Objectives: Renal grafts from hepatitis C virus-positive deceased donors, which were once discarded, can now be transplanted into recipients and treated post­transplant due to the emergence of direct-acting antivirals, significantly improving wait list time and organ shortages. Here, we compared outcomes in hepatitis C virus-positive patients who received kidneys from hepatitis C virus-positive versus –negative donors.

Materials and Methods: In this single-center retro­spective study, we divided 52 kidney transplant recipients who were viremic for hepatitis C virus pretransplant into 2 groups based on donors’ hepatitis C virus serostatus (positive/negative). Demographics, time to transplant, efficacy of direct-acting antivirals, rejection episodes, immunosuppression adjustments, and renal function were assessed in both groups.

Results: Our cohort included 50 patients receiving kidneys from deceased donors and 2 from living donors (1 related, 1 unrelated). Recipients of hepatitis C virus-positive kidneys had significantly less wait list time (36 days) than recipients of hepatitis C virus-negative kidneys (806 days; P < .001). All recipients responded well to direct-acting antivirals, with both groups showing similar sustained virologic response rates that were comparable to the general population. Intention-to-treat analyses showed rates of 91% and 100% in donor seropositive and donor seronegative groups, respectively (P = .273). Four antibody-mediated rejection episodes occurred in the donor seropositive and one mixed rejection in the donor seronegative group. Tacrolimus dose adjustments were required in 54% and 59% of recipients in the donor seropositive and seronegative groups, respectively. Recipients in the donor seropositive group had lower rates of worsening renal function than recipients in the donor seronegative group (11% vs 17.5%; P = .519).

Conclusions: In hepatitis C-positive recipients with donor negative or donor positive hepatitis C virus serostatus, response of direct-acting antiviral response was not significantly different and renal allograft function was maintained without any evidence of long-term adverse consequences to the graft.

Key words : Graft survival, Hepatitis C virus viremia, Rejection, Renal transplant

Introduction

Globally, there is an estimated 130 to 180 million individuals infected with hepatitis C virus (HCV).1 Untreated HCV and its consequences account for mortality of over 400 000 individuals per year.¹ Chronic infection with HCV independently carries an elevated risk for developing chronic kidney disease.2 Since 2008, all kidney transplant (KT) candidates have been screened for HCV.³ In the developed world, HCV affects between 5% and 15% of patients on hemodialysis, with prevalence rates higher than in the general population.^4,5 This increased prevalence is of particular concern due to the long-term consequences of HCV infection after KT, which can result in lower recipient and graft survival compared with recipients who are not infected.^6,7 Recipients with HCV infection are at an increased risk for new-onset insulin-resistant diabetes mellitus, cardiovascular disease, lymphoproliferative diseases, and sepsis in the posttransplant setting.^6,8,9 Additionally, several other conditions, including membranoproliferative glomerulonephritis with or without cryoglobulinemia, membranous nephropathy, renal thrombotic microangiopathy, and transplant glomerulopathy, are attributed to HCV infection in KT recipients.^10,11

In recent years, HCV-infected patients have received renal allografts from HCV-positive donors. Although this approach is feasible, the effects of HCV-positive donor grafts on the recipient and on graft survival are still unclear. Numerous studies have investigated the role of direct-acting antiviral (DAA) therapy for the treatment of HCV in KT patients receiving allografts from uninfected donors, in both the pretransplant and posttransplant setting. Although safety and applicability of DAA therapy in KT patients who receive HCV-infected allografts appears pro­mising, preliminary evidence has suggested possible differences in graft outcomes between these recipients and those who receive HCV-negative allografts.

In this study, we sought to evaluate and compare outcomes after DAA therapy between HCV-infected renal allograft recipients who received grafts from either HCV-infected donors or noninfected donors and to determine safety patterns, including liver and renal profiles, drug interactions, sustained virologic response (SVR) rates based on HCV donor serostatus, and impact of serostatus on transplant wait list time.

Materials and Methods

This was a single-center retrospective analysis of HCV-infected patients with end-stage renal disease (ESRD) who received a renal graft from either an HCV-positive or HCV-negative donor between May 2013 and April 2016. During the study period, 52 patients on the deceased-donor wait list who were confirmed to be HCV nucleic acid test (NAT) positive received renal allografts. Of those 52 patients, 35 consented to indicate their willingness to accept a kidney from an anti-HCV-positive donor. All 52 patients were fully evaluated to determine their suitability for placement on the United Network for Organ Sharing (UNOS) wait list using the standard screening protocol at our institution. Additionally, each patient had a hepatologic assessment and clearance as part of the pretransplant evaluation. The study was approved by the University of Miami Institutional Review Board.

Fifty KT procedures were from deceased donors and 2 from living donors (1 related and 1 unrelated). Donor HCV genotype could not be obtained at the time of transplant. Therefore, all patients were genotyped for HCV before and after KT. All recipients who received HCV-positive grafts were genotyped posttransplant to assess the presence of mixed genotypes or dominance of donor-derived HCV genotype.

Induction immunosuppression in all recipients included 3 doses of rabbit antithymocyte globulin, high-dose methylprednisolone, and 2 doses of basiliximab. Maintenance immunosuppression inclu­ded tacrolimus and mycophenolate mofetil with some variations at the discretion of the treating nephrologist. As mentioned, all patients had pretransplant hepatology evaluations, and liver fibrosis was assessed using liver biopsy and/or FibroScan (Echosens, Waltham, MA, USA). All patients received at least 12 weeks of DAA treatment with various regimens depending on the predo­minant genotype at the discretion of the treating hepatologist. The goal was to initiate DAA treatment within the first 3 months posttransplant. Demographics, time to transplant, efficacy of DAA therapy, rejection episodes, immunosuppression adjustments, and renal function were assessed in both groups.

Statistical analyses
The mean, median, and standard deviation were calculated for continuous variables. Descriptive statistics were reported for each group (Tables 1 to 4). Demographics and outcomes were compared between the 2 groups using t test. P values < .05 were considered statistically significant (Table 5).

Results

Our cohort included 52 KT patients. In an attempt to establish a ratio of 2:1, 35 recipients of HCV-positive donors and 17 recipients of HCV-negative donors were matched for biologic sex and age at transplant. Recipients were predominantly male (n = 39, 75%) and African American (n = 34, 65%), with no significant differences in race/ethnicity and biologic sex between the 2 groups (P > .05). Mean age was also similar between groups, with an overall average age of 58.7 ± 9.4 years at the time of transplant.

Four patients (2 in each group) were coinfected with human immunodeficiency virus (HIV) and on stable antiretroviral therapy. No recipients were hepatitis B surface antigen positive, and none received hepatitis B virus-positive grafts. In this ESRD cohort, before transplant, 46 patients were on hemodialysis (30 in the HCV-positive donor group and 16 in HCV-negative donor group). There were 3 recipients on peritoneal dialysis, all in HCV-positive donor group; the remaining recipients did not receive renal replacement therapy pretransplant.

Our cohort of KT recipients included 50 who received deceased-donor KT and 2 who received living-donor KT (1 related and 1 unrelated), with both in the HCV-negative donor group. In the HCV-positive donor group, 5 recipients had history of previous renal allografts that had failed and 1 patient had a prior orthotopic liver transplant. Only 1 patient in this group was highly sensitized at the time of transplant (defined as calculated panel reactive antibody level of > 40%). On the other hand, in the HCV-negative donor group, there were 3 recipients who had prior failed renal allografts. In the HCV-positive donor group, 27 of the 35 recipients were donor HCV NAT positive.

Only 13 of 52 recipients had received previous HCV treatment, with 8 in the HCV-positive and 5 in the HCV-negative donor group. All 8 patients in the HCV-positive donor group had received HCV treatment with interferon-based regimens. Of the 5 recipients in the HCV-negative donor group, 2 were previously treated with DAAs, 1 relapsed, and another did not achieve SVR. The other recipient in this group was previously treated with sofosbuvir and then sofosbuvir/ledipasvir and relapsed both times. During our study period, this patient was treated with glecaprevir/pibrentasvir and successfully achieved SVR; this case was regarded as successful treatment, leading to the 100% SVR rate reported in the HCV-negative donor group.

The median Metavir fibrosis stage from pre­transplant liver biopsy was F1 and F2 (score range of 0 to 4, with 4 representing cirrhosis) in recipients in the HCV-positive donor and HCV-negative donor groups, respectively, with none showing cirrhosis. Genotype 1A infection predominated (n = 31), with genotype 1B (n = 16), genotype 2A (n = 1), genotype 2B (n = 3), and genotype 3 (n = 1) also being present in the cohort. Genotype testing in recipients in the HCV-positive donor group identified 2 cases in which a new genotype was identified that differed from the original pretransplant genotype. This genotype was now dominant with no evidence of the recipient’s original genotype. In both cases, the patients had received a kidney from an HCV NAT-positive donor. In 1 of those cases, there was suspicion for reinfection. This patient had been lost to follow-up for numerous months and did not complete treatment; retesting of HCV genotype posttransplant did not occur until return many months later when HCV RNA polymerase chain reaction testing was in the millions and a new genotype was now identified. In all other cases, the pretransplant genotype remained unchanged when tested posttransplant.
After being activated on the UNOS KT wait list, the median wait time to transplant for recipients in the HCV-positive donor group was 427 days; however, once patients consented to accept an offer from an HCV-positive donor, the median wait time decreased to only 36 days. Median wait time for recipients in the HCV-negative donor group (806 days) was significantly different from that shown in the HCV-positive donor group (P < .001).

All recipients in the HCV-positive donor group achieved early treatment (that is, within the first 6 months posttransplant), whereas recipients in the HCV-negative donor group were treated appro­ximately within the first year posttransplant (P = .003). Based on an intention to treat analysis, 91% of recipients in the HCV-positive donor group achieved SVR and 100% of recipients in the HCV-negative donor group achieved SVR. However, in a per protocol analysis, SVR was 94% and 100% in the HCV-positive donor and HCV-positive donor groups, respectively (P = .273 and P = .412, respectively).

Three recipients in the HCV-positive donor group had treatment failure, with 1 patient noncompliant with antiviral therapy and therefore entered as a treatment failure. There were major concerns of reinfection were shown in the other 2 patients. One of these patients had achieved SVR and relapsed 1 month later; after a thorough history workup, there was concern that the patient may have been reinfected through unprotected sexual contact. The other patient was the aforementioned case of genotype change pre- and posttransplant who was ultimately retried on a different DAA regimen and is currently nonviremic and has achieved SVR. However, because the allotted treatment had failed to achieve SVR during our study period, this patient was entered as a treatment failure. In both groups, the most frequently prescribed DAA regimen was sofosbuvir and ledipasvir, with ribavirin also prescribed but more commonly in the HCV-positive donor group (57% vs 24%; P = .038).

During DAA therapy, 5 patients (9.6%) developed biopsy-proven rejection episodes. Four of these patients (11%) were in the HCV-positive donor group; these were biopsy-proven antibody-mediated rejection episodes. The other recipient (5.9%), who had a mixed rejection episode, was in the HCV-negative donor group (P = .557). Nine patients required an adjustment of the tacrolimus dose during DAA therapy to maintain therapeutic levels, with 6 of 9 requiring a dose increase. Only 1 patient, who did not have donor-specific antibodies present at the time of transplant, developed biopsy-proven mixed rejection while receiving DAA treatment. Of note, this patient had experienced a significant decrease in tacrolimus trough level during DAA therapy in the week before the rejection event. None of the patients developed donor-specific antibodies, and only 1 was highly sensitized.

Kidney function was assessed at the end of treatment with DAA therapy with SVR and 12 weeks after SVR. Six patients had no change in kidney function as measured by serum creatinine, whereas kidney function was improved in 4 patients (defined as a decrease in serum creatinine ≥ 0.3 mg/dL). Four patients had worsening kidney function (defined as an increase in serum creatinine ≥ 0.3 mg/dL), with only 1 associated with a rejection event.

An adjustment of tacrolimus dose was necessary during the course of DAA therapy in 19 of the 35 recipients in the HCV-positive donor group (53%) and 10 of the 17 recipients in the HCV-negative donor group (59%). Most recipients in both groups required an increase in tacrolimus dose. Kidney function was assessed at the end of treatment, with 4 in the HCV-positive donor group showing an improvement in function compared to 3 in HCV-negative donor group. Three recipients in the HCV-positive donor group had worsening kidney function; all had antibody-mediated rejection episodes. Three recipients in the HCV-negative donor group had worsening kidney function, with 1 having the mixed rejection episode and being also highly sensitized. Two of the 3 recipients in the HCV-positive donor group and all 3 recipients in the HCV-negative donor group showed serum creatinine levels eventually returning to baseline.

We also assessed liver function through meas­urement of transaminases before and after treatment. We observed no statistically significant differences between the 2 groups. The median follow-up time for both groups was around 1.5 years.

Discussion

In KT patients, HCV infection has been shown to lower recipient and graft survival compared with patients without HCV infection.^6,7 Ongoing HCV viremia substantially increases the risk of chronic allograft nephropathy compared with nonviremic patients who had been treated with interferon prior to transplant.¹² Additionally, in HCV-infected patients, there is an 8-fold increase in the rate of biopsy-proven de novo membranoproliferative glomerulonephritis post-KT.13 Various meta-analyses have shown a substantial decrease in overall graft survival of HCV-infected KT recipients compared with those uninfected with HCV.^14,15 Other studies have demonstrated that differences in outcomes between HCV-infected and uninfected KT recipients typically manifest at greater than 10 years posttransplant.^14,16 This in turn contributes to the high morbidity and mortality seen in the KT population. It has also been shown that outcomes in KT recipients are greatly influenced by wait list time and duration of dialysis prior to transplant, in which extended time on dialysis exposes patients to the detrimental comorbid effects of ESRD.¹⁷

Currently, the KT wait list/UNOS wait list includes over 100 000 people with an average median wait time of 5 to 10 years, depending on location within the United States.¹⁸ There is persistent disparity between supply and demand for renal allografts, which has led the transplant community to consider utilization of high-risk donor allografts, including ones infected with hepatitis B virus, HCV, and HIV. Historically, patients infected with HCV were not considered as donor candidates, but recent studies have shown increased utilization of quality grafts from this donor population, increased size of the donor pool, and significantly decreased wait times for donor organs, thereby saving lives of patients on dialysis.¹³ Unfortunately, there is still some controversy about the safety of using HCV-infected kidneys. In fact, Reese and associates reported that, between 2005 and 2014, 65% of all HCV-positive kidneys were discarded.¹⁹ Previously with interferon-based therapies, curing HCV after KT was extremely difficult due to poor efficacy, intolerable side effects, and risk of acute rejection. Direct-acting antivirals have revolutionized the treatment of HCV, with cure rates of greater than 95%.20 In the KT setting, this has opened the possibility of utilizing grafts from HCV-infected donors into HCV-infected recipients and then successfully treating HCV in the posttransplant period.²¹ With wait times markedly decreased when HCV-infected donor organs are utilized, patients can overcome extended exposure to the detrimental effects of ESRD, although this utilization of infected grafts can pose problems due to risks and complications of HCV infection.^22,23

There have been conflicting results when reporting the outcomes of HCV-positive kidneys in HCV-positive patients in the pre-DAA era.^11,12 Abbott and associates reported in their study that these patients had inferior outcomes and increased mortality.²⁴ On the other hand, Morales and colleagues showed no change in mortality and graft failure in this patient group.²⁵ However, both studies lacked pretransplant HCV NAT testing in donors and/or recipients; therefore, it was unknown whether the donor or recipient was viremic at transplant and posttransplant. Furthermore, both studies were performed before the era of DAA when treatment of chronic HCV in renal allograft recipients was an obstacle because of contraindications associated with interferon-based therapies. Direct-acting antivirals have opened a spectrum of possibilities for HCV-infected donor organs to be utilized in HCV-infected recipients and potentially HCV-negative recipients given the high rates of SVR and low complication rates. In this study, we validated that the acceptance of KT from an HCV-positive donor resulted in a significant decrease in transplant wait time. Sawinski and colleagues also showed a significant reduction in wait list time of up to 50% by including donors infected with HCV.²⁶

In 2 trials that prospectively treated KT recipients with DAAs, promising cure rates ranging from 84% to 100% were shown, with 18% to 25% requiring calcineurin inhibitor adjustment and no patients having episodes of rejection. These studies did not report on transaminase levels pre- and posttreatment and also did not compare outcomes based on HCV-donor serostatus.^25,27 On the other hand, Gupta and colleagues assessed the independent impact of HCV donor status on patient outcomes and showed that, despite matching for a variety of recipient and donor variables, HCV-negative recipients with HCV-positive grafts had inferior patient and graft survival versus HCV-negative recipients with HCV-negative grafts.²⁸ However, the investigators did not compare outcomes of HCV-positive recipients with HCV-positive versus HCV-negative grafts.

Our data showed that the response to DAA therapy was excellent, with similar SVR rates in HCV-positive recipients with HCV-positive or with HCV-negative grafts; indeed, both groups achieved 100% SVR on a per protocol analysis. Both groups required immunosuppressant dose adjustments, with most requiring increases in tacrolimus dosing to maintain therapeutic levels. These results are consistent with prior studies that observed significant modifications in the pharmacokinetics of calcineurin inhibitors that often accompany the clearance of HCV.^14,29 Although the mechanism of these alterations is not well understood, the main proposed mech­anisms include the following: (1) a possible improvement in hepatic function accompanying virus clearance, thereby affecting the metabolism of tacrolimus; and (2) drug interactions between the immunosuppression and DAA therapy used.¹⁵ Understanding the drug interaction is fundamental to improving outcomes and reducing adverse effects.¹⁶

The safety of DAA use in the post-KT setting has been a major point of concern in this population. Few cases of rejection have been reported in HCV-positive recipients with HCV-positive grafts after DAA treatment.¹⁷ In our study, although few antibody-mediated rejection episodes were noted, there was no evidence of long-term adverse consequences to the graft. Although the number of antibody-mediated rejection episodes was greater in the recipients with HCV-positive grafts, there was also no statistically significant difference between the groups. Furthermore, sample sizes were different, with the HCV-positive group having more individuals who were highly sensitized. Larger studies with longer follow-up are needed to further elucidate this potential trend. Chen and associates performed a comprehensive systemic review on DAA efficacy and safety in KT patients, corroborating their high efficacy and safety profile.³⁰

No significant change in renal allograft function has been consistently reported when comparing renal function before and after DAA treatment.^19-23 Although the renal function improved or remained unchanged in most patients in our study, there were a portion of patients with significant variations in creatinine during DAA therapy secondary to rejection episodes; this mainly occurred in patients who were highly sensitized. The high prevalence of highly sensitized patients in our cohort may explain the disparity shown in renal function compared with previous studies after DAA treatment in KT recipients.

As expected, SVR is associated with significant improvement of liver function tests in the post-KT setting when abnormal levels were previously present.^19-23,25 Interestingly, despite eradication of HCV, persistent liver inflammation was reported in up to one-third of patients in a large cohort.²⁷ In our cohort, we did not observe worsening or persistently elevated aminotransferases once SVR was achieved in both groups. Conversely, we observed significant improvement after SVR if a patient had abnormal levels pretreatment. It should be noted that our population did not have markers of advanced liver disease or steatohepatitis, conditions that, if present, may modify liver function test outcomes after SVR as shown in the literature.²⁸

Our study has limitations, including but not limited to the fact that it is a retrospective study with a small sample size and selection bias; therefore, its applicability to larger numbers of patients with longer lengths of follow-up still remains to be determined. Additionally, most of the patients were from ethnic minorities and the patients were treatment naive and without cirrhosis; therefore, our results may not be generalizable to other patient groups. It should be especially considered that treatment failure has been reported in KT recipients with HCV and cirrhosis.²³ Finally, we did not have genotype data on the donors; thus it was not possible to determine with certainty whether superinfection with the donor genotype occurred at the time of transplant. Pretreatment HCV genotyping was our alternative strategy to capture genotype discrepancy from potential donor-derived infection. In addition, payor agreement for HCV therapies is still an obstacle.

Conclusions

Our aim was to compare the outcomes of HCV-positive KT recipients with HCV-positive versus HCV-negative grafts. The absence of long-term consequences on graft function noted in our study is promising. Future studies with larger groups of HCV-positive recipients of HCV-positive grafts are needed to validate our findings. Expanding the strategy to transplant renal grafts from HCV-infected donors in uninfected recipients has already been published in the THINKER and EXPANDER studies, which are likely to become common practice in the future.31

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