Tuesday, January 8, 2013

Efficacy of the retreatment of hepatitis C virus infections after liver transplantation: Role of an aggressive approach

Efficacy of the retreatment of hepatitis C virus infections after liver transplantation: Role of an aggressive approach

Marina Berenguer1,2,3,*,
Bruno Roche4,
Victoria Aguilera1,2,
Jean-Charles Duclos-Vallée4,
Laia Navarro2,
Angel Rubín1,2,
Jose-Antonio Pons2,5,6,
Manuel de la Mata2,7,
Martín Prieto1,2,
Didier Samuel4

Article first published online: 27 DEC 2012

DOI: 10.1002/lt.23555

Abstract and discussion provided below 

A sustained virological response (SVR) is achieved by 30% of naive liver transplantation (LT) recipients treated with pegylated interferon (PEG-IFN) and ribavirin (RBV). Almost no data are available about retreatment. The aim of this study was to assess the efficacy, tolerability, and SVR predictors of retreatment. Data were collected from 4 centers on the retreatment of prior nonresponders to standard therapy or PEG-IFN (with or without RBV) and relapsers. Seventy-nine of 301 treatment-experienced LT patients (26%), who had a median age of 59 years (range = 35-77 years) and were mostly male (72%) and infected with genotype 1 (87%), were retreated with PEG-IFN and RBV at a median of 6.9 years after LT. During the first course of therapy, 35% were treated with interferon, 49% received tacrolimus, 52% received steroids, and 49.5% were relapsers. Retreatment was started at a median of 1.9 years (range = 45 days to 8.2 years) after the end of the first course. The proportion of patients with cirrhosis increased from 10% to 37% (P < 0.001). In addition, in retreated patients, full initial RBV doses (P = 0.03), growth factors [erythropoietin (P < 0.001) and granulocyte colony-stimulating factor (P = 0.048)], and transfusions (P = 0.03) were used more frequently, and the treatment duration was longer (P = 0.03). An end-of-treatment response was achieved in 61%, whereas SVR, which was associated with improved survival, occurred in 28 (35%). The variables predicting SVR were age (P = 0.04), disease severity [fibrosis (50% with F0-F2 versus 26% with F3-4), P = 0.03; bilirubin, P = 0.006; platelet count, P = 0.03], adherence, and viral kinetics. None of the patients without an early virological response achieved SVR. There was a trend of prior relapsers achieving higher SVR rates than prior nonresponders. In conclusion, SVR, which was achieved by approximately one-third of the retreated patients, can be predicted with the same variables used for naive LT recipients (age, disease severity, adherence, and viral kinetics) and is associated with enhanced survival. Liver Transpl 19:69–77, 2013. © 2012 AASLD.
After liver transplantation (LT), a response to interferon (IFN)-based therapies resulting in the permanent eradication of hepatitis C virus (HCV) is associated with improved histology, reduced disease progression, a decreased risk of clinical decompensation, and improved overall graft and patient survival.1-8 The standard current therapy in the setting of LT is pegylated interferon (PEG-IFN) with ribavirin (RBV), and a sustained virological response (SVR) is achieved by approximately one-third of patients.1-11 As for those who do not achieve SVR, there are 2 major categories: nonresponders and responders who relapse. Because of the accelerated course of recurrent HCV disease in the LT population and the limited efficacy of current antiviral therapy, it is expected that the number of prior failures with a first course of antiviral therapy will increase in the future.
Among immunocompetent patients, the retreatment of prior relapsers with PEG-IFN and RBV results in higher rates of SVR than the retreatment of prior nonresponders; this is particularly true for patients who received suboptimal therapy during the first course (ie, monotherapy with IFN, therapy for a suboptimal duration, or suboptimal doses of RBV or IFN). In contrast, the retreatment of prior nonresponders (particularly those for whom a prior course with PEG-IFN and RBV has failed) results in a significantly smaller proportion of patients achieving SVR, even when the patients are retreated with aggressive approaches such as an induction phase with high PEG-IFN doses together with the prolongation of therapy.12, 13
Triple therapy with protease inhibitors in combination with PEG-IFN and RBV has become the standard of care in immunocompetent patients with genotype 114-16 and most specifically in prior relapsers because of the high rates of SVR achieved (on the order of 85%). There are no data yet about the efficacy of these compounds in the transplant population. In order to determine adequately the benefits of these new therapies versus PEG-IFN and RBV in transplant patients, we first need to define the efficacy and tolerability of PEG-IFN and RBV in both naive and retreated recipients. Although many studies have now been published about antiviral therapy in naive recipients after transplantation,1-11 there are almost no data on retreatment in this setting9, 17, 18 or studies evaluating factors that might predict retreatment outcomes.
In this study, we aimed to determine in patients with recurrent HCV (relapsers or prior nonresponders to a previous posttransplant IFN-based course) the efficacy, safety, and benefits of retreatment with PEG-IFN and RBV. In particular, our aims were (1) to determine whether retreatment with PEG-IFN with or without RBV results in virological or clinical benefits and (2) to assess predictive factors associated with a virological response, including rapid virological response (RVR), treatment adherence, donor age, baseline immunosuppressive therapy (cyclosporine A versus tacrolimus), and baseline fibrosis.

Discussion Only
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Recurrent progressive disease is one of the major challenges in transplant centers.1 Treatment with antivirals is the only means for improving the outcome. Persistent viral eradication has indeed been shown to improve histology, decrease the risk of decompensation, and thereby increase graft and patient survival.1-10 Unfortunately, only one-third of treated patients achieve SVR when they are treated after LT, whereas another third are considered nonresponders, and one-quarter to one-third relapse after they achieve a viral response at the end of therapy.1, 9-11, 18-24 Although significant data have accumulated for the immunocompetent population with respect to treatment options for these nonresponders,12-16 there is almost no information for the transplant population.
The aim of our study was, therefore, to determine the benefits, limitations, and predictive factors of retreatment with both PEG-IFN and RBV in a relatively large number of HCV-infected LT recipients recruited at 4 transplant centers who had not achieved SVR after the first course of antiviral therapy. Although we acknowledge that PEG-IFN and RBV will soon be history and that the transplant community should be and is already focusing on testing direct antiviral agents with or without PEG-IFN and RBV to improve tolerability and SVR rates, this article sets the bar that those studies will need to exceed in the future.
The main findings of the study can be summarized as follows: (1) patients who are selected for or agree to retreatment represent a heavily biased subset of the pool of potential candidates for retreatment; (2) in this difficult-to-treat population of prior nonresponders to IFN-based regimens who are mainly infected with genotype 1 virus with a high viral load and include a high proportion of patients with an advanced stage of disease, SVR can be achieved by a substantial number of patients (30% on average); (2) SVR is associated with improved outcomes; (3) advanced disease is associated with impaired SVR rates; (4) an aggressive approach to treatment adherence results in enhanced viral eradication; and (5) viral kinetics are highly predictive of SVR.
The first important consideration is that a failure to respond to an initial course of antiviral therapy should not preclude a second course, even in the presence of negative factors for a treatment response. However, an effort should be made to retreat patients before the disease is too advanced because treatment at advanced stages of fibrosis is associated with poorer SVR rates as well as lower treatment benefits in terms of survival. Baseline severity is a variable that has been shown in previous studies to be associated with SVR in both immunocompetent patients and LT recipients. In particular, cirrhosis has been found to be associated not only with decreased treatment efficacy but also with worse tolerability after a first course of antiviral therapy.2, 4, 7, 8, 18, 22, 24 Importantly, just as with first courses of therapy,1-6 SVR was significantly associated with improved survival in the univariate analysis. Although in the multivariate analysis survival was no longer associated with SVR but mostly depended on baseline disease severity, the P value for SVR as an independent predictor of survival approached statistical significance (P = 0.08), and this emphasized the concept that treatment and/or retreatment should not be delayed until advanced stages of fibrosis.
In addition, it is also important to ensure a full course with full doses of antivirals in order to improve the results. An aggressive approach to treatment adherence (particularly RBV doses) has also been shown to improve treatment efficacy in both immunocompetent patients and LT patients.8, 22-24
Finally, just as in the nontransplant population and in transplant patients treated for the first time,1, 6, 7-9, 18-24 viral kinetics were highly predictive of SVR, with 61% of RVR patients finally achieving SVR; in contrast, none of the non-EVR patients achieved SVR. In the new era of direct antiviral agents, data on RVR and its predictability for SVR can be relevant.
Surprisingly, neither the type of response to antiviral therapy during the first course nor the type of therapy (monotherapy versus combination therapy, standard IFN versus PEG-IFN, or relapse versus nonresponse)—factors known to significantly affect treatment outcomes in immunocompetent patients12-16—had an effect on SVR in our cohort of retreated LT patients. There was a trend, however, in the type of response to prior therapy: prior nonresponders had lower probabilities of achieving SVR in comparison with prior relapsers. This might be a reflection of the sample size; alternatively, it is likely that other cofactors extremely common in the LT setting (eg, degree of immunosuppression, treatment adherence, and patients' and donors' genetic backgrounds) play a more important role in this setting. Indeed, a favorable interleukin-28B genotype in both the donor and the recipient is significantly associated with SVR.22, 25-27 Unfortunately, we had no data on interleukin-28B in our study. However, the distribution of these genotypes could not have changed between the 2 treatment courses. In immunocompetent patients treated with triple therapy (PEG-IFN, RBV, and telaprevir or boceprevir), the type of response to a prior course of therapy is the strongest predictor of retreatment outcome, so that an SVR rate of 85% can be achieved when relapsers are retreated, regardless of baseline fibrosis; however, these rates are substantially lower for prior nonresponders and range from approximately 30% for prior null responders to 50% for prior partial responders.14-16 If the same results are obtained for LT recipients, retreatment with double therapy (with which SVR is achieved in approximately 25% of prior nonresponders and in 40%-45% of prior relapsers) should no longer be used. Future studies with triple therapy in LT recipients will answer this question.
In conclusion, SVR can be achieved by approximately one-third of LT recipients retreated with a course of PEG-IFN and RBV. The treatment of patients before they reach an advanced stage of fibrosis is associated with better results. However, relatively good results can be achieved even in the presence of advanced fibrosis, with an SVR rate of approximately 25%. An aggressive approach to treatment adherence, however, is required to obtain these results. Viral kinetics are extremely helpful in this setting and have predictive values similar to those for the treatment of naive LT recipients.


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