoglu S, Danalioglu A, Akyuz F, Ermis F, Pinarbasi B, Demir K, Besisik F, Cakaloglu Y. Durability of sustained virologic response in chronic hepatitis C. Gut Liver 2013; 7:458-61. [PMID: 23898387 PMCID: PMC3724035 DOI: 10.5009/gnl.2013.7.4.458] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2012] [Revised: 11/07/2012] [Accepted: 11/17/2012] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND/AIMS The aim of this study is to investigate the rate of sustained virologic response (SVR) in chronic hepatitis C patients receiving antiviral treatment. METHODS The files of patients with chronic hepatitis C treated with interferon±ribavirin between 1995 and 2009 were reviewed retrospectively. Six months after the end of treatment, patients with negative hepatitis C virus (HCV)-RNA (<50 IU/mL, as determined by the polymerase chain reaction method) were enrolled in the study. RESULTS The mean age of 196 patients (89 males) was 46.13±11.10 years (range, 17 to 73 years). In biopsies, the mean stage was 1.50±0.94; histological activity index was 7.18±2.43. In total, 139 patients received pegylated interferon (IFN)+ribavirin, 21 patients received classical IFN+ribavirin, and 36 patients received IFN alone. The HCV genotypes of 138 patients were checked: 77.5% were genotype 1b, and 22.5% were other genotypes. After achievement of SVR, the median follow-up period was 33.5 months (range, 6 to 112 months), and in this period relapse was only detected in two patients (1.02%) at 18 and 48 months after treatment. CONCLUSIONS In total, 98.9% of patients with SVR in chronic hepatitis C demonstrated truly durable responses over the long-term follow-up period of 3 years; relapsed patients had intermittent or low-grade viremia.
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Affiliation(s)
- Ahmet Uyanikoglu
- Department of Gastroenterology, Harran University Faculty of Medicine, Sanliurfa, Turkey
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21
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Kim MN, Kim BK, Han KH. Hepatocellular carcinoma in patients with chronic hepatitis C virus infection in the Asia-Pacific region. J Gastroenterol 2013; 48:681-8. [PMID: 23463401 PMCID: PMC3698419 DOI: 10.1007/s00535-013-0770-9] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2012] [Accepted: 02/05/2013] [Indexed: 02/04/2023]
Abstract
Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related mortality worldwide. Although hepatitis B still remains the most common risk factor worldwide, chronic hepatitis C virus (HCV) infection is the driving force for the increased incidence of HCC especially in Western countries and Japan. In hepatitis B virus (HBV)-endemic areas, after successful vaccination programs against HBV, chronic HCV infection is now emerging as an important cause of chronic liver diseases. Unlike patients with chronic hepatitis B, those with chronic hepatitis C (CHC) develop HCC in the presence of established cirrhosis in most cases. However, a significant minority of CHC develops HCC in the absence of cirrhosis. Although HCV is a RNA virus with little potential for integrating its genetic material into host genome, various HCV proteins, including core, envelope, and nonstructural proteins, have oncogenic properties by inducing oxidative stress, disturbing cellular regulatory pathways associated with proliferation and apoptosis, and suppressing host immune responses. Overall, a combination of virus-specific, host genetic, environmental, and immune-related factors are likely to determine progression to HCC. Strategies aimed at eliminating the virus may provide opportunities for effective prevention of the development of HCC. Pegylated interferon plus ribavirin therapy appears to be effective at reducing the risk of HCC in patients who achieve sustained virologic responses. In summary, with the emerging importance of CHC, mechanisms of HCV-associated hepatocellular carcinogenesis should be clarified to provide insight into advanced therapeutic and preventive approaches, which eventually decrease the incidence and mortality of HCC.
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Affiliation(s)
- Mi Na Kim
- />Department of Internal Medicine, Yonsei University College of Medicine, 250 Seongsanno Seodaemun-gu, Seoul, South Korea
| | - Beom Kyung Kim
- />Department of Internal Medicine, Yonsei University College of Medicine, 250 Seongsanno Seodaemun-gu, Seoul, South Korea
| | - Kwang-Hyub Han
- />Department of Internal Medicine, Yonsei University College of Medicine, 250 Seongsanno Seodaemun-gu, Seoul, South Korea
- />Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
- />Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
- />Liver Cirrhosis Clinical Research Center, Seoul, South Korea
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Fujiwara K, Allison RD, Wang RY, Bare P, Matsuura K, Schechterly C, Murthy K, Marincola FM, Alter HJ. Investigation of residual hepatitis C virus in presumed recovered subjects. Hepatology 2013; 57:483-491. [PMID: 22729600 PMCID: PMC4523271 DOI: 10.1002/hep.25921] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2012] [Accepted: 06/12/2012] [Indexed: 12/15/2022]
Abstract
UNLABELLED Recent studies have found hepatitis C virus (HCV) RNA in peripheral blood mononuclear cells (PBMCs) of the majority of presumed recovered subjects. We investigated this unexpected finding using samples from patients whose HCV RNA and anti-HCV status had been serially confirmed. HCV RNA was detected in PBMCs from 66 of 67 chronic HCV carriers. Subpopulation analysis revealed that the viral load (log copies/10(6) cells) in B cells (4.14 ± 0.71) was higher than in total PBMCs (3.62 ± 0.71; P < 0.05), T cells (1.67 ± 0.88; P < 0.05), and non-B/T cells (2.48 ± 1.15; P < 0.05). HCV negative-strand RNA was not detected in PBMCs from any of 25 chronically infected patients. No residual viral RNA was detected in total PBMCs or plasma of 59 presumed recovered subjects (11 spontaneous and 48 treatment induced) using nested real-time polymerase chain reaction with a detection limit of 2 copies/μg RNA (from ≈ 1 × 10(6) cells). PBMCs from 2 healthy HCV-negative blood donors became HCV RNA positive, with B-cell predominance, when mixed in vitro with HCV RNA-positive plasma, thus passively mimicking cells from chronic HCV carriers. No residual HCV was detected in liver or other tissues from 2 spontaneously recovered chimpanzees. CONCLUSION (1) HCV RNA was detected in PBMCs of most chronic HCV carriers and was predominant in the B-cell subpopulation; (2) HCV detected in PBMCs was in a nonreplicative form; (3) HCV passively adsorbed to PBMCs of healthy controls in vitro, becoming indistinguishable from PBMCs of chronic HCV carriers; and (4) residual HCV was not detected in plasma or PBMCs of any spontaneous or treatment-recovered subjects or in chimpanzee liver, suggesting that the classic pattern of recovery from HCV infection is generally equivalent to viral eradication.
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Affiliation(s)
- Kei Fujiwara
- Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD
- Department of Gastroenterology and Hepatology, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Robert D. Allison
- Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD
- United States Navy, San Diego, CA
| | - Richard Y. Wang
- Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD
| | - Patricia Bare
- Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD
- Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, Buenos Aires, Argentina
| | - Kentaro Matsuura
- Department of Gastroenterology and Metabolism, Nagoya City University, Nagoya, Japan
| | - Cathy Schechterly
- Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD
| | | | - Francesco M. Marincola
- Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD
| | - Harvey J. Alter
- Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD
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Long-term follow-up of responder and super-responder chronic hepatitis C Egyptian patients treated with interferon α-2a plus ribavirin. EGYPTIAN LIVER JOURNAL 2012. [DOI: 10.1097/01.elx.0000419585.00605.bc] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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Tanwar S, Trembling PM, Dusheiko GM. Hepatitis C Therapy: Lessons of the Last Two Decades. ACTA ACUST UNITED AC 2012. [DOI: 10.1007/s11901-012-0141-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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25
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Sugden PB, Cameron B, Bull R, White PA, Lloyd AR. Occult infection with hepatitis C virus: friend or foe? Immunol Cell Biol 2012; 90:763-73. [PMID: 22546735 DOI: 10.1038/icb.2012.20] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Hepatitis C virus (HCV) infection is a global pandemic associated with a growing disease burden due to cirrhosis and the consequent morbidity and mortality. Transmission is largely via blood-to-blood contact. Following primary infection, a minority of individuals clear the infection predominantly via cellular immune mechanisms, whereas the majority become chronically infected. Recent data suggest that a third outcome may also be possible, termed 'occult' infection in which subjects who are known, or suspected to have previously been infected with HCV, no longer have viral RNA in their serum at levels detectable by sensitive commercial assays, but do have virus detected by ultra-sensitive techniques. Occult infection has also been detected in peripheral blood mononuclear cells, which may indicate an extra-hepatic reservoir of the virus. Although the clinical significance of occult infection remains unknown, most authors have raised concerns of recrudescent infection. Here we critically review the published literature, suggest further avenues of investigation and propose that occult infection may be beneficial to the host by maintaining immunological memory to protect against reinfection.
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Affiliation(s)
- Peter B Sugden
- Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia
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26
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Campos-Varela I, Castells L, Esteban JI, Bes M, Rodríguez-Frías F, Sapisochin G, Allende H, Charco R, Esteban R. Twelve-week posttreatment follow-up to predict sustained virologic response for recurrent hepatitis C infection in liver recipients. Transplantation 2012; 93:450-453. [PMID: 22262129 DOI: 10.1097/tp.0b013e318240e9dd] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND The current standard for determining sustained virologic response (SVR) in patients treated for hepatitis C virus (HCV) infection is undetectable serum HCV-RNA 24 weeks after treatment. This study evaluates the value of HCV-RNA determination at 12 weeks posttreatment (W+12) to predict SVR in liver transplant (LT) patients treated with pegylated interferon and ribavirin for recurrent HCV infection. METHODS This study, performed in 2001 to 2010, included HCV-LT patients with an end-of-treatment response (undetectable serum HCV-RNA) and HCV-RNA testing at 12 and 24 weeks posttreatment (W+12/W+24). HCV-RNA was detected with a qualitative polymerase chain reaction assay (detection limit 50 IU/mL) and, when positive, measured by quantitative PCR (detection limit 600 IU/mL) up to 2006. Since 2007, a real-time PCR-based test (detection limit 15 IU/mL) has been used. The positive predictive value (PPV) was defined as the probability that SVR would occur in patients with undetectable HCV-RNA at W+12 and W+24. RESULTS Of 162 patients treated during the study period, 57 (35%) had end-of-treatment response and were included. Of these, 45 (79%) had SVR and 12 (21%) had virologic relapse. At W+12, HCV-RNA was undetectable in 45 (79%) patients, all of whom had SVR, yielding a PPV for SVR at W+12 of 100% (95% confidence interval, 75.8%-100%). CONCLUSIONS Undetectable HCV-RNA at W+12 posttreatment has a high PPV for predicting SVR. HCV-RNA testing to assess SVR at this time point seems as valid as W+24 testing and could be considered for predicting SVR in HCV-LT patients receiving treatment with pegylated interferon and ribavirin.
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Affiliation(s)
- Isabel Campos-Varela
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
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Development of a hepatocellular carcinoma in a chronic hepatitis C patient 18 years after achieving a sustained virological response to interferon therapy: case report and literature review. Clin J Gastroenterol 2012; 5:119-26. [DOI: 10.1007/s12328-012-0284-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2011] [Accepted: 12/20/2011] [Indexed: 01/25/2023]
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Maruoka D, Imazeki F, Arai M, Kanda T, Fujiwara K, Yokosuka O. Longitudinal changes of the laboratory data of chronic hepatitis C patients with sustained virological response on long-term follow-up. J Viral Hepat 2012; 19:e97-104. [PMID: 22239532 DOI: 10.1111/j.1365-2893.2011.01512.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
There is no study that follows up longitudinal changes in laboratory data of patients with C-viral chronic liver disease (C-CLD) who achieved sustained virological esponse (SVR) with interferon treatment in a long-term study. We investigated the laboratory data in a long-term retrospective cohort study of 581 patients with C-CLD who underwent liver biopsy between January 1986 and December 2005. 467 were treated with interferon and 207 of these patients achieved SVR with follow-up periods of 8.36 ± 5.13 years. Alanine aminotransferase (ALT) levels, albumin levels, platelet counts, and the aspartate aminotransferase (AST)-to-platelet ratio index (APRI) values were serially examined during the follow-up period. None of the 207 patients with SVR exhibited hepatitis C virus (HCV) RNA positivity more than 6 months after the end of IFN treatment. Platelet counts and albumin levels increased only in those with eradication of HCV. APRI values decreased more in patients with SVR than in those with nonsustained virological responses (non-SVR). Patients who achieved SVR and had fibrosis stage 0-1 and 2-4 at enrolment had platelet counts that longitudinally increased by 2.81 ± 3.95 and 5.49 ± 4.53 × 10(3) /μL during the 10-year follow-up period, respectively. Albumin levels continuously increased during the first 2 years by 0.15 ± 0.31 and 0.33 ± 0.37 in fibrosis stage 0-1 and 2-4, respectively and then plateaued. ALT levels decreased rapidly one year after the start of treatment by 110.3 ± 140.0 and 100.5 ± 123.4 in fibrosis 0-1 and 2-4, respectively. HCV RNA negativity persisted in all patients with SVR, and laboratory data including APRI longitudinally improved during the long-term follow-up period.
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Affiliation(s)
- D Maruoka
- Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba City, Japan
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Namikawa M, Kakizaki S, Yata Y, Yamazaki Y, Horiguchi N, Sato K, Takagi H, Mori M. Optimal follow-up time to determine the sustained virological response in patients with chronic hepatitis C receiving pegylated-interferon and ribavirin. J Gastroenterol Hepatol 2012; 27:69-75. [PMID: 21649727 DOI: 10.1111/j.1440-1746.2011.06802.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
BACKGROUND AND AIM This study evaluated whether the assessment of hepatitis C virus (HCV)-RNA at 12 weeks (FW+12) post-treatment follow-up was as applicable as FW+24 to evaluate sustained virological response (SVR) using the highly sensitive real-time polymerase chain reaction (PCR) HCV assay. METHODS AND RESULTS Two hundred and twenty-two patients with chronic hepatitis C were included in this study. Pegylated interferon (Peg-IFN) and ribavirin were administered for 24-72 weeks based on the genotype and viral load. Serum HCV-RNA was measured using real-time PCR at pretreatment, the end of treatment, FW+4, FW+8, FW+12, FW+16, FW+20 and FW+24. Two hundred patients had a virological response at the end of treatment. One hundred and forty-eight of 200 (74.0%) patients with a virological response at the end of treatment had an SVR at the FW+24. The positive predictive value (PPV) to identify patients with SVR at FW+4, FW+8, FW+12 was 87.1, 96.1, 98.0%, respectively. The viral load showed a reversion to the basal level as early as 8 weeks in relapse patients. There were only three patients who relapsed after FW+12 and all three of these patients were females with genotype Ib and a high viral load. CONCLUSION The assessment of serum HCV-RNA FW+12, using the highly sensitive real-time PCR assay, is almost as effective as FW+24 to predict SVR. However, there are false negatives in female patients with a high viral load of genotype Ib when the SVR is predicted by FW+12. The current standard with FW+24 is reasonable, but the assessment of serum HCV-RNA FW+12 may be effective in most patients.
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Affiliation(s)
- Masashi Namikawa
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
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Maylin S, Laouénan C, Martinot-Peignoux M, Panhard X, Lapalus M, Nicolas-Chanoine MH, Bedossa P, Asselah T, Marcellin P. Role of hepatic HCV–RNA level on the severity of chronic hepatitis C and response to antiviral therapy. J Clin Virol 2012; 53:43-7. [DOI: 10.1016/j.jcv.2011.09.029] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2011] [Revised: 09/28/2011] [Accepted: 09/29/2011] [Indexed: 01/27/2023]
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Hosseini-Moghaddam SM, Iran-Pour E, Rotstein C, Husain S, Lilly L, Renner E, Mazzulli T. Hepatitis C core Ag and its clinical applicability: Potential advantages and disadvantages for diagnosis and follow-up? Rev Med Virol 2011; 22:156-65. [PMID: 22121001 DOI: 10.1002/rmv.717] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2011] [Revised: 09/18/2011] [Accepted: 09/19/2011] [Indexed: 12/20/2022]
Affiliation(s)
- SM Hosseini-Moghaddam
- Division of Infectious Diseases; University of Toronto, University Health Network, Transplant Infectious Diseases, Toronto General Hospital; Toronto ON Canada
- Urology and Nephrology Research Center (UNRC); Shahid Beheshti University of Medical Sciences; Tehran IR Iran
| | - E. Iran-Pour
- Islamic Azad University; Tehran Medical Branch; Tehran IR Iran
| | - C. Rotstein
- Division of Infectious Diseases; University of Toronto, University Health Network, Transplant Infectious Diseases, Toronto General Hospital; Toronto ON Canada
| | - S. Husain
- Division of Infectious Diseases; University of Toronto, University Health Network, Transplant Infectious Diseases, Toronto General Hospital; Toronto ON Canada
| | - L. Lilly
- Hepatology; University of Toronto, University Health Network, Transplant Hepatology, Toronto General Hospital; Toronto ON Canada
| | - E. Renner
- Hepatology; University of Toronto, University Health Network, Transplant Hepatology, Toronto General Hospital; Toronto ON Canada
| | - T. Mazzulli
- Virology, Department of Microbiology; University of Toronto, University Health Network, Mount Sinai Hospital; Toronto ON Canada
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Heo J. Durability of antiviral therapy for chronic hepatitis C after achieving sustained virological response. THE KOREAN JOURNAL OF HEPATOLOGY 2011; 17:180-2. [PMID: 22102383 PMCID: PMC3304652 DOI: 10.3350/kjhep.2011.17.3.180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Veerapu NS, Raghuraman S, Liang TJ, Heller T, Rehermann B. Sporadic reappearance of minute amounts of hepatitis C virus RNA after successful therapy stimulates cellular immune responses. Gastroenterology 2011; 140:676-685.e1. [PMID: 21040725 PMCID: PMC3399733 DOI: 10.1053/j.gastro.2010.10.048] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2010] [Revised: 09/24/2010] [Accepted: 10/22/2010] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Several studies have reported hepatitis C virus (HCV) RNA sequences in the circulation after treatment-induced or spontaneous recovery. We investigated whether the HCV RNA represents persistence of HCV infection or reinfection. METHODS We studied 117 patients who recovered from HCV infection (98 following therapy and 19 spontaneously). A reverse-transcription polymerase chain reaction assay was used to detect the 5'-untranslated region of HCV. T-cell responses were studied by enzyme-linked immunospot for interferon-γ. RESULTS Plasma samples from 15% of treatment-recovered patients and no spontaneously recovered patient tested positive for HCV RNA. Lymphocytes from 3 patients who responded to therapy and 1 who recovered spontaneously tested positive. The frequency of HCV RNA detection in plasma correlated inversely with the time after the end of treatment. Post-treatment HCV 5'-untranslated region sequences matched pretreatment sequences in 85% of cases. T-cell responses were significantly greater at time points with detectable trace amounts of HCV RNA than at time points without detectable HCV RNA (P = .035) and were primarily against nonstructural HCV antigens. The immune hierarchy was preserved over 5 years in patients whose post-treatment HCV RNA sequences matched pretreatment sequences, indicating HCV RNA persistence. An altered immune hierarchy with dominant immune responses, shifting from nonstructural to structural antigens, was observed in a single patient whose post-treatment HCV genotype differed from that of the pretreatment genotype, indicating HCV reinfection. CONCLUSIONS Trace amounts of HCV RNA of pretreatment sequence persisted and reappeared sporadically in the circulation within 8 years after recovery from hepatitis C but not thereafter, indicating that patients are cured of HCV infection. Reappearance of HCV RNA induced HCV-specific T-cell responses.
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Affiliation(s)
- Naga Suresh Veerapu
- Immunology Section, NIDDK, National Institutes of Health, DHHS, Bethesda, Maryland 20892-1800, USA
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Kim KA. Durability of a sustained virologic response in patients with chronic hepatitis C treated with peginterferon and ribavirin. THE KOREAN JOURNAL OF HEPATOLOGY 2011. [PMCID: PMC3304624 DOI: 10.3350/kjhep.2011.17.1.84] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Kyung-Ah Kim
- Department of Internal Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
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Swain MG, Lai MY, Shiffman ML, Cooksley WGE, Zeuzem S, Dieterich DT, Abergel A, Pessôa MG, Lin A, Tietz A, Connell EV, Diago M. A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin. Gastroenterology 2010; 139:1593-601. [PMID: 20637202 DOI: 10.1053/j.gastro.2010.07.009] [Citation(s) in RCA: 234] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2010] [Revised: 06/11/2010] [Accepted: 07/08/2010] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS A sustained virologic response (SVR) to therapy for hepatitis C virus (HCV) infection is defined as the inability to detect HCV RNA 24 weeks after completion of treatment. Although small studies have reported that the SVR is durable and lasts for long periods, it has not been conclusively shown. METHODS The durability of treatment responses was examined in patients originally enrolled in one of 9 randomized multicenter trials (n = 1343). The study included patients who received pegylated interferon (peginterferon) alfa-2a alone (n = 166) or in combination with ribavirin (n = 1077, including 79 patients with normal alanine aminotransferase levels and 100 patients who were coinfected with human immunodeficiency virus and HCV) and whose serum samples were negative for HCV RNA (<50 IU/mL) at their final assessment. Patients were assessed annually, from the date of last treatment, for a mean of 3.9 years (range, 0.8-7.1 years). RESULTS Most patients (99.1%) who achieved an SVR had undetectable levels of HCV RNA in serum samples throughout the follow-up period. Serum samples from 0.9% of the patients contained HCV RNA a mean of 1.8 years (range, 1.1-2.9 years) after treatment ended. It is not clear if these patients were reinfected or experienced a relapse. CONCLUSIONS In a large cohort of patients monitored for the durability of an SVR, the SVR was maintained for almost 4 years after treatment with peginterferon alfa-2a alone or in combination with ribavirin. In patients with chronic hepatitis C infection, the SVR is durable and these patients should be considered as cured.
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Affiliation(s)
- Mark G Swain
- Health Research Innovation Center, University of Calgary, Calgary, Alberta, Canada.
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Evolution of interferon-based therapy for chronic hepatitis C. HEPATITIS RESEARCH AND TREATMENT 2010; 2010:140953. [PMID: 21152178 PMCID: PMC2990099 DOI: 10.1155/2010/140953] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/15/2010] [Accepted: 08/23/2010] [Indexed: 12/29/2022]
Abstract
Since 1986, interferon-alfa (IFN-α) monotherapy has been administered for patients with chronic hepatitis C (CHC). However, sustained response rate is only about 8% to 9%. Subsequent introduction of ribavirin in combination with IFN-α was a major breakthrough in the treatment of CHC. Sustained virological responses (SVRs) rate is about 30% in hepatitis C virus genotype 1 (HCV-1) patients, and is about 65% in HCV-2 or -3 patients. After 2000, pegylated interferon (PegIFN) much improved the rates of SVR. Presently, PegIFN-α-ribavirin combination therapy has been current standard of care for patients infected with HCV. In patients with HCV-1, treatment for 48 weeks is optimal, but 24 weeks of treatment is sufficient in HCV-2 or -3 infected patients. Clinical factors have been identified as predictors for the efficacy of the IFN-based therapy. The baseline factor most strongly predictive of an SVR is the presence of HCV-2 or -3 infections. Rapid virological response (RVR) is the single best predictor of an SVR to PegIFN-ribavirin therapy. If patients can't achieve a RVR but achieve a complete early virological response (cEVR), treatment with current standard of care can provide more than 90% SVR rate. HCV-1 patients who do not achieve an EVR should discontinue the therapy. Recent advances of protease inhibitor may contribute the development of a novel triple combination therapy.
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Bate JP, Colman AJ, Frost PJ, Shaw DR, Harley HAJ. High prevalence of late relapse and reinfection in prisoners treated for chronic hepatitis C. J Gastroenterol Hepatol 2010; 25:1276-80. [PMID: 20594255 DOI: 10.1111/j.1440-1746.2010.06295.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Prisoners have a high prevalence of injection drug use (IDU) and chronic hepatitis C (CHC) infection. Treatment of CHC in these patients is effective; however, their long-term outcomes following treatment are unknown. We determined the durability of a sustained virological response (SVR) in prisoners treated for CHC. METHODS Patients were treated as part of routine clinical practice with interferon (IFN) and ribavirin. A retrospective review of medical records and a computerized pathology system was performed for clinical and laboratory information. RESULTS Seventy-four prisoners (70 males, mean age 34 years, IDU in 55%) were evaluable for a SVR over a 12-year period to December 2008; the mean follow-up period was 1243 days. Genotype 1, 2, 3, and 6 infection was present in 18, three, 38 and three patients, respectively; the genotype was unknown in 12. Three out of 52 biopsied had cirrhosis. Standard IFN was administered to 25 (34%; 11 with ribavirin), and 49 received pegylated IFN and ribavirin; one did not complete treatment, and two had breakthrough relapses. The end-of-treatment response was achieved in 57 and SVR in 53; 14 were non-responders. Five male patients, four with unknown genotypes and treated with standard IFN alone, relapsed late (following SVR, 9%). Five patients, all treated with pegylated IFN and ribavirin, were reinfected (one prior to and four following SVR). CONCLUSIONS Prisoners are often successfully treated for CHC. However, this retrospective study indicates that there is a high (17%) prevalence of late recurrence of viremia that is likely a reflection of reinfection due to ongoing risk-taking behavior.
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Affiliation(s)
- John P Bate
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, South Australia, Australia
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da Costa Ferreira S, de Vasconcelos Carneiro M, Souza FF, Teixeira AC, Villanova MG, de Castro Figueiredo JF, Passos ADC, Ramalho LNZ, Zucoloto S, Martinelli ADLC. Long-term follow-up of patients with chronic hepatitis C with sustained virologic response to interferon. Braz J Infect Dis 2010. [DOI: 10.1016/s1413-8670(10)70070-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Fujii H, Itoh Y, Ohnishi N, Sakamoto M, Ohkawara T, Sawa Y, Nishida K, Nishimura T, Yamaguchi K, Yasui K, Minami M, Okanoue T, Ohkawara Y, Yoshikawa T. Relapse of hepatitis C in a pegylated-interferon-alpha-2b plus ribavirin-treated sustained virological responder. Hepatol Res 2010; 40:654-60. [PMID: 20618461 DOI: 10.1111/j.1872-034x.2010.00641.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
A 41-year-old woman with chronic hepatitis C was treated with pegylated-interferon (PEG-IFN)-alpha-2b plus ribavirin for 24 weeks. She had hepatitis C virus (HCV) genotype 2a (1600 KIU/mL), and her liver histology showed mild inflammation and fibrosis. Four weeks after the start of the therapy, she achieved a rapid virological response (RVR) and then a sustained virological response (SVR). Serum alanine aminotransferase (ALT) levels remained within normal ranges and HCV RNA continued to be negative. However, ALT levels flared with the re-emergence of HCV RNA in the serum 1.5 years after discontinuation of therapy. HCV RNA obtained from sera before therapy and after relapse shared a 98.6% homology with the E2 region, and phylogenetic analyses indicated that they were the same HCV strain. These results eliminated the possibility of a re-infection and strongly indicated a late relapse of the disease. Therefore, follow-up is necessary for chronic hepatitis C patients after SVR, even if they respond well to therapy, including RVR.
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Affiliation(s)
- Hideki Fujii
- Department of Internal Medicine, Aiseikai Yamashina Hospital, Kyoto, Japan
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Martinot-Peignoux M, Stern C, Maylin S, Ripault MP, Boyer N, Leclere L, Castelnau C, Giuily N, El Ray A, Cardoso AC, Moucari R, Asselah T, Marcellin P. Twelve weeks posttreatment follow-up is as relevant as 24 weeks to determine the sustained virologic response in patients with hepatitis C virus receiving pegylated interferon and ribavirin. Hepatology 2010; 51:1122-6. [PMID: 20069649 DOI: 10.1002/hep.23444] [Citation(s) in RCA: 128] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
UNLABELLED A sustained virologic response (SVR) in patients with chronic hepatitis C receiving pegylated interferon (PEG-IFN) plus ribavirin is defined as undetectable serum HCV-RNA at 24 weeks (W+24) posttreatment follow-up. Viral load outcome in patients with virological relapse (VR) has not been explored. This study evaluated whether the assessment of serum HCV-RNA 12 weeks (W+12) after the end of treatment was as relevant as W+24 to evaluate SVR in 573 patients who received combination PEG-IFN and ribavirin and had a virological response at the end of treatment. Serum HCV-RNA was measured, using a new assay based on transcription-mediated amplification (TMA) with a lowest detection limit of 5-10 IU/mL, at W+12 and W+24 after the end of treatment. VR was defined as reappearance of detectable HCV-RNA at W+24 posttreatment follow-up. The positive predictive value (PPV) of undetectable serum HCV-RNA at W+12 was evaluated to identify patients with SVR, and the viral load outcome was measured in relapse patients. At the W+24 posttreatment follow-up, 408 (71%) patients had an SVR, 181 (71.2%) were treated with PEG-IFNalpha-2a and ribavirin, and 227 (71.1%) were treated with PEG-IFNalpha-2b and ribavirin. At W+12, serum HCV-RNA was undetectable in 409 patients, and 408 patients were SVR (PPV 99.7%, 95% confidence interval 99.1-100). In relapse patients, serum HCV-RNA levels were 5.623 +/- 0.748, 4.979 +/- 0.870, and 5.216 +/- 0.758 log(10) IU/mL at baseline, W+12, and W+24, respectively. CONCLUSION Our results show that the assessment of serum HCV-RNA 12 weeks after the end of treatment, using the highly sensitive TMA assay (PPV 99.7%), is as relevant as after 24 weeks to predict SVR and make decisions on the management of treated patients, suggesting a new definition for SVR.
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Affiliation(s)
- Michelle Martinot-Peignoux
- Institut National de la Santé et de la Recherche Médicale, U-773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, Université Paris VII, Paris, France.
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Samanta T, Das AK, Ganguly S, Sharma S, Mittal R, Thara A, Sood N, Kaur A. Profile of hepatitis A infection with atypical manifestations in children. Indian J Gastroenterol 2010; 29:31-3. [PMID: 20373084 DOI: 10.1007/s12664-010-0006-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2008] [Revised: 05/20/2009] [Accepted: 01/03/2010] [Indexed: 02/04/2023]
Abstract
We assessed the clinical course and biochemical profile of symptomatic children with viral hepatitis A who had atypical manifestations. Of 229 children with hepatitis A, atypical manifestations were found in 32 (14%) subjects. Prolonged cholestasis (n = 14), acute liver failure (9), relapse (9), ascites (8), and hematological problems (8) were the common presentations. Liver histology was suggestive of chronic liver disease in six children with protracted jaundice. Patients with atypical presentations were older (7.7 [1.6] years vs. 6.5 [2.6] years; p=0.012) and had higher total serum bilirubin (13.7 [8.1] mg/dL vs. 7.2 [4.0] mg/dL; p=<0.001) than those with typical presentation. Approximately 15% of children with acute hepatitis A infection have atypical presentation which is associated with increase in morbidity.
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Affiliation(s)
- Tryambak Samanta
- Department of Pediatrics, Nilratan Sircar Medical College and Hospital, Kolkata, 700 014, India.
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Nicot F, Kamar N, Mariamé B, Rostaing L, Pasquier C, Izopet J. No evidence of occult hepatitis C virus (HCV) infection in serum of HCV antibody-positive HCV RNA-negative kidney-transplant patients. Transpl Int 2009; 23:594-601. [PMID: 20002658 DOI: 10.1111/j.1432-2277.2009.01025.x] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Persistence of hepatitis C virus (HCV) in patients who cleared HCV is still debated. Occult HCV infection is described as the presence of detectable HCV RNA in liver or peripheral blood mononuclear cells (PBMCs) of patients with undetectable plasma HCV-RNA by conventional PCR assays. We have assessed the persistence of HCV in 26 kidney-transplant patients, followed up for 10.5 years (range 2-16), after HCV elimination while on hemodialysis. If HCV really did persist, arising out of the loss of immune control caused by institution of the regimen of immunosuppressive drugs after kidney transplantation, HCV reactivation would have taken place. Their immunosuppression relied on calcineurin inhibitors (100%), and/or steroids (62%), and/or antimetabolites (94%). An induction therapy, given to 22 patients, relied on rabbit antithymocyte globulin (59%) or anti-IL2-receptor blockers (32%). All patients had undetectable HCV RNA as ascertained by several conventional tests. At the last follow-up, no residual HCV RNA was detected in the five liver biopsies, the 26 plasma, and in the 37 nonstimulated and 24 stimulated PBMCs tested with an ultrasensitive RT-PCR assay (detection limit, 2 IU/ml). No biochemical or virologic relapse was seen during follow-up. The absence of HCV relapse in formerly HCV-infected immunocompromised patients suggests the complete eradication of HCV after its elimination while on dialysis.
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Kim CH, Park BD, Lee JW, Kim YS, Jeong S, Lee DH, Kim HG, Shin YW, Kwon KS, Lee JI. [Durability of a sustained virologic response in combination therapy with interferon/peginterferon and ribavirin for chronic hepatitis C]. THE KOREAN JOURNAL OF HEPATOLOGY 2009; 15:70-9. [PMID: 19346787 DOI: 10.3350/kjhep.2009.15.1.70] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUNDS/AIMS The ultimate goal of antiviral therapy using interferon/pegylated interferon combined with ribavirin in chronic C-viral hepatitis is to achieve a sustained virologic response (SVR). Several studies have shown that the reappearance rate of hepatitis C virus (HCV) RNA in serum after the achievement of an SVR is less than 1%; the durability of an SVR in Korean patients is not known. The aim of this study was to determine the durability of the virologic response in chronic hepatitis C patients with an SVR to antiviral therapy. METHODS A total of 156 patients who were treated successfully with interferon/peginterferon and ribavirin were evaluated retrospectively. Patients received either subcutaneous conventional interferon alpha 3x10(6) units three times a week or subcutaneous pegylated interferon (alpha-2a: 180 microgram, alpha-2b: 80-100 microgram) once a week in combination with ribavirin at 600-1,200 mg daily (depending on body weight). Patients with HCV genotype 1 were treated for 48 weeks, whereas those with non-genotype 1 were treated for 24 weeks. RESULTS Eighty-two patients underwent treatment with conventional interferon and ribavirin, whereas 74 patients were treated with pegylated interferon and ribavirin. An SVR was achieved in 73 patients (73/156, 46.8%). HCV RNA reappeared in eight patients (8/73, 11.0%; detected by qualitative PCR), including one patient with persistent viremia (1/73, 1.4%). CONCLUSIONS Reappearance of HCV RNA after earlier achievement of an SVR might appear more frequently than previously reported. Close follow-up of these patients is recommended and the implication of temporary viremia should be determined in the future.
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Affiliation(s)
- Chul Hyun Kim
- Department of Gastroenterology, Inha University College of Medicine, Incheon, Korea
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Abstract
After the discovery of the hepatitis B virus in 1968 and of the hepatitis A virus in 1973, many years were needed to identify the hepatitis C virus (HCV) in 1989. The discovery of HCV was a revolution for hepatology because of the magnitude of the global burden related to HCV infection, a major cause of cirrhosis and hepatocellular carcinoma. Therapy of hepatitis C has rapidly evolved with currently nearly 60% of sustained virological response with the combination of pegylated interferon plus ribavirin. In patients with sustained virological response, viral eradication, corresponding to the cure of infection, and regression of histological liver lesions have been demonstrated. Recently, the availability of in vitro culture systems allowed to characterize viral enzymes, potential therapeutic targets. A novel therapeutic era is open with the protease and polymerase inhibitors, used as a first step in association with pegylated interferon and ribavirin, both to increase efficacy and decrease the risk of resistance. Thanks to these new molecules with a potent antiviral activity, one can reasonably predict a rapid improvement of treatments becoming more efficient and also better tolerated with the progressive replacement of interferon and ribavirin by combinations of these virus specific enzyme inhibitors.
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Affiliation(s)
- P Marcellin
- Inserm U773 CRB3, Service d'Hépatologie, Université de Paris-7, Hôpital Beaujon, 92110 Clichy, France.
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Ueno Y, Sollano JD, Farrell GC. Prevention of hepatocellular carcinoma complicating chronic hepatitis C. J Gastroenterol Hepatol 2009; 24:531-6. [PMID: 19368633 DOI: 10.1111/j.1440-1746.2009.05814.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Chronic hepatitis C virus (HCV) infection accounts for most cases of hepatocellular carcinoma (HCC) in Japan and is the second major cause in many other countries. Development of HCC takes a considerable time after onset of HCV infection, between 20-40 years in most cases, and usually develops after cirrhosis is established. Although only a minority of HCV infections reach this stage, the high prevalence of chronic HCV infection in many countries (1-3%) is such that HCC related to HCV infection poses a significant public health issue 20-50 years after the onset of HCV epidemics. Due to advances in testing, and accessibility of clean, disposable medical apparatus including syringes and needles, and particularly screening of donor blood for anti-HCV and by nucleic acid testing, new cases of HCV infection have decreased in most countries, except for continued transmission by injection drug users (IDU). A key difference between HBV and HCV infection is that HCV can be eradicated by effective antiviral treatment. Sustained eradication of HCV reverses hepatic fibrosis, thereby preventing progression to cirrhosis and risk of HCC. Further, it has been well demonstrated that interferon-based antiviral therapy suppresses development of HCC in high-risk patients, particularly when sustained viral response (SVR) is obtained. In summary, the two key approaches to prevent development of HCV-related HCC are primary prevention of HCV infection (adequate programs to screen donor blood, universal precautions to stop medical transmission of blood-borne viruses, curbing transmission by IDU) and potent antiviral therapy of chronic HCV infection.
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Affiliation(s)
- Yoshiyuki Ueno
- Tohoku University Graduate School of Medicine, Division of Gastroenterology, 1-1 Seiryo, Aobaku, Sendai 980-8574, Japan.
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Maylin S, Martinot-Peignoux M, Ripault MP, Moucari R, Cardoso AC, Boyer N, Giuily N, Castelnau C, Pouteau M, Asselah T, Nicolas-Chanoine MH, Marcellin P. Sustained virological response is associated with clearance of hepatitis C virus RNA and a decrease in hepatitis C virus antibody. Liver Int 2009; 29:511-7. [PMID: 19076273 PMCID: PMC2711258 DOI: 10.1111/j.1478-3231.2008.01918.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
BACKGROUND/AIM Viral eradication in chronic hepatitis C patients with sustained virological response (SVR) after interferon (IFN) therapy remains controversial. METHODS During a long-term follow-up study, 157 patients with SVR to IFN-alpha-2b-based therapy were investigated with a transcription-mediated amplification (TMA) assay in serum. The hepatitis C virus (HCV) antibody was assessed by measuring the optical density (OD) (Axsym HCV v3.0) and the semiquantitative titres (RIBA HCV v3.0) of the HCV antibodies directed against the core, NS3, NS4 and NS5 proteins. A control group included 23 untreated patients with persistently normal serum alanine aminotransferase and detectable serum HCV-RNA. RESULTS The median duration of follow-up was 4.0 (0-10) years. Serum HCV-RNA remained undetectable in all patients. The mean HCV antibody OD were 93 +/- 19 and 45 +/- 21 before therapy and in the last available serum sample respectively (P=0.001). There was a marked decrease in the HCV antibodies directed against the NS3, NS4 and NS5 proteins (P=0.001), while the core protein titre remained strongly positive. The 23 control patients were followed for a median of 5 (2-14) years. The mean HCV antibody OD were 65 +/- 14 and 64 +/- 19 in the first and the last measurements, respectively (NS), and HCV antibody titres for structural and non-structural proteins remained unchanged. CONCLUSION This long-term study evaluating 157 patients demonstrated that SVR assessed by TMA is durable, and HCV antibodies were markedly decreased (mainly those directed against the non-structural proteins), emphasizing an absence of ongoing infection. These results strongly suggest that HCV infection cured in patients who achieve an SVR.
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Affiliation(s)
- Sarah Maylin
- Service de Microbiologie, Hôpital BeaujonClichy, France,INSERM, U-773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, Université Paris VII, Hôpital BeaujonClichy, France
| | - Michelle Martinot-Peignoux
- INSERM, U-773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, Université Paris VII, Hôpital BeaujonClichy, France
| | | | - Rami Moucari
- INSERM, U-773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, Université Paris VII, Hôpital BeaujonClichy, France,Service d'Hépatologie, Hôpital BeaujonClichy, France
| | - Ana Carolina Cardoso
- INSERM, U-773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, Université Paris VII, Hôpital BeaujonClichy, France,Service d'Hépatologie, Hôpital BeaujonClichy, France
| | | | | | | | | | - Tarik Asselah
- INSERM, U-773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, Université Paris VII, Hôpital BeaujonClichy, France,Service d'Hépatologie, Hôpital BeaujonClichy, France
| | | | - Patrick Marcellin
- INSERM, U-773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, Université Paris VII, Hôpital BeaujonClichy, France,Service d'Hépatologie, Hôpital BeaujonClichy, France
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Nelson DR, Davis GL, Jacobson I, Everson GT, Fried MW, Harrison SA, Hassanein T, Jensen DM, Lindsay KL, Terrault N, Zein N. Hepatitis C virus: a critical appraisal of approaches to therapy. Clin Gastroenterol Hepatol 2009; 7:397-414; quiz 366. [PMID: 19114127 DOI: 10.1016/j.cgh.2008.11.016] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2008] [Accepted: 11/16/2008] [Indexed: 02/07/2023]
Affiliation(s)
- David R Nelson
- Hepatology and Liver Transplantation, University of Florida, Gainesville, Florida 32610, USA.
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Abstract
Approximately one-third of all patients infected with hepatitis C virus (HCV) genotype 1 who complete pegylated interferon α-based therapy and have undetectable serum HCV RNA at the end of treatment will experience relapse. Although relapse is a common outcome of therapy, its pathology and strategies for optimal management are poorly understood; however, optimized ribavirin dosing is recognized as pivotal in mitigating relapse. Recent data also suggest that early viral kinetics might help identify particular patient groups, such as slow responders, who are predisposed to relapse. This review provides a comprehensive overview of the importance of relapse in patients with chronic hepatitis C, including its underlying pathobiology, potential predictors and strategies to optimize the retreatment of previous relapsers.
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Affiliation(s)
- F Fred Poordad
- Gastroenterology and Hepatology, Cedars–Sinai Medical Center, Los Angeles, CA, USA
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Affiliation(s)
- Martin-Walter Welker
- Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany
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