Treatment of HCV Recurrence: Do the Pretransplantation Rules Apply?

Transcription

1 LIVER TRANSPLANTATION 12: , 2006 EDITORIAL Treatment of HCV Recurrence: Do the Pretransplantation Rules Apply? James R. Burton, Jr., and Hugo R. Rosen Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado Health Sciences Center, Denver, CO Received February 16, 2006; accepted February 24, See Article on Page 1067 Hepatitis C virus (HCV)-induced liver disease is the leading indication for liver transplantation in the Western world, and recurrent infection occurs universally. Recurrence of HCV is a major problem for the transplant physician, as recurrent HCV infection appears to significantly impact posttransplantation survival. 1 Although nearly all patients develop some evidence of histologic recurrence, the natural history of recurrent HCV is highly variable and poorly understood. Approximately one-third will develop minimal fibrosis after 5 yrs of follow-up, 2 yet for others the natural history is accelerated, with 20 to 40% developing allograft cirrhosis after 5 yrs, compared to 3 to 20% at 20 yrs in the nontransplant setting. 3-6 In addition, it appears that rates of fibrosis progression appear to be increasing, 7,8 and once cirrhosis develops, rates of decompensation and death are high. 6 Given the impact the natural history of HCV recurrence has on graft and patient survival, several treatment strategies have been utilized to prevent or slow the progression to HCV-related graft failure. These include antiviral therapy prior to transplantation, prophylactic therapy starting at the time of transplantation to prevent allograft reinfection, preemptive therapy initiated in the early posttransplantation period before the development of clinically apparent acute hepatitis, and posttransplantation therapy at time of diagnosis of acute hepatitis or for established severe and/or progressive chronic hepatitis. A fundamental, yet unanswered, question is whether what we know regarding the treatment of the pretransplant patient translates into relevant guidelines following transplantation (Table 1). The article by Berenguer et al. 10 from Valencia in this issue of Liver Transplantation adds significantly to our evolving knowledge base in that regard. Results of antiviral therapy for recurrent HCV have been generally disappointing. Most published studies investigating the role of treating recurrent HCV with standard interferon with or without ribavirin (no longer the standard of care) have for the most part been small, single-center, or uncontrolled trials with significant variability in patient selection, type and timing of antiviral therapy administered, and study endpoints evaluated (i.e., histologic response, end of treatment response, sustained virologic response). Rates of sustained virologic response (SVR) in liver transplant patients have been far less than those achieved in the nontransplant population. Potential reasons for this difference include higher HCV ribonucleic acid (RNA) levels post-liver transplantation, a higher frequency of genotype 1 patients, and the clinical status of liver transplant patients (including cytopenias), especially in the early posttransplantation period, leading to poor tolerability and need for frequent dose reductions. Welldesigned, randomized, controlled studies are needed to determine who is most likely to benefit from treatment and to determine the optimal timing of treatment. In a series of 92 liver transplant patients with recurrent HCV infection, Samuel et al. 11 randomized 52 eligible patients to receive either no treatment (n 24) or therapy (n 28) with interferon alfa-2b (3 million units 3 times per week) plus 1,000-1,200 mg/day ribavirin for 1 yr. Treatment resulted in an SVR in 21%, yet 43% discontinued treatment due to side effects, primarily severe anemia. No significant histological improvement was noted between the treatment and control groups. Abbreviations: HCV, hepatitis C virus; SVR, sustained virologic response; EVR, early virologic response; RNA, ribonucleic acid. Address reprint requests to James R. Burton, Jr., MD, University of Colorado Health Sciences Center, Division of Gastroenterology and Hepatology, 4200 East Ninth Avenue, B154, Denver, CO Telephone: ; FAX: ; James.Burton@uchsc.edu DOI /lt Published online in Wiley InterScience ( American Association for the Study of Liver Diseases.

2 EDITORIAL 1045 TABLE 1. Comparison of Variables Associated with SVR in the Pre-Transplant and Post-Transplant Setting Pretransplantation SVR* Posttransplantation SVR Genotype Genotype 1 vs. genotype 2/ % vs. 80% 4 19% vs % 9,14,17 Baseline HCV RNA 2 million copies/ml vs. 2 million copies/ml 40% vs % No difference 10 Degree of fibrosis No/minimal fibrosis vs. bridging fibrosis/cirrhosis 50 60% vs % No difference 15 Ribavirin dose 800 mg vs. 1,000/1,200 mg 40% vs. 50% No difference 15 Duration of therapy 24 weeks vs. 48 weeks 30% vs. 50% No difference 9 80/80/80 rule 80/ 80/ 80 vs. 80/ 80/ 80 80% vs. 33% 53% vs. 25% week rule (EVR by 12 weeks) EVR vs. No EVR 70% vs. 0 2% 55% vs. 6% #10 NOTE: Posttransplantation treatment regimens of established HCV recurrence: Lavezzo et al. 9 interferon alfa 2b, 3 million units 3 times a week plus ribavirion 800 mg/day for 24 vs. 4 weeks; Berenguer et al. 10 pegylated interferon alfa-2a/2b and ribavirin, dose not defined, for 48 weeks; Biselli et al. 14 pegylated interferon alfa-2b 1.0 ( g/kg/week plus ribavirin 600 mg/day for 48 weeks; Dumortier et al. 15 pegylated inteferon alfa-2b 1.0 g/kg/week plus ribavirin 1,000 1,200 mg/day for 48 weeks; Chalasanti et al. 17 pegylated interferon alfa-2a 180 g weekly for 48 weeks. *Estimates of SVR in treating chronic HCV infection with pegylated interferon and ribavirin from References Genotype 1 only. Received 80% of total interferon dose and 80% of total ribavirin dose for 80% of the expected duration of therapy. During first 12 weeks of therapy % vs. 56% for completing 48 weeks. 15 Early virologic response, 2 log drop in HCV RNA from baseline. # 56% vs. 9% for HCV RNA ( ) vs. HCV RNA ( ) at 1 month; 100% vs. 18% for EVR at 6 months after starting treatment. 14 One patient in the treatment group developed chronic rejection. Treatment of HCV recurrence has mostly been modeled after the experience in treating HCV in the nontransplant setting, with most centers now using pegylated interferon, most often in combination with ribavirin. To date, there have been 6 trials enrolling 20 patients evaluating the efficacy of pegylated interferon with ribavirin in liver transplant patients. Sustained virological response rates have ranged from 31 to 45% This is a significant improvement over randomized controlled trials of pegylated interferon monotherapy reporting SVRs of 8% and 12% when used preemptively and for treatment of established disease, respectively. 17 Presumably, factors associated with viral clearance in the nontransplant setting, such as use of pegylated interferon and ribavirin, 18,19 non-genotype 1, 18,19 low pretreatment HCV RNA levels, 18,20 absence of bridging fibrosis or cirrhosis, 18 early virologic response (EVR, 2 log drop in HCV RNA from baseline at 3 months), 19,21 and adherence to combination therapy 22 are applicable to the transplant setting. In the retrospective analysis by Berenguer et al., patients (93% genotype 1; 64% stage 3 or 4) were treated with either standard interferon alpha-2b (46%) or pegylated interferon alpha-2a or -2b (54%), both in combination with ribavirin (doses not shown), between March 1999 and October Only those patients with at least 6 months of follow-up after discontinuing antiviral therapy were included. Patients receiving preemptive therapy were not included. Yearly protocol liver biopsies were performed at their center with the decision to treat being based on disease severity. In earlier years, when only standard interferon was available, treatment was reserved for those with bridging fibrosis or cirrhosis or cholestasis. More recently, with the availability of pegylated interferon, the authors report that therapy has generally been initiated at earlier stages, typically based on the first-year protocol biopsy or if progressive fibrosis was noted on later biopsies. Median time to treatment was 513 days and median time from biopsy to treatment was 65 days. The intended duration of therapy was 48 weeks and erythropoietin and/or granulocyte colony stimulating factor were used when considered appropriate. The primary end-point was SVR, defined as HCV RNA negative at 6 months posttreatment. Overall, 33% of patients achieved an SVR. When broken down by genotype, findings are consistent with the nontransplant setting with higher rates of SVR for nongenotype 1 (60%) vs. genotype 1 (31%). (As only 5 patients had non-genotype 1, this difference was not statistically significant.) However, these data are intriguing in light of recent studies demonstrating that a large proportion of genotype 2 or 3 patients can be treated for 12 or 16 weeks with excellent virologic response. 23,24 Consistent with the treatment of HCV in the nontransplant setting, pegylated interferon with ribavirin was associated with a higher rate of SVR compared to

3 1046 EDITORIAL standard interferon with ribavirin (50% vs. 13%, respectively; P 0.001). This SVR rate for pegylated interferon with ribavirin is similar to that seen in the nontransplant setting for genotype 1 patients 18,19 and is the highest reported SVR for pegylated interferon and ribavirin in transplant patients in any study with 20 patients to date. However, a treatment bias in favor of pegylated interferon may exist in this study as pegylated interferon was generally initiated at earlier stages of disease than standard interferon, with standard interferon historically being used predominately to treat bridging fibrosis and cirrhosis. We know from treating HCV in the nontransplant setting that presence of bridging fibrosis or cirrhosis impacts response to therapy. 18 Interestingly, in the study by Berenguer et al., 10 no difference in SVR was seen with respect to the presence or absence of significant fibrosis. In fact, patients with significant fibrosis (F3-F4) had higher percentages of SVR compared to those with minimal fibrosis (F0-F1) (33% vs. 17%). Additionally, the percentage of patients achieving SVR was identical (33%) when analyzed in terms of presence or absence of cirrhosis. Moreover, it is possible more than 6 months of follow-up after cessation of therapy are needed before a patient can be deemed to have a durable SVR. Late breakthrough after 6 months has been shown to be extremely rare in the pretransplant setting, but in the posttransplant setting, we have previously noted late breakthrough even after long-term treatment, particularly in patients with cholestatic HCV recurrence. 25 The only factor by multivariate analysis significantly associated with SVR was achieving an EVR. In this study, 55% of patients with an EVR subsequently achieved an SVR, and conversely, among those who did not have an EVR, 95% failed to develop an SVR (P 0.01). The predictability of an SVR based on EVR is similar to the nontransplant setting. 19 Biselli et al. 14 report similar findings with SVR rates about 3 times greater in patients who were HCV RNA negative at 1 month compared to those who tested positive. Additionally, patients with undetectable HCV RNA or 2 log drop from baseline levels 6 months after starting treatment were more likely to achieve an SVR than those who did not (100% vs. 18%; P 0.001). The significance between being HCV RNA negative vs. achieving a 2 log drop from baseline in the posttransplant setting is unknown. Davis et al. 21 determined in the pretransplant setting that being HCV RNA negative at 3 months after starting pegylated interferon and ribavirin is associated with an 84% rate of achieving an SVR, in comparison to a rate of 72% for those who are either HCV RNA negative or achieve a 2 log drop from baseline. The authors went on to propose a viral testing and management algorithm for genotype 1 patients that includes quantitative HCV RNA testing 3 months after starting treatment with pegylated interferon and ribavirin. Those who remain HCV RNA positive, but achieve a 2 log drop from baseline at 3 months are recommended to undergo qualitative HCV RNA testing at 6 months. Those who remain HCV RNA positive at 6 months are unlikely ( 1%) to achieve an SVR and thus should discontinue therapy. In the nontransplant setting, the overall dose and duration of therapy has been shown to be associated with an SVR. 22 In the transplant setting, rates of dose reduction and discontinuation due to side effects is high. In the Berenguer et al. 10 study, premature discontinuation (median 26 weeks in this study) and dose reductions (mostly due to cytopenias) of interferon and/or ribavirin occurred in 40% and 57%, respectively. How many patients with dose reductions who subsequently discontinued therapy is not clear. No difference in SVR was seen between those receiving 48 weeks of therapy and those with premature discontinuation (14/40 [35%] vs. 8/27 [30%], respectively). Since we do not know how many patients getting 48 weeks of treatment also had dose reductions, this may simply represent a comparison of full-duration treatment at reduced dose vs. premature discontinuation, which, extrapolating from the nontransplant setting, is likely to result in similar SVR rates. In contrast to this finding, Dumortier et al. 15 found that completion of treatment was important (100% of those with SVR completed 48 weeks of treatment vs. 56% of nonresponders completing treatment; P 0.05). Though only significant by univariate analysis, patients in the Berenguer et al. 10 study receiving 80% of the recommended dose of ribavirin and interferon during 80% of the recommended duration (48 weeks) had an SVR rate of 54% compared to an SVR rate of 25% in those who did not achieve this 80/80/80 rule (P 0.03). Taking 80% vs. 80% of the recommended dose of ribavirin trended toward significance, with an SVR in 50% vs. 25%, respectively (P 0.05). While the use of erythropoietin, presumably to allow higher doses of ribavirin to be administered, was associated an SVR (53% vs. 26%; P 0.04), other studies have suggested that use of erythropoietin does not prevent ribavirin dose reduction or discontinuation. 14,26 A similar trend as for ribavirin was noted for interferon; however, use of granulocyte colony stimulating factor was not associated with an SVR, though only 9 patients used this drug. In the nontransplant setting, prior history of relapse or nonresponse to antiviral therapy is associated with reduced likelihood of achieving an SVR when retreated, 27 unless patients are retreated with a more effective regimen. 28 In the Berenguer et al. 10 study, history of prior antiviral treatment was not associated with a reduced chance of an SVR. Whether those in this study with prior history of antiviral therapy were true nonresponders or relapsers and the type of interferon with which they were previously treated is not known. A potentially serious and controversial complication of antiviral therapy in transplant patients is rejection. Three uncontrolled trials of treatment of recurrent disease showed acute cellular rejection rates between 11 to 30%, 15,29,30 much higher than randomized controlled trials 11,17 and other uncontrolled trials (0-5%). 13,14,31 Concern exists that pegylated interferon may be associated with an increased risk of rejection because of its extended half-life. Three uncontrolled

4 EDITORIAL 1047 trials of pegylated interferon and ribavirin yielded conflicting results, with no cases of rejection in 2 studies 13,14 and a rate of 25% in another. 15 Controlled trials of pegylated interferon monotherapy as prophylactic therapy and for treatment of established disease showed no difference in rejection rates between treated and control patients. 17 In the Berenguer et al. 10 study, rejection occurred in 1 patient receiving standard interferon (3% of those treated with standard interferon) and in 5 patients receiving pegylated interferon (14% of patients receiving pegylated interferon). Though not statistically significant, this may suggest that use of pegylated interferon is a risk factor for rejection and requires further study. Moreover, data from the University of Colorado suggest that close monitoring of calcineurin inhibitor levels are necessary during antiviral therapy, as a greater proportion of antiviral responders experienced a greater reduction in immunosuppression levels than nonresponders, presumably since improved hepatic function leads to enhanced biotransformation and lower immunosuppression levels. 32 This decrease in immunosuppression levels may play a key role in predisposing these patients to rejection. So what do this and other recent studies tell us about treatment of recurrent HCV today? As has been predicted based on experience in the nontransplant setting, it appears that when used to treat established disease, the combination of pegylated interferon with ribavirin achieves far higher rates of SVR than pegylated interferon monotherapy or standard interferon with ribavirin. We still need randomized controlled trials of pegylated interferon and ribavirin compared to standard interferon and ribavirin to determine if improved tolerability equates to higher rates of SVR. Assuming the presence of fibrosis in the transplant recipient does not significantly reduce the likelihood of virologic response, we can probably afford to take a wait and treat progressive disease approach, reducing risk of rejection, allowing lower doses of immunosuppression and increasing the likelihood of patient tolerability to therapy. This approach targets therapy to those who need it, avoiding toxicity in those who are not likely to benefit from treatment. Additionally, the EVR serves as an important guide, as it does in the nontransplant setting, to whether to continue therapy (presuming lack of significant histological benefit of interferon on histology in those not achieving SVR). Further study is needed on whether to use a low accelerating dosage regimen that may require shifting determination of EVR back until 3 months of full dose therapy have been achieved. Whether empiric use of growth factors can be used initially to allow full dose from the start requires further study. In summary, the most recent paper from the Valencia group 10 adds to our rapidly evolving understanding of how best to manage patients with HCV, underscoring that some rules apply and others do not. We look forward to results from multicenter studies to more fully define the rules for treating these very challenging patients. REFERENCES 1. Forman LM, Lewis JD, Berlin JA, Feldman HI, Lucey MR. the association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology 2002;122: Charlton M, Wiesner RH. Natural history and management of hepatitis C infection after liver transplantation. Semin Liver Dis 2004;24: Gane E. 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