Hepatitis C After Liver Transplantation

• ABSTRACT
• RECURRENCE RATE OF HEPATITIS C
• NATURAL HISTORY AND SEVERITY OF RECURRENCE
• RISK FACTORS FOR RECURRENCE
• Immunosuppression
• IMMUNOSUPPRESSIVE AGENTS
• Viral Levels
• Viral Genotype
• TREATMENT OF RECURRENT HEPATITIS
• PROPHYLAXIS
• RETRANSPLANT FOR RECURRENT DISEASE
• SUMMARY
• ABBREVIATIONS
• REFERENCES

ABSTRACT

Hepatitis C is the most common cause of end-stage liver disease leading to liver transplant. The disease can recur after transplant, resulting in clinical hepatitis in up to 75% of patients and severe disease in approximately 7%. Treatment of rejection with steroid boluses and treatment of steroid-resistant rejection with OKT3 have both been shown to increase the incidence of recurrent hepatitis C. The use of OKT3 for steroid-resistant rejection is reportedly associated with more severe recurrence. The calcineurin inhibitors tacrolimus and cyclosporine have not been conclusively associated with different rates or severity of recurrence. Viral levels rise 10- to 15-fold after transplant and appear to be associated with the use of immunosuppression. Studies suggest that high viral levels, either pretransplant or early after transplant, may be associated with severe recurrent disease. Although the role of genotype is still unclear, genotype 1b is known to be associated with a poorer prognosis in nontransplanted patients and a lesser response to treatment than other genotypes. Furthermore, some reports suggest that after transplant, recurrent disease may progress more rapidly in patients with genotype 1. Treatment options after recurrence remain poor. Neither interferon nor ribavirin alone provides any true benefit. Combination therapy appears to have a better short-term outcome but may be poorly tolerated, and long-term benefits are unknown. Prophylaxis with combination therapy may be a better option but requires further study. Finally, retransplantation for recurrent hepatitis C is complicated not by rapid recurrence of disease in the new allograft but by high perioperative mortality that may be predicted by the presence of renal failure or sepsis preretransplant.

Hepatitis C virus (HCV) is now the major cause of end-stage liver disease leading to transplantation. According to United Network for Organ Sharing (UNOS) data, between 1987 and 1993, 2,378 transplants were performed for HCV or for HCV in combination with alcoholic liver disease; between 1994 and 1998, 3,883 transplants were performed for the same indication.[1]

It is now well known that hepatitis C recurs in the new liver.[2] Although most studies have yet to show a difference in survival between patients transplanted for hepatitis C and those transplanted for other diseases,[1] [3] recurrent disease is a major source of morbidity and mortality after transplant.[4] [5]

RECURRENCE RATE OF HEPATITIS C

In 1991, Martin et al.[6] were the first to describe recurrence in six patients who had undergone transplantation for hepatitis C. Five remained HCV antibody positive, three had biopsy-proven hepatitis, and one died a year posttransplant of recurrence, after receiving a second transplant for recurrent disease. Since then, sensitive tests such as polymerase chain reaction have revealed that HCV is present after transplant in virtually all patients transplanted for hepatitis C. In one of the earliest studies using these tests, Wright et al.[7] at UCSF followed 41 patients who were either HCV RNA (+) or anti-HCV(+) before liver transplant. Posttransplant, 39 (95%) were viremic and 41% had hepatitis. Quantitative studies such as the Chiron branched-chain DNA assay show that viral levels tend to run 10- to 20-fold higher posttransplant compared with pretransplant.[8]

Clinical hepatitis, defined as the presence of lobular inflammation and necroinflammatory lesions, develops in up to 75% of patients posttransplant.[9] A more severe form of hepatitis-fibrosing cholestatic hepatitis-occurs in approximately 7% of patients after orthotopic liver transplantation (OLT).[10]

NATURAL HISTORY AND SEVERITY OF RECURRENCE

Initially, early reports suggested that recurrent hepatitis C was mild[11] and would follow the indolent course of disease seen in patients with chronic hepatitis C pretransplant.[12] It is becoming increasingly clear, however, that in contrast to the slow course of hepatitis C pretransplant, recurrent disease can progress rapidly over the course of just a year. Greenson et al.,[9] for example, analyzed 81 liver biopsies from 19 patients, 14 of whom developed hepatitis. When the biopsies were separated into three groups-no hepatitis, acute lobular hepatitis, and chronic hepatitis-there was a definite correlation between biopsy findings and interval since transplant. Biopsies without hepatitis were seen early posttransplant (usually in the first 30 days), whereas biopsies showing acute lobular hepatitis and chronic hepatitis were noted at averages of 135 and 356 days, respectively.

Not only is recurrence common, but it can be severe as well. There appear to be two types of severe recurrent hepatitis C: end-stage liver disease from cirrhosis and fibrosing cholestatic hepatitis, with fibrosis and cirrhosis developing within a short time after transplant. Johnson et al.[4] reported on 67 patients who had undergone transplant for hepatitis C. At a mean follow-up of only 22 months, 56% had developed clinical hepatitis, 29% had developed fibrosis or cirrhosis, and 4 had required retransplantation for hepatitis C. Gane et al.[5] noted cirrhosis in 10 of 130 (5.4%) patients at a median of 51 months posttransplant. Five developed liver failure and either underwent retransplantation or died. In a study of 96 patients transplanted for hepatitis C at the Mount Sinai Medical Center, we found clinical recurrence in 43; 7 of the 43 required retransplant and 1 patient died of recurrent hepatitis C.[13] In a later report, we described fibrosing cholestatic hepatitis, which had previously been reported in association with recurrent hepatitis B,[14] [15] in 10 of 135 patients (7.4%) transplanted for hepatitis C.[10] In all cases, fibrosing cholestatic hepatitis led to retransplant or death. Others have reported similar poor outcomes in patients with recurrent hepatitis C and fibrosing cholestatic hepatitis.[16]

RISK FACTORS FOR RECURRENCE

Immunosuppression

It is becoming increasingly clear that immunosuppression, especially steroids, plays a role in the recurrence of hepatitis C. In a controlled trial in patients with non-A, non-B hepatitis who had not undergone transplant, progression of liver disease was significantly greater in patients treated with steroids compared with untreated patients.[17] In nontransplanted patients with chronic hepatitis C, steroid administration has been shown to result in a 5- to 10-fold increase in HCV RNA levels during treatment.[18] [19] In another study, HCV RNA levels in patients with both HCV and HIV were higher than in HCV(+) patients who were HIV(-).[20]

Augmented immunosuppression for treatment of rejection has been shown to be a particular risk factor for recurrence. In 96 patients who underwent transplant for hepatitis C, we noted recurrence in 43.[13] Recurrence and number of rejection episodes were clearly associated: 6 of 33 (18.2%) with no rejection had recurrence, versus 11 of 26 (42.3%) with one rejection episode and 26 of 37 (70.2%) with more than one episode. Fifteen of 21 patients (71.4%) who required OKT3 for steroid-resistant rejection (SRR) had recurrence, versus 28 of 75 (37.3%) who either had no SRR or developed it after recurrence was diagnosed. Furthermore, patients who had SRR recurred earlier (127 ± 31 days) than those who recurred but did not have SRR (246 ± 42 days). Others have reported similar findings. Rosen et al.[21] compared 19 patients who received OKT3 for SRR to 33 matched controls who received steroids alone for rejection. Patients receiving OKT3 had a higher recurrence rate (84.2% versus 51.5%) and a shorter interval to diagnosis of recurrence. Additionally, on long-term follow-up, 26.3% of patients who received OKT3 for SRR developed cirrhosis versus 6% of patients who received steroids alone.

Rejection episodes have also been associated with severe recurrence leading to cirrhosis. Prieto et al.[22] reported on 81 HCV(+) liver recipients followed for an average of 32 months. All underwent yearly biopsies. At time of last biopsy, 97% of patients had hepatitis; 12 had developed cirrhosis at a median of 24 months (range, 12-48) and 7 had evidence of liver failure. The actuarial rate of cirrhosis was 28% at 4 years. Rejection was significantly more common among patients with cirrhosis than among those without (83% versus 48%). Rates of cirrhosis were 5% in patients with no rejection, 15% in patients with one rejection episode, and 50% in those with two episodes. Similarly, on 2-year protocol biopsies performed in 63 transplant recipients with HCV genotype 1b, Berenguer et al.[23] noted that rejection, treatment for rejection, and a trend toward higher cumulative steroid and azathioprine doses were correlated with the presence of chronic active hepatitis. In the report from the NIDDK liver transplantation database, acute rejection and SRR each increased the risk for mortality after transplantation for hepatitis C. Similar effects were not seen in patients transplanted for other diseases, such as primary sclerosing cholangitis (PSC) or primary biliary cirrhosis (PBC).[24]

An alternative view-that hepatitis C infection promotes rejection rather than vice versa-must also be considered. Viral infection, such as with cytomegalovirus, may upregulate the immune system, and there are reported associations between cytomegalovirus infection and acute and chronic rejection.[25] [26] Farges et al.[27] studied the incidence of rejection among patients transplanted for different etiologies and noted a lower rejection rate in patients transplanted for alcoholic liver disease but no difference in rejection rates between patients transplanted for hepatitis C and other nonalcoholic diseases. We[13] reported, as did Singh et al.,[28] that overall incidences of rejection and SRR did not differ between patients transplanted for hepatitis C and those transplanted for primary biliary cirrhosis or primary sclerosing cholangitis. There have, however, been reports of chronic rejection associated with hepatitis C (unrelated to interferon use). Loinaz et al.[29] reported a 24% incidence of chronic rejection in patients transplanted for hepatitis C versus 10.3% in patients transplanted for other diseases. Similarly, Hoffmann et al.[30] reported a 23% (4/17) incidence of ductopenic rejection in patients transplanted for hepatitis C compared with patients transplanted for other diseases (6/103, 5.3%).

IMMUNOSUPPRESSIVE AGENTS

Although it is clear that steroids play an important role in recurrence of hepatitis C, little is known about the impact of other immunosuppressive agents, such as tacrolimus and cyclosporine. When cyclosporine was used to treat chronic hepatitis C in nontransplanted patients, there was a decrease in alanine transferase (ALT), but more importantly, however, viral levels did not change during treatment, which suggests that the role of cyclosporine in recurrence is not as important as that of steroids.[31] Nevertheless, whether one interleukin-2 blocker is better than the other in patients with hepatitis C is still largely unknown. It is also unclear whether primary induction immunosuppression plays a role in recurrent hepatitis C. Early studies suggested some advantage of one agent over the other, but none were randomized and all were small series. In our series of 96 patients, recurrence was more rapid in the small group of nine patients who received tacrolimus for primary immunosuppression. We also noted that OKT3 induction delayed the diagnosis of recurrent disease, presumably via a decrease in the incidence of early or severe rejection.[13] In a more recent study,[32] no advantage was seen with OKT3 induction. Johnson et al.[4] followed 74 patients transplanted for HCV, 67 of whom survived more than 2 months. Of these, 56% developed clinical hepatitis, 29% developed fibrosis or cirrhosis, and 5.9% were retransplanted for recurrent hepatitis C. There was no difference in recurrence rates among patients treated with cyclosporine, tacrolimus, or OKT3, but disease was more severe in tacrolimus-treated patients. These patients, however, had been given tacrolimus for rescue from rejection; they had received high levels of immunosuppression and previous treatment for rejection. Flamm et al.,[33] in a small retrospective study, analyzed data on 32 patients transplanted for hepatitis C, 22 of whom received cyclosporine and 10 of whom received tacrolimus. Survival was significantly lower among patients treated with tacrolimus. Casavilla et al.[34] also reported a significant decrease in 2- and 3-year survival in patients transplanted for hepatitis C under a tacrolimus regimen. More recently, this same group noted that with reduction of standard tacrolimus dosing, survival after transplantation for hepatitis C is similar to that after transplantation for other diseases.[35] Lake et al.[36] presented 5-year survival data on 113 patients transplanted for hepatitis C within the U.S. FK506 multicenter trial. Survival was significantly worse among patients randomized to receive cyclosporine.

Others, however, have found no effect of cyclosporine or tacrolimus on either the risk of recurrence or on survival. In one of the few randomized trials to compare tacrolimus with microemulsion cyclosporine (Neoral) for primary immunosuppression after transplantation for hepatitis C, Zervos et al.[37] found more rejection episodes in the Neoral group but no difference in recurrence rate between the groups. In an analysis of data from the NIDDK liver transplant database, Charlton et al.[24] reported no difference in outcome in patients transplanted for hepatitis C according to primary immunosuppression regimen. In another large series, Ghobrial et al.[38] also found no difference in patient or graft survival between patients treated primarily with either tacrolimus or cyclosporine.

The effects of the newer immunosuppressive agents, such as mycophenolate mofetil (MMF) or rapamycin, on hepatitis C are still unknown. In vitro, MMF has been reported to have antiviral effects.[39] Few clinical studies have looked at the effect of MMF on hepatitis C posttransplant. In a small series of six patients placed on MMF after the diagnosis of recurrent disease, Platz et al.[40] noted a reduction in HCV RNA levels on therapy. Paterson et al.[41] reported no difference in the incidence of infection, including infection with HCV, in patients placed on MMF versus patients receiving non-MMF immunosuppression. There is little clinical information on the effects of new agents such as rapamycin, daclizumab, and Simulect on the recurrence of hepatitis C. Whether prevention of acute rejection (perhaps allowing for early steroid withdrawal) will be of benefit will only be determined with longer follow-up.

Viral Levels

Viral levels rise dramatically posttransplant, but the role of pre- and posttransplant viral levels in predicting recurrence or severity of recurrence remains to be clarified. Chazouilleres et al.[42] analyzed viral levels before and after transplant and found that post-OLT levels were 16-fold higher than pretransplant and that patients with higher levels pretransplant tended to have higher levels posttransplant. Interestingly, there was no correlation between recurrence or severity of recurrence and viral levels. In another study, Freeman et al.[43] followed 28 patients for a mean of 22 months after transplant and found that in 75%, viral levels rose post-OLT-but again, there was no clear correlation between recurrence and viral levels.

More recent data, however, suggest that viral levels, especially pre- or early posttransplant, may be an important prognostic factor. In the report by Charlton et al.[44] on data from the NIDDK liver transplant database, patients transplanted for hepatitis C with higher pretransplant viral levels had much lower 5-year survival (57%) than those with low pretransplant levels (85%). Similarly, Doughty et al.[45] found that patients who developed fibrosing cholestatic hepatitis were more likely to have had high pretransplant viral levels.

Others, including ourselves, have found that pretransplant levels do not predict severe recurrence but that high viral levels early after transplant may have prognostic significance. In 19 patients, we found that only 1 had a negative viral level at 1-year posttransplant.[32] Pretransplant viral level did not predict recurrence in this study, but viral level at 1 month after transplant was an independent predictor of recurrence. Gane et al.[46] reported that viral levels rose 4- to 100-fold after steroid treatment of rejection; furthermore, they observed higher RNA levels in patients with acute hepatitis, with the highest levels in patients with more severe hepatitis. In a study by Berg et al.[47] of 79 patients, 40 (51%) developed recurrent hepatitis and 7 (9%) developed cirrhosis-but neither pre- nor posttransplant HCV RNA level was significantly associated with graft hepatitis. Among patients infected with subtype 1b, however, Berg's group noted a trend toward more severe recurrence in those with high viral levels early after transplant. Moll et al.[48] reported that patients with higher viral levels in the first 60 days post-OLT were more likely to develop complications of recurrent hepatitis C than those with low viral levels during that period.

Viral Genotype

In patients with chronic hepatitis C, pretransplant genotype 1b is associated with a poorer prognosis and a lesser response to treatment.[49] [50] [51] The impact of genotype on posttransplant outcome is less clear. Studies differ in terms of diagnostic criteria for severe recurrence, length of follow-up, and end points.

Initially, many studies found a relationship between genotype 1b and severity of liver disease posttransplant. Feray et al.[52] followed 60 hepatitis C(+) liver recipients, among whom the predominant genotype was 1b. Actuarial rates of acute and chronic hepatitis at 3 years were significantly higher in transplant recipients with genotype 1b (77% and 59%, respectively, versus 40% and 22%, respectively, in recipients with other genotypes). Similarly, Gordon et al.[53] noted that although recurrence rates did not differ between genotype 1b patients and non-1b patients, hepatic activity index (HAI) scores and histologic stage were higher in genotype 1b patients. Furthermore, 35% of genotype 1b patients developed cirrhosis, compared to only 8% of patients with other genotypes.

Genotype 1a has also been reported to be associated with more severe disease. Pageaux et al.[54] reported higher HCV RNA levels and more severe recurrence in patients with genotype 1 (1a and 1b). In our report on 14 patients who underwent retransplant for severe recurrent disease, all seven patients on whom genotyping was performed were genotype 1a.[55]

There are, however, a number of reports to suggest that genotype has no effect on either rate or severity of recurrence. Zhou et al.[56] followed 112 patients who were genotyped after transplant; the most predominant genotypes were 1b (32.2%) and 1a (27.3%). After a mean follow-up of 25 months (range, 1-75), there was no difference in level of viremia, ALT, aspartate aminotransferase (AST), bilirubin, or total histologic score between patients with genotype 1b versus others or genotype 1 versus all nongenotype 1 recipients. Furthermore, there was no difference in graft or patient survival at 3 years between genotypes.

Newer studies have questioned the role of genotype. Vargas et al.[57] examined the influence of genotype on recurrence of hepatitis and progression to cirrhosis after transplant in 150 patients with known genotype. After a mean of 874 days (range, 40-1,800), there was no difference in recurrence rates, survival, HAI index, or progression to cirrhosis. Similarly, in the report by Charlton et al.[44] on data from the NIDDK liver transplant database, genotype was not found to be a predictor of patient or graft survival. Longer follow-up and more multicenter studies may help elucidate the role of genotype in determining outcome after liver transplant.

TREATMENT OF RECURRENT HEPATITIS

When hepatitis C was found to recur after transplant, there were many initial reports of treatment with interferon-most with poor results. Wright et al.[58] administered interferon to 11 patients with recurrent hepatitis C, but only 1 patient responded with normalization of liver function tests (LFTs). Wright et al.[59] reported on 18 patients treated with 3 million units interferon-α subcutaneously tiw for at least 4 months. Five responded with normalizing LFTs. Similar to experience with nontransplant patients,[60] [61] responders had lower pretreatment viral and bilirubin levels than nonresponders.

Unfortunately, given the varying natural history of patients with hepatitis C and in the absence of a large randomized trial, it is difficult to ascribe any long-term benefit to treatment with interferon. Furthermore, an important potential side effect of interferon is an increase in the risk of rejection (secondary to upregulation of the immune system). Feray et al.[62] reported on 14 patients treated for recurrent disease with interferon-α at 3 million units tiw. Patients were started on therapy late after transplant, at a mean of 31 months. Five patients developed chronic rejection, compared with 1 of 32 patients who were not treated with interferon. Although the concern about chronic rejection is important, others-including Jain et al.,[63] who compared 105 patients who received interferon therapy to 132 patients who did not-have noted no difference in rejection rate or rate of chronic rejection with interferon treatment.

Ribavirin, a synthetic nucleotide with antiviral activity, has also been used against recurrent hepatitis C. Cattral et al.[64] treated 18 patients with ribavirin monotherapy. Initially, all responded with improvement in ALT; in five patients, ALT normalized. HCV RNA levels did not change during treatment, and repeat biopsy showed worsening of fibrosis in 12 patients and cirrhosis in 5. Gane et al.[65] randomized 30 patients to monotherapy for 24 months with either interferon or ribavirin. Groups were similar in age, gender, time from transplant to diagnosis of hepatitis C recurrence, or initiation of treatment. Sixteen patients received ribavirin (either 500 or 600 mg po bid, depending on body size; patients less than 70 kg received the lower dose). Ribavirin-treated patients were more likely to normalize ALT than interferon-treated patients (13/16 versus 6/14) but were less likely to have undetectable serum levels of HCV RNA (0/16 versus 5/14). Both groups, however, had either no change on liver biopsy or an increase in fibrosis, suggesting that therapy was ineffective. Both groups experienced side effects. Eight of 16 patients on ribavirin required dose reduction for hemolysis and 4 required drug discontinuation. Three patients on interferon required dose reduction for leukopenia.

Given that neither drug alone is effective against recurrent hepatitis C, combination therapy has been attempted. Bizollan et al.[66] treated 21 patients with a combination of interferon-α, 3 million units tiw, and oral ribavirin (dosage depending on body weight) for 6 months followed by ribavirin monotherapy for 6 months. The interval from transplant to initiation of antiviral treatment ranged from 3 to 24 months (mean, 9 months). Mean ALT at initiation of therapy was 233 ± 199; the mean bilirubin level was normal (1.2 ± 0.3). Twenty of the 21 patients were genotype 1b. After the first 6 months of therapy, ALT levels had normalized in all 21. Furthermore, 10 patients had undetectable HCV RNA levels, and the others had levels less than 50% of baseline. During monotherapy, one relapsed biochemically on treatment. Three patients did not tolerate ribavirin due to anemia (all had biochemical relapse). Of the 10 patients with negative RNA levels, 5 became HCV RNA positive on monotherapy with no increase in ALT. Before treatment, patients' mean HAI score was 6.3 ± 2; at 12 months after treatment, the mean score was 3 ± 1. Although this is an early treatment study with short follow-up, the results suggest that combination therapy with interferon/ribavirin is more effective than monotherapy. The finding that half the people who lost their RNA while on combination treatment became positive again on monotherapy raises the question of whether combination therapy for longer periods would be a more optimal treatment.

Most patients in Bizollon's study, however, had normal bilirubin levels when treatment began. Interferon alone has been shown to be less effective when pretreatment bilirubin is high. Whether treatment would be effective in patients with abnormal bilirubin is unclear. At Mount Sinai, we placed 15 patients with recurrent HCV (mean age, 51.4 years; r, 20-73; 4 females, 11 males) on a 12-month course of interferon/ribavirin. The mean time from OLT to start of interferon/ribavirin was 403 days (range, 30-1,055). In eight patients, interferon/ribavirin was discontinued at a mean of 46 days (range, 23-96) for adverse effects: anemia (n = 2), leukopenia (n = 3), and fatigue with weakness and nausea (n = 3). One of these eight required re-OLT for recurrent disease. Of the seven patients who tolerated treatment, one required re-OLT for disease progression. Three patients completed a year of treatment. Of the three who are still receiving interferon/ribavirin, one has been treated for less than 30 days and the other two have been treated for 98 and 265 days. Overall, the mean length of treatment for the three who completed the course and the two who remain in the protocol and have been treated for at least 30 days is 311 days. In these five patients, LFTs did not significantly differ from baseline at 3 months but were significantly different for ALT (291 ± 215 versus 54 ± 34; p = 0.05) and AST (275 ± 170 versus 57 ± 20; p = 0.05) at last follow-up. All five treated patients had reductions in transaminases and bilirubin. Two patients with baseline bilirubin levels above 5.0 remained in therapy for more than 1 year, with decreases in bilirubin level from 7.5 to 2.4 and 17.2 to 3.9. Patients who withdrew from therapy early had no statistically significant difference in AST or ALT from baseline, at a mean of 193 days after withdrawal. Only two patients became HCV RNA negative while on therapy. Overall, interferon/ribavirin was poorly tolerated, with fewer than half the patients able to stay on therapy. However, despite disease progression in one patient while on therapy, there appeared to be a biochemical response in those who tolerated treatment. Once again, the long-term outcome is still unknown in this small group of patients.

PROPHYLAXIS

Given that the long-term effectiveness of treatment, even with combinations of drugs, is still unproved, prophylaxis of posttransplant recurrence is a particularly important focus of research. At Mount Sinai, we conducted a randomized trial to determine whether administration of interferon-α2b after liver transplant would prevent or delay recurrence of hepatitis C and whether viral load affected response to therapy.[32] Because interferon/ribavirin appears to work best when pretreatment viral levels are low[59] and because in most liver recipients viral levels are lowest early after transplant, we initiated the drug within the first 2 weeks after transplant. Treatment was continued for a year in the absence of indications to discontinue. Thirty patients were randomized to interferon, 3 million units tiw; 41 patients received no treatment. Clinical features at study entry were similar between groups. Mean follow-up was 628 ± 264 days (range, 168-1,040) in interferon/ribavirin patients and 594 ± 266 days (range, 204-1,064) in no-interferon/ribavirin patients. All patients received protocol immunosuppression, including OKT3 induction immunotherapy followed by triple immunosuppression with cyclosporine, azathioprine, and steroids. Patients were converted to tacrolimus for recurrent or severe rejection or for side effects of cyclosporine. We found that patients treated with interferon were less likely to develop recurrent hepatitis than patients who were not treated. Eight interferon/ribavirin patients recurred at 194 ± 168 days (range, 69 - 496) versus 22 no-interferon/ribavirin patients at 220 ± 144 days (range, 45-830) (p = 0.02, log-rank test).

Viral level at 1 month was important in predicting both recurrence and response to interferon. One-month viral level was an independent predictor of recurrence. An HCV RNA level >100 × 10⁵ Eq/mL at 1 month increased the risk by a factor of 3.1 (p = 0.01). Although the use of interferon/ribavirin overall reduced the risk of recurrence by a factor of 0.4 (p = 0.04, Cox proportional hazards model), recurrence rates differed significantly depending on 1- and 3-month viral levels. Low, moderate, and high viral levels at 1 and 3 months were associated with significantly different recurrence rates in interferon/ribavirin patients, with significantly less recurrence in patients on interferon/ribavirin with low viral levels. In the untreated patients, high viral levels at 1 month were associated with high recurrence rates compared with patients with lower viral levels, but the difference did not achieve statistical significance.

Unfortunately, despite the decreased incidence of recurrent hepatitis in patients treated with interferon, we were unable to prevent fibrosing cholestatic hepatitis. Two patients in the treated group underwent retransplant for fibrosing cholestatic hepatitis, compared with two in the untreated group. This outcome suggests that interferon alone, even given as prophylaxis, will not solve the issue of severe recurrent hepatitis C. In a smaller study, Singh et al.[67] compared the incidence of recurrent hepatitis and severity of recurrence in 12 patients treated with prophylactic interferon and 12 patients not treated; they found no difference between the two groups in incidence or severity but found that time to recurrence was delayed.

Combination therapy with interferon and ribavirin has also been studied for prophylaxis. In a nonrandomized trial, Mazzaferro et al.[68] placed 21 patients on interferon and ribavirin within 2 weeks after transplant. Twenty patients were available for follow-up at a median of 12 months. Four had developed biopsy-proven hepatitis, and one had developed chronic active hepatitis. No patient developed cirrhosis-although median follow-up was too short to be able to draw conclusions. More importantly, HCV RNA was negative in nine patients (41%). Side effects were seen in nine patients, usually hemolysis or malaise.

RETRANSPLANT FOR RECURRENT DISEASE

It is now recognized that recurrence can result in either fibrosing cholestatic hepatitis or cirrhosis requiring retransplant. Two major concerns regarding retransplant are as follows: What is to prevent the new liver from developing the same progressive disease? Do the results of retransplantation justify these procedures, given the organ shortage?

There are few reports about retransplantation for recurrent hepatitis C. Rosen et al.[69] found no difference in survival according to etiology of graft failure. On the other hand, Feray et al.[70] found that prognosis after re-OLT was poor in patients retransplanted for recurrent hepatitis C. At Mount Sinai, in 14 patients who underwent retransplantation for recurrent hepatitis C, we noted high perioperative mortality associated with renal failure and infectious complications.[55] More recently, we reported predictors of survival after late retransplant (>6 months after initial OLT).[71] We noted that patients retransplanted for recurrent hepatitis C had poorer survival (90-day survival, 57%; 1-year survival, 43%) compared with patients retransplanted for all other indications (90-day survival, 81%; 1-year survival, 74%). This difference in survival, however, did not reach statistical significance (p = 0.09), most likely due to the small number of patients. A preoperative creatinine level >2 mg/dL predicted poor survival, and the use of all intraoperative blood products (packed red blood cells, fresh frozen plasma, and platelets) correlated strongly with outcome. Previous studies have reported an increased incidence of infections in liver transplant recipients with recurrent hepatitis C.[72] In our patients who underwent re-OLT for hepatitis C compared with patients who underwent retransplantation for other disease, however, there was no significantly higher rate of infection to explain the lower survival. The difference in survival is also not explained by recurrent disease after re-OLT, as graft failure secondary to rerecurrence of hepatitis C was seen in only 9.5% of our patients retransplanted for this indication. The high mortality associated with re-OLT for recurrent hepatitis C may reflect poor patient selection and a failure to recognize predictors of poor prognosis.

SUMMARY

Hepatitis C remains a challenge for transplant surgeons and physicians. Despite our increasing understanding of the ways in which host and immune factors affect the outcome of patients transplanted for hepatitis C, we are still unable to predict the development of severe disease after transplant in individual patients. Treatment options remain poor, with major side effects and no proven long-term efficacy. Prophylaxis with combination therapy may offer some advantages over treatment, but many patients may not tolerate therapy. Retransplantation, now being increasingly performed in patients with recurrent disease, still has a high mortality rate. New more effective antiviral agents and a better understanding of the role of immunosuppression may help reduce the incidence and severity of recurrent hepatitis C after liver transplant.

ABBREVIATIONS

ALT alanine transferase

AST aspartate aminotransferase

HAI hepatic activity index

HCV hepatitis C virus

LFT liver function test

MMF mycophenolate mafetil

OLT orthotopic liver transplantation

PBC primary biliary cirrhosis

PSC primary sclerosing cholangitis

SRR steroid-resistant rejection

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