| Abstract|| |
Background/Aim: In patients with advanced post-transplant hepatitis C virus (HCV) recurrence, antiviral treatment (AVT) with interferon and ribavirin is indicated to prevent graft failure. The aim of this study was to determine and report Canadian data with respect to the safety, efficacy, and spontaneous virologic response (SVR) predictors of AVT among transplanted patients with HCV recurrence. Patients and Methods: A retrospective chart review was performed on patients transplanted in London, Ontario and Edmonton, Alberta from 2002 to 2012 who were treated for HCV. Demographic, medical, and treatment information was collected and analyzed. Results: A total of 85 patients with HCV received pegylated interferon with ribavirin post-liver transplantation and 28 of the 65 patients (43%) with genotype 1 achieved SVR. Of the patients having genotype 1 HCV who achieved SVR, there was a significantly lower stage of fibrosis (1.37 ± 0.88 vs. 1.89 ± 0.96; P = 0.03), increased ribavirin dose (total daily dose 1057 ± 230 vs. 856 ± 399 mg; P = 0.02), increased rapid virologic response (RVR) (6/27 vs. 0/31; P = 0.05), increased early virologic response (EVR) (28/28 vs. 18/35; P = 0.006), and longer duration of therapy (54.7 ± 13.4 weeks vs. 40.2 ± 18.7; P = 0.001). A logistic regression model using gender, age, RVR, EVR, anemia, duration of therapy, viral load, years' post-transplant, and type of organ (donation after cardiac death vs. donation after brain death) significantly predicted SVR (P < 0.001), with duration of therapy having a significant odds ratio of 1.078 (P = 0.007). Conclusions: This study identified factors that predict SVR in HCV-positive patients who received dual therapy post-transplantation. Extending therapy from 48 weeks to 72 weeks of dual therapy is associated with increased SVR rates. Future studies examining the role of extended therapy are needed to confirm these findings, since the current study is a retrospective one.
Keywords: Hepatitis C virus, liver transplant, retrospective study
|How to cite this article:|
Wells MM, Roth LS, Marotta P, Levstik M, Mason AL, Bain VG, Chandok N, Aljudaibi BM. Increased duration of dual pegylated interferon and ribavirin therapy for genotype 1 hepatitis C Post-liver transplantation increases sustained virologic response: A retrospective review. Saudi J Gastroenterol 2013;19:223-9
|How to cite this URL:|
Wells MM, Roth LS, Marotta P, Levstik M, Mason AL, Bain VG, Chandok N, Aljudaibi BM. Increased duration of dual pegylated interferon and ribavirin therapy for genotype 1 hepatitis C Post-liver transplantation increases sustained virologic response: A retrospective review. Saudi J Gastroenterol [serial online] 2013 [cited 2020 Jun 7];19:223-9. Available from: http://www.saudijgastro.com/text.asp?2013/19/5/223/118133
End stage liver disease secondary to hepatitis C virus (HCV) infection is a leading indication for liver transplantation (LT), constituting approximately 30-50% of all transplants. ,,,, HCV recurrence post-LT is universal. , Once HCV recurrence occurs, liver disease progresses at an accelerated rate. In untreated patients, acute biochemical hepatitis develops in approximately 75% of HCV recipients in the first 6 months following LT, and by the fifth postoperative year over 80% of HCV-infected liver transplant recipients will develop histologic evidence of chronic allograft injury secondary to hepatitis C, with up to 20-40% developing cirrhosis. , Nearly, 2-9% of patients with HCV recurrence will develop an aggressive cholestatic variant (i.e., fibrosing cholestatic hepatitis) that is associated with accelerated graft loss and patient death. , Overall, patients who undergo LT due to HCV have impaired patient and allograft survival compared with patients who undergo LT for other indications. 
HCV treatment post-LT has been fraught with disappointing results with SVR rates of dual therapy (pegylated interferon plus ribavirin) of around 30-40%, , compared to SVR rates of 55% in HCV-positive patients treated prior to LT.  Overall, treatment is poorly tolerated, with frequent need for dose reductions, especially for cytopenias, and drug discontinuation in up to 50% of patients. Optimizing drug doses is important in maximizing SVR rates. The potential factors that influence this low SVR rate includes; high proportion of patients with genotype 1 virus; high viral load at the start of treatment; high percentage of prior non-responders to therapy; side-effects that often make the use of standard doses and duration of treatment difficult; wether growth factors are used or not; and the effect of immunosuppression. , Donor characteristics such as age (<60 years) and IL28B genotype CC (rs129789860) have been shown to be predictors of SVR in patients treated with dual therapy. 
The present retrospective medical chart review study, comparing the factors that influence HCV-treatment SVR rates post-LT, was therefore undertaken in order to evaluate the role these factors play in determining the virologic response and clinical outcome of post-transplant HCV infections.
| Patients and Methods|| |
This retrospective chart review was conducted at the liver transplant programs of the University of Alberta and Western University. The study protocol was reviewed and approved by the Independent Ethics Committee of each of the 2 participating centers.
Patients who received a LT due to hepatitis C cirrhosis were eligible for the study. Only HCV positive LT recipients who received a LT from January 1, 2002 to December 31, 2011 were included. Patients underwent protocolized liver biopsies every 6 months post-LT to assess the severity of disease recurrence and to guide treatment decisions. Once stage 1-2 fibrosis was noted on liver biopsy, HCV antiviral treatment (AVT) was initiated. The standard doses of Pegylated Interferon (PEG-IFN) alpha 2a and Ribavirin were 180 mcg and 1200 mg, respectively. Due to pancytopenia, certain patients were started on dose-reduced treatment. In the Edmonton cohort, therapy was extended from 48 weeks to 72 weeks duration in patients who were slow to respond to treatment (patients with a 2 log decrease in HCV viral load at week 12 of treatment and a negative viral load at week 24 of treatment).
Of note, 29 patients (25 from London and 4 from Edmonton) had previously been included in the NOVARTIS trial (publication in preparation).
Assessments and endpoints
Data were extracted from the original patient charts and entered into a standardized spreadsheet. All collected data were de-identified and patients were assigned a unique study subject identifier.
Study data included patient demographics including age and gender, past medical history, HCV information (including genotype and viral load), medication information (including dosages and duration of therapy of ribavirin and pegylated interferon, as well as anti-rejection medications), metavir stage of liver fibrosis on liver biopsy, side-effects to anti-HCV treatment, and response to HCV treatment (early virologic response [EVR], rapid virologic response [RVR], and SVR).
The primary outcome of the study was the association between an a priori model to predict SVR and the proportion of patients with a SVR to the post-transplant HCV antiviral therapy. The SVR was defined as undetectable HCV-RNA serum levels at the 24-week follow-up period after cessation of the antiviral therapy. It was considered a relapse if the patient was found to have a positive viral load at any time after that 24-week period. The model included the covariates of gender, age, RVR, EVR, anemia, duration of dual therapy, viral load, years' post-LT, and use of donation after cardiac death (DCD) livers.
Secondary endpoints included exploring the association of SVR with other factors including recipient age, gender, presence of HCC, viral load, biochemical tests (creatinine and total bilirubin) duration and dosing of therapy, stage, genotype, location (Edmonton or London), organ type (DCD or donation after brain death [DBD]), RVR, EVR, use of Erythropoietin, and packed red blood cell transfusions.
Multivariate logistic regression analysis was performed on outcome measures using the covariates that were identified a priori as clinically relevant to the outcome. These were used to produce adjusted estimates and comparisons of the between-group difference with respect to the primary outcome. The odds ratio (OR) and 95% confidence intervals (CI) were used as estimate of the treatment effect.
Secondary outcomes included exploring the sensitivity, specificity, and likelihood ratios of the various a priori secondary factors to predict SVR. Average estimates are presented as means + standard deviation. No imputation or replacement of missing values was performed as all analyses were conducted on observed cases. A two-tailed P < 0.05 was used as the significance level in all analyses.
All statistical analyses were performed using IBM SPSS Version 20.0.0 (see http://www-01.ibm.com/support/docview.wss?uid=swg21476197; IBM Corp. Released 2012. IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp.), Excel 2011 version 14.2.3 (Microsoft, Redmond, WA) and Cochrane's Revman 5.
| Results|| |
Approximately, 135 total liver transplants (70 at Edmonton, Alberta, Canada and 65 at London, Ontario, Canada) and 45 liver transplants for HCV cirrhosis are performed each year. This retrospective analysis was based on the review of 85 charts of patients who underwent LT secondary to HCV cirrhosis between January 1 st , 2002 and December 31 st , 2011 in 2 Canadian liver transplant centers. A total of 2 patients were excluded as their genotype was unknown. 18 patients were genotype 2 or 3 (4 had genotype 2 and 14 had genotype 3). SVR was 43% (28/65) with genotype 1 and 93% (14/18) with genotype 2 and 3 (P = 0.02). Genotype 2 had a positive likelihood ratio (+LR) of 3.42 (95% CI 1.23-9.56), a negative likelihood ratio (−LR) of 0.74 (95% CI 0.58-0.94), and an OR of 4.63 (95% CI 1.37-15.59) for achieving SVR. With respect to anti-rejection medications, the majority of patients were taking tacrolimus (55/65) while there was less use of mycophenolate mofetil (28/65) and cyclosporine (8/65).
All further analyses were performed on the 65 patients who had genotype 1 HCV. The medical and demographic characteristics at the beginning of anti-HCV treatment are presented in [Table 1]. Between patients achieving SVR and not achieving SVR, a significant difference was observed in duration of therapy (P = 0.001), stage of fibrosis (P = 0.03), ribavirin dose (P = 0.02), RVR (P = 0.05) and EVR (P = 0.006). Age, gender, genotype (1a vs. 1b), and location (Edmonton vs. London), DCD versus non-DCD organs, PEG dose, whether they had received Erythropoietin or blood transfusions, presence of HCC, whether ribavirin required dose reduction, viral load, creatinine and total serum bilirubin, revealed no significant differences between patients achieving and not achieving SVR.
|Table 1: The medical and demographic characteristics at the time of beginning anti-HCV treatment post-liver transplant |
Click here to view
[Table 2] presents the sensitivities, specificities, +LR, −LR for the a priori characteristics listed in [Table 1]. Significant factors associated with SVR were duration of therapy 48 weeks or more (+LR 2.48, CI 1.63-3.75 and -LR 0.06, CI 0.01-0.42), ribavirin dose of 1000 mg or more (+LR 1.61, CI 1.17-2.21 and -LR 0.24, CI 0.08-0.75), and presence of RVR (−LR 0.78, CI 0.64-0.95), presence of EVR (+LR 1.94, CI 1.4-2.68).
Logistic regression using gender, age, RVR, EVR, anemia, duration of therapy, viral load, years' post-transplant, and type of organ (DCD vs. DBD) to predict SVR was significant (P < 0.001). Duration of therapy had the only significant OR of 1.078 (i.e., for every extra week of therapy, SVR increased 1.078 times; P = 0.007).
|Table 2: Summary of diagnostic accuracy of variables in predicting HCV SVR post-LT |
Click here to view
[Table 3] shows the number of patients who experienced side-effects while receiving anti-HCV treatment. There was no significant difference between the rates of any specific side-effects or total side-effects between patients who achieved SVR and those who did not.
|Table 3: Side effects during dual HCV treatment post liver transplantation |
Click here to view
| Discussion|| |
The present retrospective study consisted of a Canadian cohort of patients who underwent LT for HCV-related cirrhosis and subsequently treated with dual therapy for recurrence of their HCV. It attempted to determine the factors that influence SVR rates.
Our SVR results were generally in agreement with those obtained in other post-transplant studies, although there were some differences. The SVR rate seen in this study was significantly lower for genotype 1 (43%) than for genotypes 2/3 (93%, P = 0.02). This is consistent with other trials. Selzner et al.,  demonstrated an overall SVR rate of 50% (genotype 1/4:40%; genotype 2/3:76%). In the trial by Cescon et al.,  the overall SVR rate was 25% (25/99), with logistic regression demonstrating that a viral genotype other than 1 significantly predicted SVR (OR = 4.97, 95% CI = 1.59-15.48, P = 0.006).
Previous studies have investigated the characteristics that may be important in determining SVR post-LT. The ReVIS-TC Study  found that the administration of cyclosporine A (CsA) (OR 0.37, P = 0.021) in conjunction with a longer AVT duration (OR 0.86, P = 0.024) correlated with lower relapse rate, whereas, the older age of the donor (OR 1.03, P = 0.006) and the presence of genotype 1 (OR 3.45, P = 0.032) were associated with a higher probability of relapse. Selzner et al.,  found SVR was higher on CsA (56%) than on tacrolimus (44%, P = 0.05), largely because of a lower relapse rate (6% vs. 19%, P = 0.01). In multivariate analysis, genotype 2/3, CsA use, donor age, and pre-treatment necroinflammatory activity were independently associated with SVR. SVR significantly improved the histology and long-term survival (actuarial 5-year survival 96% vs. 69% in non-responders, P < 0.0001). Cescon et al.,  demonstrated, using the logistic regression analysis, that donor age < 60 years (OR = 4.45, 95% CI = 1.39-14.19, P = 0.01), viral genotype other than 1 (OR = 4.97, 95% CI = 1.59-15.48, P = 0.006), and the use of CyA during treatment (OR = 6.85, 95% CI = 2.15-21.73, P = 0.001). CsA was reported to be clinically effective against HCV.  Controlled trials showed that a combination of CsA with IFN alpha is more effective than IFN alpha alone, especially in patients with a high viral load. , Moreover, recent in vitro studies provided evidence that CsA prevents both HCV RNA replication and HCV protein production in an IFN alpha-independent manner. ,,,, Other potential predictors of SVR with dual therapy in patients pre-LT include recipient factors (non-genotype 1, IL28B genotype CC (rs129789860), low pre-treatment viral load, mild histologic disease, lower body weight, male gender, and immunosuppression with cyclosporine), donor characteristics (donor age less than 60, and IL28B genotype CC rs129789860), and treatment factors (RVR, EVR, absence of drug interactions or reductions, and use of growth factors). 
Strengths of our study would include 100% patient follow-up and this being a dual-centred study, which captures two large provincial LT centers, making the findings more generalizable.
This study has limitations. It is a retrospective study with a relatively small sample size. This current study did not collect information on donor age, which has been previously shown to be a major determinant of fibrosis progression. , We also did not perform an analysis on the effect of anti-rejection medications on HCV SVR rates post-LT, as there was a significant amount of evidence on the topic. ,, We also failed to investigate IL28 status in both donors and recipients as this may have shed light on the SVR rates. The patients undergoing HCV treatment post-LT are highly selected, and this may in part explain differences in SVR rates amongst the published studies.
Another limitation is that this study did not assess the use of triple therapy for HCV post-LT. While use of protease inhibitors (telaprevir and boceprevir) is currently not the standard of care in treating recurrent HCV in patients having undergone LT, there is great hope that they will improve the results of pre- and post-transplant antiviral therapy and become standard of care in the future. Nevertheless, the adverse profile of triple therapy in this population is still unknown and the patients that should receive it remain undefined. However, for several reasons, there is still value in this study. The first is that, at the present time, there has only been one peer-reviewed publication in 9 patients on the use of protease inhibitors in post-transplant hepatitis,  albeit many more forthcoming. There are also concerns of interactions between the protease inhibitors and immunosuppressant medications used to prevent hepatic rejection. Thirdly, many patients will not have access to triple therapy in the foreseeable future.
In conclusion, our study has shown that a longer duration of treatment may be associated with a higher rate of sustained viral response in the treatment of post-liver transplant patients with HCV recurrence. In addition to the duration of therapy, we identified stage of fibrosis, ribavirin dose, RVR and EVR as predictors of SVR. Given the retrospective nature of this study, further prospective longitudinal studies should be undertaken to better assess these factors, especially as they relate to triple therapy, in liver transplant recipients with HCV recurrence.
| Acknowledgment|| |
The authors would like to thank Mary McCutcheon for her assistance in this retrospective review.
| References|| |
|1.||Watt K, Veldt B, Charlton M. A practical guide to the management of HCV infection following liver transplantation. Am J Transplant 2009;9:1707-13. |
|2.||Uemura T, Ramprasad V, Hollenbeak CS, Bezinover D, Kadry Z. Liver transplantation for hepatitis C from donation after cardiac death donors: An analysis of OPTN/UNOS data. Am J Transplant 2012;12:984-91. |
|3.||Forman LM, Lewis JD, Berlin JA, Feldman HI, Lucey MR. The association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology 2002;122:889-96. |
|4.||Berenguer M, López-Labrador FX, Wright TL. Hepatitis C and liver transplantation. J Hepatol 2001;35:666-78. |
|5.||O'Leary JG, Lepe R, Davis GL. Indications for liver transplantation. Gastroenterology 2008;134:1764-76. |
|6.||Charlton M, Seaberg E, Wiesner R, Everhart J, Zetterman R, Lake J, et al. Predictors of patient and graft survival following liver transplantation for hepatitis C. Hepatology 1998;28:823-30. |
|7.||Neumann UP, Berg T, Bahra M, Puhl G, Guckelberger O, Langrehr JM, et al. Long-term outcome of liver transplants for chronic hepatitis C: A 10-year follow-up. Transplantation 2004;77:226-31. |
|8.||Filipec Kanizaj T, Coliæ Cvrlje V, Mrzljak A, Ostojiæ R. Treatment of recurrent hepatitis C infection after liver transplantation. Acta Med Croatica 2009;63:451-7. |
|9.||Narang TK, Ahrens W, Russo MW. Post-liver transplant cholestatic hepatitis C: A systematic review of clinical and pathological findings and application of consensus criteria. Liver Transpl 2010;16:1228-35. |
|10.||Terrault N. Liver transplantation in the setting of chronic HCV. Best Pract Res Clin Gastroenterol 2012;26:531-48. |
|11.||Ross AS, Bhan AK, Pascual M, Thiim M, Benedict Cosimi A, Chung RT. Pegylated interferon alpha-2b plus ribavirin in the treatment of post-liver transplant recurrent hepatitis C. Clin Transplant 2004;18:166-73. |
|12.||Shepherd J, Brodin H, Cave C, Waugh N, Price A, Gabbay J. Pegylated interferon alpha-2a and-2b in combination with ribavirin in the treatment of chronic hepatitis C: A systematic review and economic evaluation. Health Technol Assess 2004;8:iii-iv, 1-125. |
|13.||Rodriguez-Luna H, Vargas HE. Management of hepatitis C virus infection in the setting of liver transplantation. Liver Transpl 2005;11:479-89. |
|14.||Selzner N, Renner EL, Selzner M, Adeyi O, Kashfi A, Therapondos G, et al. Antiviral treatment of recurrent hepatitis C after liver transplantation: Predictors of response and long-term outcome. Transplantation 2009;88:1214-21. |
|15.||Cescon M, Grazi GL, Cucchetti A, Vetrone G, Ravaioli M, Ercolani G, et al. Predictors of sustained virological response after antiviral treatment for hepatitis C recurrence following liver transplantation. Liver Transpl 2009;15:782-9. |
|16.||ReViS-TC Study Group. Cyclosporine a-based immunosuppression reduces relapse rate after antiviral therapy in transplanted patients with hepatitis C virus infection: A large multicenter cohort study. Transplant 2011;92:334-40. |
|17.||Akiyama H, Yoshinaga H, Tanaka T, Hiruma K, Tanikawa S, Sakamaki H, et al. Effects of cyclosporin A on hepatitis C virus infection in bone marrow transplant patients. Bone Marrow Transplantation Team. Bone Marrow Transplant 1997;20:993-5. |
|18.||Inoue K, Sekiyama K, Yamada M, Watanabe T, Yasuda H, Yoshiba M. Combined interferon alpha2b and cyclosporin A in the treatment of chronic hepatitis C: Controlled trial. J Gastroenterol 2003;38:567-72. |
|19.||Inoue K, Yoshiba M. Interferon combined with cyclosporine treatment as an effective countermeasure against hepatitis C virus recurrence in liver transplant patients with end-stage hepatitis C virus related disease. Transplant Proc 2005;37:1233-4. |
|20.||Goto K, Watashi K, Murata T, Hishiki T, Hijikata M, Shimotohno K. Evaluation of the anti-hepatitis C virus effects of cyclophilin inhibitors, cyclosporin A, and NIM811. Biochem Biophys Res Commun 2006;343:879-84. |
|21.||Ishii N, Watashi K, Hishiki T, Goto K, Inoue D, Hijikata M, et al. Diverse effects of cyclosporine on hepatitis C virus strain replication. J Virol 2006;80:4510-20. |
|22.||Ma S, Boerner JE, TiongYip C, Weidmann B, Ryder NS, Cooreman MP, et al. NIM811, a cyclophilin inhibitor, exhibits potent in vitro activity against hepatitis C virus alone or in combination with alpha interferon. Antimicrob Agents Chemother 2006;50:2976-82. |
|23.||Nakagawa M, Sakamoto N, Tanabe Y, Koyama T, Itsui Y, Takeda Y, et al. Suppression of hepatitis C virus replication by cyclosporin a is mediated by blockade of cyclophilins. Gastroenterology 2005;129:1031-41. |
|24.||Watashi K, Hijikata M, Hosaka M, Yamaji M, Shimotohno K. Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes. Hepatology 2003;38:1282-8. |
|25.||Berenguer M, Prieto M, San Juan F, Rayón JM, Martinez F, Carrasco D, et al. Contribution of donor age to the recent decrease in patient survival among HCV-infected liver transplant recipients. Hepatology 2002;36:202-10. |
|26.||Wali M, Harrison RF, Gow PJ, Mutimer D. Advancing donor liver age and rapid fibrosis progression following transplantation for hepatitis C. Gut 2002;51:248-52. |
|27.||Werner CR, Egetemeyr DP, Lauer UM, Nadalin S, Königsrainer A, Malek NP, et al. Telaprevir-based triple therapy in liver transplant patients with hepatitis C virus: A 12-week pilot study providing safety and efficacy data. Liver Transpl 2012;18:1464-70. |
Malcolm M Wells
Division of Gastroenterology, Victoria Hospital, 800 Commissioners Road East, London, Ontario
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3]