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The Course of Posttransplant Hepatitis C Infection

Comparative Impact of Donor and Recipient Source of the Favorable IL28B Genotype and Other Variables

Duarte-Rojo, Andres1; Veldt, Bart J.2; Goldstein, David D.3; Tillman, Hans L.3; Watt, Kymberly D.1; Heimbach, Julie K.4; McHutchison, John G.3; Poterucha, John J.1; Vargas-Vorackova, Florencia5; Charlton, Michael R.1,6

doi: 10.1097/TP.0b013e3182547551
Clinical and Translational Research
Free
SDC

Background and Aims The IL28B genotype has been linked to sustained virological response (SVR) in hepatitis C virus (HCV). Its role on disease biology and progression is less clear. We characterized the effects of IL28B genotype on HCV recurrence, allograft histology, rate of SVR, and survival after liver transplantation (LT) in HCV.

Methods Consecutive patients who underwent LT with HCV were studied. The rs12979860 genotype from both the donor was and recipient was determined. Measured endpoints included histologic HCV recurrence (inflammatory grade and fibrosis stage), acute cellular rejection, SVR, retransplantation, and death.

Results The study cohort comprised 272 consecutive LT in 255 patients. C-allele frequency was 56% in recipients and 70% in donors (P<0.001). Recipient IL28B CC genotype was associated with lower alanine aminotransferase levels and viral load at recurrence and a lower frequency of F≥2 on liver biopsy at 1 year after LT, when compared with the non–CC genotype (P=0.012). The opposite was observed in LT with donor CC genotype (P=0.003). Both recipient and donor CC genotype favored SVR, and when the two of them occurred together, the SVR rate reached 90%. Survival analysis after 5.5 years of follow-up showed a higher rate of progression to cirrhosis (hazard ratio, 5.96; 95% confidence interval, 1.29–27.6), liver-related death, or retransplantation among liver transplant recipients with a CC genotype donor.

Conclusions The IL28B genotype is predictive not only of SVR but also of the histologic diagnosis of posttransplant hepatitis C, with donor CC genotype favoring inflammation and fibrosis, and adverse outcomes during long-term follow-up. A favorable effect of donor CC genotype is manifest only after antiviral therapy.

1 Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.

2 Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

3 Duke Clinical Research Institute, Duke University Medical Center, Durham, NC.

4 Division of Transplantation Surgery, Mayo Clinic, Rochester, MN.

5 Epidemiology Unit, Division of Gastroenterology, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico.

This work has been supported by Public Health Service Grant RO1 DK069757-01 from the National Institute of Diabetes and Digestive and Kidney Diseases and Grant RR00585 from the General Clinical Research Center.

D.B.G. is a consultant for Schering Plough and GlaxoSmithKline and has patent IL28B findings and patent ITPA findings filed. J.G.M. is an employee and stock shareholder of Gilead Sciences. H.L.T. is a consultant for Novartis; is an employee of Abbott; has received grant and research support from Vertex, Novartis, Merck, Synexis, Anadys, Abbott, Idera, and Medtronic; has received speaking and teaching fees from Roche and Salix; and is a stock shareholder of Abbott. All other authors declare no funding or conflicts of interest.

6 Address correspondence to: Michael R. Charlton, M.D., Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St SW, Rochester, MN.

E-mail: charlton.michael@mayo.edu

A.D.-R. participated in data collection, assembly, and analysis and writing of the article. B.J.V. participated in data collection and analysis and correction of the article. D.D.G., H.L.T., and J.G.M. participated in genetic analysis and correction of the article. K.D.W. and J.K.H. assisted in the study design and in the preparation of the article. J.J.P. assisted in the study design, the data analysis, and correction of the article. F.V.-V. supervised the statistical analysis and participated in correcting the article. M.R.C. planned the study and participated in data collection and analysis and in preparation of the final article.

Received 23 December 2011. Revision requested 20 January 2012.

Accepted 6 March 2012.

Hepatitis C virus (HCV) is the most common chronic blood-borne infection in the United States and affects 130 to 170 million people worldwide (1). Decompensated cirrhosis due to chronic hepatitis C (CHC) continues to be the leading indication for liver transplantation (LT). Viral eradication by means of sustained virological response (SVR) with pegylated interferon and ribavirin is known to improve clinical outcomes in the long term (2, 3).

Genome-wide studies have demonstrated a strong association between allelic variations in the IL28B gene and viral eradication. Patients who are homozygous for the favorable allele are more likely to spontaneously eradicate the virus after acute infection and to achieve of SVR after treatment with peginterferon and ribavirin (4–8). Although the mechanism of action is unknown, the described single-nucleotide polymorphisms (SNPs) involve the lambda interferons (IFN-λ)—a family of type III IFN with antiviral activity (4). The study of CHC disease biology and factors that affect progression after LT is important because one third of patients develop cirrhosis, die, or require retransplantation owing to the recurrence of HCV by the fifth postoperative year (9, 10–13).

Understanding the relative impact of donor and recipient IL28B genotype on post-LT outcomes may yield insights into virus-host interactions and mechanisms applicable to both the transplant and nontransplant setting. Reports of the association between IL28B genotype and posttransplant CHC (14–18) have largely confirmed what has been observed in the nontransplant setting with regard to the effect of IL28B on SVR after antiviral treatment (AVT). Data regarding the effect of IL28B genotype on the clinical progression of specific facets of recurrence of HCV and the overall impact on survival are scarce. In the present study, we characterized the effect of IL28B genotypes on HCV recurrence, as measured by allograft histology, the rate of SVR, and patient and graft survival.

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RESULTS

A total of 328 LT were performed in 308 patients with CHC. IL28B genotype could not be determined in 37 LT (mostly because of DNA unavailability), 17 patients demonstrated negative HCV RNA at the time of LT. One patient experienced spontaneous clearance of HCV RNA after LT—this patient demonstrated a CT genotype and received a CC allograft. The final cohort thus consisted of 272 LT performed in 255 patients with CHC (Fig. 1). IL28B genotyping was successful in 239 explanted livers (recipients, R-IL28B) and 241 allografts (donors, D-IL28B). Donor DNA was extracted from back table biopsies obtained before implantation. A total of 126 liver transplant recipients (46%) received post-LT AVT.

FIGURE 1

FIGURE 1

The distribution of IL28B genotypes differed between recipients (R-IL28B: CC 31%, CT 49%, and TT 20%; n=239) and donors (D-IL28B: CC 52%, CT 37%, and TT 11%; n=241); the difference being significant for the comparison of CC genotype against non-CC (P<0.001). R-IL28B did not deviate from the genotype distribution expected under the Hardy-Weinberg equilibrium (C-allele frequency=0.558; χ2 test, P=0.83), but there was a trend for deviation from equilibrium in D-IL28B (C-allele frequency=0.701; χ2 test, P=0.09). Baseline characteristics for the 239 LT with IL28B genotyping are shown in Table 1. Viral genotypes were not distributed evenly across the different R-IL28B, with a predominance of genotype 1 in TT and CT.

TABLE 1

TABLE 1

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Hepatitis C Recurrence and Allograft Histology

Fibrosing cholestatic hepatitis was identified in 12 LT involving 11 patients. Nine of these died. There was no association or notable trend for association between either D-IL28B or R-IL28B and fibrosing cholestatic HCV.

Histologic features of recurrence of HCV were apparent in 232 LT (91%) after a median follow-up of 2.6 years (range, 1.1–5.7 years). Patients with the R-CC genotype demonstrated a longer time to recurrence of HCV when compared with R-nonCC genotype, 4.6 months (range, 3.7–13 months) versus 4.1 months (range, 2.4–6.9 months), respectively, P=0.006 (Table 2). No significant relationship was found with D-CC. Patients with R-CC presented with lower levels of alanine aminotransferase (ALT) and viral load and higher albumin when compared with their R-nonCC counterparts, whereas the opposite effect was observed for ALT and viral load for D-CC versus D-nonCC. In the multivariate analysis, only a trend for the effect of R-CC on time to recurrence remained (P=0.06).

TABLE 2

TABLE 2

The frequency of patients developing significant fibrosis (F≥2) on protocol biopsies was 8% (n=232), 32% (n=217), 53% (n=158), 61% (n=97), and 75% (n=63) at 4 months at 1, 3, 5, and more than 5 years after transplant, respectively. The frequency of inflammatory grade 2 or higher in serial biopsies was 23% (n=224), 53% (n=210), 50% (n=155), 55% (n=94), and 48% (n=61) at the same time points. The 1-year time point was used to explore the effect of IL28B on HCV histologic stage and grade (Fig. 2). A higher proportion of patients with R-nonCC and D-CC had progressed to F≥2 by the first year after LT, and this was paralleled by more inflammatory activities in D-CC. Analysis of results with patients censored at initiation of AVT yielded similar results.

FIGURE 2

FIGURE 2

A total of 113 recipients (43%) demonstrated at least one episode of acute cellular rejection (ACR) during follow-up. The proportion of patients having at least one episode of ACR according to IL28B genotype is shown in Figure 2. There was a numerically higher rate of ACR in both R-nonCC (46% vs. 35%, P=0.12) and D-CC (48% vs. 38%, P=0.12), although differences did not reach statistical significance.

Multivariate analysis assessing the magnitude of the effect of IL28B on clinically relevant fibrosis at 1 year is shown in Table 3. Both R- and D-CC genotypes were independently associated with progression to F≥2 at 1 year after LT, the former being protective and the latter being predictive of increased risk.

TABLE 3

TABLE 3

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SVR

A total of 120 liver transplant recipients -without fibrosing cholestatic hepatitis- (46%) received at least one dose of AVT. Distribution of genotypes was as follows: genotype 1, 76%; genotype 2, 12%; genotype 3, 8%; and genotype 4, 3%; genotype was unknown in two patients. Of all the treated patients, 39% achieved SVR, 42% demonstrated no response, and 10% experienced either a breakthrough or a relapse. At the time of the analysis, 12 patients were still undergoing AVT. SVR varied significantly with R-IL28B, with the greatest response among patients who received liver transplants with recipient CC genotype, intermediate for CT, and low for TT (Fig. 3). A similar pattern was observed for D-IL28B genotypes. When both R- and D-IL28B genotypes were grouped together in CC–nonCC pairs, an additive effect was observed, with SVR reaching 90% among the 10 patients who received liver transplants bearing both R-CC and D-CC. A multivariate analysis confirmed the independence of the effect of IL28B on SVR and the greater effect of viral genotype (Table 4). Donor age also affected SVR, with a decrease of 4% for each older year. Importantly, the use of either tacrolimus or cyclosporine did not influence SVR.

TABLE 4

TABLE 4

FIGURE 3

FIGURE 3

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Survival Analysis

After a median follow-up of 5.5 years (range, 2.2–9 years), there were 53 deaths (23%), 32 of which were liver-related deaths (14%), 10 retransplantations (4%), and 29 (12%) allografts progressing to F4. Although there was no relationship between the IL28B genotypes and death, liver-related death or retransplantation (data not shown), it was noted that the R-IL28B genotypes were associated with progression to F4, and this significance persisted when combined in a composite endpoint with liver-related death and retransplantation. This combined endpoint was observed in 82 patients (35%). Because it was presumed that the beneficial effect of IL28B polymorphisms on the SVR rate could affect their association with the composite endpoint, further analyses were performed after censoring treated patients on the day AVT was started. With this approach (censoring on day of initiation of AVT), the association between R-IL28B and the composite endpoint was lost, although it was now observed with D-IL28B (Fig 4). To assess the magnitude of the effect regression models were built, and because of colinearity between the CT and TT genotypes, these were grouped as non-CC and compared with CC for both R-IL28B and D-IL28B. Results of the univariable and multivariable models are shown in Table 5. Only D-CC was independently associated with an increased risk of an adverse outcome (progression to cirrhosis, liver-related death, or retransplantation). The time of anhepatic phase before LT was also associated with an increased risk of adverse outcome, and a trend was observed for CMV infection during follow-up.

TABLE 5

TABLE 5

FIGURE 4

FIGURE 4

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DISCUSSION

The persistence of liver disease related to HCV infection as the most common indication for LT, and recurrence of HCV infection as the most common cause of posttransplant graft loss and mortality, has resulted in a high level of interest in factors that affect posttransplant outcomes. This study of predictors of key outcomes after LT for HCV infection has several potentially important new observations.

A central aspect of our current analysis is that the predictive usefulness of IL28B genotype for SVR is independent of other known predictors of response, including viral genotype. We observed that the relative predictive usefulness of the IL28B genotype for SVR, although highly significant, is one quarter that of the HCV genotype. Our study also confirms the association of both R-IL28B and D-IL28B CC genotypes with SVR in a larger and more complete cohort than reported previously (14–18). It is important to consider how our findings compare with those of others. Our findings contrast those of Coto-Llerena et al. (18) who reported that, although recipients with a CC genotype demonstrated a higher frequency of SVR when compared with non-CC recipients, a significant difference was not observed when the donor genotype was assessed (41% and 28%, respectively, P=0.179). The magnitude of the effect of donor CC genotype is, however, similar to that observed in our study, suggesting the lack of significance may be based on power. Two other studies have noted a positive association between the D-IL28B favorable genotype and successful AVT (14, 17). On balance, in magnitude and direction of effect, both recipient and donor IL28B genotypes seem to influence the frequency of SVR, with the response being enhanced when both R- and D- have the favorable genotype.

The mechanism through which the IL28B SNP genotype influences response to AVT is yet to be determined and merits some consideration. IFN-λ3, the product of IL28B gene, belongs to the type III interferon family, causing induction of interferon-stimulated genes (ISGs), maturation and differentiation of dendritic cells, modulation of TH1 and TH2 immune responses, and inhibition of Treg cells (19–22). Thus, IFN-λ3 is a proinflammatory cytokine, linking innate and adaptive immune responses (23). Favorable IL28B SNPs are associated with decreased levels of intrahepatic ISG (24, 25). Lower pretreatment ISG levels are predictive of ultimate SVR in the nontransplant setting (26).

A further potentially important aspect of our study is the differential predictivity of donor and recipient IL28B genotype for key clinical and histologic outcomes. We observed that recipients with a CC genotype have relatively slower histologic recurrence, with decreased ALT levels and viral load when compared with non-CC genotype, with the opposite association for donor CC genotype. Others have reported a significantly lower ALT and viral load in association with recipient CC genotype and significantly higher ALT among CC genotype donors (15–17). The clinical relevance of this paradoxical influence of IL28B CC genotype according to origin was evident when assessing the histologic data at 1 year after LT, when it was seen that recipient CC genotype was associated with lesser degrees of fibrosis than non-CC recipients, and the converse for donors. The survival analysis was consistent with histologic results, with a negative association of donor CC genotype with progression to cirrhosis, liver-related death, and retransplantation. Because of the suggestion of proinflammatory roles for the CC genotype, we explored associations of IL28B with risk for ACR. Although a higher frequency of ACR was seen in association with donor CC, the difference was not statistically significant. Although ACR was predictive of fibrosis in univariate modeling, its usefulness was lost in the multivariate analysis. It is possible, however, that an independent effect of ACR on propensity for more advanced fibrosis would be seen in a larger study and that part of the risk for more advanced fibrosis associated with donor CC and recipient non–CC genotype is conferred through an increased risk of ACR.

Taken together, these results suggest that a more aggressive course of recurrence of HCV is associated with a donor CC genotype in patients who do not receive AVT. The overall superior posttransplant outcomes associated with donor CC genotype occur by virtue of greater frequency of attainment of SVR during AVT. Because of a substantially increased risk of more severe histologic recurrence and greater likelihood of responding favorably to AVT, it is particularly important that AVT is administered when possible to patients who receive an allograft from a donor with a CC IL28B genotype.

Studies of variation in fibrosis progression with IL28B genotype have been inconsistent. In the nontransplant setting, Marabita et al. (27) found no significant difference in the frequency of advanced fibrosis between CC, CT, and TT genotypes (26%, 25%, and 15%, P=0.46). A study including patients with HCV/human immunodeficiency virus coinfection observed a higher rate of cirrhosis in CC when compared with CT/TT (24% and 13%, P=0.01) (28). It is possible that the effect of IL28B on liver fibrosis is only observed in populations with accelerated fibrosis such as human immunodeficiency virus coinfection or LT. Two studies in patients who underwent LT have examined the possibility of associations of IL28B genotype and histologic outcomes. Eurich et al. (16), in a study in which only recipient IL28B genotype was determined, did not find significant differences in fibrosis progression between genotypes. Similarly, Lange et al. (17) did not observe associations with either recipient or donor IL28B genotype and cirrhosis. The authors noted, however, that they lacked power to detect a meaningful difference in histologic outcomes. There are other important differences between our present study and those of Eurich et al. and Lange et al. in design (biopsies being or not mandatory at every time point during follow-up), patient numbers (91 transplants in the study by Lange et al. vs. 272 in our study), IL28B genotyping method (rs8099917 vs. rs12979860), approach to AVT, and prevalence of other risk factors for fibrosis. In the study by Eurich et al., IL28B genotyping was performed only in recipients, making an interaction between donor and recipients IL28B genotype impossible to examine (the interaction was very important in our analysis).

The basis for a fibrosing phenotype in association with recipient and donor IL28B genotypes cannot, of course, be determined from our study. Greater expression of IL28B messenger RNA has been documented in both explanted and allograft livers with the favorable antiviral genotype (14). Persistence of CC genotype donor dendritic and lymphocytic cells within the allograft could theoretically create an immunologic environment favoring inflammation and fibrogenesis in the absence of viral eradication.

There are several limitations to our study, including the fact that it was not possible, for example, to characterize the IL28B genotype in 27% of our patients. There were, however, no baseline differences between patients who underwent LT with and without available IL28B genotype. In addition, the distribution of IL28B genotypes among donors showed a trend for deviation from the Hardy-Weinberg equilibrium. The C-allele frequency was similar, however, to that reported among other liver transplant recipient populations and is likely a reflection of an enrichment of nonresponders to AVT and failure to clear HCV during acute infection among liver transplant recipients.

In conclusion, the clinical evolution of posttransplant HCV infection varies with the origin of the CC genotype. We also confirm the favorable association of both recipient and donor CC genotype on response to AVT. In the absence of viral eradication, donor CC genotype is associated with a greater frequency of a composite endpoint including progression to cirrhosis, liver-related death, and retransplantation. It is particularly important that patients who receive an allograft from a donor with a CC IL28B genotype receive AVT. The interplay between donor and recipient genotypes is clearly complex in liver transplant recipients. Studies of the relative impact of donor and recipient IL28B genotype on ISG and IFN-λ1-3 expression are eagerly awaited.

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MATERIALS AND METHODS

Patients

The study included patients with CHC who underwent LT between January 1995 and July 2010 at our center. All patients were followed up according to a standard protocol. DNA was collected from recipients and donors. Available liver biopsies included mandatory biopsies at day 7 and at 4 and 12 months after LT and yearly thereafter and those requested by the treating physician for clinical reasons. Quantification of HCV RNA in the serum was performed with COBAS AMPLICOR HCV Test, version 2.0 assay (Roche Molecular Systems). The study protocol was approved by the institutional review board of the Mayo Clinic.

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DNA Extraction and IL28B Genotyping

DNA was extracted from stored paraffin-fixed liver tissue blocks using the QIAamp DNA Mini Kit (Qiagen, Valencia, CA) assay. Donor and recipient DNA was tested for the polymorphism rs12979860 using the ABI TaqMan allelic discrimination kit and the ABI7900HT Sequence Detection System (Applied Biosystems, Carlsbad, CA).

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Clinical Endpoints

Hepatitis C Recurrence and Allograft Histology

Recurrent hepatitis C infection was defined as a panlobular or portal lymphocytic infiltrate, with detection of quantifiable HCV RNA in the serum, and in the absence of any alternative cause. All liver biopsies were reviewed for evidence of ACR (29). Fibrosis stage and inflammation grade were evaluated in a standard fashion at years 1, 3, and 5 after LT and at the last biopsy (if >5 years) (30).

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SVR

A subset of patients received AVT with peginterferon ± ribavirin. In these, SVR was assessed and defined as undetectable HCV RNA at 24 weeks after the end of treatment.

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Survival

A composite endpoint consisting of liver-related death and/or allograft failure (retransplantation or progression to F4) was used as the primary endpoint. Patients with death or retransplantation during the first 90 days after LT, hepatic artery thrombosis, or biliary strictures at anytime during follow-up were excluded.

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Statistical Analysis

Continuous variables are summarized as mean (SD) or median (interquartile range). Comparisons were made with t test and analysis of variance or Mann-Whitney U and Kruskal-Wallis tests according to the distribution of data. Categorical variables were compared by means of the chi-square test. Analyses were performed considering all genotypes for IL28B (CC, CT, and TT) and grouping them as favorable versus nonfavorable (CC vs. nonCC). Univariate (multiple linear, logistic, and Cox) regression analyses were applied to build final multivariate models assessing risk factors for time to recurrence of HCV, fibrosis progression, and SVR, respectively. Factors in the univariate analysis showing P<0.2 were entered in the multivariate analyses. The final model included the covariates with the best fit to the data. All statistical analyses were performed with Stata (version 9.2; Stata Corp, College Station, TX).

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Keywords:

Acute cellular rejection; Fibrosis; Histologic grade; Interferon λ; Survival; Sustained virological response

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