There are unresolved issues regarding sustained virological response (SVR), tolerance and risk of rejection following antiviral therapy in liver transplantation (LT). The aim of our study was to determine efficacy, rejection risk and factors associated with SVR. HCV-infected LT patients with at least 6 months of follow-up following end-of-therapy (EOT) received combination therapy of ribavirin (Rbvr) + standard (n=31)/pegIFN (n=36) between 1999 and 2004 (95% genotype 1). An EOT and SVR was obtained in 46% and 33%, respectively. Type of antiviral therapy, use of erythropoietin, compliance, and early virologic response (EVR) were predictive of SVR, but only the latter remained in the multivariate analysis. Premature discontinuation, not impacted by the use of erythropoietin or GCSF, occurred in 40% patients. None of the variables predicted rejection (acute n=2, chronic n=4). A SVR occurred in 3/4 patients with chronic rejection. In conclusion, the efficacy of pegIFN-Rbvr is similar to the non-transplant population. An EVR at 3 months is useful to predict lack of response. The type of calcineurin inhibitor and history of prior non-response to IFN before LT do not influence the outcome of therapy. Severe rejection may lead to graft loss, a complication difficult to predict. Liver Transpl 12:1067–1076, 2006. © 2006 AASLD.
Hepatitis C-related end-stage liver disease is currently the most common indication for liver transplantation in the United States and Europe. Unfortunately, recurrent viremia is a universal event with potential serious consequences within 5 to 10 yr posttransplantation.1, 2 Indeed, several large multicenter and single-center studies show a reduced 5- and 10-yr survival of these patients compared to uninfected recipients,3–5 largely as a consequence of the recurrence of the original disease. Antiviral agents to treat recurrence, such as interferon and ribavirin, are limited by their low efficacy and low tolerance profile.2, 6 In fact, interferon-alpha monotherapy has not proven to be efficacious in this setting. While the efficacy has increased with the addition of ribavirin, it still yields limited success, with a rate of sustained viral eradication of about 20% ranging from 10% to 30%.2, 6 As in nontransplant patients, the best results reported to date have been achieved with the combination pegylated interferon-ribavirin with a sustained response ranging from 26 to 45%.7–11 Studies using these agents though are few and include small cohorts so that the effectiveness still needs to be confirmed in clinical practice. In addition, there are a number of unresolved issues regarding this therapy, including: 1) defining predictors of response, particularly at an early stage so that a toxic therapy is not continued in the subgroup of patients with a low likelihood of response; 2) evaluating whether rejection is still a matter of concern as initially suggested in studies based on interferon monotherapy12; and 3) determining whether the underlying immunosuppression plays a role in achieving a sustained viral eradication. Indeed, there are preliminary data suggesting that the rate of sustained viral eradication is higher among patients undergoing treatment with cyclosporine,13 possibly as a consequence of the hypothetical antiviral effect shown in vitro of this immunosuppressive agent.14
We report our experience with antiviral therapy (either standard or pegylated interferon in combination with ribavirin) in hepatitis C liver transplant recipients in a university hospital-based hepatology clinic. We hypothesized that the sustained virologic response (SVR) as a marker of effectiveness would be as follows: 1) better with pegylated interferon-ribavirin than with standard interferon-ribavirin; 2) similar under cyclosporine-based regimes than under tacrolimus; and 3) worse in previously treated (before transplantation) as opposed to treatment-naive patients. We also hypothesized that the same predictors of response described in the immune competent population, namely genotype and viral load pretherapy and at 3 months of therapy, would apply to the liver transplant patients. Finally, we hypothesized that, possibly due to its longer half-life, pegylated interferon would trigger rejection episodes more frequently than standard interferon.
The aims of this study were therefore: 1) to determine the SVR and the proportion of patients who required dose reduction/premature discontinuation of therapy; 2) to identify baseline and on-treatment factors associated with an SVR; and 3) to define the rate of rejection associated with antiviral therapy and potential risk factors that might predict this complication.
PATIENTS AND METHODS
A retrospective chart review was performed on all hepatitis C virus (HCV)-infected liver transplant patients who received combination therapy of standard/pegylated interferon and ribavirin at the Hepatology Clinic between March 1999 and October 2004. Only patients with at least 6 months of follow-up following the discontinuation of antiviral therapy are included in this analysis.
Yearly protocol liver biopsies are routinely performed in HCV-infected recipients at our institution. Additional liver biopsies are performed if clinically indicated, generally within the first months posttransplantation to exclude coexistent diseases or complications such as rejection. In fact, all patients had an initial liver biopsy to assess the severity of liver disease. The decision to initiate treatment was individualized and made jointly by the patient and attending hepatologist. In general, though, during the first era when only standard interferon was available and data regarding its efficacy were very limited and disappointing, therapy was only initiated when there was evidence of disease progression between several yearly biopsies or if the first biopsy showed signs of aggressive disease (i.e., cholestatic hepatitis, bridging fibrosis, or cirrhosis). In the last 2 yr though, following the introduction of pegylated interferon with improved efficacy and simpler administration demonstrated in the nontransplant population,15 therapy was generally initiated at an earlier stage, typically based on the first-yr protocol liver biopsy. This policy was based on previous studies, including our own, that had demonstrated that a first-yr liver biopsy showing portal fibrosis is a predictor of subsequent progressive disease.16, 17 In addition, therapy was also initiated when in a “clinically-indicated liver biopsy” there were changes compatible with aggressive disease (i.e., progression to fibrosis and/or moderate-to-severe necroinflammation within the first yr posttransplantation; change in the stage of fibrosis of more than 1 unit in a short period of time; and change in the pattern of recurrent hepatitis to a more cholestatic form during follow-up). Patient acceptance to undergo antiviral therapy was always taken into account. Viral load did not impact on the decision process. These guidelines were standardized for all patients.
No patient without established recurrence (i.e., preemptive therapy) was included. Other causes of graft dysfunction including rejection, biliary or vascular complications, and other viral infections had been carefully excluded by Doppler ultrasound, cholangiograms, cultures, and histological examination of the graft (multiple if necessary).
Patients with ongoing rejection, evidence of autoimmune hepatitis, and a history of heart disease were not treated. In addition, therapy was stopped in patients who developed a severe episode of rejection under interferon therapy.
Antiviral Treatment Regimen
Standard interferon alfa 2b (Intron A; Schering-Plough, Kenilworth, NJ), pegylated interferon (Pegasys, Roche, Basel, Switzerland; Pegintron, Schering-Plough) and ribavirin (Rebetol; Schering-Plough) were started at full or reduced doses depending on the hemoglobin, total white blood cell count, absolute neutrophil count, or platelet count. Doses were modified according to standard criteria taking into consideration the known effects of both drugs. Adjuvant therapies including erythropoietin and granulocyte colony stimulating factor injections were used whenever considered appropriate by the hepatologist in charge. The intended duration of therapy was 48 weeks whenever possible.
A biochemical response was defined by normalization of liver enzyme levels (serum alanine aminotransferase and aspartate aminotransferase). In addition, a virological response was defined by the negativity of HCV ribonucleic acid in serum by qualitative polymerase chain reaction. The response was considered complete if it occurred at the end of completion of therapy. A sustained response was achieved when both a biochemical and virological responses were observed 6 months after completion of therapy. In addition, histological improvement was defined by the decrease of at least 2 points in the activity grade or 1 point in the fibrosis stage in posttreatment biopsies.
HCV ribonucleic acid was detected in serum at baseline, at 4, 12, 24, and 48 weeks of therapy, and at 24 weeks posttreatment. HCV-ribonucleic acid (qualitative) was detected using the Cobas Amplicor HCV test v2.0 (Roche Diagnostics, Branchburg, NJ).
HCV-ribonucleic acid quantitation was performed either with the Cobas Amplicor HCV Monitor test v2.0 (Roche Diagnostics), or with the branched-DNA (bDNA) assay v3.0 (Bayer Diagnostics, Tarrytown, NY). The viral load values (in IU/mL) obtained with the 2 techniques within their respective dynamic range have been shown to be highly correlated.18 HCV genotyping was performed using a commercial reverse-hybridization genotyping assay (Inno-LIPA HCV II; Innogenetics, Zwijndrecht, Belgium).
Liver biopsies were available before therapy and subsequently at the end of completion of therapy, if possible. All biopsy specimens were read by a single pathologist (J.M.R.) who was blinded to biochemical and virological responses of the patient. Histological recurrence of HCV and disease severity were defined as previously described.19 Briefly, the specimens were scored according to a slight modification of the histologic activity index proposed by Knodell, and their histological grade (activity) and stage (fibrosis) were evaluated separately. The grade was determined by combining the histologic activity index scores for periportal necrosis, scored 0-6 (0, none; 1, mild piecemeal necrosis; 3, moderate piecemeal necrosis; 4, marked piecemeal necrosis; 5, moderate piecemeal necrosis plus bridging necrosis; and 6, marked piecemeal necrosis plus bridging necrosis), lobular degeneration and necrosis (0-4), and portal inflammation (0-4), and was defined as follows: 1 to 2, minimal; 3 to 6, mild; 7 to 10, moderate; and 11 to 14, severe. In addition, liver biopsy samples were staged according to the original histologic activity index fibrosis score: 0, none; 1, fibrous portal expansion; 3, bridging fibrosis; and 4, cirrhosis.
Graft biopsy specimens were also examined for features of acute and chronic rejection. Cellular rejection was always based on histological findings, including mixed portal infiltrate, venous endothelitis, and bile duct injury. A formal Banff score was not given due to the overlap with recurrent hepatitis C. Chronic rejection was defined by the presence of bile duct atrophy/pyknosis, bile duct paucity, and foam cell obliterative arteriopathy.
The primary end-point of the analysis is SVR. Secondary end-points are end-of-treatment biochemical and virological responses, histological improvement, and tolerability of treatment with particular emphasis on rejection-induced episodes. Baseline characteristics and measures of tolerability and efficacy of treatment are described as proportions or medians and range. Comparisons between sustained responders and nonresponders are made using 2-sided Fisher's exact and Wilcoxon's tests. Multivariate analysis was performed to identify independent predictors of SVR using logistic regression. A P value of < 0.05 was considered statistically significant.
This study included 67 hepatitis C-infected liver transplant patients treated with either standard or pegylated interferon in combination with ribavirin for recurrent HCV-related liver disease with a minimum of 6 months since discontinuation of antiviral therapy (Table 1). Of these, 67% were men and the median age was 54 yr (range 30-67). The median patient body mass index was 26 (17.5-38.0). The majority of the patients were infected with HCV genotype 1 (n = 62, 92.5%). Except for 1 patient, the remainder had elevated alanine aminotransferase levels before starting therapy (median 198 IU/L; range 26-1,547). While 63 patients were treated for recurrent hepatitis C after a first liver transplant, 4 were treated following retransplantation for recurrent HCV-graft failure of the first graft at 56, 82, 133, and 581 days post-retransplantation, respectively. The median time to treatment after liver transplantation was 513 days (56-3,978 days). Sixty-five patients had a baseline liver biopsy before starting therapy. In 2 patients with elevated transaminases for more than 1 yr since transplantation, an immediate pretherapy biopsy was not available because it was considered to be too risky due to comorbidities. The median time from pretreatment biopsy to treatment was 65 days (2-852 days). Nine (15%) patients had biopsy-proven cirrhosis, whereas 6 (9%) had histological signs compatible with severe acute lobular hepatitis with cholestasis. While none of the patients had clinical evidence of hepatic decompensation, 11 (16.5%) had a bilirubin level higher than 3 gm/dL. In addition, 17 (25%) of the patients had a platelet count <100,000/mm3, 6 (9%) had a leukocyte count <3,000/mm3, and 8 (12%) had hemoglobin <12 gm/dL. Immunosuppression consisted of cyclosporine Neoral in 28 (42%) and tacrolimus in 39 (58%). The vast majority were off steroids at initiation of therapy (n = 59, 88%).
Table 1. Baseline Features (n = 67)
|Gender (% Male)||45 (67%)|
|Age at therapy (yr)||54 (30–67)|
|Genotype (% 1)||62 (92.5%)|
|Viral load pretherapy (IU/mL)||7.1 × 104 (0.2 × 104 − 77 × 105)|
|Pretransplantation antiviral therapy||13 (19%)|
|History of rejection (%)||14 (22%)|
|Baseline Immunosuppression|| |
| Cyclosporine||28 (42%)|
| Tacrolimus||39 (58%)|
|Steroids at initiation of therapy||8 (12%)|
|Type of therapy|| |
| IFNα-Rbv||31 (46%)|
| Pegα2a-Rbv||23 (34.5%)|
| Pegα2b-Rbv||13 (19.5%)|
|Hstology at initiation*|| |
| Acute hepatitis||4 (6%)|
| Chronic hepatitis|| |
| F = 0||3 (4.5%)|
| F = 1||15 (23%)|
| F = 3||34 (51%)|
| F = 4||9 (13%)|
|Body mass index at initiation||26 (17.5-38)|
|Time to therapy since transplantation (months)||17.1 (1.86-132.6)|
|Time to therapy since baseline liver biopsy (days)||65 (2-852)|
End-of-Treatment and Sustained Biochemical and Virological Responses
End-of-treatment biochemical response and end-of-treatment virological response were seen in 34 (51%) and 31 (46%) of patients, respectively. Sustained biochemical response and SVR were seen in 23 (34%) and 22 (33%) of patients, respectively.
Dose Reductions and Premature Termination of Therapy.
Twenty-seven (40%) patients had premature discontinuation of either interferon (n = 24, 36%), ribavirin (n = 25, 37%) or both agents secondary to adverse events including: anemia (22%), rejection episodes (22%), intolerance (15%), miscellaneous (41%). The premature discontinuation of either drug was not impacted by the use of either erythropoietin or granulocyte stimulating factor (data not shown). In addition, 38 (57%) patients had adverse events, mainly anemia, neutropenia, or thrombocytopenia, necessitating interferon (n = 24, 36%) or ribavirin (n = 30, 45%) dose reductions.
SVR rates were not significantly impacted by premature discontinuation of antiviral therapy (both interferon and ribavirin). In fact, an SVR was achieved in 29.5% (n = 8/27) of the patients who prematurely discontinued therapy at a median of 26 weeks from initiation compared to 35% (n = 14/40) in those who finished the established 48 weeks of treatment (Table 2). Therapy had been discontinued in 3 of 8 cases due to chronic rejection at 171, 161, and 174 days from start of therapy. In the remainder, the cause and time of discontinuation were intolerance (81 and 191 days), chest pain (213 days), and anemia (296 and 325 days). Although not statistically significant, discontinuation of interferon had a greater impact on virologic response than discontinuation of ribavirin (SVR in 37% of those not discontinuing interferon compared to 25% of those with premature discontinuation of interferon compared to 33% and 32% in the case of ribavirin). Dose reductions though appeared to influence outcome with an SVR achieved in 52% (10/19) of those who had received more than 80% of the dose for more than 80% of the time compared to only 25% (12/48) in those receiving less than 80% during less than 80% of the time (P = 0.03) (Table 2).
Table 2. Impact of Dose and Duration of Combination Antiviral Therapy on Sustained Virologic Response
|Duration of therapy (days)||349.5 (81-385)||365 (13-462)||ns|
|Early Discontinuation|| || || |
| Yes (n = 27)||30%||70%||ns|
| No (n = 40)||35%||65%|| |
|IFN early discontinuation|| || ||ns|
| Yes (n = 24)||25%||75%|| |
| No (n = 43)||37%||63%|| |
|Rbvr early discontinuation|| || ||ns|
| Yes (n = 25)||32%||68%|| |
| No (n = 42)||33%||67%|| |
|Dose reductions|| || || |
| Yes (n = 38)||32%||68%||ns|
| No (n = 29)||35%||65%|| |
|IFN dose reduction|| || ||ns|
| Yes (n = 24)||33%||67%|| |
| No (n = 43)||33%||67%|| |
|Rbv dose reduction|| || ||ns|
| Yes (n = 30)||30%||70%|| |
| No (n = 37)||35%||65%|| |
|IFN dose|| || ||ns|
| >80% recommended (n = 25)||44%||56%|| |
| <80% recommended (n = 33)||27%||73%|| |
|Rbv dose|| || ||0.05|
| >80% recommended (n = 22)||50%||50%|| |
| <80% recommended (n = 36)||25%||75%|| |
|Overall dose and duration|| || ||0.03|
| >80/80/80 (n = 19)||54%||46%|| |
| <80/80/80 (n = 48)||25%||75%|| |
Histologically documented rejection developed in 6 patients, 1 under interferon therapy and 5 under pegylated interferon (Table 3). The rate of rejection was hence 3% in those treated with standard interferon compared to 14% in those treated with pegylated interferon. The rejection episodes were acute in 2 cases and chronic in 4. Antirejection therapy consisted of 3 grams of methyl-prednisolone in the acute cases, whereas in patients with chronic rejection, baseline immunosuppression was switched to a more potent 1 (change from cyclosporine to tacrolimus, addition of mycophenolate mofetil and prednisone). A SVR was achieved in 3 of 4 patients who developed chronic rejection, but in none of the acute rejection cases. All chronic rejection episodes occurred after viral clearance. The outcome was variable. The 2 patients developing acute rejection responded to 3 boluses of methylprednisolone; 1 is alive with progressive HCV-disease (patient 1), while the second died due to recurrent HCV disease (patient 6). Regarding the 4 cases of chronic rejection, 2 (patients 2 and 3) have shown a progressive improvement in the liver function after changing their baseline immunosuppression without reaching though, a complete normalization of all laboratory parameters (in particular, gamma-glutamyl transpeptidase and alkaline phosphatase) despite viral clearance in 1 of them. Of the remainding 2 cases of chronic rejection, 1 is alive following retransplantation with no detectable HCV ribonucleic acid in serum (patient 5), while the other died waiting for retransplantation despite an initial improvement following the introduction of potent immunosuppressive agents (patient 4). None of the variables analyzed, including the degree of fibrosis at baseline, age, gender, donor age, baseline immunosuppression, type of antiviral therapy, time from transplantation, use of growth factors, maintenance ribavirin, and trough levels of calcineurin inhibitors at baseline and at 1 month, were predictive of rejection (data not shown).
Table 3. Treatment and Outcome of Rejection After Interferon Therapy for Recurrent Hepatitis C
|1||53||M||Tac||CH: moderate A, portal F||IFN-Rbv||410||Severe AR with cholestasis||3 g. MP||Progressive improvement in liver enzymes. Follow-up biopsy one year later: chronic hepatitis C with moderate activity and portal fibrosis||206||NR|
|2||44||M||Cyc||CH: mild A, no F, significant cholestasis||PegIFN-Rbv||419||CR||Switch to FK, Add P||Slow but progressive improvement in LFT.||77||NR|
|3||43||M||Cyc/MMF/P||CH: moderate A, bridging F, significant cholestasis||PegIFN-Rbv||122||CR||Switch to FK. Continue MMF and P||Slow but progressive improvement in LFT||174||SVR|
|4||61||M||Cyc/MMF||CH: severe A, bridging F||PegIFN-Rbv||408||Severe AR → CR||3 g. MP. Switch to FK. Add MMF||Death while in the waiting list for re-LT||171||SVR|
|5||61||F||Cyc||CH: severe A, bridging F||Peg/Rbv||488||CR||Re-LT||Alive 6 months post-reLT||161||SVR|
|6||65||M||Cyc||CH: severe A, bridging F||IFNpeg-Rbv||484||AR||3 g. MP||Dead due to decompensated recurrent HCV disease||13||NR|
Paired biopsies at baseline and at end-of-therapy/end-of-follow up were available in 38 patients, 25 who had completed therapy and 13 who had prematurely discontinued treatment due to side effects. A comparison of activity scores between month 0 and months 12 to 18 showed significant improvements in activity in 60% of virological responders; in contrast, improvement in fibrosis was only observed in 20%. The changes in activity and fibrosis scores observed following therapy are shown in Table 4.
Table 4. Comparison of Histological Findings Between Pretherapy and Posttreatment liver biopsy (n = 38)
|Fibrosis|| || ||ns|
| Better||20%||14%|| |
| No change||40%||47%|| |
| Worse||40%||39%|| |
|Activity|| || ||ns|
| Better||60%||37%|| |
| No change||30%||37%|| |
| Worse||10%||26%|| |
Predictors of SVR (Table 5)
Univariate analysis demonstrated that there was a significant difference in SVR between those treated with standard as opposed to pegylated interferon (13% vs. 50%). The response was also substantially higher among those in whom erythropoietin had been used as opposed to those who did not use this factor (53% vs. 26%, P = 0.04). In addition, viral load at 3 months of therapy was significantly associated with SVR, so that a SVR was achieved in 55% of those with an early virological response (defined as a decline in viral load higher than 2 logs from baseline) as opposed to 5% in those with persistent viremia (>2 logs) at 3 months of therapy (P = 0.001). Among patients with genotype, 2 of 3 patients were more likely to achieve an SVR than those infected with genotype 1 (60% vs. 30%), but there were only 5 non-genotype 1 infected patients and the difference did not reach statistical significance.
Table 5. Baseline and “On-Treatment” Predictive Factors of Sustained Virological Response
|Type of therapy|| || || |
| Standard IFN (n = 31)||4 (13%)||27 (87%)||0.001|
| Peg-IFN (n = 36)||18 (50%)||18 (50%)|| |
|Genotype|| || || |
| Genotype 1 (n = 62)||19 (31%)||43 (69%)||ns|
| Genotypes non-1 (n = 5)||3 (60%)||2 (40%)|| |
|Viral load at baseline (IU/L)||5.0 × 105 (4.5 × 104 − 19 × 106)||10.5 × 105 (2.1 × 104 − 16.1 × 106)||ns|
|Acute hepatitis pretherapy|| || || |
| Yes (n = 6)||1 (17%)||5 (83%)||ns|
| No (n = 59)||20 (34%)||39 (66%)|| |
|Gender|| || || |
| Male (n = 43)||15 (33%)||30 (67%)||ns|
| Female (n = 22)||7 (32%)||15 (68%)|| |
|Age at therapy (yr)||47 (30-64)||54 (33-67)||ns|
|Body mass index at therapy||26 (17-31)||26 (20-38)||ns|
|Donor age (yr)||41 (17-69)||47 (16-76)||ns|
|Fibrosis pretherapy|| || || |
| F 0-F 1 (n = 18)||3 (17%)||15 (83%)||ns|
| F 3-F 4 (n = 43)||17 (33%)||26 (60.5%)|| |
|Cirrhosis pretherapy|| || || |
| Yes (n = 9)||3 (33%)||6 (67%)||ns|
| No (n = 52)||17 (33%)||35 (67%)|| |
|Necroinflammatory grade pretherapy||9 (6-13)||9 (0-13)||ns|
|Antiviral therapy in the past (before transplantation)|| || ||ns|
| Yes (n = 13)||4 (31%)||9 (69%)|| |
| No (n = 54)||18 (33%)||36 (67%)|| |
|Prior rejection episode|| || || |
| Yes (n = 14)||4 (29%)||10 (71%)|| |
| No (n = 49)||18 (37%)||31 (63%)||ns|
|Immunosuppression|| || || |
| Cyclosporine (n = 28)||11 (39%)||17 (61%)||ns|
| Tacrolimus (n = 39)||11 (28%)||28 (72%)|| |
|Time from transplantation to therapy (yr)||571 (122-3978)||480 (156-3055)||ns|
|Early VR at 3 months|| || ||0.0001|
| Yes (n = 29)||16 (55%)||13 (45%)|| |
| No (n = 20)||1 (6%)||19 (95%)|| |
|Erythopoietin use|| || || |
| Yes (n = 17)||9 (53%)||8 (47%)||0.04|
| No (n = 50)||13 (26%)||37 (74%)|| |
|GCSF use|| || || |
| Yes (n = 9)||5 (56%)||4 (44%)||ns|
| No (n = 58)||17 (29%)||41 (71%)|| |
SVR rates were not significantly impacted by transient dose reductions of either drug alone. However, dose reductions or premature terminations of therapy that resulted in the patient not reaching 80% of the recommended dose of both drugs during 80% of the recommended duration resulted in lower response rates (Table 2). The SVR rate among patients achieving at least 80% of recommended dose for each drug and 80% of recommended duration of therapy was 54% vs. 25% for patients who were unable to achieve all criteria (P = 0.03).
The remainder variables analyzed including gender, age, pretransplantation antiviral therapy, or history of significant alcohol consumption, Child-Turcotte-Pugh classification and hepatocellular carcinoma at transplantation, baseline immunosuppression, disease severity, laboratory tests, and body mass index at initiation of therapy, time from transplantation to therapy, use of granulocyte colony growth factors, or past rejection episodes, had no significant effect on SVR (Table 5). In particular, an SVR was achieved in the same proportion of patients under cyclosporine compared to those under tacrolimus (11/28, 39% vs. 11/39, 28%; P = 0.3). Baseline characteristics that differed between the cyclosporine and tacrolimus group were: a higher proportion of patients with advanced fibrosis (F3 and F4) (81% vs. 55%, P = 0.035) and a longer duration from transplant to antiviral therapy in the former vs. the latter group (median 1,251 vs. 473 days, P = 0.03). All remaining baseline characteristics did not differ among these 2 groups (data not shown). Likewise, the proportion of patients achieving a SVR was similar in those who had been previously treated with antivirals compared to those who had not received antiviral agents prior to liver transplantation (31% vs. 33%, P = 0.8). The only variable that differed between these 2 groups was donor age (median of 22 yr in the group of patients who had received antiviral therapy in the past compared to 47 yr in those never treated; P = 0.03). The remaining variables did not differ among these 2 groups (data not shown).
The same results were obtained when only genotype 1 infected patients were analyzed (data not shown).
Multivariate analysis using logistic regression analysis was performed for the variables that showed a level of significance of P < 0.1. The only variable that remained in the model was “the early virologic response at 3 months” (P = 0.01). The same results were found when only patients with genotype 1 were analyzed (data not shown).
The need to optimize outcomes for hepatitis C-infected recipients is one of the most pressing issues facing transplant physicians.1, 2 Antivirals have been used in an attempt to modify the course of HCV-disease. Indeed, data from prior studies suggest that sustained viral eradication leads in most cases to histologic improvement.20, 21 Changes in histology, though, are generally not immediate but rather occur several years after viral clearance. However, while substantial improvements have been made in the treatment of chronic hepatitis C in the non-immune compromised host in the last few years, with the combination of interferon-ribavirin and more lately peg-interferon/ribavirin,15 results in the liver transplant setting have been less impressive.6 With standard interferon in combination with ribavirin,6 an SVR is achieved in only 22% of treated transplant recipients, a percentage significantly lower to that reported in the immune competent population treated with the same regime.6, 15, 19, 22 Reasons for this lower response include a high prevalence of factors known to be associated with lack of response in the nontransplant population (high viral load, high prevalence of HCV genotype 1, low tolerability with difficulties in achieving full-dose treatment, and high prevalence of prior nonresponders) and presumably, a lower response to HCV therapy in patients with impaired immune function. The recent success of pegylated interferon with ribavirin in the nonimmunosuppressed population15 has prompted most centers to switch from standard interferon to pegylated interferon. Data on this approach though are scarce,6–11 and there are still several issues which remain to be addressed. In particular, determining pre and on-treatment factors associated with viral clearance and defining the risk of rejection. These aspects, which we believe are extremely relevant in the management of transplant recipients, were the 2 major aims of our study. The conclusions from this study based on “a treatment-on-recurrence strategy” may be summarized as follows: 1) HCV clearance is achieved in a significantly higher proportion of HCV-infected liver transplant recipients treated with pegylated interferon-ribavirin compared to standard interferon-ribavirin; 2) A lack of early virologic response at 3 months of therapy is a very useful tool to predict failure of therapy; 3) The type of calcineurin inhibitor used does not influence the outcome of antiviral therapy; 4) A history of prior nonresponse to interferon therapy before transplantation does not influence the outcome following posttransplantation antiviral therapy; 5) Although HCV clearance is achieved in a significant proportion of HCV-1b infected liver transplant recipients treated with pegylated or standard interferon- ribavirin, treatment may be hampered by the development of severe rejection, potentially leading to graft loss; and 6) Rejection following the use of interferon/pegylated interferon therapy is difficult to predict with current easily obtainable variables, but appears to be more common with the pegylated form of interferon.
In our study, an SVR was achieved in 47% of HCV-genotype 1 patients treated with the combination pegylated interferon-ribavirin and in 75% of those infected with genotypes 2 or 3. These results are in accordance with some of the earlier studies reporting their experience with this new therapy,7, 8, 10 thus confirming the significant improvement achieved with the introduction of the pegylated form of interferon as opposed to standard interferon. In fact, the results from our and other studies suggest that, as opposed to standard interferon, the rate of sustained viral clearance is relatively similar in transplant and nonimmunosuppressed patients. In addition, results in this study were similar regardless of time of initiation (in the acute vs. chronic phase of the disease) as recently suggested by Castells et al.23 We believe, though, that patients treated after several months from transplantation are less sick and debilitated and more eager to receive a “difficult-to-tolerate” therapy than those treated in the first months following the surgery. In addition, it is known from previous studies that a substantial proportion of patients have a nonprogressive disease and that histological findings in the early biopsies, performed either by protocol or due to clinical indication, are extremely helpful in predicting subsequent progressive disease.17, 19 Finally, it is clear from this and other studies that therapy with interferon in the transplant population is associated with serious side-effects, including chronic rejection.24, 25 Based on these assumptions, we believe that antiviral therapy with pegylated interferon and ribavirin should be preferentially recommended in patients in whom disease progression is evidenced in serial liver biopsies.
Factors known to negatively influence response to antiviral therapy in the nontransplant population appear to also apply in the transplant population. Indeed, response was higher in genotypes 2 and 3 infected patients than in those infected with genotype 1, although due to the small number of non-genotype 1 patients, the difference did not reach statistical significance. Viral load at 3 months was very useful in predicting the failure to achieve a sustained viral clearance. Indeed, only 1 of 18 among those who did not achieve an early virological response had an SVR. These findings, already useful in the nontransplant population,15 are more relevant in the liver transplant setting, in which side effects are more frequent and also more problematic to deal with. However, given the progressive nature of hepatitis C in the liver transplant setting, it may be worthwhile, at least in recipients with advanced disease and relatively good tolerance to antiviral therapy, to continue the treatment despite a lack of early virologic response in order to stabilize and/or improve histologic damage. However, whether continuing therapy in this context will eventually lead to an improvement in outcome needs to be fully explored in a prospective randomized way.
Interestingly, the duration of therapy did not appear to impact treatment response. Almost 1 of 3 patients who had treatment interrupted before reaching month 12 due to side-effects had an SVR percentage not statistically different from that found in patients who did not interrupt therapy prematurely. However, the combination of dose and duration of therapy was found to be predictive of outcome with the rule 80 × 80 × 80 also applying in our transplant population. These results emphasize the importance of support to maximize treatment compliance with an interferon-based regimen. In that sense, the use of erythropoietin, a variable found to be predictive of response in univariate analysis, may be a useful tool in enhancing patient adherence, and therefore optimizing dosing and duration of therapy.
As reported previously in several studies assessing antiviral therapy in the liver transplant population,6, 11–15 the tolerance was problematic with more than half of the patients requiring dose reductions, specially of ribavirin; in addition, therapy was prematurely discontinued in 40%. Neither the use of erythropoietin nor granulocyte stimulating factor had an apparent effect on treatment discontinuation. Treatment was discontinued in 35% of those using erythropoietin as opposed to 42% of those in whom this drug was not used, and in 44% of those in whom granulocyte stimulating factor was used compared to 40% of those in whom granulocyte stimulating factor was not used. However, these results may reflect the small number of patients treated with either agent.
One of the most severe side effects leading to treatment discontinuation was rejection. This complication occurred in 6 patients, 1 under standard interferon therapy and 5 under pegylated interferon. Though not statistically significant, possibly due to the small number of events, patients were relatively equally-divided between standard interferon and pegylated interferon, suggesting that the use of pegylated interferon is a risk factor for rejection. Unfortunately, none of the variables analyzed were predictive of rejection, again possibly reflecting the small number of patients developing this complication. In contrast to other studies,26 the levels of immunosuppressive agents before the development of rejection were in the correct range (data not shown). Interestingly, an SVR was achieved in 3 of 4 patients who developed chronic rejection despite the early termination of therapy and the addition of potent immunosuppressive agents to treat rejection.
Recently, some studies have suggested that cyclosporine may have an antiviral effect,14 which may in turn increase the rate of viral clearance.13 We were, however, unable to show differences in treatment response among those immunosuppressed with cyclosporine as opposed to those who used tacrolimus. However, treatment had been started at a later stage in those under cyclosporine (higher proportion of patients with advanced fibrosis), probably reflecting the more recent introduction of tacrolimus (longer time elapsed from transplantation to antiviral therapy in those under cyclosporine than in those under tacrolimus).
Likewise, a history of prior treatment with antivirals before liver transplantation did not appear to impact treatment success following antiviral therapy in the posttransplantation period. While this is an interesting observation, it must be interpreted with caution, since in most cases we were unable to assess whether both the dose and duration of therapy in the past had been adequate.
In conclusion, our results indicate that response of hepatitis C liver transplant patients to pegylated interferon-ribavirin can closely mirror the response obtained in the nontransplant population. The tolerance though is unsatisfactory, and rejection remains a matter of concern in these patients.