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Volume: 17 Issue: 1 February 2019

FULL TEXT

ARTICLE
Impact of Sofosbuvir-Based Regimens for the Treatment of Hepatitis C After Liver Transplant on Renal Function: Results of a Canadian National Retrospective Study

Objectives: We assessed the impact of sofosbuvir-based regimens on renal function in liver transplant recipients with recurrent hepatitis C virus and the role of renal function on the efficacy and safety of these regimens.

Materials and Methods: In an expanded pan-Canadian cohort, 180 liver transplant recipients were treated with sofosbuvir-based regimens for hepatitis C virus recurrence from January 2014 to May 2015. Mean age was 58 ± 6.85 years, and 50% had F3/4 fibrosis. Patients were stratified into 4 groups based on baseline estimated glomerular filtration rate (calculated by the Modification of Diet in Renal Disease formula): < 30, 30 to 45, 46 to 60, and > 60 mL/min/173 m2. The primary outcome was posttreatment changes in renal function from baseline. Secondary outcomes included sustained virologic response at 12 weeks posttreatment and anemia-related and serious adverse events.

Results: Posttreatment renal function was improved in most patients (58%). Renal function declined in 22% of patients, which was more marked in those with estimated glomerular filtration rate < 30 mL/min/173 m2, advanced cirrhosis (P = .05), and aggressive hepatitis C virus/fibrosing cholestatic hepatitis (P < .05). High rates (80%-88%) of sustained virologic response at 12 weeks posttreatment were seen across all renal function strata. Cirrhotic patients with glomerular filtration rates < 30 mL/min/173 m2 had sustained virologic response rates at 12 weeks posttreatment comparable to the overall patient group. Rates of anemia-related adverse events and transfusion requirements increased across decreasing estimated glomerular filtration rate groups, with notably more occurrences with ribavirin-based regimens.

Conclusions: Sofosbuvir-based regimens improved overall renal function in liver transplant recipients, with sustained virologic response, suggesting an association of subclinical hepatitis C virus-related renal disease. Sustained virologic response rates at 12 weeks posttreatment (80%-88%) were comparable regardless of baseline renal function but lower in cirrhosis.


Key words : Direct-acting antiviral, Efficacy, Renal failure

Introduction

Hepatitis C virus (HCV) infection and renal disease represent important populations as they pose major health burdens worldwide.1,2 These two conditions are linked in several important ways, which include direct mesangial injury by HCV infection, Toll-like receptor-related immune response, systemic immune response to HCV infection mediated by cryoglobulins, and nonimmunologically mediated injury (elevated levels of fasting insulin, insulin resistance, and higher prevalence of diabetes).3-6

In several large-scale observational studies, HCV was associated with increased prevalence of renal insufficiency and end-stage renal disease.7-9 A large population-based study in Taiwan showed a 4-fold risk of mortality from renal disease in participants with anti-HCV seropositivity, and those with high HCV-RNA levels had almost 10-fold risk of renal mortality compared with anti-HCV seronegative participants.10 Similarly, a meta-analysis reported higher all-cause mortality, increased rates of liver fibrosis, and the possibility of a negatively affected renal graft in HCV-infected kidney transplant recipients.11

The treatment for hepatitis C has rapidly evolved in recent years, with many new agents available and several in the pipeline, either in late phases of development or awaiting approval. Direct-acting anti-virals (DAAs) target various parts of the HCV lifecycle. Most DAAs are metabolized primarily via the liver, and dose adjustment is not necessary for patients with renal impairment.12,13 Sofosbuvir is a potent nucleotide analogue inhibitor of the HCV NS5B polymerase that has been approved for the treatment of HCV in combination with a variety of other agents. Unlike other agents, it is excreted via the kidneys and not recommended for patients with severe renal failure. A single dose of sofosbuvir resulted in higher levels of the major systemic metabolite GS-331007 among patients with mild, moderate, and severe renal dysfunction compared with individuals with normal renal function.14 Renal function in cirrhotic and noncirrhotic patients treated with sofosbuvir-based regimens both before and after liver transplant is often compromised yet has been poorly assessed. Here, we assessed the impact of sofosbuvir-based regimens on renal function in patients treated for recurrent HCV after liver transplant and assessed the impact of renal dysfunction on the efficacy and safety of these regimens.

Materials and Methods

Patients
We reviewed data of an expanded cohort from a previously published study.15 Patients were enrolled from 6 transplant sites in Canada from January 2014 through May 2015. Eligible patients were 18 years of age or older who had biopsy-proven HCV recurrence and received current or previous treatment after liver transplant with sofosbuvir-based antiviral regimens. All genotypes were included. Selection of the antiviral therapy was at the discretion of the clinician at each center, as determined by drug availability and local standard of care. Four treatment regimens were used in the study cohort: sofosbuvir + simeprevir ± ribavirin, sofosbuvir + ribavirin, sofosbuvir + ledipasvir ± ribavirin, and sofosbuvir + pegylated interferon + ribavirin (Figure 1). This study was approved by the institutional review board or independent ethics committee of the participating study sites.

Baseline estimated glomerular filtration rate (eGFR) was calculated by the Modification of Diet in Renal Disease formula. Patients were stratified into 4 groups according to their baseline renal function: unimpaired (eGFR > 60 mL/min/1.73 m2), mildly impaired (eGFR of 46-60 mL/min/1.73 m2), moderately impaired (eGFR of 30-45 mL/min/1.73 m2), and severely impaired (eGFR ≤ 30 mL/min/1.73 m2). Serum HCV RNA was measured by means of the COBAS AmpliPrep/COBAS TaqMan HCV quantitative test version 2.0 (Roche Molecular Systems, Pleasanton, CA , USA), with a lower limit of quantification of 15 IU/mL.

The primary outcome was posttreatment renal function compared with baseline function. Secondary endpoints included the rate of sustained virologic response, which was defined as an HCV RNA level of less than 15 IU/mL at 12 weeks after the end of treatment in all patients, serious adverse events, anemia-related adverse events, and treatment discontinuations because of adverse events or death.

Statistical analyses
Baseline characteristics of all patients treated with sofosbuvir-based regimens were described using count and percent or median and range. Baseline and follow-up values were compared using paired sample t tests. Ninety-five percent confidence intervals were calculated using the exact formula. Signs and symptoms experienced during DAA therapy use were determined from chart review, and the number of patients experiencing each potential adverse effect was tabulated. All analyses were performed with SPSS software (SPSS: An IBM Company, version 28, IBM Corporation, Armonk, NY, USA). For all comparisons, a two-sided P < .05 was considered to indicate statistical significance.

Results

Baseline characteristics
Our study included 180 patients with HCV recurrence who were treated with sofosbuvir-based regimens; patients were stratified into 4 groups with respect to their baseline renal function. Patient characteristics are shown in Table 1. Overall, the characteristics of patients were generally balanced among the 4 study groups, with expected differences between patients with severe renal impairment and in terms of advanced and decompensated cirrhosis.

Half of these patients had some degree of renal impairment at baseline (n = 90). Moderate renal impairment was seen in 30 patients (17%) and severe renal impairment in 10 patients (6%). The mean patient age was 58 ± 6.85 years, with most patients being male (80%), having genotype 1, and white. About half of the patients had advanced cirrhosis (66% compensated and 34% decompensated), and 21% of patients had aggressive recurrent HCV/fibrosing cholestatic hepatitis (FCH) within the first year of transplant. More than two-thirds of patients (78%) were treatment experienced before transplant, including 14% with previous failed first-generation protease inhibitor treatment. The median time from liver transplant to treatment was 27 months (range, 1-309 mo). Most patients were on tacrolimus-based immunosuppression.

Impact of sofosbuvir-based regimens on renal function
Renal function was improved in most patients (58%) after treatment (Figure 2). In patients with mild renal impairment, 20 of 50 patients (40%) showed improvement from baseline, whereas 24 patients (48%) had stable renal function and only 6 patients (12%) had worsening of renal function. Similarly, in the moderate renal impairment group, 47% and 43% had improved and stabilized renal function, respectively. Only one patient had worsening of renal function. In the severe renal impairment group, 3 of 10 patients showed worsening of renal parameters requiring renal replacement therapy. Only 1 patient showed improvement, whereas the remaining 6 patients had stabilized renal function as baseline. Of patients in the unimpaired renal function group, 14 of 90 patients (15%) developed mild to moderate renal impairment.

A decline in eGFR was seen in 42 patients (23%) from the study cohort. A minor decrease (< 10%) from baseline was observed in 21 patients, a mild decrease (10%-20%) in 10 patients, a moderate decrease (20%-30%) in 4 patients, and a severe decrease (> 30%) in renal function was noted in 7 patients. A worsening of renal function was more marked in patients with poorest renal function (eGFR< 30 mL/min/173 m2), advanced cirrhosis (P = .05), and aggressive HCV/FCH (P < .05).

Impact of renal function on the efficacy of sofosbuvir-based regimens
The overall SVR12 rate was 86% in the study cohort. Response rates were 88%, 87%, 82%, and 80% in unimpaired, mild, moderate, and severe renal impairment groups, respectively. No significant differences were seen when the response rate was further compared with treatment regimens and fibrosis stage (Figure 3). Cirrhotic patients with eGFR < 30 mL/min/173 m2 had SVR12 rates comparable to the overall patient group. Lower SVR12 rates were seen in cirrhotic versus noncirrhotic patients irrespective of baseline eGFR (79% vs 95%; P = .006).

Impact of renal function on the safety of sofosbuvir-based regimens
The frequencies of adverse events in the 4 groups are shown in Table 2. Most adverse events were of mild or moderate intensity in all groups. In our patient cohort, 12 patients died, and most deaths were liver related. Serious adverse events, anemia, and transfusion requirements were seen more in the severe renal impairment group than in the other groups. Rates of anemia were notably higher with ribavirin-based therapy. Cardiac serious adverse events were reported in 2 patients (1 with cardiac arrest, 1 with myocardial infarction). Immunosup­pression had no effect on renal function.

Discussion

Our study demonstrated that HCV eradication with sofosbuvir-based regimens was associated with improved overall renal function in liver transplant recipients. The improvement of eGFR was also associated with virologic response to treatment in the vast majority of patients, suggesting an association of subclinical HCV-related renal disease. Although calcineurin inhibitors have been associated with nephrotoxicity after liver transplant, their role may be overestimated or the cause of posttransplant renal dysfunction in HCV transplant recipients is multifactorial, and other contributing factors should remain in a clinician's differential diagnosis. The association of HCV infection with renal dysfunction at the population level has been examined by Tsui and associates9 and by several other studies7,16,17 but has not been well-explored in the post-liver transplant setting.

The improvement of posttreatment eGFR was associated with improved liver function in 92% of patients. However, this improvement was neither associated with levels of calcineurin inhibitors nor with the type of immunosuppression. Dose reduction was seen in 21% of patients, dose increase was seen in 17%, and no major changes were seen in most patients (61%).

In our study, increased risk for renal insufficiency was associated with baseline severe renal impairment (eGFR < 30 mL/min/173 m2). This has also previously been observed in the HCV-target study.18 Other predictors of significant decreases (> 20% decrease in eGFR from baseline) in renal function in our study were obesity, advanced fibrosis, and aggressive HCV/FCH (Table 3). Our cohort displayed encouraging virologic response with SVR rate of 86%, and no on-therapy viral breakthrough was seen.

This study has several limitations. First, the number of patients with severe renal impairment was small; second, there are no dosing guidelines for sofosbuvir in patients with eGFR < 30 mL/min/1.73 m2. Therefore, it is difficult to interpret the results accurately. The clinical data in regard to proteinuria were missing, which may have supported the association of HCV-related renal disease, as noted previously.19 Similarly we did not exclude long-standing diabetes status in these patients, which may have an effect on our results.

In conclusion, sofosbuvir-based treatment improves overall renal function in liver transplant recipients with sustained virological response, suggesting an association of subclinical HCV-related renal disease. In short, HCV eradication after liver transplant not only improves liver function but also renal function. Sustained virologic response rates 12 weeks posttreatment were comparable regardless of baseline renal function but lower in cirrhosis.


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Volume : 17
Issue : 1
Pages : 59 - 63
DOI : 10.6002/ect.2017.0201


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From the 1Organ Transplant and Hepatobiliary Department, King Abdulaziz Medical City/National Guard Health Sciences, Riyadh, Saudi Arabia; the 2Liver Unit, Department of Medicine, Université de Montréal, Montréal, Québec, Canada; the 3Department of Gastroenterology, London Health Sciences, University of Western Ontario and King Saud University Riyadh, Saudi Arabia; the 4Hepatology, Dalhousie University/Queen Elizabeth II Health Science Center, Halifax, Nova Scotia, Canada; the 5Department of Gastroenterology, University of British Columbia and Vancouver General Hospital, Vancouver, British Columbia, Canada; the 6Solid Organ Transplantation Unit, University of British Columbia and Vancouver General Hospital, Vancouver, British Columbia, Canada; 7Department of Gastroenterology and Hepatology, University of McGill, Montreal, Quebec, Canada; the 8Department of Gastroenterology and Hepatology and the 9Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada; and the 10Multi-Organ Transplant Unit, University Health Network/Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
Acknowledgements: No grants and/or financial support were received for this work. E. Yoshida has been an investigator of clinical trials sponsored by Gilead Sciences, Merck Inc, Abbvie Inc, Janssen Inc, and Intercept Inc. and received honoraria for CME/Ad Board lectures from Gilead Canada, Merck Canada, Celgene Canada, and Abbvie Canada. M. P. Ghali has been a consultant for Gilead and served on the Advisory Board for Merck and Gilead for the last 2 years. The other authors have no competing interests to declare. This work was presented as a podium presentation at the Liver Meeting of the American Association for the Study of Liver in November 2015, San Francisco, CA, USA.
Corresponding author: Nabiha Faisal, 917-35 Thorncliffe Park Drive, Toronto, M4H 1J3 Ontario, Canada
Phone: +1 647 607 6371
E-mail: nabiha.faisal@gmail.com