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High Incidence of Allograft Cirrhosis in Hepatitis C Virus Genotype 1b Infection Following Transplantation: Relationship With Rejection Episodes

Martín Prieto¹, Marina Berenguer¹, José Miguel Rayón², Juan Córdoba³, Lidia Argüello, Domingo Carrasco¹, Antonio García-Herola¹, Vicente Olaso¹, Manuel De Juan⁴, Miguel Gobernado³, José Mir⁴, and Joaquín Berenguer¹

From ¹Hepatogastroenterology Service, ²Pathology Service, ³Microbiology Service, and ⁴Liver Transplantation and Surgery Unit, Hospital Universitario La Fe, Valencia, Spain.

ABSTRACT

The natural history of hepatitis C virus (HCV) infection following liver transplantation and predictors of disease severity remain controversial. The aims of the study were to assess in a homogeneous population of 81 cyclosporine-based HCV-infected liver transplant recipients mostly infected with genotype 1b and undergoing strict protocol annual biopsies: 1) the histological progression of posttransplantation HCV disease and, in particular, the incidence of HCV-related graft cirrhosis within the first 5 years after surgery; and 2) the relationship between progression to cirrhosis and i) rejection episodes and ii) first-year liver biopsy findings. We studied 81 consecutive HCV-RNA-positive patients (96% genotype 1b) undergoing liver transplantation between 1991  and 1996 with a minimum histological follow-up of 1 year. All patients received cyclosporine-based immunosuppression and underwent protocol yearly liver biopsies for the first 5 years. The mean histological follow-up was 32 months (range, 12-60 months). Biopsies were scored according to the histological activity index (HAI), with separate evaluation of grade (activity) and stage (fibrosis). Histological hepatitis, present in 97% of patients in the most recent biopsy, was moderate or severe in 64%. Twelve patients developed HCV-related cirrhosis at a median time of 24 months (range, 12-48 months), with an actuarial rate of HCV-cirrhosis of 3.7%, 8.5%, 16%, 28%, and 28% at 1, 2, 3, 4, and 5 years, respectively. Rejection was significantly more common among patients with cirrhosis versus those without (83% vs. 48%; P = .02), with an association between the incidence of cirrhosis and the number of rejection episodes: 5%, 15%, and 50% in patients without rejection, one and two episodes, respectively (P = .001). The degree of activity and fibrosis score in the first-year biopsy were higher in patients who developed cirrhosis than in those who did not (P = .008 and .18, respectively). In conclusion, HCV genotype 1b-infected liver recipients are at a high risk of developing graft cirrhosis in the first 4 to 5 years following transplantation, especially those with previous rejection episodes. First-year liver biopsies may help to sooner identify patients at the highest risk, improving further patient management. (HEPATOLOGY 1999;29:250-256.)

INTRODUCTION

Cirrhosis related to chronic infection with the hepatitis C virus (HCV) has emerged as one of the leading indications for orthotopic liver transplantation (OLT) worldwide, accounting for 50% of transplantation in Spain.¹ Although recurrence of HCV infection is universal following transplantation,² the natural history of posttransplantation hepatitis C is variable,^3-6 and while the disease course after a short-term follow-up of 1 to 2 years is typically mild, an accelerated course leading to cirrhosis within 5 years has been described.⁷ The reasons for the variation in disease expression remain uncertain, although rejection episodes,⁸ donor-recipient HLA matching,⁹ level of pre-and posttransplantation viremia,¹⁰ and viral genotype^5,11,12 have been proposed as contributory variables. Discrepancies exist, however, between studies, probably related to the presence of several confounding factors such as a low incidence of genotype 1b in some series, the use of different immunosuppressive regimens, and the lack of studies assessing the natural history of HCV infection using protocol liver biopsies. To avoid these potential biases, we evaluated the outcome of a very homogeneous population of HCV liver transplant recipients, characterized by: 1) strict histological follow-up with protocol annual liver biopsies obtained in all the patients for the first 5 years posttransplantation; 2) cyclosporine-based immunosuppression; and 3) infection with HCV genotype 1b in the vast majority of patients.

The aims of the study were to assess in this homogeneous population: 1) the histological progression of posttransplantation HCV disease and, in particular, the incidence of HCV-related graft cirrhosis within the first 5 years after surgery; 2) the impact of rejection episodes on the severity of posttransplantation hepatitis C; 3) whether first-year liver biopsy histological findings could predict the outcome of HCV infection after transplantation; and 4) whether biochemical and clinical data are correlated with histological findings.

This is the first report to address these issues in genotype 1b-infected liver transplant recipients in which annual liver biopsies were routinely available.

PATIENTS AND METHODS

Patients

Between January 5, 1991, and May 15, 1996, 239 patients underwent 258 OLTs at our institution. One hundred eighteen of these patients underwent transplantation for cirrhosis secondary to chronic HCV infection, defined by the presence of anti-HCV antibody by a second generation enzyme-linked immunosorbent assay and confirmed by a recombinant immunoblot assay. Only patients who had HCV infection posttransplantation defined as positivity of serum HCV RNA by reverse-transcription polymerase chain reaction and a minimum histological follow-up of 1 year were included in this study. Thirty-nine patients were excluded from the analysis for the following reasons: 1) survival less than 1 year posttransplantation (n =  28); 2) hepatitis B virus infection posttransplantation (n = 4); 3) inadequate histological follow-up (n = 4); 4) concurrent biliary complications (n = 2); and 5) no HCV recurrence posttransplantation (n = 1). The cause of death in those excluded for survival <1 year was only related to HCV infection in 1 patient. In the remaining patients, the cause of death included: sepsis (n = 5), neurological (n = 5), multiorgan failure (n = 3), perioperative (n = 2), renal complications (n = 2), cytomegalovirus disease (n = 2), lymphoma (n = 2), primary nonfunction of the graft (n = 1), and others (n = 5). Two patients who developed posttransplantation de novo HCV infection were also included into the study. Therefore, 81  patients (56 males, 25 females; mean age, 54 ± 8 years; range, 24-65 years), 79 with recurrent HCV infection and 2 with de novo HCV infection, were included in this retrospective study and formed the study group. The indications for transplantation were either end-stage cirrhosis (n = 64) or cirrhosis with hepatocellular carcinoma (HCC) (n = 17). Small HCC were discovered incidentally in the explanted liver in 2 additional cases. Five patients with HCC received pre-OLT chemoembolization while they were on the waiting list. Age, sex distribution, prior alcohol intake, and prevalence of HCC at the time of surgery were not different between patients included and those excluded from the study.

Serological Assays

Anti-HCV antibodies were determined using a commercial second-generation enzyme-linked immunosorbent assay (ELISA 2.0, Ortho Diagnostic System, Raritan, NJ). Positive serum samples were confirmed using a second-generation recombinant immunoblotting assay (RIBA 2.0, Chiron Corporation, Emeryville, CA).

HCV RNA and HCV Genotype

HCV-RNA Detection. Qualitative HCV RNA was determined by a nested reverse-transcription polymerase chain reaction using primers from the 5'untranslated region of the HCV genome, as previously described.¹³

HCV Genotyping. Viral genotype was assessed in serum samples obtained after transplantation using a first-generation line-probe assay¹⁴ (Inno-Lipa HCV, Innogenetics, Zwijndrecht, Belgium). Briefly, after RNA extraction from serum, as described by Chomcynski and Sacchi,¹⁵ we used a sensitive PCR protocol for the highly conserved 5'untranslated region with sets of nested, universal primers. The amplification products obtained were hybridized to type-specific oligonucleotides immobilized as parallel lines on membrane strips and directed against the 5'untranslated region (reverse-hybridization principle).

Immunosuppression

Induction immunosuppression consisted of standard triple therapy with cyclosporine, azathioprine (1-2 mg/kg/d), and methylprednisolone given intravenously with tapering of the dose from 200 mg to 20  mg at day 6, at which time 20 mg/d of prednisone was administered orally. As a result of postoperative renal failure, 1 patient received OKT3 as part of the induction immunosuppression. The center's policy on long-term immmunosuppression has evolved over time, but in none of the patients was there a switch to tacrolimus during the follow-up. Azathioprine was discontinued in 76 patients (94%) at a median of 190 days (range, 23-1,260 days) after transplantation and continued in 5 patients at the discretion of the hepatologist. Prednisone dosage was progressively decreased to 2.5 to 5 mg/d at first-year postransplantation. At the time of the most recent follow-up, prednisone had been discontinued in 75 patients (93%) at a median time of 720 days (range, 210-1,800 days) after surgery. Decisions regarding a change in immunosuppression depending on the graft function were not uniform throughout the study period. Nevertheless, there was a trend toward diminishing cyclosporine and corticosteroid doses in patients who had developed recurrent hepatitis C. The immunosuppression protocol was not different for the patients with HCC.

Histologically confirmed moderate or severe acute cellular rejection episodes were treated with methylprednisolone "boluses" (1 g/d for 3 days), followed by steroid taper. Mild rejection episodes were usually left untreated unless accompanied by significant deterioration of liver tests. If repeat liver biopsy confirmed ongoing rejection with associated biochemical graft dysfunction, OKT3 (5 mg/d for 14 days) was administered, which occurred in 5 patients (6%) of the study group.

Histological Assessment

Protocol liver biopsies were performed yearly for the first 5 years posttransplantation. Additional liver biopsies were performed for unexplained elevations in liver tests if serum transaminase levels were at least 1.5 times the upper limit of normal, and to confirm the histological resolution of rejection after antirejection therapy. In the 81 patients who formed the study group, a total of 202 protocol liver biopsies were available for histological analysis. The mean histological follow-up following transplantation was 32 ± 17 months (range, 12-60 months). Length of histological follow-up was distributed as follows: 1 year (n = 21), 2 years (n = 22), 3 years (n = 17), 4 years (n = 8), and 5 years (n =  13).

All biopsy specimens were reviewed by a single pathologist (J.M.R.) in a blinded fashion. The specimens were scored according to a slight modification of the histological activity index (HAI) proposed by Knodell,¹⁶ and their histological grade (activity) and stage (fibrosis) were evaluated separately.¹⁷ The grade was determined by combining the HAI scores for periportal necrosis, scored 0-6 (0, none; 1, mild piecemeal necrosis; 3, moderate piecemeal necrosis; 4, marked piecemeal necrosis; 5, moderate piecemeal necrosis plus bridging necrosis; 6, marked piecemeal necrosis plus bridging necrosis), lobular degeneration and necrosis (0-4), and portal inflammation (0-4), and was defined as follows: 1 to 2, minimal; 3 to 6, mild; 7 to 10, moderate; 11 to 14, severe. In addition, liver biopsy samples were staged according to the original HAI fibrosis score: 0, none; 1, fibrous portal expansion; 3, bridging fibrosis; and 4,  cirrhosis.

Rejection was diagnosed on the basis of a liver specimen showing bile duct damage, mixed portal inflammatory infiltration, eosinophils, and endothelitis, and was graded according to standard histological criteria.¹⁸ In four cases of graft dysfunction, all of them occurring after the first month posttransplantation, findings consistent with hepatitis C and rejection coexisted. Three of these patients were treated for rejection with methylprednisolone boluses and were classified as rejection. We arbitrarily defined early rejection as rejection occurring within the first 4 weeks following transplantation and late rejection as rejection occurring after 4  weeks.

Data Collection

Age, sex, presence of HCC at the time of transplantation, and number and dates of rejection episodes occurring within the first post-OLT year were recorded for each patient. In addition, immunosuppression administered during the first year, including "boluses" of methylprednisolone, cumulative doses of prednisone and azathioprine at 3, 6, 9, and 12 months after surgery, mean whole-blood cyclosporine trough levels at 3, 6, 9, and 12 months, and the use of OKT3 for steroid-resistant rejection episodes were retrospectively recorded.

Statistical Analyses

Categorical data were compared using a ² test or Fisher's exact test when indicated. When categorical variables were ordered, comparisons were performed using a ² test for trend. Continuous variables were expressed as mean ±  SD and compared by the t test. When a normal distribution could not be assumed, continuous variables were summarized as medians and ranges and compared by the Mann-Whitney test. Kaplan-Meier curves were calculated to estimate patient survival over time, and to estimate the cumulated probability of developing HCV-related graft cirrhosis in patients with posttransplantation HCV infection using the date of diagnosis of cirrhosis as the end-point. The log rank test was used to compare probability curves. P  .05  was considered to be significant.

RESULTS

Hepatitis C Genotype Distribution

Serum was available for HCV genotyping after transplantation in 77 of 81 (95%) patients. The following genotypes were identified: 1b (n = 73), 1a-1b (n = 1), 1a-2 (n = 1), 1a (n = 1), and 4 (n  = 1). HCV genotypes in the two patients with de novo HCV infection were 1b and 4.

Prevalence and Evolution of Histological Hepatitis C Following Transplantation

In the most recent biopsy, there was histological evidence of hepatitis C (HAI > 0) in 79 of 81 patients (97.5%). The activity of hepatitis C was minimal in 15.1%, mild in 20.2%, moderate in 40.5%, and severe in 24.1% (table 1).

The evolution of the activity of hepatitis in the first 5 years following transplantation is shown in table 2. When the biopsy specimens obtained at 1 year were compared with those obtained at 5 years, there were no significant differences in the number of grafts without hepatitis (P = .45), grafts with minimal hepatitis (P = .42), grafts with mild hepatitis (P = .29), grafts with moderate hepatitis (P = .76), or grafts with severe hepatitis (P = .26). In 11 patients, biopsy specimens were available from the first to the fifth year posttransplantation. Activity of hepatitis in this subset of patients appeared to increase with time, but this trend did not reach statistical significance (data not shown).

Prevalence and Evolution of Fibrosis Following Transplantation

Histological evidence of fibrosis (fibrosis >0) was present in 52 of 81 (64.2%) patients in the most recent liver biopsy, 32% of whom had fibrous portal expansion, 17.3% bridging fibrosis, and 14.8% cirrhosis (table 1). Evolution of fibrosis is shown in table 2. When the biopsy specimens obtained at 1 year were compared with those obtained at 5 years, there were no significant differences in the number of grafts without fibrosis (P = .13) and those with fibrous portal expansion (P = .53). By contrast, grafts with bridging fibrosis were less frequent at 1 year than at 5 years (P = .057). In 11 patients in whom biopsy specimens were available from the first to the fifth year posttransplantation, fibrosis appeared to increase with time, but this difference was statistically significant only when comparing fibrosis at first year versus that at 5 years (0.1 ± 0.3 vs. 1.3 ± 1.2; P < .05).

Transaminase Levels and Relationship to Severity of Hepatitis

Serum alanine transaminase (ALT) levels were lower in patients with minimal hepatitis than in those with mild, moderate, or severe hepatitis (P = .001), but did not differ between the three latter groups (Fig. 2). Overall, 30% of the 79 patients with hepatitis had serum ALT levels in the normal range (0-40 U/L). Ninety-two percent of the patients with minimal hepatitis had normal serum ALT levels, as did 37.5% of those with mild hepatitis, 9.4% of those with moderate hepatitis, and 10.5% of those with severe hepatitis (P = .0001). All patients with graft cirrhosis and 65% of the noncirrhotic subjects had increased serum ALT levels (>40 U/L) (P = .01).

Characteristics and Outcome of the Patients With HCV-Related Graft Cirrhosis

Twelve patients developed HCV-related graft cirrhosis. There were 6 males and 6 females, with a mean age of 53.2 ± 10.8 years. Five were doing well at a mean time of 8.2 ± 2.5 months (range, 6-12 months) after the diagnosis of cirrhosis. Liver failure developed in the remaining 7: 3 died of decompensated cirrhosis, 1 was retransplanted but eventually died in the immediate postoperative period, and 3 are alive but require frequent hospital admissions for complications of their cirrhosis.

Factors at 1 Year Predictive of Subsequent HCV-Related Graft Cirrhosis

Age, sex distribution, rejection episodes within the first year posttransplantation, rejection therapy, OKT3 use, cumulative 1-year steroids and azathioprine doses, mean whole-blood cyclosporine trough levels within the first year posttransplantation, serum transaminase levels at 1 year, and histological findings at 1  year were evaluated.

Rejection Within the First Posttransplantation Year. Fifty-three acute rejection episodes occurred within the first posttransplantation year in 43 patients of the study group, 70% of which occurred within the first month (median time, 9 days; range, 5-29 days) and 30% after the first month (median time, 76 days; range, 36-353 days) following transplantation. Rejection treatment was administered in 81% of rejection episodes.

Eighty-three percent of patients who developed HCV-related graft cirrhosis had experienced at least one episode of acute cellular rejection within the first year posttransplantation as compared with 48% of those who did not develop cirrhosis (P = .02) (table 3). There was a strong association between the number of rejection episodes and the incidence of HCV-related cirrhosis: 5% in patients without rejection, 15% in patients with one rejection episode, and 50% in patients experiencing two rejection episodes (P = .001). The number of patients treated for rejection and the number of methylprednisolone "boluses" were also significantly higher in patients with graft cirrhosis (table 3). Seventeen percent of the patients who developed HCV-related cirrhosis received OKT3 for steroid-resistant rejection as compared with 4% of those without cirrhosis (P = .32) (table 3).

Cumulative steroid (excluding methylprednisolone "boluses") and azathioprine doses, and mean whole-blood cyclosporine trough levels within the first year posttransplantation were not different between the patients with and without HCV-related graft cirrhosis (data not shown).

First-Year Liver Biopsy Findings. For the assessment of the predictive value of first-year histological findings on the subsequent development of HCV-related graft cirrhosis, only 57 patients with a histological follow-up longer than 1 year were analyzed. In addition, 3 patients who already had cirrhosis in the first-year liver biopsy were excluded from this analysis. Activity of hepatitis C in the first-year liver biopsy was significantly higher in the patients who eventually developed HCV-related graft cirrhosis than in those who did not (7.6 ± 3.4 vs. 4.4 ± 3.1; P = .008) (table 4). Although the fibrosis score was also higher among patients with subsequent cirrhosis, the difference did not reach statistical significance (P = .18).

Cirrhosis developed in none of the 5 patients with a normal histology in the first-year liver biopsy, in 2 of 27 (7%) with minimal or mild hepatitis, and in 7 of 25 (28%) with moderate or severe hepatitis (P = .07). Cirrhosis developed in 3 of 35  (8.6%) patients with no fibrosis in the first-year liver biopsy as compared with 6 of 22 (27%) patients with a fibrosis score of 1 or more (P = .06).

First-Year Liver Tests. Serum transaminase levels at the time of the first-year liver biopsy were higher in the 9 patients who subsequently developed graft cirrhosis than in those who did not (table 4). Graft cirrhosis developed more frequently in patients with first-year serum ALT levels higher than 100 U/L than in those with values less than 100 U/L (29.2% vs. 5.9%; P = .02). Similarly, graft cirrhosis developed in 34.8% of patients with first-year serum aspartate transaminase levels higher than 70 U/L as compared with 2.8% of those with aspartate transaminase levels less than 70 U/L (P =  .0008). By contrast, first-year serum bilirubin, alkaline phosphatase, and -glutamyl transpeptidase levels were not different between both groups (data not shown).

Patient Survival

Nine patients of the study group (11%) had died at a median time of 31 months (range, 12.3-43 months) following transplantation, 6 of them as a result of HCV-related complications, including decompensation of HCV cirrhosis (n = 3), multiorgan failure following retransplantation for HCV-cirrhosis (n = 1), and HCV-related glomerulopathy (n = 2). The other 3 deaths were unrelated to hepatitis C: chronic rejection (n = 1), cerebral hemorrhage (n = 1), and lung cancer (n =  1).

Overall, patient survival of the study population was 95%, 91%, and 84% at 2, 3, and 5 years following transplantation, compared with 96%, 92%, and 83%, respectively, in patients transplanted for non-HCV cirrhosis at our institution and surviving at least 1 year following transplantation (P = ns). None of the patients with HCC developed recurrent HCC. In the group of patients who developed graft cirrhosis, cumulative survival rates were 82% after 2 years, 72% after 3 years, and 54% after 4 years, as compared with rates of 97%, 94%, and 86%, respectively, in the noncirrhotic group (P = .01) (Fig. 3).

DISCUSSION

Several factors may account for the variability in HCV-related disease severity following liver transplantation, but data regarding these issues are conflicting. Major reasons include: 1) lack of a uniform definition of disease severity with very few studies assessing it by histological means; and 2) heterogeneity in the study population. We tried to avoid these problems by assessing the natural history of hepatitis C posttransplantation in a relatively pure population of HCV genotype 1b-infected liver transplant recipients. The high prevalence of HCV genotype 1b in our study population (96%) is consistent with data from the immunocompetent population in Spain,¹⁹ but is much higher than that reported in previous series from the United States^12,20,21 and Europe.^5,11 Induction immunosuppression consisted in all patients on cyclosporine, azathioprine, and prednisone, and only 1 patient was treated with interferon alfa after transplantation. Finally, strict annual liver biopsy protocol with differentiation between activity and fibrosis allowed for close monitoring of disease severity and progression. Previous studies that relied on liver tests to assess the outcome of recurrent hepatitis C have likely underestimated the percentage of patients with disease.

Our study supports that posttransplantation HCV infection is not as benign as previously considered. Results can be summarized as follows: 1) Histological evidence of hepatitis develops in the vast majority of HCV-infected patients (97%), a proportion much higher than that previously reported (50%-60%),² and in nearly two thirds of them, activity of hepatitis is moderate or severe. The high prevalence of recurrent hepatitis C in the present study could be related to the fact that we defined recurrent hepatitis by histological means and not by biochemical markers. Alternatively, it may be a result of the high prevalence of genotype 1b-infected patients, indirectly supporting that patients infected with this genotype may develop hepatitis more frequently than other genotypes. Finally, the difference between the incidence of recurrent hepatitis reported in the present study and elsewhere may be reflecting different histological criteria. 2) Although the rate of cirrhosis development increases with time, the activity of the hepatitis does not seem to progress over time. 3) The "healthy HCV carrier state" is as rare a situation in patients with persistent HCV infection posttransplantation as it appears to be in the nontransplantation setting.¹³ 4) Serum ALT levels are a poor indicator of the histological disease severity, a characteristic already observed in immunocompetent patients. This further emphasizes the importance of performing protocol liver biopsies in the follow-up of patients with posttransplantation HCV infection. 5) Fibrosis develops in almost two thirds of HCV-infected recipients (64%), with a high incidence of cirrhosis (15%) within the first 5 years after surgery. The cumulative probability of developing graft cirrhosis increases over time and in our series reached 28% at 4 and 5 years following transplantation. The burden of HCV-cirrhosis is likely to increase in the future, because an additional percentage of patients (17%) were found to have advanced stages of fibrosis in their most recent biopsy.

As expected, graft cirrhosis was associated with a bad short-term prognosis, with 7 of 12 cirrhotic patients developing liver failure shortly after the diagnosis. While 3 died waiting for a second transplantation, 1 died immediately after retransplantation, probably as a result of the marked clinical deterioration at the time of retransplantation. As the proportion of patients who develop graft cirrhosis and eventually liver failure increases with longer follow-up, retransplantation may represent an ethical dilemma, given current limitations in organ supply.

Variables that determine why some patients are more susceptible than others to liver damage are currently being evaluated, but it is likely that several interrelated factors play a role. Predictors of disease severity include viral factors such as HCV genotype. As in immunocompetent patients, viral genotype 1b has been associated with a severe outcome following liver transplantation, but reports are conflicting. In general, European studies^5,11 have found an association between genotype 1b and a more aggressive HCV disease after transplantation, while most American studies^20,21 have failed to find such an association. Although several reasons may account for the differences observed, it is likely that the association found in European series may be a reflection of the higher prevalence of genotype 1b. Because of the overwhelming preponderance of genotype 1b, we did not analyze its effect on the outcome of HCV infection comparing it to other genotypes.

Recently, interest has been focused on the role of immunosuppression, both the amount and the type of administered immunosuppression, as possible predictors of disease severity. Although no clear relationship exists between severity of HCV recurrence and the type of immunosuppression used, quantitative immunosuppression appears to play a role. In most studies, recurrent hepatitis C is more frequent in patients who have multiple episodes of allograft rejection.⁸ The relationship between rejection and severity of posttransplantation hepatitis C is, however, less evident with discrepant results between studies.^8,22 Reasons that may explain discrepancies include differences in genotype distribution and differences in the means by which disease severity is assessed, with very few studies using histological criteria uniformly in all patients evaluated. We found that in genotype 1b-infected patients, there was an association between the presence, severity, and number of rejection episodes within the first year posttransplantation and the development of cirrhosis in the first 4 to 5 years following transplantation. The reasons that may explain that association are currently unclear, but may include: 1) increased HCV viremia caused by immunosuppresion²³; 2) generalized up-regulation of the immune system by rejection episodes so that recognition of viral antigens as well as HLA antigens is enhanced; and 3) an overlap of histological findings between cellular rejection and recurrent hepatitis C. Our rigorous biopsy protocol and blinded histological review allowed us to use consistent criteria and, to some extent, to minimize the latter possibility. In addition, in doubtful cases, additional biopsies were subsequently performed. However, the histological differentiation between recurrent hepatitis C and rejection is sometimes difficult to establish, particularly when graft dysfunction occurs after the first post-OLT month. In these cases, we now usually adopt an expectant approach and avoid using methylprednisolone boluses.

Early identification of patients at risk for developing severe posttransplantation HCV-related liver disease may allow for better patient management following transplantation, including early institution of antiviral therapy and rationale changes in immunosuppression. Unfortunately, and in contrast to hepatitis B, variables that predict histological severity of posttransplantation hepatitis C are lacking. We found that the histological findings in the first-year liver biopsy, including the degree of activity and the fibrosis score, were helpful in differentiating patients who eventually developed HCV-related graft cirrhosis from those who did not. The applicability of first-year liver biopsy findings to other populations of HCV-infected patients must be investigated in future studies. If, as it has been previously reported, the incidence of HCV-related graft cirrhosis is not as high in populations infected with other genotypes, then the predictive value of first-year liver biopsies may be considerably lower in these populations. Although additional longitudinal prospective studies should confirm these results, important implications may be drawn in an era in which protocol liver biopsies have been abandoned by some centers and their usefulness has been questioned. Treatment of recurrent hepatitis C has met with limited success when either interferon²⁴ or ribavirin²⁵ were used as single agents. Preliminary results of combination therapy are encouraging, mainly in patients treated early in the course of the disease.²⁶ Protocol liver biopsies not only may help in predicting the future course of the disease, but may also allow for early detection of histological recurrence, when therapeutic agents can achieve best results. In addition, first-year liver serum transaminase levels were also found to be helpful in predicting the development of graft cirrhosis.

In conclusion, we found that HCV infection posttransplantation is associated with a high rate of graft cirrhosis in the first 4 to 5 years posttransplantation, especially in those patients infected with genotype 1b who have rejection episodes. The development of graft cirrhosis is accompanied by a decreased survival of this population. Finally, first-year protocol liver biopsies may help to identify patients with a more severe HCV-related liver disease posttransplantation, allowing for early intervention and better patient management.

Abbreviations

Abbreviations: HCV, hepatitis C virus; OLT, orthotopic liver transplantation; HCC, hepatocellular carcinoma; HAI, histological activity index; ALT, alanine transaminase.

Footnotes

Received June 10, 1998; accepted August 26, 1998.

Presented in part at the AASLD meeting, November 1997, Chicago, IL.

Address reprint requests to: Martín Prieto, Servicio de HepatoGastroenterología, Hospital Universitario La Fe, Avenida Campanar, 21, 46009 Valencia, Spain. E-mail: mprieto@iname.com; fax: (34) 96-3987333.

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Copyright © 1999 by the American Association for the Study of Liver Diseases.

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