Clinical outcomes of hepatitis C treatment before and after kidney transplantation and its impact on time to transplant: A multicenter study

1 INTRODUCTION

Kidney transplantation (KT) decreases healthcare costs and increases available life years for patients.1, 2 However, significant organ shortage exists.3 The annual incidence of hepatitis C virus (HCV) infection in end-stage renal disease (ESRD) patients awaiting KT ranges from 1.4% to2.1%, with prevalence approaching 12%-23% in the United States, which is approximately 100–1000 times higher than the general population.4-8 However, less than one-third of patients with HCV will receive a HCV-positive kidney, and HCV-positive kidneys are 2.6 times more likely to be discarded.9 Nearly two-thirds of HCV-positive kidneys, accounting for thousands of potentially usable organs over a 10-year period, were discarded.10

Underutilization of HCV-positive organs in HCV-positive recipients is likely multifactorial. Receipt of HCV-positive organs was shown to increase the risk of death, though risk is delayed for approximately 2 years.11 Direct acting antiviral therapies (DAA) boast HCV-cure rates in excess of 95%. However, renal failure poses a unique challenge as many DAA-based regimens are not currently approved for use in ESRD.

Although there is concern that DAA therapy may temporarily cause allograft dysfunction and lead to the need for closer immunosuppression monitoring, most data suggest DAA therapy is well tolerated and effective with treatment responses of 96%-100%.12-16 Patients may benefit from being left viremic going into transplant because of substantial reduction in waitlist time (WLT) from years to ≤ 2 months.9, 15 However, untreated HCV post-KT could have a more severe course because of the permissive effects of chronic immunosuppression on HCV viral replication, which could lead to progression of liver disease.17, 18 Optimal timing of HCV treatment remains unknown. Given this uncertainty, we compared the impact of HCV treatment pre- vs post-KT on organ access as judged by WLT between 2 large-volume KT centers within the same health system with identical KT management protocols with the exception of timing of HCV treatment.

2 MATERIALS AND METHODS

3 RESULTS

3.3 Impact on access to transplant and waitlist time

At center A, 8 patients were listed for KT and 1 underwent KT. The WLT was 148 days in the transplanted patient. The median (IQR) WLT as calculated from the date of listing to the date of transplant or last follow-up was 650 (354; 1133) days. In 28 patients at center B who underwent transplant, median WLT was 122 (IQR 22; 531) days (Figure 1). Significant difference was noted between the centers with respect to WLT (P = .02). The 1-year transplantation rate was significantly different: 12.5% at center A and 67.9% at center B (P = .0013).

4 DISCUSSION

KT remains a treatment modality for ESRD and offers benefits with regard to morbidity and mortality.20 In a large multinational cohort, approximately 10% of patients on HD were infected with HCV.21 In patients considered otherwise eligible for KT, optimal timing of HCV treatment is unknown. In our study we have compared 2 approaches to HCV eradication. Both resulted in eradication of HCV. However, deferring HCV treatment until post-KT resulted in significant decreases in transplant WLT without influencing safety or efficacy of HCV DAA-based therapy.

According to UNOS, nearly 97 000 people await KT in the United States. Approximately 19 000 received a transplant in 2016. Five-hundred kidneys are discarded annually because of HCV infection.10 Currently, transplantation of HCV-positive grafts into negative recipients is limited to controlled clinical trials. Our study highlights that there does not appear to be additional risk to the patient or graft in transplanting a HCV-positive kidney into a positive recipient. Added benefits include decreased WLT, higher transplant rate, and potentially avoidance of discarding organs that could be used in lifesaving transplantation.

Liver transplant data show that leaving patients HCV-viremic entering transplant decreases WLT and increases access.22 Data show that transplantation of HCV-positive kidneys into negative recipients decreased WLT to a median of 58 days.15, 23 Median WLT in our study was higher at 122 days. However, either strategy shortens WLT compared with national and regional averages. For comparison, at the time of our study, national WLT was 701 days, with center A’s regional WLT time at 726 days and center B’s regional WLT at 915 days. It should be noted in December 2014, which fell during the study period, WLT was redefined as initiation date of dialysis among other factors. Patients with long dialysis times were moved up the list. Time on dialysis is associated with increased risk of HCV.24 We believe this change should have affected our centers similarly given length on dialysis was not different and all patients had HCV. However, we would recommend caution in comparing the WLT regionally and nationally with our cohort. Ongoing study to determine the exact impact of leaving patients HCV viremic pre-KT is needed.

By transplanting HCV-positive kidneys into positive recipients, no patient was newly infected with HCV. The costs of infecting a naive patient with HCV are not fully elucidated. Additionally, the possibility of transmitting a resistant infection may become a reality.

Response to HCV treatment was favorable in the KT population both pre- and posttransplant. Previously reported eradication rates exceed 90%; 100% achieved SVR in our study. Given the lack of approval of sofosbuvir, the backbone of most HCV treatment regimens, in ESRD, treatment is limited to elbasvir/grazoprevir or glecaprevir/pibrentasvir. However, treatment options targeting all genotypes are expanded with improved renal function post-KT. Therapy appears well tolerated pre- and post-KT. It is unclear what drives the increase in side effects post-KT, and whether factors such as post-KT immunosuppression may play a role; reporting bias could have affected the results. Headache and fatigue were the most common reported adverse events. Headache is commonly associated with calcineurin inhibitor (CNI) use.

A risk of waiting until post-KT is that HCV therapy may be delayed, resulting in graft and liver damage due to enhanced viral replication in the setting of immunosuppression. However, median time to initiation of HCV treatment was 77 days, likely an insufficient amount of time to cause significant permanent renal or hepatic injury. With the advent of more DAA regimens with improved safety profiles and lower drug–drug interaction rates, duration from transplant to treatment further may be reduced. Data have previously demonstrated that sofosbuvir-containing regimens are largely safe and effective in the post-KT setting. HCV treatment may affect CNI levels.14 All patients in our study were on a combination of therapy with CNI, mycophenolic acid, and prednisone. Only 1 patient suffered an episode of suspected rejection while on treatment, which did not result in graft loss. Therapeutic CNI trough levels argued against an HCV-treatment induced rejection. Closer monitoring of CNI-troughs during HCV treatment is warranted.

Concern over kidney allograft quality may contribute to underutilization of HCV-positive allografts. The KDPI is used to assess allograft quality.25 The KDPI is reported as a percentage representing the graft’s risk of failure compared to other allografts. For example, a KDPI of 40% indicates that the particular allograft has a risk of graft failure greater than 40% of all allografts. A lower KDPI indicates a more optimal organ. The score is derived from several donor factors including age, height/weight, ethnicity, history of hypertension, diabetes, cause of death, serum creatinine, DCD status, and notably HCV status. High-risk organs are those with a KDPI in excess of 85%. There is bias that higher KDPI scores may result in increased likelihood of discarding an organ.26 Our study shows that median donor KDPI score is 47%. Additionally, pathologic review shows that these kidneys are of comparable quality to those that are not infected with HCV. This is likely because of the exclusion of suboptimal grafts during procurement assessment, perhaps with greater scrutiny, knowing they are exposed to HCV. It is possible that with prompt treatment posttransplant that a patient is receiving an organ that is of higher quality than what KDPI reflects, given that within a few months post-KT the allograft is rid of HCV and if KDPI were performed on identical donors would be substantially lower if HCV-negative. However, long-term outcomes with the use of HCV-positive kidneys are not as yet fully elucidated.

Our study has several strengths in that it evaluates 2 very large transplant centers with a large cohort of HCV-positive patients and compares practices between 2 otherwise similar institutions within the same health system, using identical pre-and post-KT management and immunosuppression protocols. The only notable practice divergence is timing of HCV treatment. Additionally, we report allograft pathology for HCV-positive kidneys. Limitations lie in the small overall number of patients transplanted in one center compared with the other, and retrospective nature of the study.

In conclusion, in a multicenter study between 2 nearly identical transplant centers, we show that a strategy of deferring HCV treatment in patients with ESRD until post-KT increases access to transplant and decreases WLT. HCV treatment efficacy and tolerability is similar regardless of treatment timing. Additionally, kidney allograft quality does not appear to be jeopardized by leaving patients viremic.

DISCLOSURE

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.