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Moghimi M, Tavakoli F, Doosti M, Ahmadi-Vasmehjani A, Akhondi-Meybodi M. Correlation between interleukin-28 gene polymorphism with interleukin-28 cytokine levels and viral genotypes among HCV patients in Yazd, Iran. BMC Res Notes 2019; 12:626. [PMID: 31551080 PMCID: PMC6760063 DOI: 10.1186/s13104-019-4651-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 09/17/2019] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVES Recent studies using genome-wide association studies (GWAS) have shown the strong association between polymorphisms near the interleukin-28B (IL-28B) gene and spontaneous clearance of hepatitis C virus (HCV). The present study was designed to evaluate the association of interleukin-28 gene polymorphism with interleukin-28 cytokine levels in different viral genotypes among HCV patients in Yazd, Iran. RESULT The most prevalent genotype in chronic cases was genotype 3a, and the lowest one was 2/3a. There were statistically significant differences in genotype frequency between the two studied groups for IL-28B rs12979860C/T. The frequency of CC genotype of IL-28B at rs12979860 SNP was higher in spontaneously cleared patients in comparison with chronic HCV patients. Significant association was found when serum levels of IL28B were compared to various IL-28 genotypes. There was a significant difference between IL-28 polymorphism and HCV genotypes (p = 0.003).
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Affiliation(s)
- Mansour Moghimi
- Department of Pathology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Forough Tavakoli
- Virology Department, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoud Doosti
- Infectious and Tropical Diseases Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Department of Medical Virology, Faculty of Medical Sciences, Tarbiat Modares University (TMU), Tehran, Iran
| | - Abbas Ahmadi-Vasmehjani
- Virology Department, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohsen Akhondi-Meybodi
- Gastroentrology Department, Shahid Sadoughi Hospital, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
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The impact of the recipient and donor interferon lambda-3 polymorphism on the course of HCV infection following liver transplantation. Clin Exp Hepatol 2017; 3:152-158. [PMID: 29062905 PMCID: PMC5649482 DOI: 10.5114/ceh.2017.68401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2017] [Accepted: 05/02/2017] [Indexed: 11/23/2022] Open
Abstract
Aim of the study Aim of the study was to assess the impact of the recipient and donor interferon lambda-3 (IFNL3) single-nucleotide polymorphisms (SNPs) rs12979860 and rs8099917 on the course of hepatitis C virus (HCV) reinfection following liver transplantation. Material and methods The study involved 141 subjects after liver transplantation for HCV-induced cirrhosis, performed between 2000 and 2015. It assessed the impact of both SNPs on the outcomes of interferon/ribavirin (IFN/RBV) treatment following transplantation, HCV viral load, laboratory test results, histological lesions in the liver graft, the risk of acute rejection, and the development of hepatocellular carcinoma (HCC) in patient’s own liver. Results In the case of rs12979860, SVR was achieved in 58.8% of recipients with the CC genotype, and only 12% of recipients with the TT genotype (p = 0.016). Recipients with the rs12979860 CC variant had lower viral load and lower alanine transaminase (ALT) activity than recipients with a non-CC variant. Opposite effects were demonstrated in the analysis of the donors’ genotype. Recipients with the unfavorable variants (rs12979860 TT and rs8099917 GG) had a lower risk of graft rejection and tended to have a higher risk of developing HCC in their own liver. Conclusions The IFNL3 rs12979860 polymorphism may be considered a predictor for IFN/RBV effectiveness following liver transplantation. The course of HCV reinfection following liver transplantation may be more aggressive if an unfavorable variant in the recipient coexists with a promising variant in the donor. Particularly careful monitoring for HCC in recipients with unfavorable IFNL3 variants is warranted.
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Association of TNF-α and CCL5 with response to interferon-based therapy in patients with HCV 1 genotype. Clin Exp Hepatol 2017; 3:16-22. [PMID: 28856285 PMCID: PMC5497450 DOI: 10.5114/ceh.2017.65279] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 01/03/2017] [Indexed: 01/16/2023] Open
Abstract
Aim of the study To evaluate the role of potential genetic predictors –308G/A TNF-α and –403G/A CCL5 in treatment for HCV 1 genotype. Material and methods Treatment results of 130 patients with chronic hepatitis C 1 genotype according to different genotypes of IL28B, CCL5, and TNF-α were analysed using multiple logistic regression. Results IL28B genotypes CC/CT/TT were found in 27 (20.8%), 74 (56.9%), and 29 (22.3%) patients. Genotypes GG/GA/AA of –308G/A TNF-α were revealed in 98 (75.4%), 30 (23.1%), and 2 (1.5%) patients. Genotypes GG/GA/AA of –403G/A CCL5 were revealed in 86 (66.2%), 39 (30%), and 5 (3.8%) patients, respectively. The previously known effect of IL28B was observed. IL28B TT genotype decreased end of treatment response (EOTR) rates by a factor of 29.0 (95% CI: 6.4-183). The combination of CCL5 GG and IL28B CT genotypes increased the risk of failure to achieve EOTR by a factor of 28.5 (95% CI: 7.2-160). Genotypes GA and AA of TNF-α (–308) G/A SNP increased the risk of relapse in patients who achieved EOTR (OR = 9.4; 95% CI: 2.4-48). Conclusions Practitioners may benefit from using these predictors when considering indications for the antiviral therapy and deciding on the treatment regimen.
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Mueller JL, King LY, Johnson KB, Gao T, Nephew LD, Kothari D, Simpson MA, Zheng H, Wei L, Corey KE, Misdraji J, Lee JH, Lin MV, Gogela NA, Fuchs BC, Tanabe KK, Gordon FD, Curry MP, Chung RT. Impact of EGF, IL28B, and PNPLA3 polymorphisms on the outcome of allograft hepatitis C: a multicenter study. Clin Transplant 2016; 30:452-460. [PMID: 26854475 PMCID: PMC4868041 DOI: 10.1111/ctr.12710] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/01/2016] [Indexed: 01/03/2023]
Abstract
Hepatitis C virus (HCV) infection is accelerated following liver transplantation (LT). Single nucleotide polymorphisms (SNPs) near the epidermal growth factor (EGF) (rs4444903), IL28B (rs12979860), and PNPLA3 (rs738409) loci are associated with treatment response, fibrosis, and hepatocellular carcinoma in non-transplant hepatitis C, but allograft population data are limited. We sought to determine the role of these SNPs in 264 patients with HCV who underwent LT between 1990 and 2008. Genotypes were determined from donor wedge/allograft biopsies and recipient explants. Cox proportional hazards model was used to assess time to cirrhosis, liver-related death, and retransplantation, adjusting for donor age and sustained virological response (SVR). Over a median follow-up of 6.3 yr, a trend toward increased progression to graft cirrhosis was observed among recipients of an EGF non-AA vs. AA donor liver (adjusted HR 2.01; 95% CI 0.93-4.34; p = 0.08). No other genotypes predicted cirrhosis development or graft survival. The CC IL28B variant in both recipients and donors was associated with increased rate of SVR (R-CC/D-CC 8/12[67%], R-non-CC/D-CC or R-CC/D-non-CC 23/52[44%], R-non-CC/D-non-CC 12/45[27%], p linear trend = 0.009). Recipient EGF, IL28B, and PNPLA3, and donor IL28B and PNPLA3 genotypes do not predict adverse outcomes in HCV LT recipients. A potential association exists between donor EGF genotype and cirrhosis.
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Affiliation(s)
- Jessica L. Mueller
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA
- Harvard Medical School, Boston, MA
| | - Lindsay Y. King
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA
- Harvard Medical School, Boston, MA
| | - Kara B. Johnson
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA
- Harvard Medical School, Boston, MA
| | - Tian Gao
- Division of Gastroenterology, Department of Medicine, Boston Medical Center, Boston, MA
| | - Lauren D. Nephew
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania Health System, Philadelphia, PA
| | - Darshan Kothari
- Harvard Medical School, Boston, MA
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconness Medical Center, Boston
| | - Mary Ann Simpson
- Division of Gastroenterology, Department of Medicine, Lahey Hospital & Medical Center, Burlington
| | - Hui Zheng
- Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA
| | - Lan Wei
- Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Kathleen E. Corey
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA
- Harvard Medical School, Boston, MA
| | - Joseph Misdraji
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Joon Hyoek Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - M. Valerie Lin
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA
- Harvard Medical School, Boston, MA
| | - Neliswa A. Gogela
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA
- Harvard Medical School, Boston, MA
| | - Bryan C. Fuchs
- Harvard Medical School, Boston, MA
- Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Kenneth K. Tanabe
- Harvard Medical School, Boston, MA
- Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Fredric D. Gordon
- Harvard Medical School, Boston, MA
- Division of Gastroenterology, Department of Medicine, Lahey Hospital & Medical Center, Burlington
| | - Michael P. Curry
- Harvard Medical School, Boston, MA
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconness Medical Center, Boston
| | - Raymond T. Chung
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA
- Harvard Medical School, Boston, MA
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Burra P, De Martin E, Zanetto A, Senzolo M, Russo FP, Zanus G, Fagiuoli S. Hepatitis C virus and liver transplantation: where do we stand? Transpl Int 2016; 29:135-152. [PMID: 26199060 DOI: 10.1111/tri.12642] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Revised: 03/06/2015] [Accepted: 07/15/2015] [Indexed: 12/14/2022]
Abstract
The hepatitis C virus (HCV) infects more than 180 million people globally, with increasing incidence, especially in developing countries. HCV infection frequently progresses to liver cirrhosis leading to liver transplantation or death, and HCV recurrence still constitutes a major challenge for the transplant team. Antiviral therapy is the only available instrument to slow down this process, although its actual impact on liver histology, in responders and nonresponders, is still controversial. We are now facing a "new era" of direct antiviral agents that is already changing the approach to HCV burden both in the pre- and in the post-liver transplantation settings. Available data on sofosbuvir/ledipasvir and sofosbuvir/simeprevir in patients with decompensated cirrhosis sustain a SVR12 of 89% , but one-third of patients do not clinically improved. The sofosbuvir/ribavirin treatment in stable cirrhotic patients with HCC before liver transplantation is associated with 2% recurrence rate if liver transplantation is performed at least one month after undetectable HCV-RNA is achieved. The treatment of recurrence with the new antiviral drugs is associated with a SVR that ranges between 60 and 90%. In this review, we have focused on the evolution of antiviral therapy for HCV recurrence from the "old" interferon-based therapy to the "new" interferon-free regimens, highlighting useful information to aid the transplant hepatologist in the clinical practice.
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Affiliation(s)
- Patrizia Burra
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Eleonora De Martin
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
- Centre Hepato-Biliaire Paul Brousse, Villejuif, France
| | - Alberto Zanetto
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Marco Senzolo
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Francesco Paolo Russo
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Giacomo Zanus
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Stefano Fagiuoli
- Gastroenterology and Transplant Hepatology, Papa Giovanni XXIII Hospital, Bergamo, Italy
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Analysis of Post-Liver Transplant Hepatitis C Virus Recurrence Using Serial Cluster of Differentiation Antibody Microarrays. Transplantation 2015; 99:e120-6. [PMID: 25706280 DOI: 10.1097/tp.0000000000000617] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV) reinfection of the liver allograft after transplantation is universal, with some individuals suffering severe disease recurrence. Predictive markers of recurrent disease severity are urgently needed. In this study, we used a cluster of differentiation (CD) microarray to predict the severity of HCV recurrence after transplantation. METHODS The CD antibody microarray assays of live leukocytes were performed on peripheral blood taken in the first year after transplantation. The results were grouped into phases defined as; Pre-transplant (day 0), Early (day 3 to week 2), Mid (week 4 to week 10), and Late (week 12 to week 26). Hepatitis C virus severity was based on fibrosis stages in the first 2 years (F0-1 mild and F2-4 severe). RESULTS Serial blood samples from 16 patients were taken before and after liver transplantation. A total of 98 assays were performed. Follow-up was 3 years or longer. Comparing recurrence severity, significantly greater numbers of CD antigens were differentially expressed on the pretransplant samples compared to any posttransplant timepoints. Five differentially expressed CD antigens before transplantation (CD27 PH, CD182, CD260, CD41, and CD34) were significantly expressed comparing severe to mild recurrence, whereas expression of only CD152 was significant in the late phase after transplantation. No relationship was observed between the donor or recipient interleukin-28B genotypes and HCV recurrence severity. CONCLUSIONS This study shows that circulating leukocyte CD antigen expression has utility in assessing recurrent HCV disease severity after liver transplantation and serves as a proof of principle. Importantly, pretransplant CD antigen expression is most predictive of disease outcome.
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Spontaneous clearance of HCV accompanying hepatitis after liver transplantation. Clin J Gastroenterol 2015; 8:323-9. [PMID: 26342292 DOI: 10.1007/s12328-015-0602-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Accepted: 08/20/2015] [Indexed: 12/18/2022]
Abstract
Re-infection by the hepatitis C virus (HCV) occurs rapidly after liver transplantation (LT), and spontaneous clearance of HCV is rare under immunosuppressive conditions. Here, we report on two patients who underwent LT to treat liver cirrhosis and hepatocellular carcinoma. The immunosuppressants prescribed were short-term corticosteroids, tacrolimus, and mycophenolate mofetil. A 50-year-old woman underwent LT, with her brother as the donor. She acquired HCV of serological type 1 after LT; the HCV RNA level was 6.0 logIU/mL. Corticosteroids were discontinued within 24 days, with a total dose of 669 mg (adjusted) prednisolone (PSL). The serum alanine aminotransferase (ALT) level increased to 700 U/L by day 55 post-LT. Surprisingly, HCV RNA was not detected on day 87. A 52-year-old man underwent LT, with his sister as the donor. He became rapidly re-infected with HCV of serological type 2; the HCV RNA level was 6.9 logIU/mL. Corticosteroids were given for 24 days, with a total dose of 827 mg (adjusted) PSL. The serum ALT level increased continuously and his HCV cleared 115 days after LT. Both donor and recipient had the major IL28B genotype. HCV was eliminated spontaneously, even under immunosuppressive conditions, after PSL discontinuation without interferon treatment. Minimal use of immunosuppressants and the presence of hepatitis may have contributed to HCV clearance. However, it is important to evaluate additional relevant cases.
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Aguilera V. Hepatitis C virus recurrence after liver transplantation: how to treat and when. Transplant Proc 2015; 46:3100-3. [PMID: 25420834 DOI: 10.1016/j.transproceed.2014.09.177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Chronic hepatitis C (CHC) is an important cause of cirrhosis and hepatocellular carcinoma and a common indication of liver transplantation (LT). Recurrence of hepatitis C occurs universally after LT with an accelerated course of the natural history of CHC in the graft. Treatment of hepatitis C before transplantation is the most effective strategy because it prevents graft reinfection, but applicability is low with pegylated interferon regimens. Treatment after LT is the strategy more frequently used. A sustained viral response (SVR) is achieved by one-third of those treated with dual therapy and is associated with better outcomes after LT. Triple therapy with protease inhibitors after LT has efficacy to 60%-70% of SVR but is associated with higher rates of secondary effects and drug-drug interactions that require an intensified and frequent monitoring of calcineurin inhibitors during treatment. In the near future, interferon-free regimens with new oral antiviral drugs will likely prevent viral reinfection before or after LT, and shorter treatment regimens and less toxicity are expected.
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Affiliation(s)
- V Aguilera
- Hospital Universitari i Politècnic la Fe, Valenza, Valencia, Spain Valencia, Spain.
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Lim KBL, Sima HR, Fiel MI, Khaitova V, Doucette JT, Chernyiak M, Ahmad J, Bach N, Chang C, Grewal P, Kim-Schluger L, Liu L, Odin J, Perumalswami P, Florman SS, Schiano TD. Utility of the low-accelerating-dose regimen in 182 liver recipients with recurrent hepatitis C virus. World J Gastroenterol 2015; 21:6236-45. [PMID: 26034358 PMCID: PMC4445100 DOI: 10.3748/wjg.v21.i20.6236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2014] [Revised: 02/09/2015] [Accepted: 03/12/2015] [Indexed: 02/06/2023] Open
Abstract
AIM To describe our experience using a low-accelerating-dose regimen (LADR) with pegylated interferon alpha-2a and ribavirin in treatment of hepatitis C virus (HCV) recurrence. METHODS From 2003, a protocolized LADR strategy was employed to treat liver transplant (LT) recipients with recurrent HCV at our institution. Medical records of 182 adult patients with recurrent HCV treated with LADR between 1/2003 and 1/2011 were reviewed. Histopathology from all post-LT liver biopsies were reviewed in a blinded fashion. Paired recipient and donor IL28B status were assessed. A novel technique was employed to ascertain recipient and donor IL28B (rs12979860) Gt data using DNA extracted from archival FFPE tissue from explanted native livers and donor gallbladders respectively. The primary endpoint was SVR; secondary endpoints examined include (1) patient and graft survival; (2) effect of anti-viral therapy on liver histology (fibrosis and inflammation); (3) incidence of on-treatment development of ACR, CDR, or PCH; (4) association of recipient and donor IL28B genotype with SVR; and (5) incidence of anti-viral therapy-associated adverse events (anemia, leukopenia, thrombocytopenia, depression) and hepatic decompensation. RESULTS The overall SVR rate was 38% (29% Gt1, 67% Gt2, 86% Gt3 and 58% Gt4). HCV Gt (P < 0.0001), donor age (P = 0.003), cytomegalovirus mismatch (P = 0.001), baseline serum bilirubin (P = 0.002), and baseline viral load (P = 0.04) were independent predictors for SVR. SVR rates were significantly higher in the recipient-CC/donor-non CC pairs (P = 0.007). Neither baseline fibrosis nor change in fibrosis stage after anti-viral therapy were associated with SVR. Fibrosis progressed in 72% of patients despite SVR. Median graft survival was 91 mo. Five-year patient survival was superior in patients who achieved SVR (97% vs 82%, P = 0.001). Pre-treatment ALP ≥ 150 U/L (P = 0.01), total bilirubin ≥ 1.5 mg/dL (P = 0.001) and creatinine ≥ 2 mg/dL (P = 0.001) were independently associated with patient survival. Only 13% of patients achieving SVR died during the follow-up period. Treatment discontinuation and treatment-related mortality occurred in 35% and 2.2% of patients, respectively. EPO, G-CSF and blood transfusion were needed in 89%, 40% and 23% of patients, respectively. Overall hospitalization rate for treatment-related serious adverse events was 21%. Forty-six (25%) of the patients were deceased; among those who died, 25 (54%) were due to liver-related complications, and 4 deaths (9%) occurred while receiving therapy (2 patients experienced hepatic decompensation and 2 sepsis). CONCLUSION LADR strategy remains relevant in managing post-LT recurrent HCV where access to DAAs is limited. SVR is associated with improved survival, but fibrosis progression still occurs.
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Farnik H, Zimmermann T, Herrmann E, Bechstein WO, Kronenberger B, Galle PR, Labocha S, Ferreiros N, Geisslinger G, Zeuzem S, Sarrazin C, Welker MW. Telaprevir drug monitoring during antiviral therapy of hepatitis C graft infection after liver transplantation. Liver Int 2015; 35:176-83. [PMID: 24649882 DOI: 10.1111/liv.12532] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Accepted: 03/13/2014] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Recurrence of hepatitis C virus (HCV) infection after orthotopical liver transplantation (OLT) is common and associated with reduced graft and patient survival. The protease inhibitor telaprevir may enhance virological response rates in patients after OLT in combination with pegylated interferon-alfa and ribavirin. Pharmacokinetic studies have shown significant drug-drug interactions between telaprevir and immunosuppression (IS), but telaprevir pharmacokinetics in OLT patients with IS are unknown. Aim of the present study was to analyse telaprevir plasma concentrations in patients with HCV genotype 1 infection after OLT in comparison to patients without OLT and IS. METHODS Five patients with HCV genotype 1 infection after OLT and 37 HCV genotype 1-infected patients patients without prior OLT were treated with telaprevir 2250 mg daily, ribavirin 1000/1200 mg daily and pegylated interferon-alfa-2a 180 μg once weekly (triple therapy). Telaprevir plasma concentrations were analysed by liquid chromatography-electrospray-ionization-tandem mass spectrometry. HCV RNA was assessed by automatized reverse-transcription polymerase chain-reaction. RESULTS Median (range) telaprevir plasma concentrations of TW 4, 8 and 12 were 3970 (1980-4430) ng/ml and 2520 (1870-8730) ng/ml in patients after OLT and ciclosporin- or tacrolimus-based IS, respectively, as compared to 2790 (1870-3140) in non-OLT patients (P = 0.3). In one patient with tacrolimus-based IS, telaprevir dose had to be adjusted to achieve virological response. Telaprevir plasma concentrations were steady at treatment weeks 4, 8 and 12 in patients with and without IS. CONCLUSIONS Telaprevir drug monitoring may be necessary in patients with tacrolimus-based IS in patients with HCV graft infection after OLT.
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Affiliation(s)
- Harald Farnik
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, Frankfurt, 60590, Germany
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Zhang L, Lu Q, Yang Z, Wang X, Cai L, Liu X, Liao R, Yang X, Chen Y, Yang Z. Association of rs12979860 and rs8099917 polymorphisms near IL28B with SVR in hepatic allograft recipients with HCV recurrence undergoing PEG-IFN/RBV therapy: a meta-analysis. Hum Immunol 2014; 75:1268-1275. [PMID: 25225180 DOI: 10.1016/j.humimm.2014.09.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Revised: 06/05/2014] [Accepted: 09/03/2014] [Indexed: 02/06/2023]
Abstract
The association of rs12979860 and rs8099917 single nucleotide polymorphisms (SNPs) near IL28B with sustained virological response (SVR) in hepatic allograft recipients undergoing treatment with PEGylated interferon (PEG-IFN) plus ribavirin (RBV) for recurrent hepatitis C virus (HCV) infection remains inconclusive. We therefore performed a meta-analysis to estimate this association. A search of the literature published prior to November 1, 2013, was conducted using various databases. Eleven eligible studies were included in the meta-analysis. The pooled results revealed that rs12979860 genotype CC in the recipient, donor, and recipient/donor pair was significantly related to high SVR in the recipients (recipient: odds ratio [OR]=3.06, 95% confidence interval [CI]=2.18-4.30; donor: OR=2.65, 95% CI=1.83-3.85; recipient/donor pair: OR=6.05, 95% CI=3.16-11.58). A similar association was observed with rs8099917 genotype TT (recipient: OR=3.84, 95% CI=2.37-6.22; donor: OR=2.44, 95% CI=1.12-5.28; recipient/donor pair: OR=5.43, 95% CI=2.51-11.75). These results suggest that rs12979860 genotype CC and rs8099917 genotype TT contribute to a high SVR in the recipient after antiviral treatment.
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Affiliation(s)
- Ling Zhang
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Qian Lu
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Zhiqing Yang
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Xiaojun Wang
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Lei Cai
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Xiangde Liu
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Rui Liao
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Xing Yang
- Department of Hepatobiliary Surgery, 324 Hospital of People's Liberation Army (PLA), Chongqing 400038, China
| | - Yinzhi Chen
- School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Zhanyu Yang
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
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Abstract
Chronic HCV infection is the leading indication for liver transplantation. However, as a result of HCV recurrence, patient and graft survival after liver transplantation are inferior compared with other indications for transplantation. HCV recurrence after liver transplantation is associated with considerable mortality and morbidity. The development of HCV-related fibrosis is accelerated after liver transplantation, which is influenced by a combination of factors related to the virus, donor, recipient, surgery and immunosuppression. Successful antiviral therapy is the only treatment that can attenuate fibrosis. The advent of direct-acting antiviral agents (DAAs) has changed the therapeutic landscape for the treatment of patients with HCV. DAAs have improved tolerability, and can potentially be used without PEG-IFN for a shorter time than previous therapies, which should result in better outcomes. In this Review, we describe the important risk factors that influence HCV recurrence after liver transplantation, highlighting the mechanisms of fibrosis and the integral role of hepatic stellate cells. Indirect and direct assessment of fibrosis, in addition to new antiviral therapies, are also discussed.
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Fernández-Carrillo C, Coto-Llerena M, González P, Crespo G, Mensa L, Caro-Pérez N, Gambato M, Navasa M, Forns X, Pérez-del-Pulgar S. IFNL4 polymorphism predicts response to hepatitis C treatment after liver transplantation. J Clin Virol 2014; 61:282-5. [PMID: 25130512 DOI: 10.1016/j.jcv.2014.07.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Revised: 07/17/2014] [Accepted: 07/22/2014] [Indexed: 12/16/2022]
Abstract
BACKGROUND Recent studies in chronic hepatitis C patients have shown that rs368234815 polymorphism nearby IL28B is a better predictor of response to antiviral treatment with pegylated interferon and ribavirin than IL28B polymorphisms (rs12979860 and rs8099917). Its effect could be related to interferon lambda 4 (IFNL4), a protein which seems to confer some paradoxical disadvantages in hepatitis C virus (HCV) immune response. OBJECTIVES To assess the role of IFNL4 rs368234815 polymorphism on the response to antiviral treatment after liver transplantation (LT). STUDY DESIGN IFNL4 and IL28B polymorphisms were genotyped in 86 HCV-infected LT recipients and in their donors; all patients had undergone antiviral treatment with pegylated interferon and ribavirin after LT. RESULTS IFNL4 polymorphism strongly correlated with IL28B ones (p < 0.001). The favorable IFNL4 genotype (TT/TT) was significantly more frequent among donors than recipients (60% donors vs. 22% recipients, p <0.001). Recipient TT/TT genotype was associated with a higher sustained virological response rate after LT (p = 0.024). Nevertheless, the highest sustained virological response frequency was found when both donors and recipients had favorable genotypes (73% vs. 25%, p = 0.002), suggesting a role for donor genotype. CONCLUSIONS Our study demonstrates that IFNL4 rs368234815 polymorphism is an important predictor of response to antiviral treatment in the LT setting. These findings warrant further studies on IFNL4 role in immune response against HCV.
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Affiliation(s)
| | | | | | - Gonzalo Crespo
- Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain.
| | - Laura Mensa
- Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain.
| | | | - Martina Gambato
- Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain.
| | - Miquel Navasa
- Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain.
| | - Xavier Forns
- Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain.
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14
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Campos-Varela I, Esteban JI, Bes M, Caralt M, Allende H, Rodríguez-Frías F, Salcedo MT, Sauleda S, Charco R, Guardia J, Esteban R, Castells L. Early predictors of antiviral treatment response in liver transplant recipients with recurrent hepatitis C genotype 1. J Viral Hepat 2014; 21:e118-e128. [PMID: 24620835 DOI: 10.1111/jvh.12246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Accepted: 01/14/2014] [Indexed: 12/09/2022]
Abstract
The success of current antiviral treatment for hepatitis C virus (HCV) recurrence in liver transplant (LT) recipients remains limited. We aimed at evaluating the value of IL28B genotype and early viral kinetics to predict response to standard treatment in the transplant setting. We retrospectively evaluated 104 LT recipients treated for HCV genotype 1 recurrence between 2001 and 2010. Baseline variables, including IL28B genotype, and early viral kinetics were compared among patients who did or did not achieve a sustained virological response (SVR). Logistic regression analyses of candidate variables were conducted to generate a reliable predictive model based on the minimum set of variables. Twenty-nine (28%) achieved an SVR. On multivariate analysis, the magnitude of HCV RNA decline at 4 weeks (OR: 3.74, 95% CI: 1.64-9.39; P = 0.003) and treatment compliance (OR: 35.27, 95% CI: 3.35-365.54; P = 0.003) were the only independent predictors of SVR. Favourable recipient IL28B genotype significantly correlates with virological response at week 4 (OR 3.23; 95% CI, 1.12-9.15; P = 0.03). By logistic regression analysis, a model including donor age, recipient rs12979860 genotype and viral load at 4 weeks showed the best predictive value for SVR with an area under the receiver operating curve of 0.861. Favourable recipient IL28B genotype strongly correlates with the viral response at week 4 which is the strongest predictor of response. The combination of recipient IL28B genotype and donor age with the week 4 response reliably estimates the probability of SVR early on-treatment and may facilitate therapeutic strategies incorporating new antiviral agents.
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Affiliation(s)
- I Campos-Varela
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
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15
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Grassi A, Ballardini G. Post-liver transplant hepatitis C virus recurrence: an unresolved thorny problem. World J Gastroenterol 2014; 20:11095-11115. [PMID: 25170198 PMCID: PMC4145752 DOI: 10.3748/wjg.v20.i32.11095] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Revised: 02/15/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV)-related cirrhosis represents the leading cause of liver transplantation in developed, Western and Eastern countries. Unfortunately, liver transplantation does not cure recipient HCV infection: reinfection universally occurs and disease progression is faster after liver transplant. In this review we focus on what happens throughout the peri-transplant phase and in the first 6-12 mo after transplantation: during this crucial period a completely new balance between HCV, liver graft, the recipient's immune response and anti-rejection therapy is achieved that will deeply affect subsequent outcomes. Nearly all patients show an early graft reinfection, with HCV viremia reaching and exceeding pre-transplant levels; in this setting, histological assessment is essential to differentiate recurrent hepatitis C from acute or chronic rejection; however, differentiating the two patterns remains difficult. The host immune response (mainly cellular mediated) appears to be crucial both in the control of HCV infection and in the genesis of rejection, and it is also strongly influenced by immunosuppressive treatment. At present no clear immunosuppressive strategy could be strongly recommended in HCV-positive recipients to prevent HCV recurrence, even immunotherapy appears to be ineffective. Nonetheless it seems reasonable that episodes of rejection and over-immunosuppression are more likely to enhance the risk of HCV recurrence through immunological mechanisms. Both complete prevention of rejection and optimization of immunosuppression should represent the main goals towards reducing the rate of graft HCV reinfection. In conclusion, post-transplant HCV recurrence remains an unresolved, thorny problem because many factors remain obscure and need to be better determined.
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16
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Gerold G, Pietschmann T. The HCV life cycle: in vitro tissue culture systems and therapeutic targets. Dig Dis 2014; 32:525-37. [PMID: 25034285 DOI: 10.1159/000360830] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Hepatitis C virus (HCV) is a highly variable plus-strand RNA virus of the family Flaviviridae. Viral strains are grouped into six epidemiologically relevant genotypes that differ from each other by more than 30% at the nucleotide level. The variability of HCV allows immune evasion and facilitates persistence. It is also a substantial challenge for the development of specific antiviral therapies effective across all HCV genotypes and for prevention of drug resistance. Novel HCV cell culture models were instrumental for identification and profiling of therapeutic strategies. Concurrently, these models revealed numerous host factors critical for HCV propagation, some of which have emerged as targets for antiviral therapy. It is generally assumed that the use of host factors is conserved among HCV isolates and genotypes. Additionally, the barrier to viral resistance is thought to be high when interfering with host factors. Therefore, current drug development includes both targeting of viral factors but also of host factors essential for virus replication. In fact, some of these host-targeting agents, for instance inhibitors of cyclophilin A, have advanced to late stage clinical trials. Here, we highlight currently available cell culture systems for HCV, review the most prominent host-targeting strategies against hepatitis C and critically discuss opportunities and risks associated with host-targeting antiviral strategies.
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Affiliation(s)
- Gisa Gerold
- TWINCORE - Institute of Experimental Virology, Centre for Experimental and Clinical Infection Research, Hannover, Germany
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17
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Kamal SM. Pharmacogenetics of hepatitis C: transition from interferon-based therapies to direct-acting antiviral agents. Hepat Med 2014; 6:61-77. [PMID: 25114601 PMCID: PMC4075960 DOI: 10.2147/hmer.s41127] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Hepatitis C virus (HCV) has emerged as a major viral pandemic over the past two decades, infecting 170 million individuals, which equates to approximately 3% of the world’s population. The prevalence of HCV varies according to geographic region, being highest in developing countries such as Egypt. HCV has a high tendency to induce chronic progressive liver damage in the form of hepatic fibrosis, cirrhosis, or liver cancer. To date, there is no vaccine against HCV infection. Combination therapy comprising PEGylated interferon-alpha and ribavirin has been the standard of care for patients with chronic hepatitis C for more than a decade. However, many patients still do not respond to therapy or develop adverse events. Recently, direct antiviral agents such as protease inhibitors, polymerase inhibitors, or NS5A inhibitors have been used to augment PEGylated interferon and ribavirin, resulting in better efficacy, better tolerance, and a shorter treatment duration. However, most clinical trials have focused on assessing the efficacy and safety of direct antiviral agents in patients with genotype 1, and the response of other HCV genotypes has not been elucidated. Moreover, the prohibitive costs of such triple therapies will limit their use in patients in developing countries where most of the HCV infection exists. Understanding the host and viral factors associated with viral clearance is necessary for individualizing therapy to maximize sustained virologic response rates, prevent progression to liver disease, and increase the overall benefits of therapy with respect to its costs. Genome wide studies have shown significant associations between a set of polymorphisms in the region of the interleukin-28B (IL28B) gene and natural clearance of HCV infection or after PEGylated interferon-alpha and ribavirin treatment with and without direct antiviral agents. This paper synthesizes the recent advances in the pharmacogenetics of HCV infection in the era of triple therapies.
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Affiliation(s)
- Sanaa M Kamal
- Department of Medicine, Division of Hepatology, Gastroenterology and Tropical Medicine, Ain Shams Faculty of Medicine, Cairo, Egypt ; Department of Medicine, Salman Bin Abdul Aziz College of Medicine, Kingdom of Saudi Arabia
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18
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Bunchorntavakul C, Reddy KR. Management of Hepatitis C Before and After Liver Transplantation in the Era of Rapidly Evolving Therapeutic Advances. J Clin Transl Hepatol 2014; 2:124-33. [PMID: 26357623 PMCID: PMC4521260 DOI: 10.14218/jcth.2014.00002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2014] [Revised: 02/13/2014] [Accepted: 02/20/2014] [Indexed: 12/14/2022] Open
Abstract
Management of hepatitis C (HCV) in liver transplantation (LT) population presents unique challenges. Suboptimal graft survival in HCV+ LT recipients is attributable to universal HCV recurrence following LT. Although eradication of HCV prior to LT is ideal for the prevention of HCV recurrence it is often limited by adverse events, particularly in patients with advanced cirrhosis. Antiviral therapy in LT candidates needs careful monitoring, and prophylaxis with HCV antibodies is ineffective. Early antiviral therapy after LT has been investigated, but no clear benefit has been demonstrated. Protocol liver biopsy is generally recommended in HCV+ LT recipients, and antiviral therapy can be considered in those with severe/progressive HCV recurrence. Sustained virological response (SVR) can be achieved in approximately 30% of LT recipients with pegylated interferon/ribavirin (PEG-IFN/RBV) with survival benefit, but adverse effects are common. Favorable patient characteristics for response to therapy include non-1 genotype, previously untreated, low baseline HCV-RNA, and donor IL28B genotype CC. Direct acting antiviral (DAA)-based triple therapy is associated with higher rates of SVR, but with similar or slightly higher rates of side effects, and immunosuppressive regimens need to be closely monitored and adjusted during the treatment period. Notably, the safety and efficacy of HCV treatment are very likely to improve with newer generation DAA. The benefit of immunosuppressive strategy on the natural history HCV recurrence has not been well elucidated. Based upon available evidence, cyclosporine A (CSA), mycophenolate mofetil (MMF), and sirolimus appear to have a neutral or small beneficial impact on HCV recurrence. Donor interleukin 28 B (IL28B) polymorphisms appear to impact the course and treatment outcomes in recurrent HCV. Retransplantation should be considered for patients with reasonable survival probability.
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Affiliation(s)
- Chalermrat Bunchorntavakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Bangkok, Thailand
| | - K. Rajender Reddy
- Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA, USA
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19
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Manousou P, Cholongitas E, Samonakis D, Tsochatzis E, Corbani A, Dhillon AP, Davidson J, Rodríguez-Perálvarez M, Patch D, O'Beirne J, Thorburn D, Luong T, Rolles K, Davidson B, McCormick PA, Hayes P, Burroughs AK. Reduced fibrosis in recurrent HCV with tacrolimus, azathioprine and steroids versus tacrolimus: randomised trial long term outcomes. Gut 2014; 63:1005-1013. [PMID: 24131637 PMCID: PMC4033276 DOI: 10.1136/gutjnl-2013-305606] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Revised: 09/06/2013] [Accepted: 09/25/2013] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Early results of a randomised trial showed reduced fibrosis due to recurrent HCV hepatitis with tacrolimus triple therapy (TT) versus monotherapy (MT) following transplantation for HCV cirrhosis. We evaluated the clinical outcomes after a median 8 years of follow-up, including differences in fibrosis assessed by collagen proportionate area (CPA). DESIGN 103 consecutive liver transplant recipients with HCV cirrhosis receiving cadaveric grafts were randomised to tacrolimus MT (n=54) or TT (n=49) with daily tacrolimus (0.1 mg/kg divided dose), azathioprine (1 mg/kg) and prednisolone (20 mg), the last tailing off to zero by 6 months. Both groups had serial transjugular biopsies with hepatic venous pressure gradient (HVPG) measurement. Time to reach Ishak stage 4 was the predetermined endpoint. CPA was measured in all biopsies. Factors associated with HCV recurrence were evaluated. Clinical decompensation was the first occurrence of ascites/hydrothorax, variceal bleeding or encephalopathy. RESULTS No significant preoperative, peri-operative or postoperative differences between groups were found. During 96 months median follow-up, stage 4 fibrosis was reached in 19 MT/11 TT with slower fibrosis progression in TT (p=0.009). CPA at last biopsy was 12% in MT and 8% in TT patients (p=0.004). 14 MT/ three TT patients reached HVPG≥10 mm Hg (p=0.002); 10 MT/three TT patients, decompensated. Multivariately, allocated MT (p=0.047, OR 3.23, 95% CI 1.01 to 10.3) was independently associated with decompensation: 14 MT/ seven TT died, and five MT/ four TT were retransplanted. CONCLUSIONS Long term immunosuppression with tacrolimus, azathioprine and short term prednisolone in HCV cirrhosis recipients resulted in slower progression to severe fibrosis assessed by Ishak stage and CPA, less portal hypertension and decompensation, compared with tacrolimus alone. ISRCTN94834276--Randomised study for immunosuppression regimen in liver transplantation.
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Affiliation(s)
- Pinelopi Manousou
- The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute of Liver and Digestive Health, London, UK
| | - Evangelos Cholongitas
- The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute of Liver and Digestive Health, London, UK
| | - Dimitrios Samonakis
- The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute of Liver and Digestive Health, London, UK
| | - Emmanuel Tsochatzis
- The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute of Liver and Digestive Health, London, UK
| | - Alice Corbani
- The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute of Liver and Digestive Health, London, UK
| | - A P Dhillon
- Department of Histopathology, Royal Free Hospital, London, UK
| | - Janice Davidson
- Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - Manuel Rodríguez-Perálvarez
- The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute of Liver and Digestive Health, London, UK
| | - D Patch
- The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute of Liver and Digestive Health, London, UK
| | - J O'Beirne
- The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute of Liver and Digestive Health, London, UK
| | - D Thorburn
- The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute of Liver and Digestive Health, London, UK
| | - TuVinh Luong
- Department of Histopathology, Royal Free Hospital, London, UK
| | - K Rolles
- The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute of Liver and Digestive Health, London, UK
| | - Brian Davidson
- The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute of Liver and Digestive Health, London, UK
| | - P A McCormick
- Liver Unit, St Vincent's University Hospital, Dublin, Ireland
| | - Peter Hayes
- Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - Andrew K Burroughs
- The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital and UCL Institute of Liver and Digestive Health, London, UK
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20
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Layden JE, Tayo BO, Cotler SJ, Clark NM, Baraoidan K, Friedman SL, Cooper RS. Association of genetic variants with rapid fibrosis: progression after liver transplantation for hepatitis C. Transplantation 2014; 97:1072-8. [PMID: 24770613 PMCID: PMC4524502 DOI: 10.1097/01.tp.0000440953.06886.a3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
BACKGROUND Recurrence of hepatitis C, the main indication for liver transplantation in the United States, leads to rapid fibrosis progression and worse outcomes compared to other indications. While clinical variables play a role, they are insufficient to explain all inter-patient variability in posttransplant fibrosis progression. Genetic factors associated with hepatitis C virus (HCV) outcomes have been identified, but limited studies have been conducted in the context of HCV-related liver transplantation. Therefore, the purpose of this study was to examine candidate genes related to the immune response and rate of fibrosis in subjects undergoing liver transplantation for HCV. METHODS One hundred twelve recipients with detailed posttransplant fibrosis and clinical information were genotyped using 25 single nucleotide variants (SNVs), including five SNVs within the IL28B gene region. Associations between SNVs and rapid fibrosis progression were performed controlling for pertinent clinical variables and haplotype analyses for the IL28B gene were completed. RESULTS Significant multivariable associations were found for rs8099917 (IL28B), rs1991401 (DDX5), rs4969168 (SOC3), and rs7976497 (MLEC). The minor allele was protective against rapid fibrosis progression for the IL28B SNV (G allele), MLEC SNV (T allele), and DDX5 SNV (G allele). For the SOC3 SNV, the minor allele (A) increased the risk for rapid fibrosis progression. Additionally, two recipient haplotype structures for IL28B were significantly associated with rapid fibrosis progression. CONCLUSIONS These findings indicate that recipient genetic factors play a role in posttransplant HCV-related fibrosis progression. Molecular studies of these pathways may elucidate the pathogenesis of posttransplant fibrosis progression and provide risk prediction markers.
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Affiliation(s)
- Jennifer E. Layden
- Department of Public Health Sciences, Stritch School of Medicine, Loyola University Medical School, Maywood, IL
- Department of Medicine, Loyola Stritch School of Medicine, Loyola University Medical School, Maywood, IL
| | - Bamidele O. Tayo
- Department of Public Health Sciences, Stritch School of Medicine, Loyola University Medical School, Maywood, IL
| | - Scott J. Cotler
- Department of Medicine, Loyola Stritch School of Medicine, Loyola University Medical School, Maywood, IL
| | - Nina M. Clark
- Department of Medicine, Loyola Stritch School of Medicine, Loyola University Medical School, Maywood, IL
| | | | - Scott L. Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mt Sinai, New York, NY
| | - Richard S. Cooper
- Department of Public Health Sciences, Stritch School of Medicine, Loyola University Medical School, Maywood, IL
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21
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Dhanasekaran R, Firpi RJ. Challenges of recurrent hepatitis C in the liver transplant patient. World J Gastroenterol 2014; 20:3391-3400. [PMID: 24707122 PMCID: PMC3974506 DOI: 10.3748/wjg.v20.i13.3391] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2013] [Revised: 11/22/2013] [Accepted: 03/10/2014] [Indexed: 02/06/2023] Open
Abstract
Cirrhosis secondary to hepatitis C virus (HCV) is a very common indication for liver transplant. Unfortunately recurrence of HCV is almost universal in patients who are viremic at the time of transplant. The progression of fibrosis has been shown to be more rapid in the post-transplant patients than in the transplant naïve, hence treatment of recurrent HCV needs to be considered for all patients with documented recurrent HCV. Management of recurrent HCV is a challenging situation both for patients and physicians due to multiple reasons as discussed in this review. The standard HCV treatment with pegylated interferon and Ribavarin can be considered in these patients but it leads to a lower rate of sustained virologic clearance than in the non-transplanted population. Some of the main challenges associated with treating recurrent HCV in post-transplant patients include the presence of cytopenias; need to monitor drug-drug interactions and the increased incidence of renal compromise. In spite of these obstacles all patients with recurrent HCV should be considered for treatment since it is associated with improvement in survival and a delay in fibrosis progression. With the arrival of direct acting antiviral drugs there is renewed hope for better outcomes in the treatment of post-transplant HCV recurrence. This review evaluates current literature on this topic and identifies challenges associated with the management of post-transplant HCV recurrence.
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22
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Harada N, Tamura S, Sugawara Y, Togashi J, Ishizawa T, Kaneko J, Aoki T, Sakamoto Y, Hasegawa K, Tanaka T, Yamashiki N, Kokudo N. Impact of donor and recipient single nucleotide polymorphisms of IL28B rs8099917 in living donor liver transplantation for hepatitis C. PLoS One 2014; 9:e90462. [PMID: 24599320 PMCID: PMC3944011 DOI: 10.1371/journal.pone.0090462] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Accepted: 01/31/2014] [Indexed: 02/06/2023] Open
Abstract
Single nucleotide polymorphisms of interleukin-28B (IL28B) rs8099917 are reported to be associated with virologic clearance in interferon-and ribavirin -based treatment for hepatitis C virus (HCV)-infected patients. We examined virologic response in accordance with IL28B polymorphisms in our living donor liver transplantation series under a preemptive interferon and RBV treatment approach. Adequate DNA samples from both the recipient and donor for the study of single nucleotide polymorphisms of IL28B were available from 96 cases and were the subjects of the present study. Various clinical factors related with virologic response including early virologic response (EVR) and sustained virologic response (SVR) were examined. Totally 51% presented with EVR and 44% achieved SVR. Presence of the major allele (TT) in either the recipient or the donor corresponded to SVR of 53% and 48%. Presence of the minor allele (TG or GG) corresponded to SVR of 26% and 32%. Multivariate analysis revealed that genotype of HCV or EVR, but not IL28B polymorphisms in either the recipient or donor, was an independent factor for achieving SVR. When virologic response to treatment was incorporated into analysis, the impact of IL28B polymorphism on virological clearance remained relative to other factors and was not significantly independent.
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Affiliation(s)
- Nobuhiro Harada
- Division of Artificial Organ and Transplantation, The University of Tokyo Hospital, Tokyo, Japan
| | - Sumihito Tamura
- Division of Artificial Organ and Transplantation, The University of Tokyo Hospital, Tokyo, Japan
| | - Yasuhiko Sugawara
- Division of Artificial Organ and Transplantation, The University of Tokyo Hospital, Tokyo, Japan
- Organ Transplantation Service, The University of Tokyo Hospital, Tokyo, Japan
| | - Junichi Togashi
- Division of Artificial Organ and Transplantation, The University of Tokyo Hospital, Tokyo, Japan
| | - Takeaki Ishizawa
- Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, The University of Tokyo Hospital, Tokyo, Japan
| | - Junichi Kaneko
- Division of Artificial Organ and Transplantation, The University of Tokyo Hospital, Tokyo, Japan
| | - Taku Aoki
- Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, The University of Tokyo Hospital, Tokyo, Japan
| | - Yoshihiro Sakamoto
- Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, The University of Tokyo Hospital, Tokyo, Japan
| | - Kiyoshi Hasegawa
- Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, The University of Tokyo Hospital, Tokyo, Japan
| | - Tomohiro Tanaka
- Organ Transplantation Service, The University of Tokyo Hospital, Tokyo, Japan
| | - Noriyo Yamashiki
- Organ Transplantation Service, The University of Tokyo Hospital, Tokyo, Japan
| | - Norihiro Kokudo
- Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, The University of Tokyo Hospital, Tokyo, Japan
- Organ Transplantation Service, The University of Tokyo Hospital, Tokyo, Japan
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23
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Campos-Varela I, Esteban JI, Bes M, Dopazo C, Allende H, Rodríguez-Frías F, Salcedo MT, Sauleda S, Charco R, Guardia J, Esteban R, Castells L. Outcome of early vs. deferred antiviral treatment for recurrent hepatitis C in liver transplant recipients. Ann Hepatol 2014; 13:219-230. [PMID: 24552864 DOI: 10.1016/s1665-2681(19)30885-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
The optimal timing to treat recurrent hepatitis-C virus (HCV) after liver transplantation (LT) remains uncertain. We compared the outcome of early (acute phase) and deferred (chronic phase) antiviral treatment for recurrent HCV infection in this population. Consecutive HCV genotype-1 infected LT patients receiving antiviral therapy between 2001-2010 were retrospectively classified according to histology at treatment start into the early or deferred treatment group. Measured endpoints included sustained virological response (SVR) rates and long-term survival. The study cohort comprised 105 patients: 60 (57%) received early treatment (ET) and 45 (43%) deferred treatment (DT). The median interval from LT to antiviral start was 3 (1-9) and 18 months (11-74) in ET and DT respectively. The SVR rate was similar in both treatment groups (23% ET and 36% DT; p = 0.27). After a median follow-up of 5.8 years, all-cause and liver-related mortality were similar in both groups. Variables independently associated with mortality included pre-treatment bilirubin > 2 mg/dL (HR 6.1, 95%CI: 2.8-13.7; p < 0.001), donor age > 60 (HR 3.1, 95%CI: 1.4-6.7; p = 0.01), and failure to achieve SVR (HR 10.3, 95%CI: 1.3-18.3; p = 0.03). In conclusion, early treatment of recurrent HCV is safe, but does not lead to higher SVR rates. In HCV-infected LT recipients, elevated bilirubin, older donor age, and failure to achieve SVR are independently associated with increased mortality.
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Affiliation(s)
- Isabel Campos-Varela
- Liver Unit, Department of Internal Medicine, Universitat Autònoma de Barcelona. Barcelona, Spain
| | - Juan Ignacio Esteban
- Liver Unit, Department of Internal Medicine, Universitat Autònoma de Barcelona. Barcelona, Spain
| | - Marta Bes
- Marta Bes Transfusion Safety Laboratory, Banc de Sang i Teixits (BST), Universitat Autònoma de Barcelona. Barcelona, Spain
| | - Cristina Dopazo
- Liver Transplant Unit, Department of HPB-Surgery and Transplant, Universitat Autònoma de Barcelona. Barcelona, Spain
| | - Helena Allende
- Pathology Department, Universitat Autònoma de Barcelona. Barcelona, Spain
| | - Francisco Rodríguez-Frías
- Biochemistry Laboratory. Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona. Barcelona, Spain
| | - María Teresa Salcedo
- María Teresa Salcedo Pathology Department, Universitat Autònoma de Barcelona. Barcelona, Spain
| | - Silvia Sauleda
- Transfusion Safety Laboratory, Banc de Sang i Teixits (BST), Universitat Autònoma de Barcelona. Barcelona, Spain
| | - Ramón Charco
- Liver Transplant Unit, Department of HPB-Surgery and Transplant, Universitat Autònoma de Barcelona. Barcelona, Spain
| | - Jaime Guardia
- Liver Unit, Department of Internal Medicine, Universitat Autònoma de Barcelona. Barcelona, Spain
| | - Rafael Esteban
- Liver Unit, Department of Internal Medicine, Universitat Autònoma de Barcelona. Barcelona, Spain
| | - Lluis Castells
- Liver Unit, Department of Internal Medicine, Universitat Autònoma de Barcelona. Barcelona, Spain
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Kawaguchi-Suzuki M, Frye RF. The role of pharmacogenetics in the treatment of chronic hepatitis C infection. Pharmacotherapy 2014; 34:185-201. [PMID: 24114761 DOI: 10.1002/phar.1349] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Hepatitis C virus (HCV) chronically infects 170 million people worldwide. Until recently, combination therapy with peginterferon-α (pegIFN) and ribavirin (RBV) has been the standard of care. However, for many patients, especially those infected with the most common HCV genotype 1 (HCV-1), this treatment has resulted in unsatisfactory treatment response rates. Many clinical factors, including pharmacogenetics, influence the treatment response rate. Genetic variation in the interleukin 28B (IL28B) gene is the major determinant of treatment response, a finding that has been replicated in multiple independent cohorts. This review focuses on the association between pharmacogenetics and conventional pegIFN/RBV therapy in patients infected with HCV non-genotype 1; patients reinfected with HCV after liver transplantation; and patients coinfected with HCV and human immunodeficiency virus. We also review the pharmacogenetic data for boceprevir and telaprevir triple therapy in patients with HCV-1 infection, as well as viral genomic polymorphisms and genetic variants that may protect against anemia. Pharmacogenetic information offers a personalized medicine approach to help clinicians and patients make better informed decisions to maximize response and minimize toxicity for the treatment of chronic HCV infection.
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Affiliation(s)
- Marina Kawaguchi-Suzuki
- Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida
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25
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Lee TH, Tillmann HL, Patel K. Individualized therapy for hepatitis C infection: focus on the interleukin-28B polymorphism in directing therapy. Mol Diagn Ther 2014; 18:25-38. [PMID: 24022240 DOI: 10.1007/s40291-013-0053-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatitis C virus—a major global cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma—affects millions of people worldwide. Pegylated interferon (Peg-IFN) and ribavirin (RBV) had been the standard treatment for a decade until availability of the protease inhibitors in 2011. However, current antiviral therapy is still IFN-based and is associated with significant side effects and variable treatment response. Thus, various host and viral factors have been evaluated before and during treatment for the prediction of sustained virologic response to antiviral therapy. In 2009, genome-wide association studies found the single-nucleotide polymorphisms, located near the host interleukin-28B (IL28B) gene that encodes IFN-λ3, to be the best pretreatment predictor of virologic response to Peg-IFN and RBV therapy in chronic hepatitis C genotype 1 patients. Additionally, inosine triphosphatase (ITPA) gene variants were found to be associated with RBV-induced hemolytic anemia, which could affect treatment dose for selected patients. IL28B, ITPA, and other treatment predictors allowed for a potential individualized approach to treat hepatitis C. In the era of increased overall virologic response rates and good tolerability of the rapidly developing non-IFN oral direct-acting antiviral therapy regimens, the need for individualized treatment is likely to diminish. Various predictors of response, including IL28B will likely be of reduced importance in the near future.
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Howell J, Angus P, Gow P. Hepatitis C recurrence: the Achilles heel of liver transplantation. Transpl Infect Dis 2013; 16:1-16. [PMID: 24372756 DOI: 10.1111/tid.12173] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2013] [Revised: 06/12/2013] [Accepted: 08/03/2013] [Indexed: 12/18/2022]
Abstract
Hepatitis C virus (HCV) infection is the most common indication for liver transplantation worldwide; however, recurrence post transplant is almost universal and follows an accelerated course. Around 30% of patients develop aggressive HCV recurrence, leading to rapid fibrosis progression (RFP) and culminating in liver failure and either death or retransplantation. Despite many advances in our knowledge of clinical risks for HCV RFP, we are still unable to accurately predict those most at risk of adverse outcomes, and no clear consensus exists on the best approach to management. This review presents a critical overview of clinical factors shown to influence the course of HCV recurrence post transplant, with particular focus on recent data identifying the important role of metabolic factors, such as insulin resistance, in HCV recurrence. Emerging data for genetic markers of HCV recurrence and their usefulness for predicting adverse outcomes will also be explored.
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Affiliation(s)
- J Howell
- Liver Transplant Unit, Austin Hospital, Melbourne, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia
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Ackefors M, Nyström J, Wernerson A, Gjertsen H, Sönnerborg A, Weiland O. Evolution of fibrosis during HCV recurrence after liver transplantation--influence of IL-28B SNP and response to peg-IFN and ribavirin treatment. J Viral Hepat 2013; 20:770-8. [PMID: 24168256 DOI: 10.1111/jvh.12099] [Citation(s) in RCA: 8] [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: 12/14/2012] [Accepted: 02/14/2013] [Indexed: 01/01/2023]
Abstract
The IL-28 gene is associated with sustained viral response (SVR) after treatment with peg-IFN and ribavirin in liver transplant recipients with chronic hepatitis C genotype 1 infection. We analysed the importance of recipient and donor IL-28B genotype for response to treatment and fibrosis progression in 54 liver transplant recipients. Fibrosis stage (F) was defined as mild when F≤2 and severe when F≥3 in a liver biopsy or according to liver elasticity analysis. We found a significantly lower prevalence of IL-28B SNP CC in the recipients (22%) than in the donors (67%), P<0.0001. SVR was seen in 61% of the recipients with mild and 27% with severe fibrosis pretreatment, P=0.01. Recipients with IL-28 CC and non-CC had mild fibrosis in 64% and 38% prior to treatment, P=0.13. At follow-up, after treatment, significantly more recipients with CC had mild fibrosis than non-CC recipients (75% versus 32%, P=0.0072), and all with CC and SVR had mild fibrosis. The strongest baseline factor predicting SVR was genotype. Hence, 13/19 (68%) genotype non-1 patients reached SVR versus only 9/35 (26%) genotype 1 patients, P=0.0022. In summary, we found that liver transplant recipients with IL-28B CC tended to have less advanced fibrosis prior to and significantly less after SOC treatment and that all recipients with IL-28B CC who achieved SVR had mild fibrosis at follow-up. A significantly higher SVR rate was achieved in recipients with mild than severe fibrosis pretreatment and with genotype non-1 than 1 infection. Our findings indicate that treatment for post-transplant HCV recurrence should be offered before advanced fibrosis is seen in the recipient.
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Affiliation(s)
- M Ackefors
- Division of Infectious Diseases, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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Bitetto D, De Feo T, Mantovani M, Falleti E, Fabris C, Belli LS, Fagiuoli S, Burra P, Piccolo G, Donato MF, Toniutto P, Cmet S, Cussigh A, Viganò R, Airoldi A, Pasulo L, Colpanij M, De Martin E, Gambato M, Rigamonti C. Interaction between calcineurin inhibitors and IL-28B rs12979860 C>T polymorphism and response to treatment for post-transplant recurrent hepatitis C. Dig Liver Dis 2013; 45:927-32. [PMID: 23722013 DOI: 10.1016/j.dld.2013.04.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2013] [Revised: 03/14/2013] [Accepted: 04/21/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND The impact of calcineurin inhibitors on achievement of sustained virological response to antiviral therapy for post-transplant recurrent hepatitis C is controversial. This study aimed at investigating the interactions between calcineurin inhibitors and interleukin-28B (IL-28B) gene polymorphisms and sustained virological response. METHODS Retrospective study of 147 liver transplant recipients with recurrent hepatitis C, who received 48 weeks of peg-interferon-α (N=113) or standard interferon (N=34), in association with ribavirin. Cyclosporine and tacrolimus were administered in 68 and 79 patients, respectively. IL-28B rs12979860 allele frequency was assessed in both donors and recipients. RESULTS Overall, 57 patients (38.8%) obtained sustained virological response; no difference was found between cyclosporine and tacrolimus-treated patients (42.6% vs. 35.4%, p=0.371). Recipient and donor IL-28B genotypic frequencies were C/C=30.6%, C/T=51.7%, T/T=17.7% and C/C=44.9%, C/T=50.3%, T/T=4.8%, respectively. Combining donor and recipient alleles, response rates decreased from cyclosporine-treated patients carrying ≤ 1 T allele (56.1%) to tacrolimus-treated patients carrying ≤ 1 T allele (44.7%) to patients carrying ≥ 2 T alleles (25.0%, p=0.0009). CONCLUSIONS Donor and recipient rs12979860 alleles synergistically influence sustained virological response rate to antiviral treatment for recurrent hepatitis C. In patients carrying <2 T alleles cyclosporine favours a better response than tacrolimus, while no difference was found in the presence of ≥ 2 T alleles.
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Affiliation(s)
- Davide Bitetto
- Medical Liver Transplant Unit, Department of Medical Sciences Experimental and Clinical, University of Udine, Italy
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Gerold G, Pietschmann T. Opportunities and Risks of Host-targeting Antiviral Strategies for Hepatitis C. CURRENT HEPATITIS REPORTS 2013; 12:200-213. [PMID: 32214912 PMCID: PMC7089091 DOI: 10.1007/s11901-013-0187-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) infects more than 2 % of the world population with highest prevalence in parts of Africa and Asia. Past standard of care using interferon α and ribavirin had adverse effects and showed modest efficacy for some HCV genotypes spurring the development of direct acting antivirals (DAAs). Such DAAs target viral proteins and are thus better tolerated but they suffer from emergence of vial resistance. Furthermore, DAAs are often HCV genotype specific. Novel drug candidates targeting host factors required for HCV propagation, so called host-targeting antivirals (HTAs), promise to overcome both caveats. The genetic barrier to resistance is usually considered to be high for HTAs and all HCV genotypes presumably use the same host factors. Recent data, however, challenge these assumptions, at least for some HTAs. Here, we highlight the most important host-targeting strategies against hepatitis C and critically discuss their opportunities and risks.
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Affiliation(s)
- Gisa Gerold
- TWINCORE – Centre for Experimental and Clinical Infection Research, Institute of Experimental Virology, Feodor-Lynen-Str. 7, 30625 Hannover, Germany
| | - Thomas Pietschmann
- TWINCORE – Centre for Experimental and Clinical Infection Research, Institute of Experimental Virology, Feodor-Lynen-Str. 7, 30625 Hannover, Germany
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Agarwal K, Barnabas A. Treatment of chronic hepatitis C virus infection after liver transplantation. Dig Liver Dis 2013; 45 Suppl 5:S349-54. [PMID: 24091115 DOI: 10.1016/j.dld.2013.07.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Accepted: 07/01/2013] [Indexed: 12/11/2022]
Abstract
Chronic hepatitis C virus infection is a leading cause of end stage liver disease and one of the leading indications for liver transplantation. Furthermore, hepatitis C virus recurrence is universal post-transplant leading to decreased graft and patient survival. Recurrent disease related to hepatitis C virus can lead to between 20 and 30% of patients developing recurrent cirrhosis within 5 years. Treatment options with antiviral therapy are limited and are associated with a significant side-effect profile, suboptimal tolerability and inferior response rates. Attention has therefore turned to strategies that can reduce hepatitis C virus recurrence rates post-transplant. Approximately only 30% of patients will achieve a sustained virologic response with current therapy with pegylated interferon and ribavirin. Successful hepatitis C virus eradication is the only factor associated with improved graft and patient survival post liver transplantation. Here we provide an overview of antiviral treatment in patients in the transplant arena and the potential opportunities and challenges with the introduction of new directly acting antivirals in G1 patients.
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Affiliation(s)
- Kosh Agarwal
- Institute of Liver Studies, King's College Hospital, London, UK.
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31
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Seto WK, Tsang OTY, Liu K, Chan JMC, Wong DKH, Fung J, Lai CL, Yuen MF. Role of IL28B and inosine triphosphatase polymorphisms in the treatment of chronic hepatitis C virus genotype 6 infection. J Viral Hepat 2013; 20:470-7. [PMID: 23730840 DOI: 10.1111/jvh.12047] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2012] [Accepted: 11/03/2012] [Indexed: 01/12/2023]
Abstract
IL28B and inosine triphosphatase (ITPA) polymorphisms are able to predict treatment response and degree of ribavirin-related anaemia, respectively, in the treatment of chronic hepatitis C virus (HCV) infection. However, their roles in the treatment of chronic HCV genotype 6 remain undetermined. Sixty patients who were infected with HCV genotype 6 were commenced on 48 weeks of combination pegylated interferon and ribavirin therapy. Response to therapy, profiles of haemoglobin changes and platelet counts during therapy and their associations with IL28B rs8099917 and ITPA rs1127354 polymorphisms were analysed. The overall sustained virologic response (SVR) rate was 91.7%. 18 patients (30.0%) required a reduction in ribavirin dosage. The distribution of IL28B rs8099917 TT/TG genotypes and ITPA rs1127354 CC/CA genotypes were in Hardy-Weinberg equilibrium. IL28B rs8099917 TT genotype, when compared to TG genotype, was significantly associated with an increased SVR rate (96.2% and 62.5%, respectively) and was the only clinical parameter that predicted SVR (P = 0.014). The same significant association was observed when analysing allelic frequencies (T vs G, P = 0.001). ITPA rs1127354 CA genotype, when compared to CC genotype, was associated with lesser degree of anaemia throughout therapy (P < 0.05 for all time points). ITPA polymorphisms showed no association with changes in platelet count throughout therapy (P > 0.05 for all time points) and was not associated with SVR (P = 0.640). In chronic HCV genotype 6 infection, IL28B polymorphisms were associated with response to therapy. ITPA polymorphisms influenced the degree of anaemia but not thrombocytopenia during therapy.
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Affiliation(s)
- W-K Seto
- Department of Medicine, the University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong
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32
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Crespo G, Carrión JA, Coto-Llerena M, Mariño Z, Lens S, Pérez-Del-Pulgar S, García-Retortillo M, Miquel R, Bosch J, Navasa M, Forns X. Combinations of simple baseline variables accurately predict sustained virological response in patients with recurrent hepatitis C after liver transplantation. J Gastroenterol 2013; 48:762-9. [PMID: 23011083 DOI: 10.1007/s00535-012-0680-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2012] [Accepted: 08/29/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND The efficacy of antiviral therapy in patients with hepatitis C recurrence after liver transplantation (LT) is far from optimal and a careful selection of candidates with the best chances to achieve sustained virological response (SVR) is relevant. Moreover, investigating the effects of sustained viral clearance on clinical outcomes is particularly significant. We aimed to identify and combine the best baseline predictors of SVR and to assess the clinical outcomes of antiviral therapy after LT. METHODS We studied 144 hepatitis C virus (HCV)-infected LT recipients who underwent antiviral therapy following transplantation. Baseline predictors of SVR including donor and recipient interleukin IL28B (IL28B) rs12979860 genotype were evaluated, and the long-term effects of antiviral therapy on clinical outcomes were assessed. RESULTS The presence of an IL28B CC genotype with either low viral load (VL), young donor age, or cyclosporine A (CsA)-based immunosuppression identified individuals with 69-80 % probabilities of SVR. In contrast, only 20% of recipients with a CT/TT IL28B genotype and either high VL, old donor age, or non-CsA immunosuppression achieved an SVR (p = 0.004). Regarding clinical outcomes, the 5-year cumulative probability of graft loss was 2% for the SVR patients and 48% for non-responders (p < 0.001). CONCLUSIONS The use of simple combinations of baseline variables including IL28B polymorphisms identifies HCV-infected LT recipients with different probabilities of response to antiviral treatment. SVR is associated with improved clinical outcomes.
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Affiliation(s)
- Gonzalo Crespo
- Liver Unit, Institut de Malalties Digestives, Hospital Clínic, CIBERehd, IDIBAPS, Villarroel 170, 08036, Barcelona, Spain
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Berenguer M, Schuppan D. Progression of liver fibrosis in post-transplant hepatitis C: mechanisms, assessment and treatment. J Hepatol 2013; 58:1028-41. [PMID: 23262248 DOI: 10.1016/j.jhep.2012.12.014] [Citation(s) in RCA: 117] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Revised: 12/10/2012] [Accepted: 12/10/2012] [Indexed: 12/12/2022]
Abstract
Liver fibrosis results from an excessive wound healing response in most chronic liver diseases, such as hepatitis C. Despite great advances in antiviral therapy in recent years, progressive liver fibrosis remains a major problem for patients with recurrent hepatitis C after liver transplantation. Liver biopsy remains a central tool in the management of HCV-positive liver transplant recipients, but reliable non-invasive methods for the assessment of liver fibrosis, such as ultrasound elastography, are increasingly being incorporated in the management of post-transplant patients, helping predict prognosis, guide treatment decisions, and stratify patients for emerging antifibrotic therapies. In this manuscript, we will review the natural history as well as tools to monitor fibrosis progression in the HCV-positive liver transplant recipient, the mechanisms underlying rapid fibrosis progression in up to 30% of these patients, the effect of antiviral therapies and highlight promising antifibrotic approaches.
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Affiliation(s)
- Marina Berenguer
- University Valencia, Dept. of Medicine, Hepatology & Liver Transplantation Unit, La Fe Hospital and CIBEREHD, National Network Center for Hepatology and Gastroenterology Research, Instituto de Salud Carlos III, Spain.
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Biggins SW, Trotter J, Gralla J, Burton JR, Bambha KM, Dodge J, Brocato M, Cheng L, McQueen M, Forman L, Chang M, Kam I, Everson G, Spritz RA, Klintmalm G, Rosen HR. Differential effects of donor and recipient IL28B and DDX58 SNPs on severity of HCV after liver transplantation. J Hepatol 2013; 58:969-76. [PMID: 23333445 PMCID: PMC3878646 DOI: 10.1016/j.jhep.2012.12.027] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2012] [Revised: 12/01/2012] [Accepted: 12/27/2012] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS IL28B single nucleotide polymorphisms are strongly associated with spontaneous HCV clearance and treatment response in non-transplant populations. A DDX58 single nucleotide polymorphism is associated with the antiviral response of innate lymphocytes. We aimed at evaluating the associations of donor and recipient IL28B (rs12979860 and rs8099917) and DDX58 (rs10813831) genotypes with severity of HCV recurrence after liver transplantation. METHODS In a case-control study of 523 liver transplantation recipients with HCV, we matched severe with mild recurrent HCV based on 2-year clinical and histologic follow-up. A total of 440 liver transplantation recipients (severe, n=235; mild, n=205) with recipient DNA and 225 (severe, n=123; mild, n=102) with both recipient and donor DNA were analyzed. RESULTS IL28B [rs12979860, non-CC (vs. CC) and rs8099917, non-TT (vs. TT)] in the recipient-only analysis had higher risk of severe recurrent HCV [OR 1.57 and 1.58, p<0.05]. However, for the 225 with donor and recipient DNA, IL28B rs12979860 CC (vs. non-CC) and rs8099917 TT (vs. non-TT) and DDX58 rs10813831 non-GG (vs. GG) were associated with more (not less) severe recurrent HCV. The greatest risk of severe recurrent HCV was for rs12979860 CC donors in non-CC recipients (OR 7.02, p <0.001, vs. non-CC donor/recipient) and for rs8099917 TT donors in non-TT recipients (OR 5.78, p=0.001, vs. non-TT donor/recipient). These associations persisted after controlling for donor age, donor race, and donor risk index. CONCLUSIONS IL28B and DDX58 single nucleotide polymorphisms that are favorable when present in the non-transplant setting or in the recipient are unfavorable when present in a donor liver graft.
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Affiliation(s)
- Scott W Biggins
- University of Colorado Denver, Division of Gastroenterology and Hepatology, Aurora, CO 80045, United States.
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35
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Pol S, Aerssens J, Zeuzem S, Andreone P, Lawitz EJ, Roberts S, Younossi Z, Foster GR, Focaccia R, Horban A, Pockros PJ, Van Heeswijk RPG, De Meyer S, Luo D, Botfield M, Beumont M, Picchio G. Limited impact of IL28B genotype on response rates in telaprevir-treated patients with prior treatment failure. J Hepatol 2013; 58:883-889. [PMID: 23321318 DOI: 10.1016/j.jhep.2012.12.023] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2012] [Revised: 11/22/2012] [Accepted: 12/26/2012] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Nucleotide polymorphisms upstream of the interleukin 28B (IL28B) gene are strongly associated with hepatitis C virus (HCV) clearance in treatment-naïve patients treated with peginterferon/ribavirin (PegIFN/RBV). This subanalysis of the REALIZE study evaluated the impact of IL28B polymorphisms on sustained virologic response (SVR) in telaprevir-treated, HCV genotype 1-infected patients with prior PegIFN/RBV treatment failure. METHODS Treatment-experienced patients were randomized to 12 weeks of telaprevir (750 mg every 8h) with/without a 4-week PegIFN/RBV lead-in, or placebo, each with PegIFN-α-2a (180 μg/week) and ribavirin (1000-1200 mg/day) for 48 weeks overall. Data from telaprevir arms were pooled. RESULTS Eighty percent (527/662) of patients consented to genetic testing and were included. Similar proportions of patients had IL28B CC, CT and TT genotypes across treatment arms; baseline characteristics were generally well balanced. SVR rates were higher in the pooled telaprevir versus placebo group for all IL28B genotypes; CC: 79% versus 29%, respectively; CT: 60% versus 16%, respectively; TT: 61% versus 13%, respectively. Within each prior response category (relapse, partial or null response), SVR and viral breakthrough rates with telaprevir-based treatment were comparable across IL28B genotypes. IL28B genotype did not significantly affect SVR (2-step multivariate analyses; p >0.16 in pairwise comparison among CC, TT, and CT). Variations in rapid virologic response and relapse rates were noted in certain patient subgroups. CONCLUSIONS Our findings suggest that IL28B genotype has a limited impact on SVR rates with telaprevir-based therapy in treatment-experienced patients. IL28B genotyping may have limited utility in the baseline evaluation of similar patients considered for telaprevir-based therapy.
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Affiliation(s)
- Stanislas Pol
- Université Paris Descartes, INSERM Unité 1016, and Assistance Publique-Hôpitaux de Paris, Cochin Hospital, Paris, France.
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Hepatitis C virus treatment and liver transplantation in the era of new antiviral therapies. Curr Opin Organ Transplant 2013; 17:216-24. [PMID: 22476221 DOI: 10.1097/mot.0b013e3283534d64] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW The new standard-of-care treatment for genotype 1 hepatitis C virus infection is a combination of PEG-interferon (PEG-IFN), ribavirin (RBV) and a protease inhibitor - telaprevir or boceprevir. As triple therapy is not yet approved for use in decompensated cirrhotics and liver transplant recipients, we examine the efficacy and safety of PEG-IFN, RBV and protease inhibitors in nontransplant populations to inform the current and future treatment paradigms for transplant candidates and recipients. RECENT FINDINGS Protease inhibitor-based triple therapy is more efficacious than PEG-IFN and RBV in nontransplant genotype 1 patients, so sustained virologic response rates are predicted to be higher in waitlisted candidates and transplant recipients treated with protease inhibitor-triple therapy. Because of the need to use a backbone of PEG-IFN and RBV, tolerability of therapy will remain a major challenge. Anemia, a well recognized side-effect with PEG-IFN and RBV, will be especially common with protease inhibitor-triple therapy. Both protease inhibitors can modify the levels of drugs metabolized by the CYP3A/4 pathway, and in posttransplant patients, the protease inhibitors increase the levels of cyclosporine and tacrolimus, with the magnitude of the drug-drug interactions varying with protease inhibitor and type of calcineurin inhibitor (CNI). SUMMARY Given the complexities of treatment, it is best undertaken by experienced clinicians and only after a detailed discussion of risks-benefits with the patient. To maximize the benefit while minimizing risk, only Child-Turcott-Pugh A (CPT-A) cirrhotics should be considered for pretransplant protease inhibitor-triple therapy. For transplant recipients, very close monitoring and adjustment of CNI levels is critical during protease inhibitor-triple therapy. Cytopenias, especially anemia, will require aggressive management.
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New insights in recurrent HCV infection after liver transplantation. Clin Dev Immunol 2013; 2013:890517. [PMID: 23710205 PMCID: PMC3655463 DOI: 10.1155/2013/890517] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Revised: 03/17/2013] [Accepted: 03/31/2013] [Indexed: 12/15/2022]
Abstract
Hepatitis C virus (HCV) is a small-enveloped RNA virus belonging to the Flaviviridae family. Since first identified in 1989, HCV has been estimated to infect 170 million people worldwide. Mostly chronic hepatitis C virus has a uniform natural history, from liver cirrhosis to the development of hepatocellular carcinoma. The current therapy for HCV infection consists of a combination of Pegylated interferon and ribavirin. On the other hand, HCV-related liver disease is also the leading indication for liver transplantation. However, posttransplant HCV re-infection of the graft has been reported to be universal. Furthermore, the graft after HCV re-infection often results in accelerated progression to liver failure. In addition, treatment of recurrent HCV infection after liver transplantation is often compromised by enhanced adverse effects and limited efficacy of interferon-based therapies. Taken together, poor outcome after HCV re-infection, regardless of grafts or recipients, poses a major issue for the hepatologists and transplant surgeons. The aim of this paper is to review several specific aspects regarding HCV re-infection after transplant: risk factors, current therapeutics for HCV in different stages of liver transplantation, cellular function of HCV proteins, and molecular mechanisms of HCV entry. Hopefully, this paper will inspire new strategies and novel inhibitors against recurrent HCV infection after liver transplantation and greatly improve its overall outcome.
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Piluso A, Giannini C, Fognani E, Gragnani L, Caini P, Monti M, Petrarca A, Ranieri J, Urraro T, Triboli E, Laffi G, Zignego AL. Value of IL28B genotyping in patients with HCV-related mixed cryoglobulinemia: results of a large, prospective study. J Viral Hepat 2013; 20:e107-14. [PMID: 23490377 DOI: 10.1111/jvh.12017] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2012] [Accepted: 09/03/2012] [Indexed: 12/19/2022]
Abstract
HCV-related mixed cryoglobulinemia (MC) is characterized by clonal expansion of B cells producing a polyreactive natural antibody (rheumatoid factor) and interferon (IFN)-based therapy is the first therapeutic option in mild-moderate MC. Single nucleotide polymorphisms (SNPs) proximal to genes involved in the innate response (IL28B/IFN-λ gene family) are strongly associated with spontaneous and IFN-induced viral clearance in hepatitis C, but no data exist about their role in HCV-positive MC. A large cohort of patients with HCV and MC was studied to evaluate the influence of IL28B genotype on the response to treatment and/or the evolution to MC of HCV infection. The rs12979860/rs8099917 IL28B polymorphisms were analysed in 481 consecutive HCV-positive subjects (250 with MC and 231 without MC, as controls) using real-time PCR and direct sequencing. Hundred and fifteen HCV patients with MC received standard anti-HCV therapy, and the results were evaluated according to the IL28B SNP distribution. Similar IL28B SNPs allele frequencies were recorded for patients and controls. IL28B major allele homozygosis (for both SNPs tested) was tightly correlated with virological and clinical response (P = 0.002). A statistically significant association was limited to 'difficult-to-treat' (G1/4) HCV genotypes. The IL28B genotype was a strong independent predictor of response (P = 0.007, OR 6.06; CI 1.65-22.22). The IL28B genotype was confirmed to be a useful predictor of response to IFN-based therapy in patients with HCV and MC. The very close correlation between IL28B SNP distribution, virological and clinical response definitively confirmed the key role played by HCV in MC. Conversely, the IL28B genotype does not seem to influence the evolution to MC.
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Affiliation(s)
- A Piluso
- Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department of Internal Medicine, University of Florence, Florence, Italy
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Joshi D, Carey I, Agarwal K. Review article: the treatment of genotype 1 chronic hepatitis C virus infection in liver transplant candidates and recipients. Aliment Pharmacol Ther 2013; 37:659-71. [PMID: 23432320 DOI: 10.1111/apt.12260] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Revised: 12/20/2012] [Accepted: 02/03/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND Recently, the therapeutic landscape with regard to anti-HCV therapy has changed dramatically. The new directly acting anti-virals (DAAs) have demonstrated improved sustained virological response (SVR) compared with pegylated-interferon and ribavirin. AIM To examine and present the latest data with regard to anti-viral therapy in genotype 1 HCV-positive transplant candidates and recipients. METHODS An electronic search using Medline was performed. Search terms included 'HCV, DAA and protease inhibitor' in combination with 'treatment pre-transplantation' and 'treatment post-transplantation'. RESULTS Patients with advanced fibrosis and cirrhosis have inferior SVR rates compared with patients with minimal fibrosis. A low accelerating dose regimen (LADR) of pegylated interferon and ribavirin (PR) appears to be a safe therapeutic option. Side effects also appear to be more pronounced in patients with advanced disease. Data from the large registration studies with triple therapy (boceprevir or telaprevir plus PR) demonstrated improved SVR rates even in patients with advanced disease, although virological relapse rates were highest amongst these patients. In transplant recipients, initial data are being reported on the use of triple therapy, and although no SVR data are available, promising results are accruing. The drug-drug interactions appear to be manageable. Side effects in particular anaemia appear to be markedly increased in the posttransplant setting. CONCLUSIONS The use of the new DAAs in patients with advanced fibrosis/cirrhosis pretransplant and posttransplant appears possible, with manageable side effects and drug-drug interactions, and improved early virological response rates. We recommend that these patients are managed in centres with the appropriate expertise.
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Affiliation(s)
- D Joshi
- Institute of Liver Studies, King's College Hospital, London, UK.
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Abstract
Hepatitis C virus (HCV) infections become chronic in the majority of infected individuals, and chronic hepatitis C (CHC) can lead to cirrhosis and hepatocellular carcinoma. The innate immune system is central to host-virus interactions during the entire natural course of the disease. The HCV NS3/4A protease efficiently cleaves and inactivates two important signaling molecules in the sensory pathways that react to HCV pathogen-associated molecular patterns (PAMPs) to induce interferons (IFNs), i.e., mitochondrial antiviral signaling protein (MAVS) and Toll-IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF). Despite this viral escape mechanism, the innate immune system strongly reacts to HCV within the first days after infection. The sensory pathways, the type(s) of IFNs involved and the cellular source of IFNs are largely unknown. After 4-8weeks, HCV specific T cells are recruited to the liver. IFN-γ-stimulated genes get strongly expressed in the liver. In about 30% of patients, the virus is eliminated during the acute phase of the infection by T cell-mediated antiviral mechanisms. In the remaining 70% of patients, HCV persists for decades. During this phase, T cell-derived IFN-γ cannot be detected any more in liver biopsies. Instead, in about half of the patients, hundreds of type I or III IFN-stimulated genes become again strongly expressed. However, this innate immune reaction is ineffective against HCV. Moreover, patients with constitutive IFN-stimulated gene (ISG) expression have a poor response to treatment with pegylated IFN-α (PegIFN-α) and ribavirin. The viral escape mechanisms that protect HCV from IFN-mediated innate immune reactions are not entirely understood, but might involve blockade of ISG protein translation at the ribosome, localization of viral replication to cells with refractory IFN signal transduction pathways or to cell compartments that are not accessible to antiviral IFN-stimulated effector systems. Recently, genetic variations near the IL28B (IFN-λ3) were found to be strongly associated with spontaneous clearance of HCV and response to treatment with PegIFN-α and ribavirin. The finding supports a central role of the innate immune response in host-viral interactions. The signaling pathways that link genetic variants of IL28B with immune answers to HCV remain to be elucidated. The present review article attempts to summarize current knowledge of some central aspects of the interactions of HCV with the innate immune system.
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Affiliation(s)
- Markus H Heim
- Division of Gastroenterology and Hepatology, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
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Levitsky J, Doucette K. Viral hepatitis in solid organ transplantation. Am J Transplant 2013; 13 Suppl 4:147-68. [PMID: 23465008 DOI: 10.1111/ajt.12108] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Affiliation(s)
- J Levitsky
- Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
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42
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Lange CM. The importance of IL28B genotype in hepatitis C virus-associated liver transplantation. Liver Int 2013; 33:169-71. [PMID: 23295049 DOI: 10.1111/liv.12071] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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Abstract
In the direct-acting antiviral (DAA) era of hepatitis C virus (HCV) therapy, health care providers must be knowledgeable about genotype and subtype of HCV infection and interpretation of quantitative HCV viral assays to monitor treatment responses. They may also choose to assess interleukin 28B genotypes or resistance-associated variants after ineffective DAA therapy. DAA therapies require understanding of performance characteristics of quantitative HCV RNA assays and the definitions of terms used to report results. Only quantitative HCV RNA assays with a limit of detection of 10 to 15 IU/mL are appropriate for managing patients on DAA therapy.
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Affiliation(s)
- John M Vierling
- Department of Medicine, Liver Center, Baylor College of Medicine, Houston, TX 77030, USA.
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Allam SR, Krüger B, Mehrotra A, Schiano T, Schröppel B, Murphy B. The association of IL28B polymorphism and graft survival in patients with hepatitis C undergoing liver transplantation. PLoS One 2013; 8:e54854. [PMID: 23382988 PMCID: PMC3559776 DOI: 10.1371/journal.pone.0054854] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2012] [Accepted: 12/17/2012] [Indexed: 12/16/2022] Open
Abstract
Hepatitis C virus (HCV) infection is the leading cause of liver transplantation (LT) in Western countries. Polymorphism in the IL28B gene region has a major impact on the natural history and response to antiviral treatment in HCV. We investigated whether IL28B polymorphism was associated with graft survival in patients with or without HCV undergoing LT. 1,060 adult patients (age >18 years) underwent LT between years 2000 and 2008. Patients with previous LT, living donor LT and patients dying or requiring retransplants within 30 days of LT were excluded. DNA samples of 620 (84%) recipients and 377 (51%) donors were available for genotyping of IL28B rs12979860C>T. Donor IL28B genotypes had no significant differences in graft survival irrespective of HCV status. There was no difference in graft outcome in the non-HCV cohort (n = 293) based on recipient IL28B genotype. In the HCV group (n = 327), recipients with CC or CT genotype had better graft survival compared to TT genotype (62% vs. 48%, p = 0.02). HCV recipients with CC or CT genotype had delayed time to clinically relevant HCV recurrence compared to TT (10.4 vs. 6.7 months, p = 0.002). The beneficial effect of the CC/CT genotype on HCV recurrence and graft survival was independent of antiviral treatment. In conclusion, our study demonstrated that in contrast to donor IL28B genotype recipient IL28B was associated with graft survival and clinically relevant HCV recurrence in HCV infected recipients. No effect of IL28B genotype was manifest in non-HCV LT recipients.
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Affiliation(s)
- Sridhar R. Allam
- Division of Nephrology, Mount Sinai School of Medicine, New York, New York, United States of America
| | - Bernd Krüger
- V. Medizinische Klinik, Universitätsmedizin Mannheim, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany
| | - Anita Mehrotra
- Division of Nephrology, Mount Sinai School of Medicine, New York, New York, United States of America
| | - Thomas Schiano
- Division of Liver Diseases, Mount Sinai School of Medicine, New York, New York, United States of America
- Recanati Miller Transplantation Institute, Mount Sinai School of Medicine, New York, New York, United States of America
| | - Bernd Schröppel
- Division of Nephrology, Mount Sinai School of Medicine, New York, New York, United States of America
| | - Barbara Murphy
- Division of Nephrology, Mount Sinai School of Medicine, New York, New York, United States of America
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Akamatsu N, Sugawara Y. Living-donor liver transplantation and hepatitis C. HPB SURGERY : A WORLD JOURNAL OF HEPATIC, PANCREATIC AND BILIARY SURGERY 2013; 2013:985972. [PMID: 23401640 PMCID: PMC3564275 DOI: 10.1155/2013/985972] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/17/2012] [Accepted: 01/01/2013] [Indexed: 12/19/2022]
Abstract
Hepatitis-C-virus- (HCV-) related end-stage cirrhosis is the primary indication for liver transplantation in many countries. Unfortunately, however, HCV is not eliminated by transplantation and graft reinfection is universal, resulting in fibrosis, cirrhosis, and finally graft decompression. In areas with low deceased-donor organ availability like Japan, living-donor liver transplantation (LDLT) is similarly indicated for HCV cirrhosis as deceased-donor liver transplantation (DDLT) in Western countries and accepted as an established treatment for HCV-cirrhosis, and the results are equivalent to those of DDLT. To prevent graft failure due to recurrent hepatitis C, antiviral treatment with pegylated-interferon and ribavirin is currently considered the most promising regimen with a sustained viral response rate of around 30% to 35%, although the survival benefit of this regimen remains to be investigated. In contrast to DDLT, many Japanese LDLT centers have reported modified treatment regimens as best efforts to secure first graft, such as aggressive preemptive antiviral treatment, escalation of dosages, and elongation of treatment duration.
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Affiliation(s)
- Nobuhisa Akamatsu
- Department of Hepato-Biliary-Pancreatic Surgery, Saitama Medical Center, Saitama Medical University, 1981 Tsujido-cho, Kamoda, Kawagoe, Saitama 350-8550, Japan
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Yasuhiko Sugawara
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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46
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Duarte-Rojo A, Deneke MG, Charlton MR. Interleukin-28B polymorphism in hepatitis C and liver transplantation. Liver Transpl 2013; 19:49-58. [PMID: 23008132 DOI: 10.1002/lt.23554] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2012] [Accepted: 07/30/2012] [Indexed: 12/15/2022]
Abstract
The discovery of interleukin-28B (IL-28B) single-nucleotide polymorphisms has opened an important new area of research in liver transplantation (LT) for hepatitis C virus (HCV). Both recipient- and donor-derived IL-28B genotypes affect the post-LT treatment response, with sustained virological response (SVR) rates oscillating from >50% in homozygotes for the favorable allele (up to 90% when this is present in both the recipient and the donor) to <15% in homozygotes for the unfavorable allele and from 30% to 50% in heterozygotes. Other key posttransplant outcomes affected by the IL-28B genotype are the time to histological recurrence, HCV RNA and alanine aminotransferase levels, histological variables (including the rate of fibrosis progression), and hepatocellular carcinoma. Interactions between donor and recipient IL-28B genotypes are complex and may affect outcomes not directly related to HCV infections, such as acute cellular rejection (ACR) and metabolic diseases. A preferential allocation system in which livers from donors homozygous for the favorable allele are given to HCV patients might be postulated to improve SVR rates and post-LT outcomes in recipients with HCV infections (a 25% increase in SVR and an 8% decrease in mortality at 5 years). Although negative effects from this are difficult to predict, they could include an accelerated progression of fibrosis in patients with failed HCV eradication and an increase in ACR in non-HCV patients. Our knowledge of the precise role of IL-28B genotypes in the course of post-LT HCV is evolving, but existing knowledge suggests the possibility of exploring strategies that use IL-28B genotyping to reduce the impact of post-LT adverse outcomes.
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Affiliation(s)
- Andres Duarte-Rojo
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
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Firpi RJ, Dong H, Clark VC, Soldevila-Pico C, Morelli G, Cabrera R, Norkina O, Shuster JJ, Nelson DR, Liu C. CC genotype donors for the interleukin-28B single nucleotide polymorphism are associated with better outcomes in hepatitis C after liver transplant. Liver Int 2013; 33:72-8. [PMID: 23107586 PMCID: PMC3518691 DOI: 10.1111/liv.12013] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2012] [Accepted: 09/05/2012] [Indexed: 12/26/2022]
Abstract
BACKGROUND/AIMS Interleukin-28B (IL-28B) polymorphism is the strongest pretreatment predictor of viral clearance in the hepatitis C (HCV) population. Donor and recipient IL-28B genomic background may play an important role in post-transplant HCV recurrence. We sought to examine the role of IL-28B polymorphisms of donor and recipients in liver transplant patients with recurrent HCV and its impact on the response to interferon-based therapy. METHODS The cohort study consisted of 135 adult liver transplant patients who received interferon-based therapy for recurrent HCV between 1996 and 2005 at the University of Florida. IL-28B single nucleotide polymorphism (rs. 12979860) was characterized using liver tissue from all donors and recipients. RESULTS The CC genotype was observed in approximately 30% of donors and recipients. Sustained viral response (SVR) to HCV therapy was 100% if both recipient and donor were CC genotype, while the SVR was only 25% if neither donor nor recipient had a CC genotype. (Recipient, P = 0.025, Donor, P < 0.001). Recipients and donors with CC genotype had less fibrosis than recipients with genotypes CT and TT, but the difference was not statistically significant. IL-28B genotype did not seem to play a role in the overall survival in these patients. CONCLUSION In conclusion, recipient and donor CC genotype is associated with a better treatment response to interferon-based therapy after liver transplant. Our study suggests that using CC genotype donor livers for HCV patients may improve the overall clinical outcome after liver transplantation.
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Affiliation(s)
- Roberto J. Firpi
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition Section of Hepatobiliary Diseases and Liver Transplantation, University of Florida, Gainesville, FL
| | - Huijia Dong
- Department of Pathology, University of Florida, Gainesville, FL
| | - Virginia C. Clark
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition Section of Hepatobiliary Diseases and Liver Transplantation, University of Florida, Gainesville, FL
| | - Consuelo Soldevila-Pico
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition Section of Hepatobiliary Diseases and Liver Transplantation, University of Florida, Gainesville, FL
| | - Giuseppe Morelli
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition Section of Hepatobiliary Diseases and Liver Transplantation, University of Florida, Gainesville, FL
| | - Roniel Cabrera
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition Section of Hepatobiliary Diseases and Liver Transplantation, University of Florida, Gainesville, FL
| | - Oxana Norkina
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition Section of Hepatobiliary Diseases and Liver Transplantation, University of Florida, Gainesville, FL
| | - Jonathan J. Shuster
- Department of Health Outcomes and Policy College of Medicine, University of Florida, Gainesville, FL
| | - David R. Nelson
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition Section of Hepatobiliary Diseases and Liver Transplantation, University of Florida, Gainesville, FL
| | - Chen Liu
- Department of Pathology, University of Florida, Gainesville, FL
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Berenguer M, Roche B, Aguilera V, Duclos-Vallée JC, Navarro L, Rubín A, Pons JA, de la Mata M, Prieto M, Samuel D. Efficacy of the retreatment of hepatitis C virus infections after liver transplantation: role of an aggressive approach. Liver Transpl 2013; 19:69-77. [PMID: 23008144 DOI: 10.1002/lt.23555] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2012] [Accepted: 07/29/2012] [Indexed: 12/26/2022]
Abstract
A sustained virological response (SVR) is achieved by 30% of naive liver transplantation (LT) recipients treated with pegylated interferon (PEG-IFN) and ribavirin (RBV). Almost no data are available about retreatment. The aim of this study was to assess the efficacy, tolerability, and SVR predictors of retreatment. Data were collected from 4 centers on the retreatment of prior nonresponders to standard therapy or PEG-IFN (with or without RBV) and relapsers. Seventy-nine of 301 treatment-experienced LT patients (26%), who had a median age of 59 years (range = 35-77 years) and were mostly male (72%) and infected with genotype 1 (87%), were retreated with PEG-IFN and RBV at a median of 6.9 years after LT. During the first course of therapy, 35% were treated with interferon, 49% received tacrolimus, 52% received steroids, and 49.5% were relapsers. Retreatment was started at a median of 1.9 years (range = 45 days to 8.2 years) after the end of the first course. The proportion of patients with cirrhosis increased from 10% to 37% (P < 0.001). In addition, in retreated patients, full initial RBV doses (P = 0.03), growth factors [erythropoietin (P < 0.001) and granulocyte colony-stimulating factor (P = 0.048)], and transfusions (P = 0.03) were used more frequently, and the treatment duration was longer (P = 0.03). An end-of-treatment response was achieved in 61%, whereas SVR, which was associated with improved survival, occurred in 28 (35%). The variables predicting SVR were age (P = 0.04), disease severity [fibrosis (50% with F0-F2 versus 26% with F3-4), P = 0.03; bilirubin, P = 0.006; platelet count, P = 0.03], adherence, and viral kinetics. None of the patients without an early virological response achieved SVR. There was a trend of prior relapsers achieving higher SVR rates than prior nonresponders. In conclusion, SVR, which was achieved by approximately one-third of the retreated patients, can be predicted with the same variables used for naive LT recipients (age, disease severity, adherence, and viral kinetics) and is associated with enhanced survival.
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Affiliation(s)
- Marina Berenguer
- Liver Transplantation and Hepatology Unit, La Fe Hospital, Valencia, Spain.
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Abstract
Genome-wide association studies have identified polymorphisms located near the gene encoding IL28B, which turned out to be the best predictor of response to pegylated interferon plus ribavirin for chronic hepatitis C virus (HCV) genotype 1 infection. This association was extended to spontaneous clearance of HCV, suggesting shared mechanisms of treatment and natural control of this virus. In addition to the biologic implications for innate immunity and HCV, a variety of clinical studies have suggested possible translation to a useful genetic test for practitioners. This article reviews the discovery, biology, and potential clinical applications that have stemmed from the seminal observation that IL28B polymorphisms are a main predictor of HCV clearance.
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Affiliation(s)
- Christoph T. Berger
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard Medical School
- Department of Internal Medicine and Department of Biomedicine, University Hospital Basel, Switzerland
| | - Arthur Y. Kim
- Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
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50
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McCaughan GW. New therapies against HCV: expected risks and challenges associated with their use in the liver transplant setting. J Hepatol 2012; 57:1361-7. [PMID: 22885390 DOI: 10.1016/j.jhep.2012.07.035] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2012] [Revised: 07/20/2012] [Accepted: 07/20/2012] [Indexed: 02/07/2023]
Affiliation(s)
- Geoffrey W McCaughan
- Centenary Research Institute, A.W. Morrow Gastroenterology and Liver Center, Australian National Liver Transplant Unit, Royal Prince Alfred Hospital University of Sydney, Sydney, Australia.
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