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Clinical Transplantation

INTERFERON-α AND RIBAVIRIN FOR THE TREATMENT OF RECURRENT HEPATITIS C AFTER LIVER TRANSPLANTATION1

de Vera, Michael E.2,3; Smallwood, Gregory A.3; Rosado, Kathia4; Davis, Laurel3; Martinez, Enrique5; Sharma, Shobha4; Stieber, Andrei C.3 and; Heffron, Thomas G.3

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Abstract

It has been estimated that up to 4 million people in the United States are infected with the hepatitis C virus (HCV) (1). Chronic liver disease develops in 85% of these persons, and 20% ultimately progress to end-stage liver disease. Currently, cirrhosis due to HCV infection is the leading indication for liver transplantation (LT) in the United States (2). Although LT for HCV cirrhosis is life-saving, the virus is never eradicated and chronic infection inevitably occurs after the transplant. Recurrent disease is usually mild and asymptomatic, but in 5–10% of cases, a more aggressive form of cholestatic recurrence that quickly leads to allograft failure may be seen (3–6). Interferon-α was first used in the early 1990s to combat HCV reinfection in LT recipients (7–8). Results were marginal because only 10–20% of patients achieved biochemical and virological responses. The combination of the purine nucleoside analog, ribavirin with interferon-α, seemed to be more promising, improving response rates to 40% in some cases (9–12). Here we report the results of an open-label, single-center prospective study looking at the efficacy and safety of interferon-α and ribavirin for the treatment of recurrent HCV infection in LT patients.

PATIENTS AND METHODS

Patients and immunosuppression.

Between May 1, 1989 and October 30, 2000, 151 patients underwent LT for HCV cirrhosis at Emory University Hospital. Age, gender, race, and blood groups were obtained from a database. Baseline immunosuppression consisted of tacrolimus or cyclosporine along with corticosteroids. Mycophenolate mofetil (MMF) was utilized in selected patients to decrease the toxic effects of calcineurin inhibitors or as a third agent for treatment of rejection. Beginning 1998, a single dose of the interleukin-2 receptor antagonist, daclizumab, was used in some patients on postoperative day 1 allowing us to withhold tacrolimus or cyclosporine for at least 7 days (13).

Diagnosis of recurrent HCV.

After LT, recurrent HCV infection was suspected whenever a rise in serum aminotransferases occurred (1.5 times the upper limit of normal). A liver biopsy confirmed recurrent HCV as well as ruled out acute cellular rejection. Hepatitis activity scores were graded by a transplant pathologist using Knodell’s classification (14). Other causes of hepatitis or biliary tract pathology were ruled out when necessary with appropriate studies. Serum qualitative HCV polymerase chain reaction (PCR) was performed (Roche Molecular Systems, Pleasanton, CA) and viral load was quantitated using a branched DNA signal amplification system (version 2.0; Bayer, Emeryville, CA), the Accuquant HCV PCR assay (performed by Specialty Labs, Santa Monica, CA), or the Amplicor Monitor HCV (version 2.0 assay; Roche Molecular Systems). All three assays have acceptable correlations and are reliable in predicting response to interferon-α and/or ribavirin therapy for chronic HCV infection (15–17). Recently, the first international standard for nucleic acid amplification technology for HCV RNA was established by the World Health Organization Collaborative Study Group (18). This standard is calibrated in international units and provides a basis for the quantitation and comparison of different HCV RNA assays. For standardization, viral load units were converted from genome equivalents/milliliter in the branched DNA assay to HCV RNA International Units (IU) by dividing the genome equivalents by 6.4 and from copies/milliliter in the PCR assays to HCV RNA IU by multiplying copies/milliliter by 0.72. These conversion factors were derived from information provided by the manufacturers and from parallel testing in our laboratory (Frederick Nolte, personal communications, Clinical Laboratories, Emory University Hospital, 2000). HCV genotype was determined using the reverse hybridization line probe assay (LiPA; Innogenetics, Ghent, Belgium).

Interferon-α/ribavirin treatment protocol.

Patients with recurrent HCV infection after LT as determined by a rise in serum aminotransferases, viremia, and histological evidence of hepatitis were treated for a minimum of 12 months. Patients who did not receive treatment included those with an absolute neutrophil count of less than 1,000, a platelet count of less than 50,000/μl, a hemoglobin of less than 8.5 g/dl, and a bilirubin over 5 mg/dl. Treatment was also withheld in patients whom we felt could not tolerate treatment based on their clinical status.

Interferon-α (Intron-A; Schering-Plough, Kenilworth, NJ) was initiated at 1.5 to 3 million units subcutaneously three times a week (t.i.w.). Patients started on 1.5 million units t.i.w. were increased to 3 million units t.i.w. as tolerated. Ribavirin (Rebetol; Schering-Plough) was administered at 400–1000 mg/day p.o. Lower doses were slowly escalated to a goal of 1000 mg/day as tolerated by patients. Six to ten thousand units of erythropoietin (Epogen; Amgen, Thousand Oaks, CA) and 5 μg/kg of granulocyte colony-stimulating factor (G-CSF) (Neupogen, Amgen, Thousand Oaks, CA) were administered for a hemoglobin less than 10 g/dl or a white blood cell count of less than 1200/μl, respectively. Those who experienced continued and severe adverse effects had their medications discontinued or the doses reduced appropriately. Liver function tests (total bilirubin, alanine aminotransferase [ALT], aspartate aminotransferase [AST], and gamma-glutaryl transferase [GGT]), serum chemistries, and a complete blood count were monitored weekly for the first month, then every month thereafter or when clinically indicated. HCV quantitative PCR was checked at 3, 6, 9, and 12 months in most patients, and a liver biopsy was performed when clinically indicated and after 1 year of treatment. Biochemical response (BR) was defined as normalization of serum aminotransferases, whereas virological response (VR) was defined as clearance of HCV RNA from serum. End-of-treatment response was defined as either a biochemical or virological response upon completion of treatment while sustained response was defined as a biochemical or virological response that was maintained at least 6 months after cessation of therapy.

Statistical analysis.

Categorical variables were analyzed by Fischer’s exact test. Continuous variables were presented as mean ± SE and were analyzed using two-tailed t test. P <0.05 was considered as significant. All analyses were performed using SPSS for Windows software.

RESULTS

Patient characteristics and immunosuppression.

Forty patients met the inclusion criteria and had received interferon-α and ribavirin after LT. Eight had less than 3 months of treatment and were excluded from this analysis. Table 1 shows the patient demographics of the remaining 32 patients we analyzed. The median time from LT to the first biopsy documenting HCV recurrence was 181 days (range, 30 to 1915 days), and follow-up ranged from 81 to 1049 days (median, 430 days) from the initiation of interferon-α and ribavirin therapy. The median survival was 846 days (range, 416 to 5409 days) after transplantation. Three patients died during the study, for an overall survival of 91%. Two deaths resulted from infectious complications directly related to allograft failure from recurrent HCV (aspergillus pneumonia and sepsis at 25 and 211 days after LT, respectively). Both patients developed cholestatic recurrence that progressed rapidly to liver failure 3–4 months after initiation of interferon-α and ribavirin therapy, at which time treatment was stopped. The patient who died from aspergillus pneumonia expired 3 weeks after his second LT. The third patient also expired from allograft failure from recurrent HCV 58 months after transplantation. One other patient in this series who had more than one transplant, is doing well 5 years after a third LT for de novo HCV that developed in her second allograft.

T1-19
Table 1:
Patient demographics

Two thirds of the patients received tacrolimus-based immunosuppression. Sixty-nine percent were receiving steroids and 56% were on MMF at the time of diagnosis of recurrent HCV. The majority of patients were weaned off steroids and MMF 3–4 months after initiation of therapy. Ten patients received a single dose of daclizumab the day after transplantation. Eleven patients experienced acute cellular rejection before the diagnosis of recurrent HCV. All episodes of rejection responded to steroid boluses with or without a standard taper and no patients required treatment with OKT3.

Completion of therapy and BR.

All thirty-two patients in this report have been on interferon-α and ribavirin for at least 3 months (Table 2). Twenty-four have received at least 6 months of therapy, including 13 patients who have been on treatment for 12 or more months (Fig. 1). Before the initiation of interferon-α and ribavirin therapy, the mean liver function test values were as follows: total bilirubin, 1.5±0.1; ALT, 194.9±34.5; AST, 158.3±19.5; and GGT, 552.7±102.2. After 3 months of therapy, 26 (81%) of 32 patients had normalization of their total bilirubin and serum aminotransferases (mean values: total bilirubin, 1.1±0.2; ALT, 39.9±2.9; AST, 43.6±2.6). GGT levels were significantly lower but remained elevated at 163.2±33.9. Of the six patients who did not respond biochemically after 3 months, patients 2 and 9 died from cholestatic recurrence and sepsis. Patient 21 had her treatment discontinued after she became markedly jaundiced; liver biopsy showed possible drug-induced hepatitis. An incidental bile duct stricture was treated with dilatation and a percutaneous transhepatic stent resulting in normalization of her liver function tests. The three other subjects (patients 10, 11, and 17) with persistently elevated serum aminotransferases are otherwise clinically asymptomatic. Aside from patient 21, three others (patients 14, 23, and 27) had severe side effects and were taken off treatment after 4.7, 3.0, and 3.1 months, respectively (Table 3). All are clinically stable at this time.

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Table 2:
Clinical status of patients receiving interferon-α and ribavirin
F1-19
Figure 1:
Disposition of patients receiving interferon-α and ribavirin.
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Table 3:
Characteristics of patients discontinued from therapy

To determine whether there were any clinical variables that could predict a BR, patient characteristics were assessed after 3 months of treatment (Table 4). Responders were younger than nonresponders (P =0.01). Race, gender, the ability of patients to tolerate interferon-α or ribavirin, the number of patients who reached target doses of either medication, genotype, pretreatment liver function tests, and pretreatment histological scores were similar in both groups. Nonresponders had significantly lower pretreatment viral loads as measured by serum quantitative HCV PCR (P =0.004). Neither primary immunosuppression (tacrolimus versus cyclosporine) nor the use of steroids or MMF alone seemed to make any difference in determining BR. However, patients who received daclizumab and both MMF daclizumab were more likely to be nonresponders after 3 months of therapy (P =0.05 and P =0.03, respectively).

T4-19
Table 4:
Clinical variables after 3 months of treatment

After 6 months of interferon-α and ribavirin, 15 (63%) of 24 patients had a BR. Of the 9 patients with persistently elevated serum aminotransferases, 3 had progressive allograft failure: patient 4 recently expired, whereas patients 6 and 18 both have developed moderate ascites and portal hypertension (patients 4 and 18 were taken off treatment, whereas patient 6 finished the 12-month course of therapy). Patients 10, 11, 17, and 28 continued to have elevated liver function tests but remained clinically asymptomatic, whereas patient 24 had a BR 11 months into the treatment course. All four patients with the exception of patient 11 had intolerable side effects warranting cessation of therapy. Patient 8 had a transient elevation of her serum aminotransferases after 6 months of therapy but at last check had normal liver function tests. Four other patients (patients 13, 19, 25, and 26) were prematurely taken off treatment after 6 months of therapy (Tables 2 and 3). All are clinically stable with the exception of patient 25 who developed posttransplant lymphoproliferative disease (PTLD).

Ten (77%) of 13 patients who received 12 or more months of interferon-α and ribavirin had a BR. One of the three patients who did not have a BR is currently clinically asymptomatic and continues on interferon-α and ribavirin (patient 11). Another subject has ascites and portal hypertension as described earlier (patient 6), whereas the third patient (patient 15) had a rise in his liver function tests 4 weeks after completing 12 months of treatment. Liver biopsy showed moderate acute cellular rejection and ongoing chronic hepatitis with portal/periportal fibrosis. His liver function tests normalized 8 weeks after he was treated with steroids and restarted on interferon-α and ribavirin. One other patient has been restarted on interferon-α and ribavirin (patient 1). This patient had an end-of-treatment (EOT) BR; however, his serum aminotransferases increased 5 months after stopping treatment and he also had persistent viremia as well as worsening of the hepatitis as demonstrated by liver biopsy. Eight patients are off treatment (Fig. 1) and six (75%) of them had an EOT response. Of the seven patients who had a follow-up of greater than 6 months after cessation of therapy (range, 6.2–23.7 months), 5 (71%) had a sustained BR. To date, all 13 patients who have received 12 months or more of interferon-α and ribavirin are doing well clinically with the exception of patient 6. Five of the 32 patients in the entire series have, therefore, progressed clinically to allograft failure and three of them have expired.

Analysis of the same clinical variables discussed previously revealed that after 1 year of treatment, patients who had been receiving MMF were more likely to be nonresponders (P =0.02, not shown). There were no other differences noted between responders and nonresponders with respect to age, race, gender, the ability to tolerate interferon-α and ribavirin, genotype, liver function tests, pretreatment histological scores, pretreatment viral loads, or immunosuppression (not shown).

VR to therapy.

Twenty-eight of 30 patients who had completed at least 3 months of interferon-α and ribavirin therapy had serum HCV RNA levels drawn at 3, 6, and/or 12 months of therapy (patients 2 and 9 did not have HCV RNA levels drawn after therapy was initiated). The overall mean viral load before initiation of therapy was 3,980,138±860,059 IU. Three months into the treatment course, a 77% decrease in mean viral load was obtained (Table 5). A similar degree of reduction in viremia was seen after 6 months (76%) and 12 months (68%) of treatment. One patient initially became serum HCV RNA negative at 3 months but became viremic again at 6 months. Two of the 13 patients (patients 3 and 8) treated for more than 1 year have a sustained VR (mean follow-up of 7 months after cessation of treatment). Another patient also cleared the virus despite receiving only 140 days of interferon-α and ribavirin (patient 14). She currently has a sustained VR 13 months after cessation of treatment. Overall, 3 patients (9%) are, therefore, serum HCV RNA negative and all have a sustained BR as well. These patients had similar pretreatment serum aminotransferases and mean viral loads compared with the nonvirological responders (not shown).

T5-19
Table 5:
Mean viral loads

Histology.

Liver biopsies were obtained in all patients before the initiation of therapy. Biopsy specimens were scored using Knodell’s classification (14). The mean pretreatment hepatitis activity index (HAI) score was 4.0±0.3, and one patient (patient 14) had evidence of periportal fibrosis. Of note, this patient had a VR despite receiving only 4 months of interferon-α and ribavirin. Eleven patients have had biopsies after receiving at least 12 months of treatment. No significant difference was noted in the mean HAI score for these patients before (3.9±0.8) or after (3.9±0.5) interferon-α and ribavirin therapy. None of these subjects had fibrosis before treatment, but 3 patients had histological progression during their treatment course—patient 15 had portal and peri-portal fibrosis, whereas patients 6 and 8 were found to have bridging fibrosis. In addition, 2 of the patients who did not complete the 12-month course of therapy also had histological progression of their recurrent disease. Patient 4 was found to have bridging fibrosis, whereas patient 18 had cirrhosis.

Treatment side effects.

Treatment was prematurely discontinued in 15 patients (Table 3). Thirteen had severe adverse reactions and two had their treatment discontinued when they developed cholestatic recurrence that progressed rapidly to liver failure and death 3–4 months after initiation of interferon-α and ribavirin therapy (patients 2 and 9). Patient 4 also recently expired from progressive allograft failure. All of the remaining patients are clinically stable with the exception of patient 18 (cirrhosis) and patient 25 (PTLD). Of note, patient 14 became HCV RNA negative despite only 140 days of treatment. Overall, 13 (40%) of the 32 patients in this study required either a half-dose reduction or temporary cessation of interferon-α. All patients complained of fatigue, although it was also hard to determine at times whether this symptom was due to or worsened by concomitant anemia from ribavirin. Other adverse reactions attributable to interferon-α that the majority of patients experienced included flu-like symptoms, headaches, leukopenia, and depression. Only nine patients (28%) were able to tolerate the target dose of 3 million units t.i.w. Dose reductions of interferon-α usually took place within 4 months after initiation of therapy. Twelve patients (37%) required G-CSF for the treatment of leukopenia. Five patients were able to maintain their dose or avoid discontinuation of interferon-α by receiving G-CSF. Because MMF may cause bone marrow suppression and leukopenia, we investigated whether MMF affected patients’ ability to tolerate interferon-α. The number of patients taking MMF was not significantly different in the group who tolerated interferon-α versus the cohort of patients who required discontinuation or dose adjustments (P =0.27, not shown). In addition, the number of patients who tolerated the maximum dose of interferon-α was similar between the patients who were taking MMF and those who were not (P =0.41).

The main adverse effect of ribavirin was hemolytic anemia. Sixteen patients (50%) developed anemia severe enough to require a dose reduction or temporary discontinuation of ribavirin. Overall, only four patients were able to tolerate the target dose of 1,000 mg/day. In addition, we were successful in maintaining any sustained increases in the dose of ribavirin in only two patients. Nine patients (28%) received erythropoietin; however, it seemed that erythropoietin did not prevent anyone from having ribavirin discontinued or their dose decreased. Another adverse reaction possibly attributable to interferon-α and ribavirin was a cerebrovascular accident that occurred in patient 6 just after completion of the 1-year course of treatment.

DISCUSSION

Cirrhosis due to HCV infection is now the leading indication for orthotopic LT in the United States (2). Although recurrent disease is nearly universal, few patients develop severe graft dysfunction initially. Thus, the 5-year survival rates of patients who have undergone LT for HCV cirrhosis in the absence of hepatocellular carcinoma is approximately 70%, similar to other causes of end-stage liver disease (3,4,19). Nonetheless, it is estimated that 60–90% of patients will eventually develop chronic active hepatitis and that 15–25% will progress to cirrhosis within 5 years after transplantation (3,5,20,21). Therefore, it is likely that in the near future we will experience an increasing number of recurrent HCV infections leading to allograft failure.

The use of interferon-α for the treatment of recurrent HCV infection after LT has not been effective, with BR and VR attained in only 10–20% of patients (7,8). Several workers, however, have shown marked improvement in response rates when interferon-α is combined with the purine nucleoside analog, ribavirin (Table 4). Bizollon et al. (9) reported on 21 patients treated with interferon-α (3 million units s.q. three times a week) and ribavirin (1200 mg p.o. every day) for 6 months, after which maintenance monotherapy with ribavirin was continued for an additional 6 months. Combination therapy was effective—all patients normalized their serum aminotransferases, 10 patients (48%) cleared HCV RNA from their serum, and improvement in histological score was seen in all patients. During the monotherapy phase, three patients had ribavirin discontinued because of severe anemia. Nevertheless, ALT remained normal in 17 of 18 patients who tolerated the drug, HCV RNA only reappeared in 5 patients, and comparison of pretreatment and postribavirin monotherapy liver biopsy specimens showed histological improvement in 17 of 18 patients. Dodson (10) and others reported on eight patients treated with interferon-α and ribavirin. Seven of eight patients normalized their ALT, and of three patients who finished a 6-month course of treatment, two became serum HCV RNA negative. A more recent study from the Mayo Clinic reported on 21 liver transplant patients with recurrent HCV treated with interferon-α and ribavirin (11). Serum HCV RNA clearance occurred in 6 (38%) of 16 patients after 3 months of treatment. A significant number of patients (14/21) had either dose reductions of ribavirin secondary to anemia or discontinuation of both medications due to severe toxicity. Another group prophylactically treated 21 patients with interferon-α/ribavirin starting from the third week after transplantation (12). Forty-one percent had a negative seroconversion of HCV RNA and 81% had no evidence of hepatitis in the allograft after 1 year of treatment. Nine patients (43%) in this study required dose reductions due to various side effects, although no patient had therapy discontinued.

Other studies on the use of interferon-α and ribavirin after LT have shown poorer results (Table 6). Götz et al. (22) reported on 10 patients treated for 3 months with combination therapy. Patients who had a VR were continued on interferon monotherapy for another 9 months. After 4 weeks of interferon-α/ribavirin, 50% of patients had a BR and six subjects had a greater than 50% reduction in their serum HCV RNA levels. However, only 1 of 10 patients cleared HCV RNA from the serum. Leukopenia (<2.0/nl) occurred in 50% of patients. Fischer and others (23) reported on 8 patients treated for 6 months of which only 5 completed the entire treatment course. BR occurred in seven patients during treatment and only one became HCV RNA negative. After cessation of therapy, four patients developed elevated liver function tests requiring retreatment and no patient had a sustained VR. All patients developed anemia, two requiring blood transfusions and two requiring erythropoietin. Six patients had their ribavirin doses decreased and two were taken off ribavirin.

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Table 6:
Studies utilizing interferon-α and ribavirin for recurrent HCV infection after liver transplantation

In the present study, we were able to obtain an excellent BR in liver transplant recipients treated with interferon-α and ribavirin. The majority of patients (81%) normalized their serum aminotransferases after 3 months. Seventy-five percent of patients an had end-of-treatment BR and 71% achieved a sustained response. Comparison of biochemical responders and nonresponders revealed that after 3 months of treatment, patients who had a BR were younger (Table 4). Analysis of other clinical variables indicated that those who received daclizumab and MMF/daclizumab were less likely to have a BR (P =0.03 and P =0.05, respectively). Paradoxically, we also found that the patients who had a BR had significantly higher levels of pretreatment serum HCV RNA compared with the nonresponders (P =0.004). Thus, a higher pretreatment viral load was not readily associated with treatment failure in our study. Gender, race, genotype, pretreatment serum aminotransferase levels, pretreatment histological scores, and primary immunosuppression with either tacrolimus or cyclosporine along with prednisone were similar between both groups. We also looked at patients who were diagnosed with recurrent HCV less than a year from their transplant (n=20) and compared them with those who were diagnosed after 1 year (n=12). We found no differences between the two cohorts when we looked at BR after 3 months of therapy, end-of-treatment BR, pretreatment viral loads, pretreatment HAI, toxicity, and the ability of patients to tolerate interferon-α or ribavirin (not shown). Therefore, the time to diagnosis of recurrent HCV was not a factor in this study and was not predictive of treatment response. When we analyzed the patients who completed 12 months of therapy, the only difference we found between biochemical responders and nonresponders was that those who received MMF were less likely to have a BR (P =0.02, not shown).

The role of immunosuppression in the progression of HCV infection after LT remains unclear. Numerous reports have demonstrated no differences in graft and patient survival using either tacrolimus or cyclosporine for primary immunosuppression along with corticosteroids (3,4,19). The impact on HCV recurrence of newer agents such as MMF or the interleukin-2 receptor antagonist, daclizumab, has not yet been established. However, preliminary data from our center has demonstrated no increase in rates of recurrence with either agent with short-term follow-up (24,25). We were interested to see whether immunosuppression would influence patient response to interferon-α and ribavirin. Our analysis demonstrated that tacrolimus, cyclosporine, or prednisone had no apparent effect on BR or VR. However, we found that daclizumab and/or MMF may decrease the likelihood of a BR, suggesting that prudent use of these immunosuppressive agents in these patients may be warranted.

Although interferon-α and ribavirin treatment resulted in significant reductions in mean viral loads for our patients (Table 5), we were not able to obtain the ∼40% VR rates reported by others (9–12). Instead, only 3 (9%) of 32 patients became serum HCV RNA negative by PCR. In one of these patients, treatment was only administered for 4 months before being discontinued because of severe anemia and angina. A fourth patient transiently cleared HCV RNA after 3 months of treatment but became viremic again. We did not find any significant differences in pretreatment serum aminotransferases or mean viral loads between the patients who achieved a VR and those failed to clear the virus. Histologically, there was no appreciable improvement in the HAI scores of nine patients who have completed at least 12 months of therapy and, thus far, have been biopsied. In fact, histological progression to fibrosis was seen in five patients. These results contrast markedly with some of the studies previously mentioned in which the majority of patients either had histological improvement or showed no evidence of hepatitis after treatment (9,12). No correlation was noted between the degree of hepatitis and the BR or VR to treatment.

The results of this study, therefore, indicate that interferon-α and ribavirin is successful in normalizing serum biochemistries and decreasing the viral load. However, combination therapy is ineffective in clearing the virus or improving the degree of histological damage. It is not readily apparent why our results were not comparable to other studies mentioned previously (9–12). One plausible explanation is that a significant number of our patients were unable to tolerate interferon-α and/or ribavirin. About half of the patients required dose reductions or temporary cessation of either agent, and treatment was also permanently discontinued in 13 patients because of severe adverse reactions. Leukopenia was the predominant side effect of interferon-α, whereas hemolytic anemia occurred frequently with ribavirin. These results are less favorable compared with nontransplant patients being treated for chronic HCV infection. The latter patients seem to have a better tolerance of interferon-α and ribavirin in that only 10–20% require dose adjustments or discontinuation of therapy (26,27). Overall, LT recipients seemed physically less tolerant of these medications and the concomitant side effects. Nevertheless, when we compared the biochemical responders to the nonresponders, we found no significant differences in the number of patients who reached target doses of the medications. In addition, the number of patients who required dose reductions and/or discontinuation of therapy were similar in both groups. We were quite aggressive in administering either G-CSF and/or erythropoietin in an attempt to reach target doses or to simply keep patients in the study. Although we were able to maintain interferon-α in five patients with leukopenia by administering G-CSF, we were not able to avoid discontinuation of ribavirin in patients with anemia by using erythropoietin. Currently, we continue to administer G-CSF and/or erythropoietin liberally to prevent severe leukopenia and/or anemia.

In summary, this study has shown that good BR rates may be obtained after a 12-month course of interferon-α and ribavirin for the treatment of recurrent HCV infection after LT. However, although there was a marked reduction in mean viral loads, only 9% of patients were able to clear the virus. Furthermore, no significant improvements in histological scores were noted. A significant number of patients were unable to tolerate the side effects of these medications and thus required dose reductions or discontinuation of therapy. Whether treatment of recurrent HCV infection with these agents will delay or prevent progression to cirrhosis, the development of hepatocellular carcinoma, and ultimately, retransplantation for allograft failure remains to be seen. Nonetheless, it would seem that a more efficacious and better-tolerated treatment regimen is required.

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