Objectives: Studies have demonstrated worse graft and patient survival among hepatitis C virus-positive patients following kidney transplant. Eradication of hepatitis C virus infection before renal transplant with interferon should be considered in hepatitis C virus-infected patients undergoing dialysis who are on the waiting list for transplant. We investigated whether pretransplant hepatitis C virus infection treatment affected graft and patient survival, and we evaluated other contributing factors to these outcomes.

Materials and Methods: We enrolled 83 antihepatitis C virus-positive patients who were diagnosed with chronic hepatitis C virus infection by serology or histopathology and had renal transplant at Baskent University Ankara Hospital from 1982 to 2013. Data were obtained from patient medical files retrospectively. Patients were divided into 2 groups that had or did not have interferon treatment.

Results: In 83 renal transplant patients with chronic hepatitis C virus infection (57 male [69%] and 26 female [31%]), median age was 46 years (range, 26 - 69 y), and most patients were genotype 1-dominant (92%). Interferon monotherapy was received by 30 patients before renal transplant and 28 of 30 patients had long-term follow-up data. There were 14 of 28 patients (50%) who achieved sustained virologic response, and only 1 patient had relapse. Graft survival was significantly lower in patients who had treatment (6 y vs 9 y; P ≤ .003). However, patient survival rates were similar between groups. Patients who had interferon were younger and had longer hemodialysis duration before renal transplant than patients without treatment. Higher viral load was associated with higher mortality which was caused by sepsis.

Conclusions: Pretransplant hepatitis C virus infection treatment, although recommended before renal transplant, does not always have good outcomes. Pretransplant dialysis treatment period, age of recipient, and posttransplant higher viral replication rates may be important contributing factors related to graft and patient survival.

Key words : End-stage renal disease, Interferon, Outcomes

Introduction

Studies in developed countries indicate that 3.4% to 32.1% patients who are on maintenance hemodialysis are positive for antibodies against hepatitis C virus (HCV), and HCV positivity in less developed countries is 49%.^1,2 The diversity of these rates results from differences between centers, countries, and geographic areas.³ The prevalence of HCV infection is higher in renal transplant recipients (11% to 49%) than the hemodialysis population.^4,5

There is controversy regarding the long-term outcomes following kidney transplant between patients who have or do not have HCV. Although previous studies with relatively short-term follow-up have found similar outcomes, several studies have demonstrated worse graft and patient survival among HCV-positive patients following kidney transplant after follow-up for 10 and 20 years.^6,7

The main causes of mortality for renal transplant recipients, either HCV-positive or negative, were sepsis, cardiovascular disease, and malignancy.⁸ However, survival advantage associated with transplant still is present in HCV-infected patients who have end-stage renal disease (ESRD).9 It was shown that the relative risk of mortality was 0.36 for kidney transplant recipients, a 64% lower risk of death than individuals on the waiting list.¹⁰

The primary goal of HCV treatment is to achieve sustained virologic response (SVR) which is defined as undetectable serum HCV RNA (< 50 IU/mL) at 6 months after stopping treatment. The SVR is associated with normalization of alanine aminotransferase (ALT) levels and improved histology in most treated patients.¹¹ Gordon and coworkers published long-term HCV RNA outcomes in a systematic review and stated that probability of remaining HCV RNA-negative test was 86% for patients followed on hemodialysis or 95% for renal transplant recipients at 48 months after achieving SVR.¹² Thus, eradication of HCV infection before renal transplant is rational, and treatment with interferon (IFN) should be considered in HCV-infected patients undergoing dialysis who are on the waiting list for transplant.

In this study, we investigated whether pre­transplant HCV infection treatment had an effect on graft and patient survival, and we searched for the effect of other contributing factors to these outcomes.

Materials and Methods

Patients
In this study, we enrolled 83 anti-HCV-positive patients who were diagnosed with chronic HCV infection by serology or histopathology and had renal transplant at Baskent University Ankara Hospital from 1982 to 2013. Data were obtained from patient medical files retrospectively. Inclusion criteria were regular evaluation at our center; diagnosis as anti-HCV-positive ≥ 6 months before renal transplant; serologically diagnosed patients with positive anti-HCV and HCV RNA tests, or anti-HCV positive and HCV RNA negative tests; patients with histopathologically proven chronic HCV infection; and age from 20 to 70 years.

Exclusion criteria were patients with irregular evaluation, HCV RNA-negative patients with biopsy findings incompatible with chronic HCV infection, or alcohol or drug addiction.

Patients were divided into 2 groups as having or not having IFN treatment. Response to treatment was classified as: (1) early viral response (EVR) (≥ 2 logarithm decrease in basal HCV RNA or negative HCV RNA at week 12 of treatment); (2) SVR (serum HCV RNA negative at 6 months after stopping treatment); and (3) end-of-treatment response (EOTR) (serum HCV RNA negative and normal ALT levels at the end of treatment); and (4) graft survival (time between renal transplant and cessation of immunosuppressive drugs and beginning hemo­dialysis); or (5) relapse after renal transplant (reappearance of HCV RNA after renal transplant which was negative before renal transplant).

Assays
Serum anti-HCV positivity was diagnosed with a microparticle enzyme assay (AxSYM HCV version, MEIA, Abbott Diagnostics, Chicago, IL, USA) and chemiluminescent microparticle assay (The Architect System CMIA, Abbott). Serum HCV RNA was diagnosed with nested polymerase chain reaction from 1994 to 2003, new technology (LightCycler, Roche Diagnostics, Basel, Switzerland) from 2003 to 2005, and real-time polymerase chain reaction assays (Serum HCV RNA 10-time PCR, COBAS TaqMan 48 HCV, Roche).

Statistical analyses
Data analysis was performed with statistical software (SPSS, Version 16.0, SPSS Inc., Chicago, IL, USA). Numerical data were reported as median (range, minimum to maximum) or mean ± standard deviation. Comparison between groups was performed with Mann-Whitney test, Fisher exact test, chi-square test, Cox proportional hazards regression model, and Kaplan-Meier method. Statistical significance was defined by P ≤ .05.

Results

There were 83 renal transplant patients with chronic HCV infection enrolled in the study (57 male [69%] and 26 female patients [31%]; median age, 46 years [26 to 69 y]). There were 76 patients (92%) who were on hemodialysis, 1 patient who had peritoneal dialysis, and 6 patients who used both methods at different times. Median was 48 months (range, 1 to 276 mo) for all patients. The most frequent causes of ESRD were glomerulonephritis (19% patients), hypertension (9%), pyelonephritis (9%), and unknown (36%). Living-related transplant was performed in 68 patients (81.9%) and deceased-donor renal transplant in 15 patients (18.1%).

Patients were on combined immunosuppressive treatment with cyclosporine (86.7%), azathioprine (32.5%), mycophenolate mofetil (45.8%), tacrolimus (30.1%), and other drugs.

Genotypes of the patients were genotype 1b in 56 patients (68%), genotype 1a in 19 patients (24.6%), and genotype 4 in 8 patients.

There were 30 patients who received IFN monotherapy before renal transplant, and 28 of 30 patients had long-term follow-up data. Median treatment was 6 months in 10 patients and > 12 months in 20 patients (median, 12 mo; range, 12 to 19 mo). No patient had antiviral treatment after renal transplant. There was EVR in 22 of 30 patients (75.8%) and EOTR in 20 of 30 patients (68.9%). There were 2 patients who were lost to follow-up; in the other 28 patients, SVR was achieved in 14 of 28 patients (50%). During long-term follow-up, only 1 patient had relapsed.

Graft survival was significantly lower in patients who had treatment (6 y vs 9 y; P ≤ .003). However, patient survival rates were similar between groups. The duration of treatment (< 12 mo or > 12 mo) had no effect on EVR, EOTR, or SVR rates (P > .05). Patients who had IFN treatment were younger than patients without treatment (P ≤ .01), and hemo­dialysis duration before renal transplant was significantly longer in patients who had IFN treatment (P ≤ .001). Other variables such as ESRD etiology, sex, and immunosuppressive protocols were similar between patients who had or did not have treatment.

Median viral load before renal transplant was 55 000 000 IU/mL (range, 0 to 98 000 000 IU/mL) and viral load was not statistically associated with EVR, EOTR, and SVR rates. However, higher viral load was associated with higher mortality due to sepsis (P ≤ .008).

There were 39 patients who were HCV RNA-negative before renal transplant and 28 of 39 patients (72%) became HCV RNA-positive after renal transplant. Tacrolimus use was associated with less probability of reappearance of HCV RNA after renal transplant (P ≤ .01)

Discussion

The HCV infection remains a major health problem in ESRD patients and renal transplant recipients. The HCV in patients with ESRD on hemodialysis ranges between 10% and 30%, which is > 5 times the frequency in the general population.¹³

A large cohort study which included 73 707 kidney transplant recipients, including 535 patients with HCV, showed no difference in patient and graft survival at 8 years following transplant between patients with and without HCV.¹⁴ Previous studies with short-term follow-up (< 10 y) have shown patient and graft outcomes similar after transplant between HCV-positive and negative groups.^15-17 However, after long-term follow-up study results (> 10 y) were published, data about the negative effect of HCV infection on patient and graft survival began to accumulate.^18-20 The reported relative risk of mortality in patients with HCV was 1.59 to 1.93, and relative risk of graft loss was 1.5. Liver-related mortality accounted for at least some of the excess mortality, and most deaths were from sepsis and cardiovascular causes. Although viremia increases after transplant, the progression of liver fibrosis possibly slows.^21,22 This might explain the delayed adverse effect of HCV on survival. Fabrizi and coworkers showed that the presence of anti-HCV antibodies was an independent risk factor for graft failure (relative risk, 1.56).²³ In a systematic review of 18 studies, the combined hazard ratio in HCV-infected recipients was 1.56-fold greater than in HCV-negative recipients. Potential explanations for the different study results include heterogeneous patient populations, small numbers of groups with short-term follow-up, differences in the stage of liver disease at transplant, prevalence of associated comorbidities such as diabetes and cardiovascular disease in the transplant recipients, and differences in immunosuppressive regimens.

Although there is controversy about the effect of HCV infection on the course of ESRD and graft and patient survival after renal transplant, it is generally accepted that HCV has a negative effect on these outcomes. Therefore, all hemodialysis patients with confirmed detectable HCV RNA who have not previously received treatment for HCV infection should be considered as candidates for antiviral therapy based on IFN-α. American Gastroenterological Association and American Association for the Study of Liver Diseases guidelines recommend reduced doses of pegylated IFN-α (PEG-IFN) as monotherapy and consider ribavirin as contraindicated in this setting.^24,25

Studies about HCV treatment in ESRD patients with IFNs reveal that response rates are acceptable and better than response in patients who have normal renal function, but there is high cost and sometimes intolerable adverse effects. The data of 482 patients derived from 25 published studies indicated that patients who received IFN monotherapy had SVR rates of 33% to 39%.^26,27 The subanalysis results showed SVR rates 26% to 30.6% in patients with genotype 1. These SVR rates were higher than those reported in nondialysis patients who received non-PEG-IFN monotherapy (6% to 19%).²⁸ Possible explanations could be increased IFN exposure in dialysis patients as a result of the lower clearance of IFN or possible viral clearance with hemodialysate membranes.²⁹Alavian and coworkers compared standard and PEG-IFN therapy results of 21 studies conducted with 491 hemodialysis patients who used standard IFNα and 12 studies conducted with 279 hemodialysis patients who used PEG-IFNα.³⁰ The pooled SVR rates for standard IFN monotherapy was 39.1% and PEG-IFNα mono­therapy was 39.3%. Dropout rates were high (IFNα , 22.6%; PEG-IFNα, 29.7%). Only age < 40 years was significantly associated with SVR. The HCV RNA level, HCV genotype, ALT pattern, female sex, duration of infection, liver fibrosis stage, and treatment duration were not associated with SVR.30 However, 1 head-to-head, randomized trial showed that the overall efficacy and safety were better in patients treated with PEG-IFN than conventional IFN.³¹

In our study 30 patients treated with either PEG-IFN or standard IFN before transplant and 14 of 28 patients (50%) who had long-term follow-up data had SVR rates. Our patient group mainly included genotype 1 patients, all patients used only IFN monotherapy, no patients used additional ribavirin, and we believe that our results are compatible with results in the literature.

Only 1 patient with SVR had relapse after transplant. In our study, graft and patient survival rates and factors which could affect these parameters were investigated. Graft survival rates were significantly lower in patients who were treated with IFN than patients who did not have HCV treatment (P ≤ .003). Although our patients had 50% SVR rates after treatment, graft survival rates were poorer than expected. Therefore, in addition to high SVR rates, we believe that other factors should be taken into consideration. Treated patients were younger (P ≤ .01), and average hemodialysis duration before transplant was longer in these patients than in nontreated patients (P ≤ .001). Our follow-up was 48 months and patient number was too small in comparison with large meta-analysis results. These factors could explain our results. However, these results could point out the importance of hemodialysis duration before renal transplant and younger age as negative contributing factors for graft survival.

Rostami and associates analyzed the results of 18 observational studies including 8348 HCV-infected patients from 123 228 living- and deceased-donor renal transplant recipients.³² They found that the combined hazard ratio for patient mortality in HCV-infected recipients was 1.69-fold (P ≤ .0001) greater than in HCV-negative recipients. Their results were consistent with previous surveys, and all causes of mortality were significantly higher in HCV-infected patients.

In our study, overall patient survival was similar between patients who had or did not have treatment (P = .053), with a tendency toward better results in untreated patients. Mortality of patients with higher viral replication rates was higher (P ≤ .008), and sepsis was the main risk factor for mortality in highly viremic patients.

In conclusion, we suggest that pretransplant HCV infection treatment, although recommended before renal transplant, does not always have good outcomes. Pretransplant dialysis treatment duration, age of recipient, and higher posttransplant viral replication rates may be important contributing factors related to graft and patient survival.

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