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Keywords:

  • Hepatitis C;
  • liver transplantation;
  • interferon;
  • preemptive;
  • ribavirin

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Study Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Preliminary studies suggest preemptive anti-HCV therapy in liver transplant recipients may enhance the rates of viral clearance, but the applicability and tolerability of preemptive therapy has not been evaluated in a contemporary cohort. In this randomized study, the safety and tolerability of preemptive standard (IFN) or pegylated (peg-IFN) interferon alfa-2b (3 MU thrice weekly or 1.5 μg/kg weekly), or IFN/peg-IFN plus ribavirin (600 mg increased to 1.0–1.2 g daily) was initiated 2–6 weeks post-transplantation and continued for a total of 48 weeks. Only 51 (41%) of 124 transplant recipients were eligible for preemptive treatment; eligible patients had lower model for end-stage liver disease (MELD) and Childs-Pugh scores pre-transplantation and were more frequently live donor transplant recipients than ineligible patients. Dose reductions and discontinuations were required in 85% and 37% of patients, respectively, and 27% experienced serious adverse events. Growth factor (GF) use (erythropoietin and GCSF) in the latter half of the study did not significantly affect the frequency of dose reductions. Only 15% of patients were able to achieve full-dose treatment during treatment. End-of-treatment and sustained virological responses were 13.6% and 9.1%, respectively, with most responders in the combination therapy group. We conclude that preemptive antiviral therapy is applicable to only a portion of transplant recipients, with ‘sicker’ patients less likely to be managed by this approach. Living donor liver transplant recipients were more frequently eligible for treatment than deceased donor recipients. Virological response rates are low, likely related to the poor tolerability of therapy and the lack of achievement of target drug doses. Future studies should focus on alternative dosing schedules with more aggressive use of adjuvant therapies, including GFs.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Study Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Hepatitis C virus (HCV)-related liver disease is the leading indication for liver transplantation. Recurrent hepatitis resulting in cirrhosis and graft loss is observed in approximately 20% and 10% of patients, respectively, within 5 years of transplantation (1,2) and the risk increases with time (3). As the number of liver transplant recipients with recurrent and severe HCV disease increases, various HCV treatment strategies have been explored. At present, the mainstay of therapy is treatment of histologically progressive disease post-transplantation. Overall, response rates with combination interferon plus ribavirin are approximately 20%, indicating this treatment approach is unlikely to be successful in the majority of patients (4). Other studies have focused on initiating treatment at early timepoints. Preemptive antiviral therapy, defined as antiviral therapy initiated in the early post-transplant period prior to clinical evidence of recurrent HCV disease, has been evaluated in both controlled and uncontrolled studies (5). Results from these earlier studies of preemptive therapy were mixed but tolerance of therapy was reported to be high (6–10).

The rationale for preemptive antiviral therapy lies in the recognition that HCV RNA viral titers tend to be low and severity of histological disease (especially fibrosis) is mild in the early post-transplant period, and at least in non-transplant patients, these factors positively influence response to antiviral therapy. Thus antiviral therapy initiated in the early post-transplant period may be more likely to result in virological clearance and amelioration of histological injury than treatment started only after histological disease is established. Earlier studies evaluating the efficacy of preemptive antiviral therapy suggested that antiviral treatment started within weeks of liver transplantation reduced the risk and severity of post-transplant HCV disease. However, data on the safety and tolerability of preemptive antiviral therapy in a contemporary U.S. cohort of liver transplant recipients are lacking. The severity of illness among patients undergoing liver transplantation may limit the ability to use a preemptive antiviral treatment strategy.

There is very limited information on the use of growth factors (GFs) as adjuvant therapy during antiviral therapy, especially in liver transplant patients. In the non-transplant population, the ability to take full-dose therapy increases the likelihood of sustained virological response (11,12). Extrapolating these data to the post-transplant population, tolerability of full-dose antiviral therapy would be predicted to enhance treatment efficacy. Moreover, use of GFs may improve patient tolerability, especially in the early post-transplant period when cytopenias related to immunosuppressive therapy are common (13,14).

In this randomized controlled clinical study, the safety and efficacy of two different preemptive antiviral treatment regimens, interferon (IFN) and IFN plus ribavirin, were compared and the impact of GF use on ability to achieve early and full-dose therapy was determined. The limitations of the preemptive antiviral strategy are highlighted, particularly the difficulties in initiating treatment with IFN and ribavirin in the early post-transplant period and in achieving target doses of the antiviral drugs.

Study Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Study Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

The study was approved by the local ethics committee and all patients provided written informed consent.

Study population

Consecutive adult patients undergoing liver transplantation for end-stage liver disease secondary to HCV at the University of California, San Francisco between December 1998 and June 2002 were considered for preemptive antiviral therapy. Patients were included if they met all of the following criteria: ≥18 years of age; pre-transplant diagnosis of HCV-associated cirrhosis; and clinical stability with white cell count (WBC) >3.0/mm3, hemoglobin >10.0 g/dL, platelets >45 000/mm3, creatinine (Cr) <1.5 mg/dL; INR (international normalized ratio) <2.0; AST (aspartate aminotransferase) <200 IU; ALT (alanine aminotransferase) <200 IU and total bilirubin <2.5 mg/dL. Patients were excluded if any of the following were present: serum anti-HIV or hepatitis B surface antigen positive prior to transplantation; acute rejection (by clinical and histological criteria) within 14 days of consent; vascular and biliary complications post-transplantation resulting in need for interventions; current untreated infection; abnormal TSH; medically uncontrolled psychosis or depression; history of hemoglobinopathies or any cause of chronic hemolysis; clinically significant retinopathy; uncontrolled diabetes mellitus; inability to practice effective contraception (male or female) during the treatment period; medical history of concomitant autoimmune disease; continued need for ICU support or unstable cardiopulmonary status including myocardial infarction within preceding 4 weeks.

Treatment protocol

The targeted time for initiation of antiviral therapy was between 2 and 6 weeks post-transplantation. Eligible patients were randomized to either IFN alfa-2b (standard and pegylated) alone or in combination with ribavirin. During the first 8 weeks of treatment (induction phase), all patients received IFN daily. IFN was started at a dose of 1.5 MU (million units) daily and increased to 3 MU daily after 2 weeks if blood counts were in the acceptable range. Patients randomized to combination therapy received ribavirin 400 mg daily for 2 weeks, then 800 mg daily for 2 weeks and then 1000–1200 mg daily (depending upon body weight) for the duration of therapy. During the maintenance phase (weeks 9–48 of treatment), the IFN dose was decreased to standard treatment doses using IFN alfa-2b 3 MU three times weekly or pegylated interferon (peg-IFN) alfa-2b 1.5 μg/kg weekly or to the maximum dose achievable. IFN alfa-2b was used for patients started on treatment between December 1998 and July 2001 (N = 34); peg-IFN alfa-2b was used for patients started on treatment between August 2001 and July 2002 (N = 10). The change from standard IFN to peg-IFN reflected the changing ‘standard of care’ for HCV during the 4-year recruitment period. Ribavirin was continued at the maximum dose obtained during the induction phase. During the last 4 weeks of the maintenance phase (weeks 44–48), IFN and ribavirin doses were tapered with the goal of reducing risk of biochemical ‘flares’ with treatment discontinuation (8).

A liver biopsy was not required prior to initiation of antiviral treatment. Liver biopsies were obtained at the end of the treatment period in all patients and as clinically indicated. Biochemical and virological responses were assessed at the end of the 48-week treatment. A biochemical response was defined as normal AST and ALT values. A virological response was defined as undetectable HCV RNA by qualitative assay.

Management of adverse events

Anemia, leukopenia and thrombocytopenia are common side effects of IFN, and ribavirin is associated with hemolytic anemia. In the initial phase of the study, GF use was not routine and dose reduction was the primary method used to manage cytopenias. The dosage of interferon was reduced by 50% if the WBC was less than 1.5/mm3 or absolute neutrophil count (ANC) was less than 1000 or if the platelet count was less than 40 000/mm3. The ribavirin dose was reduced by 50% if the hemoglobin was less than 9.0 g/dL or if the patient had significant symptoms related to anemia. Treatment doses were reduced by a further 50% if cytopenias persisted despite initial dose reductions. IFN and ribavirin were discontinued if there was persistence of cytopenia despite two dose reductions or if severe symptoms requiring hospitalization were present.

Routine use of GFs (G-CSF and erythropoietin) began in July 2001. G-CSF (Neupogen®, Amgen, Thousand Oaks, CA) 150–300 μg twice weekly was administered to patients with ANC <1000, and erythropoietin (Procrit®, Ortho Biotech, Bridgewater, NJ; Epogen®, Amgen) 40 000 IU once weekly was administered to patients with hemoglobin < 9.0 g/dL.

If patients developed mild or moderate acute rejection during HCV treatment, HCV treatment was held for 2 weeks and then restarted at prior doses of IFN and ribavirin. If patients developed severe acute rejection requiring lymphocyte-depleting therapy, antiviral treatment was discontinued permanently as this was considered a serious adverse event.

Immunosuppression

All patients received tacrolimus, mycophenolate mofetil and prednisone as their primary immunosuppression. Prednisone was tapered to 5 mg/day by the end of the first month. In some patients, prednisone was gradually tapered and discontinued after 1 year post-transplantation, but this was not a uniform practice. Mycophenolate mofetil (maximum dose: 1.5 g b.i.d.) was tapered off by 2–6 months post-transplantation except in patients who could not tolerate calcineurin inhibitor therapy. Target blood tacrolimus levels were set at 8–12 μg/L during the first 3 months, with maintenance levels of 6–8 μg/L during the remainder of the treatment period.

Biopsy-proven acute rejection was treated in a standardized manner. Initial treatment of mild-to-moderate rejection included methlyprednisolone intravenously 1 g daily for 2 days followed by prednisone starting at 200 mg/day, tapered by 40 mg/day until 20 mg/day, and then tapered by 2.5 mg per week until the dose of 5 mg/day is reached. Severe acute rejection or acute rejection unresponsive to corticosteroids was treated with OKT3 5 mg intravenously daily for 7–10 days.

Statistical analysis

Median, mean, range and quartiles were used as appropriate. Comparison between groups was performed using χ2 and Fisher exact test (for categorical variables) and Mann-Whitney U test (for continuous variables).

With our sample size of 47 patients, we had ≥80% power to detect a ≥20% difference between groups, assuming the virological response rate in the monotherapy group is 5% or less, and using a one-tailed alpha of 0.05.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Study Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Demographics

A total of 124 patients with HCV-related cirrhosis underwent liver transplantation at UCSF during the study period (December 1998 through June 2002) (Table 1). A total of 51 patients (41% of transplanted patients) were eligible for preemptive antiviral therapy; 37.6% of deceased donor recipients were eligible for treatment, and 66.7% of live donor recipients were eligible (p = 0.033). Of the 51 eligible patients, 47 patients were enrolled. Three patients did not receive treatment due to withdrawal of consent or the development of an intercurrent complication preventing initiation of treatment and therefore a total of 44 patients were randomized to IFN monotherapy (N = 22) or IFN plus ribavirin combination therapy (N = 22).

Table 1.  Patient characteristics
 All transplanted patients N = 124 (%)Eligible for study N = 51 (%)Ineligible for study N = 73 (%) p-value**
  1. *Includes one split-liver deceased donor. **Compares characteristics in eligible and ineligible patients.

  2. CPS: Childs-Pugh score; MELD: model of end-stage liver disease; HCC: hepatocellular carcinoma.

Age50 (35–70)50 (39–70)50 (35–70)0.61
Gender: Male89 (71.8%)40 (78.4%)49 (67.1%)0.17
UNOS
 Status 2b or 363 (50.8%)34 (66.7%)29 (39.7%)-
 Status 2a61 (49.2%)17 (33.3%)44 (60.3%)0.0032
 Biologic MELD median (range)18 (7–49)15 (7–39)21 (8–49)<0.0001
 CPS median (range)11 (5–14)10 (5–14)12 (5–14)<0.0001
 Hospital days pre-transplant median (range)11 (0–89)1.0 (0–63)8.5 (0–89)0.004
 Hospital days post-transplant median (range)9 (0–37)7.0 (3–13)11.5 (0–37)<0.001
 HCC44 (35.4%)15 (29.4%)29 (39.7%)0.23
OLT
 Deceased donor*109 (87.9%)41 (80.4%)68 (93.2%)-
 Living related15 (12.1%)10 (19.6%)5 (7.8%)0.032

Reasons for ineligibility

Seventy-three patients were ineligible for the study. Reasons for ineligibility included persistent anemia (12 patients), acute rejection (3 patients), death (8 patients), significant infectious complications (5 patients), acute renal failure (4 patients), perioperative myocardial infarction (4 patients), persistent hyperbilirubinemia (2 patients), prolonged ICU stay (4 patients), severe psychiatric complications (4 patients), poor functional status (4 patients), a Jehovah's witness (1 patient), portopulmonary hypertension (1 patient), early re-transplantation (2 patients), neurotoxicity from tacrolimus (1 patient), severe thrombocytopenia (1 patient) and a complicated biliary leak (1 patient). Additionally, 8 patients declined to participate and 8 patients were not staying the San Francisco area for 18 months post-transplantation.

About 54% of patients with United Network of Organ Sharing (UNOS) status 2b or 3 were eligible for study, whereas only 28% of UNOS status 2a were eligible for study (p = 0.0032). Ineligible patients had a median Childs-Pugh score (CPS) of 12 (range: 5–14) versus eligible patients who had a median CPS of 10 (range: 5–14), p < 0.0001. Ineligible patients had a median biological MELD score of 21 (range: 8–49) versus eligible patients with a median biological MELD score of 15 (range: 7–39), p ≤ 0.0001. Ineligible patients had a significantly higher median number of hospital days pre-transplant compared to eligible patients, p = 0.004. Ineligible patients also had a greater median number of hospital days post-transplant of 11.5 days (range: 0–36) versus eligible patient's median post-hospital stay of 7.0 days (range: 3–13), p < 0.001.

Tolerability of preemptive antiviral therapy

Of the 44 patients who received at least one dose of INF, 18 (41%) patients discontinued treatment early; the median time to early discontinuation was 9.1 weeks (range: 0.9–43.6 weeks). Discontinuation rates did not differ by type of IFN used (47% with IFN vs. 50% with peg-IFN, p = 0.87). The most common reasons for discontinuation of treatment were acute rejection (6 patients), persistent pancytopenia (2 patients) and severe headaches (2 patients). Other reasons for discontinuation were worsening of peripheral neuropathy (1 patient), severe depression unresponsive to medications (1 patient), move out of the state (1 patient) and personal request to discontinue treatment (1 patient). Serious complications occurred in four patients. One patient developed biliary sepsis followed by myocardial infarction and multiorgan failure, another developed retinal artery occlusion with partial loss of the visual field, another developed new onset ulcerative colitis, and another had intercurrent cytomegalovirus infection.

Altogether, 7 of the 44 patients on preemptive therapy were able to achieve full-dose therapy. Five of these seven patients were on IFN monotherapy. Only two patients on IFN/ribavirin combination therapy were able to achieve full-dose treatment (p = 0.21). Ten of the 44 patients were able to achieve at least 80% of the total treatment doses for at least 80% of the treatment duration; three of these patients were on IFN/ribavirin combination therapy, and seven were on IFN monotherapy (p = 0.17) (Table 2).

Table 2.  Treatment adherence
 IFN (N = 22)IFN + RBV (N = 22) p-value*
  1. *Fischer exact test, one-tailed, comparing IFN monotherapy and IFN/ribavirin groups.

Full-dose treatment achieved (%)5 (23%)2 (9%)0.21
>80% treatment dose and >80% treatment duration achieved (%)7 (32%)3 (14%)0.14

Acute rejection

Acute rejection treated with corticosteroids or lymphocyte-depleting therapy occurred in 18 (40.9%) of the 44 patients receiving at least one dose of antiviral therapy. Two patients required treatment with OKT3 and as per the study protocol, treatment was discontinued in these patients. There was no difference in the proportion of acute rejection episodes occurring prior to initiation of antiviral therapy (N = 8, 44% of total acute rejection episodes) versus during therapy (N = 10, 56%), but both episodes of acute rejection requiring OKT3 occurred during antiviral therapy. Among patients who had an episode of acute rejection treated with corticosteroids on treatment (N = 10), there was no difference in the proportion who completed 48 weeks of treatment versus discontinued early (p = 0.61)

Impact of GFs

Anemia was the most common reason for ineligibility for preemptive antiviral treatment. GFs were not used routinely until July 2001. The number of patients excluded from consideration of preemptive therapy due to the presence of cytopenias was 11 (26%) of 43 patients prior to July 2001 and 3 (19%) of 16 patients after GFs were routinely used (p = 0.74). The median hemoglobin at the time of transplant was 10.0 g/dL (range: 7.1–16) in the patients who were ineligible for treatment, and 11.9 g/dL (range: 8.4–16) in the group eligible for preemptive treatment (p < 0.0001). One patient was started on erythropoietin prior to July 2001, and four patients were started after July 2001.

Anemia, leukopenia and thrombocytopenia were frequent during therapy. The number of patients requiring treatment discontinuation due to refractory cytopenias was two patients prior to July 2001 and no patients after this date. The median cell counts at the initiation of treatment were hemoglobin 11.6 g/dL, WBC 5.8/mm3, and platelets 173 000/mm3. There was no significant difference in hemoglobin values between the IFN monotherapy group as compared to the IFN plus ribavirin combination therapy group at initiation of treatment. Median hemoglobin nadir during treatment was 10.3 g/dL, with a median change of hemoglobin of 0.8 g/dL (range: −1.1 to 5.2). In nearly half of the treated patients, the nadir of hemoglobin decline occurred in the first 6 weeks of treatment and few occurred after week 20. There was a statistically significant difference in the change of hemoglobin values between treatment groups. In the IFN monotherapy group, the median decrease in hemoglobin was 0.50 g/dL (range: −1.1 to 4.7), whereas in the IFN plus ribavirin combination therapy group, the median hemoglobin decrease was 1.6 g/dL (range: −0.2 to 5.2; p = 0.017). The median WBC nadir was 2.0/mm3, with a median change in WBC count of 3.9/mm3 (range: 0.2–6.8), with no significant difference between the two treatment groups (p = 0.22). The WBC nadir occurred within the first 8 weeks of treatment in two-thirds of patients. The median platelet nadir was 77 000/mm3, with a median change in platelet values of 86 000/mm3 (range: 7000–256 000) and no significant difference between treatment groups (p = 0.39). The median hemoglobin level at termination of treatment was 13.0 g/dL, median WBC 3.8/mm3 and median platelet count 127 000/mm3.

A total of 11 patients received GFs prior to or during antiviral therapy. Three patients were treated with erythropoietin, six patients were treated with G-CSF and two patients received both G-CSF and erythropoietin. Patients receiving erythropoietin (40 000 IU weekly) had a median hemoglobin of 10.9 g/dL (range: 8.9–11.3) at initiation of treatment and a median change in hemoglobin of 5.0 g/dL (range: −0.6 to 7.2). Hemoglobin levels normalized at a median of 7.8 weeks (range: 5.4–11.4) in three of five patients treated with erythropoietin. The dose of ribavirin could not be escalated in any of the patients receiving erythropoietin but three of the patients were able to complete the treatment course without further reductions in ribavirin dose. The median hemoglobin level at the termination of erythropoietin usage was 13.2 g/dL (range: 9.8–15.2).

The median WBC at the initiation of G-CSF therapy was 2.1/mm3 (range: 0.7–5.). Doses of G-CSF ranged from 150 to 480 mcg twice weekly, with most patients receiving 300 mcg twice weekly. All eight patients were able to normalize their WBC with G-CSF use. Four of six patients were able to escalate their IFN dosage with G-CSF support, whereas two patients were able continue IFN treatment at the same dose without need for further IFN dose reductions.

Assessment of tolerability and efficacy

Among the 44 patients who received at least one dose of antiviral therapy, biochemical responses were more frequent than virological responses (Table 3). End-of-treatment biochemical responses were sustained at 6 months post-treatment in 70.8%. End-of-treatment and sustained virological responses were obtained in 13.6% and 11.4% overall, with a trend towards higher rates of response in the combination therapy group (Table 3). While there was a tendency for patients who completed 48 weeks of treatment and who received at least 80% of the target drug doses, to achieve end-of-treatment virological responses, none of the differences were statistically significant (p > 0.05).

Table 3.  End-of-treatment and sustained responses
 IFN (N = 22)IFN + RBV (N = 22) p-value*
  1. Includes patients who received at least one dose of antiviral therapy. Patients lost to follow-up or dying during the study period are counted as non-responders.

  2. *Fischer exact test, one-tailed, comparing IFN monotherapy and IFN/ribavirin groups.

End-of-treatment biochemical response50%63.6%0.18
End-of-treatment virological response4.54%22.7%0.093
End-of-follow-up biochemical response45.4%31.8%0.11
End-of-follow-up virological response4.54%18.2%0.17

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Study Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Preemptive antiviral therapy is aimed at preventing or mitigating HCV disease progression after liver transplantation. Prior limited studies have evaluated the efficacy of preemptive therapy, but none have addressed the challenges encountered in using a preemptive antiviral treatment strategy in the current era of prolonged waiting times and increasingly sick patients undergoing liver transplantation. This is the first report detailing the limitations and complications related to the preemptive antiviral approach. We have shown that preemptive therapy is applicable to less than half of the patients undergoing liver transplantation. Cytopenias (especially anemia), post-operative complications including acute rejection, infections, myocardial events, renal dysfunction and severe debilitation (related to severity of illness pre-transplantation) limit the application of interferon and ribavirin the very early post-transplant period. While more aggressive management of anemia post-transplantation would have increased the number of patients eligible for treatment by approximately 10%, the majority of patients had contraindications that would not allow early treatment initiation and were reflective of poor pre-transplant clinical status. The current organ prioritization results in the most severely ill patients receiving liver transplants. We found that sick patients were poor candidates for preemptive antiviral therapy. Patients who were ineligible to start preemptive antiviral therapy had significantly higher MELD score and CPS pre-transplantation and more frequently had high UNOS status (2a vs. 2b or 3).

Preemptive therapy may be more applicable to living donor recipients as these patients have a lower average MELD score and CPS as compared to deceased liver transplant recipients. In our study, 66.7% of live donor transplant recipients were eligible for treatment as compared to 37.6% of deceased liver transplant recipients, suggesting live donor recipients may be better candidates for antiviral therapy in the early post-transplant period. Future studies investigating the use of a preemptive antiviral therapy in this patient population are warranted.

Another challenge in using antiviral therapy preemptively is that achieving target doses of drugs is difficult and treatment discontinuation is frequent. Recent studies in non-transplant patients with chronic HCV infection treated with antiviral therapy emphasize the importance of achieving target doses of the medications (11,12,15,16). Patients who receive at least 80% of the interferon and ribavirin doses for at least 80% of the planned treatment duration exhibit higher sustained response rates compared to those receiving less than 80%. Achieving full-dose antiviral treatment in transplant patients, especially in the early post-transplant period, is difficult, as highlighted by our experience. Only 10 (24%) of 42 patients were able to achieve 80% of target treatment doses for at least 80% of the planned treatment duration. Only 7 (16%) of 42 patients were able to achieve full treatment doses with only two patients on combination therapy receiving full doses of both the IFN and ribavirin. This inability to achieve target drug doses and treatment duration likely contribute to the low rate of virological response in our study.

The appropriate dose of ribavirin in a transplant population is not known. Standard non-transplant doses of ribavirin were tolerated by the minority of patients in our study; similar to findings in studies of liver transplant recipients with recurrent HCV disease receiving antiviral therapy (4,17–19). In utilizing antiviral therapy preemptively, the issues related to ribavirin dosing may be even more pronounced. Persistent renal dysfunction in the early post-transplant period is not uncommon due to pre-transplant renal dysfunction, drug toxicity related to tacrolimus and cyclosporine, and fluctuating volume status, all of which may affect ribavirin pharmacokinetics. Altered renal function, which in turn affects ribavirin elimination, is the most likely explanation for our inability to reach ‘standard’ ribavirin doses in this study. In a post hoc analysis of the effect of renal function on ability to attain full-dose therapy, we found that patients who discontinued treatment had a lower calculated creatinine clearance (CrCl) (by Cockroft–Gault method) at median 90 cc/min (range: 41–152) compared to patients who did not require treatment discontinuation (median CrCl: 109 cc/min, range: 56–174; p = 0.080). Standard interferon clearance is also reduced by altered renal function, although the impact appears to be much less than for ribavirin (20–22).

Multiple studies have shown that hematologic changes are the most common laboratory abnormalities leading to dose reductions and discontinuations (12,23). Although intuitively one might predict that GF use would allow more people to be eligible for treatment, we did not find the number of patients excluded due to baseline cytopenias was reduced by the routine application of GFs. However, the study was underpowered to evaluate the use of GFs in correcting early post-transplant anemia. Moreover, the relatively narrow window for initiation of antiviral therapy (within the first 6 weeks post-transplantation) may have been insufficient to allow response to GFs, especially erythropoietin. While use of GFs infrequently lead to increased drug doses to target levels, we found that patients receiving GFs were able to continue treatment at the same doses without the need for further dose reductions. Additionally, when we used GFs routinely, there were no patients who had treatment discontinued due to cytopenias. These data suggest that routine use of GFs in this population may be important in preventing dose reductions and treatment discontinuation due to cytopenias. In non-transplant HCV-infected patients receiving INF plus ribavirin therapy, erythropoietin supplementation in patients with hemoglobin levels of 12 g/dL or less was associated with enhanced ability to maintain ribavirin doses (24). The endogenous erythropoietin response in liver transplant recipients with chronic HCV with ribavirin-induced anemia is unknown and additional studies evaluating the role of GFs in managing anemia post-transplantation and within the context of ribavirin therapy are needed. Additionally, more recent clinical studies in non-transplant populations have utilized lower ANC (to 500 mm3) and platelet counts (to 35 000/mm3) before initiating dose reductions. Whether lower values for ANC and platelet counts can be tolerated safely in an immunosuppressed transplant population is unknown but is another aspect of antiviral therapy worthy of further study.

The overall rates of sustained virological response were low, similar to other published series. Comparison between INF monotherapy and combination treatment arms confirmed the importance of combination therapy in achieving higher response rates. Thus, although the use of ribavirin in a transplant population is more challenging, its inclusion as a component of treatment appears to be essential in achieving a virological response. Biochemical responses were more frequent than virological responses, occurring in over half of the treated patients. In the absence of virological clearance, a biochemical response may be an important secondary endpoint, especially if the effects can be sustained after treatment is discontinued. In our study, 70.8% of those with normal serum aminotransferase levels at the end of treatment sustained these effects during follow-up. The long-term durability of this response needs to be defined, but these results raise the intriguing issue of whether preemptive antiviral can alter the natural history of HCV infection post-transplantation, even in the absence of achieving a virological response.

In conclusion, our study highlights the difficulties in utilizing a preemptive antiviral treatment strategy in the current era of transplantation. In contrast to earlier reports (8,10), we found the tolerability of preemptive antiviral therapy was poor. Only about one-third of patients were stable and well enough to start antiviral therapy within the first few weeks following transplantation and treatment discontinuation rates were high. Our results suggest that patients with lower pre-transplant MELD or Child's score may be best suited for this therapeutic approach. Living donor liver transplant recipients may be good candidates. Additionally, our study highlights the need for more detailed study of ribavirin dosing and use of GFs to optimize tolerability and safety of these drugs in the post-transplant setting with the goal of enhancing rates of viral clearance.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Study Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

The study was supported by Fugisawa Healthcare, Inc., and the UCSF Liver Center P30 DK26743 Clinical and Translational Core.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Study Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
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