The kidney transplant population has a higher prevalence of hepatitis C virus (HCV) infection, compared to the low rates observed in the United States overall.1,2 Compared with those without infection, kidney recipients with HCV infection have increased risks of death,3-5 allograft loss,6-8 and posttransplant complications, such as new-onset diabetes, infections, and proteinuria.
Until recently, interferon-based regimens were the backbone of HCV treatment in kidney transplant recipients, although this approach has been limited by relatively low efficacy and poor tolerability.9 The newly available direct-acting antivirals (DAAs) target nonstructural viral proteins, such as NS3, NS4A, NS4B, NS5A, and NS5B, and when used in combination, permit interferon-free treatment of HCV infection. These regimens have achieved sustained virologic response rates at 12 weeks after completion of therapy (sustained viral response [SVR]12) in excess of 90% in the treatment-naive general population10-12 and, more recently, in liver transplant recipients.13-15 Two studies16,17 evaluating the effectiveness of DAAs in kidney transplant patients have been published, with 100% SVR12 rates observed in both reports.
Unlike their uninfected counterparts, HCV-infected transplant candidates may have the option of being offered and accepting a kidney from an HCV+ donor. The HCV+ donors contributed 2402 kidneys to the donor pool between 2005 and 2014 in the United States18; these organs would have otherwise been discarded. Because acceptance of these kidneys has been associated with decreased wait times,19 use of HCV-infected kidneys in candidates with HCV infection is an effective way to both expand the pool of utilizable kidneys as well as to facilitate faster times to transplant for these patients. The largest series20 of HCV+ donors transplanted into HCV+ recipients demonstrated equivalent 5- and 10-year patient survivals (P = 0.25) compared with those who received an HCV− donor, but inferior allograft survival in those with HCV+ kidneys (P = 0.006). Because of these suboptimal allograft outcomes of HCV+ kidneys in HCV+ recipients, as well as the possible risk of genotype superinfection, not all transplant clinicians have embraced use of these organs. The emergence of DAA-based regimens offers the opportunity to delay treatment of HCV-infected candidates until posttransplant, transplant these patients with kidneys from HCV+ donors to reduce waiting time, and initiate antiviral therapy after transplant. The impact of donor HCV status on effectiveness of DAA therapy is not known.
Our center started treating HCV-infected kidney recipients offlabel with DAA-based regimens in January of 2014. To date, 4 different interferon-free HCV treatment regimens have been used. The purpose of this single-center study was to examine the effect of donor HCV serostatus on DAA efficacy.
MATERIALS AND METHODS
A retrospective cohort study of all adult HCV-infected kidney transplant recipients treated for HCV using DAAs at the University of Pennsylvania was conducted. All kidney transplant recipients, older than 18 years, followed at the University of Pennsylvania transplant program, with evidence of HCV infection and agreeable to DAA treatment were included. Patients with human immunodeficiency virus/HCV coinfection were excluded from this report. Patients were enrolled from January 2014 through October 2015. This study was approved by the institutional review board.
All patients were referred to a transplant hepatologist for HCV treatment. Genotype was confirmed, and viral load was measured. Hepatitis C virus genotype was determined using either the HCV Genotype Assay (ARUP Laboratories, Salt Lake City, UT), Versant HCV Genotype 2.0 assay (Siemens Medical Solutions USA, Malvern PA), or Invader HCV Genotyping 1.0 assay (Third Wave Technologies Inc., Madison, WI). Viral load was measured using either the COBAS AmpliPrep/COBAS TaqMan HCV Test or COBAS AmpliPrep/COBAS TaqMan HCV Test, v2.0 (Roche Diagnostics USA, Indianapolis, IN).The DAA combination was selected on the basis of prior treatment history and response, HCV genotype, estimated glomerular filtration rate (GFR) and liver transplant status, in accordance with the American Association for the Study of Liver Diseases/Infectious Diseases Society of America guidelines. Treatment was mostly for 12 weeks unless determined otherwise by the hepatologist (on the basis of advanced liver fibrosis and prior treatment failure; 1 patient was treated for 16 weeks, and 3 patients were treated for 24 weeks). All patients received “standard” DAA doses within different regimens (sofosbuvir [SOF] 400 mg daily, simeprevir [SIM] 150 mg daily, ledipasvir [LDV] 90 mg daily), and only ribavirin (RBV) dosing was weight based with adjustments made for on-treatment anemia. Treatment of patients with a GFR less than 30 mL/min was discussed with the transplant nephrologist before initiating therapy but DAA doses were not modified for GFR less than 30 mL/m. Only 2 patients had an MDRD GFR less than 30 mL/m at the time of treatment initiation. One patient had a GFR of 28 mL/m and was treated with SOF/SIM and the other had a GFR of 27 mL/m and was treated with LDV/SOF, both at standard doses.
Maintenance immunosuppression comprised a calcineurin inhibitor (CNI) in conjunction with an antimetabolite and prednisone. Induction therapy consisted either of rabbit antithymocyte globulin (Thymoglobulin; Genzyme, Cambridge, MA), dosed at 1.5 mg/kg intravenously, for 3 to 5 doses according to immunological risk, or basiliximab (Simulect; Novartis Pharmaceuticals Corporation, East Hanover, NJ) 20 mg administered intraoperatively and on postoperative day 3.
The following clinical and demographic data were collected on patients in the study: sex, race, age at transplant, donor HCV serostatus, prior transplant and organ type, induction and maintenance immunosuppression, cause of end-stage renal disease (ESRD), pretransplant diabetes, HCV viral load and genotype, hepatitis B status, renal biopsy date and result, liver biopsy date and result, patient survival and allograft survival. Data were analyzed using STATA version 14.1 (Statacorp, College Station, TX). Descriptive statistics were generated. Continuous variables were analyzed using paired Student t test or Wilcox rank sum, as appropriate. Change on analysis was used to compare the slopes of the change in pretreatment and posttreatment serum creatinine (Scr) and tacrolimus levels. Categorical variables were analyzed using χ2 or Fisher exact test.
We identified 43 kidney transplant recipients who were treated for HCV with DAAs at our institution from January 2014 through September 2015. The cohort was predominantly men (76.7%) and African American (62.8%). Retransplantation was common; 12 patients had a prior kidney transplant, 5 patients had a prior liver transplant, and 5 patients received a simultaneous liver-kidney transplant during their most recent transplant episode. Only 3 patients received a kidney from a living donor and 19 (47.5%) of the 40 deceased donor kidney transplants were from a HCV+ donor. Of these 19 HCV antibody-positive donors, 15 had nucleic acid testing performed as part of their infectious screening and 11/15 were nucleic acid testing-positive at the time of donation; no donor genotype information was available.
The majority of recipients (90.7%) had genotype 1 infection. The HCV treatment with interferon-based regimens had been attempted in 21 patients in the past before transplant but none cleared the virus. More than half of the cohort (n = 23) was administered LDV/SOF (with an additional 4 patients treated with LDV/SOF plus RBV) but 28% (n = 12) were treated with SOF/SIM instead. At the discretion of the treating hepatologist, patients were treated with 12 weeks of therapy with the exception of 1 patient treated for 16 weeks and 3 patients who were treated with 24 weeks of LDV/SOF due to prior interferon failure plus evidence of cirrhosis on biopsy. We did not detect any differences in Scr before or after treatment in the cohort overall (pretreatment median Scr, 1.39 mg/dL; IQR, 1.07-1.73 and posttreatment median Scr, 1.44 mg/dL; IQR, 1.08-1.74; P = 0.62; Figure 1a) or in subgroup analysis stratified by DAA regimen (Figure 1b), but we did observe a lower median tacrolimus level in the entire cohort (median posttreatment tacrolimus level, 4.9 ng/mL; IQR, 4.2-6.2 vs median pretreatment tacrolimus level, 5.8 ng/mL; IQR, 4.9-7.4; P = 0.02; Figure 2a) by rank sum testing. The slope of the decrease in tacrolimus levels was significantly steeper than the slope of the increase in Scr (−0.88 ± 0.33 difference in slope, P < 0.001), and this difference in tacrolimus levels was driven by the SOF/SIM subgroup (pretreatment median tacrolimus level, 6.3 ng/mL; IQR, 5.2-7.6 vs posttreatment median tacrolimus level, 4.8 ng/mL; IQR, 3.7-5.6; P = 0.05); tacrolimus levels in all other subgroups were not significantly different before/after treatment (Figure 2b). The after therapy decline in tacrolimus levels was not associated with physician dose changes, degree of liver fibrosis on biopsy, or liver transplant status. We did not detect any differences in efficacy on the basis of the particular DAA regimen selected; all patients achieved an SVR12 regardless of regimen used. All patients are alive with functioning allografts with a median follow-up time of 368 days (IQR, 298-586) since DAA treatment in the cohort overall. We did not detect a significant difference in proteinuria before or after treatment by the end of follow-up.
When we stratified the cohort on the basis of donor HCV status (Table 1), the 2 cohorts were generally similar, with a few important differences. Median patient age was the same (58 years, P = 0.18) and proportions of African Americans (P = 0.55) and men (P = 0.25) were similar. Cause of ESRD did vary between the groups, with more patients who had hypertension or congenital renal disease in the HCV− donor group. All patients receiving a HCV+ kidney were genotype 1, whereas 16% of the recipients of HCV-uninfected donor kidneys were genotype 2. Median viral load at start of therapy was not significantly different (6.3 log copies/mL in HCV+ donor recipients and 6.6 log copies/mL in HCV− donor recipients; P = 0.31), but almost twice as many patients in HCV+ donor group had failed prior HCV therapy with interferon (68.4% vs 33.3%, P = 0.02). Ledipasvir/sofosbuvir was the most common regimen used in both cohorts regardless of donor HCV serostatus. Metavir fibrosis stages were generally lower in recipients of HCV− donors, with 29% of HCV− donor recipients having F3 or F4 stage fibrosis on biopsy compared with 42.1% of HCV+ donor recipients. The median number of days since transplant to HCV treatment was not different between the groups (HCV+ donor, 1123 vs HCV− donor, 1064; P = 0.47) nor was the medium number of days required to clear the virus (days to first negative viral load HCV+ donor 55 versus HCV− donor 33; P = 0.13). The HCV donor serostatus did not have an effect on HCV clearance by DAAs. Median Scr at treatment start was not different on the basis of donor HCV serology (HCV+ donor, 1.34 mg/dL vs HCV− donor, 1.46 mg/dL; P = 0.89) nor at the end of therapy (HCV+ donor, 1.35 mg/dL vs HCV− donor, 1.49 mg/dL; P = 0.42). Likewise, tacrolimus levels did not vary by donor HCV status (pre-DAA: HCV+ donor, 6.2 ng/mL vs HCV− donor, 5.6 ng/mL; P = 0.24; post-DAA: HCV+ donor, 4.6 ng/mL vs HCV− donor 5.2 ng/mL; P = 0.09).
Importantly, acceptance of a HCV+ donor shortened wait times to transplantation in our cohort. The median number of total days spent on the waitlist for patients who accepted an HCV+ donor was 485 days (IQR, 228-783), which was significantly shorter than the wait for those who received a HCV− donor (969 days; IQR, 452-2008; P = 0.02), after excluding patients who received a living donor or a simultaneous liver-kidney transplant. We did not detect a difference in time spent active versus inactive on the waiting list on the basis of donor HCV serology but not all patients had detailed data on dates of waitlist status changes available for review.
This single-center case series reports our experience treating a cohort of HCV-infected kidney transplant recipients using DAA regimens without interferon. These regimens are highly effective with 100% of patients achieving viral clearance and an SVR12 in a “real world” setting despite induction and maintenance immunosuppression. Patients transplanted with an HCV+ donor kidney responded equally well to those who were transplanted with a kidney from a HCV− donor, and recipients of HCV+ organs experienced significantly shorter wait times to transplantation. We did not detect differences in response on the basis of DAA regimen used although the majority of patients in our cohort were treated with LDV/SOF. Ledipasvir-sofosbuvir is a substrate of P-glycoprotein, without effects on cytochrome P450; it therefore does not affect CNI levels, and this lack of drug-drug interactions makes this combination an attractive choice for transplant recipients. Renal excretion of SOF on the other hand, limits the use of this drug in patients with poor kidney function. It is difficult to propose an “optimal regimen” given the rapidity of entry of new DAAs into the clinical arena and the choice of DAA in our study reflects what was clinically available at the time that patients were referred for therapy.
These findings are not unexpected. In the liver transplant literature, there are several case series describing use of DAA regimens for treatment of HCV infection after transplant. Kwo and colleagues13 described 34 HCV genotype 1-infected liver transplant recipients who were treated for 24 weeks with ombitasvir-ABT-450/r, dasabuvir and RBV; a SVR12 was achieved in 97% of patients but significant CNI dose adjustments were required due to the ritonavir boosting in this regimen. Charlton et al14 observed a 70% SVR rate in their cohort of 40 liver transplant recipients treated with 24 weeks of SOF and RBV; 83% of the cohort was infected with genotype 1, and unlike the previous report, there were no significant drug dosing interactions with CNIs. Gutierrez and colleagues15 reported their experience treating 61 liver transplant recipients with SOF and SIM for 12 weeks; all patients were genotype 1-infected and overall SVR12 rates of 93% were achieved. Two single-center reports16,17 of DAA usage in renal transplant recipients have been published. In the first of these,16 25 patients were treated with SOF-based regimens; 100% achieved an SVR and a decline in CNI levels after completion of therapy was observed. Our group reported a series of 20 renal transplant recipients17 treated with predominantly SOF/SIM and again a 100% SVR rate with minimal adverse events was observed. Our current study extends our prior report, comprising 1 of the larger kidney recipient cohorts to date treated for HCV with DAA regimens and, in reflection of current clinical practice, predominantly with LDV/SOF.
The optimal timing of HCV therapy (pretransplant versus posttransplant) is an area of active debate. In our cohort, patients were referred for treatment as soon as they were identified during their routine posttransplant care, without a specific time frame being targeted and pretransplant treatment on dialysis was not attempted. Although effective DAA regimens for patients with a GFR < 30 mL/min or on dialysis21 now exist, the benefit of pretransplant HCV eradication on patient outcomes has not yet been established and must be balanced against the significant financial costs associated with these regimens. Clearance of HCV before transplant could plausibly improve waitlist survival and prevent posttransplant complications; however, the downside of such a strategy would be the loss of access to HCV+ donor organs. As observed in our cohort, the wait times for kidneys from HCV+ donors are typically shorter than those for kidneys from uninfected donors. This observation has significant implications for patients listed in regions where waiting times for kidneys are especially long. Longer wait times for patients may reduce their likelihood of ever being transplanted due to waiting list attrition from ESRD-related complications and death. Furthermore, this would also result in greater discard rates of HCV+ organs; from 2005 to 2014, 3273 HCV+ deceased donors contributed 2402 kidneys to the donor pool,18 and discard of these organs due to lack of HCV+ recipients to accept them would indirectly increase wait times for all recipients. Use of HCV+ organs also has the potential to decrease the costs associated with providing ESRD care for HCV+ patients (Table 2), mostly on the basis of shortening their wait time on dialysis. Assuming an average cost per year for dialysis of US $77 200 (US $84 550/year for hemodialysis and US $69 919/year for peritoneal dialysis),22 an average wait time of 1 year for a kidney from an HCV-infected donor, the cost of a DAA regimen US $80000 and the cost of transplantation and 1 year of follow up US $145000,23 transplanting a patient with an HCV+ organ and treating within the first posttransplant year will cost US $302 200 by the end of that year. Transplanting a patient with a HCV− kidney in a short-wait area (1.5 years dialysis + DAA+ transplant) will cost US $340 800, whereas in medium-wait areas (5.25 years dialysis + DAA+ transplant = US $630 300) and long-wait areas (6+ years dialysis + DAA + transplant = US $688 200) the expense will be significantly higher. Deferred DAA treatment with use of a HCV+ donor represents a savings of US $38000 to US $ 386 000 per patient depending on local wait times, entirely realized by minimizing the expense of dialysis exposure. On this basis, we would suggest deferring antiviral therapy until the posttransplant setting, coupled with a plan to implement very early postoperative initiation of DAAs to prevent HCV-associated complications or genotype superinfection. We have previously proposed that exceptions to this approach could include candidates with approved, compatible living donors, those in very short wait areas or with blood group AB, on the basis of patient preference, or candidates whose liver disease is so advanced that a delay in treatment could jeopardize their kidney transplant candidacy.24
Although our SVR12 rates are striking, it remains to be determined if eradication of HCV infection after transplant with the DAAs will improve long-term recipient and allograft outcomes, prevent or reverse complications such a proteinuria, posttransplant glomerulonephritis, and new-onset diabetes. Extrapolation from the interferon literature suggests an improvement in these complications may be expected. We did not observe any changes in proteinuria in our cohort, although follow-up was short. Alternatively, it is conceivable that longer follow-up times may be required or that extrahepatic HCV-related complications cannot be reversed once they become established comorbidities; it is not clear that timing of HCV therapy will impact these extrahepatic complications. We did not observe any effect on patient mortality or allograft survival in the short period of follow-up.
Our study has limitations including its retrospective design, brief follow-up period and moderate sample size. Nucleic acid testing was available for most but not all HCV+ donors, and donor HCV genotype was not available for any donors. However, given that all patients had their HCV genotype reassessed before the start of therapy, no recipients switched genotype or were found to have multiple genotypes at the time of initiating DAA therapy, argue against genotype superinfection through transplant. Additional follow-up time and a larger cohort will be required to demonstrate that viral clearance translates into superior HCV-related patient and allograft outcomes.
In conclusion, we report a series of successful HCV clearance using 4 different interferon-free, DAA-based regimens in genotypes 1 and 2 infected kidney transplant recipients. The DAAs were effective and well tolerated in a “real world” setting. Use of HCV+ donors were associated with shorter waiting times and did not adversely affect posttransplant HCV clearance rates. Larger-scale investigations are needed to identify the optimal regimen for treating HCV kidney transplant candidates and recipients from the standpoint of efficacy, timing relative to transplant, posttransplant clinical outcomes, and cost.
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