Tuesday, April 7, 2015

Hepatitis C virus recurrence after liver transplantation: A 10-year evaluation

World J Gastroenterol 2015 April 7; 21(13): 3912-3920

View Full Text: Introduction, Tables, Results and References, here

Because LT is agreed to be a life-saving therapy for end-stage liver disease, HCV has become one of its leading indications. Re-infection of the graft is virtually universal and HCV recurrence after LT is a “new disease” whose clinical, virological and immunological characteristics are determined by complex, and almost unknown, interactions between patient, graft and the virus. However, it is well known that fibrosis progression is accelerated in HCV recurrence compared with the pre-LT period and a small proportion of patients (approximately 5%) show a fast and aggressive disease after LT[22]. In this context, it can be very complex to decide whether and when it is appropriate to treat the HCV recurrence.

Berenguer et al[7] compared 89 treated patients with 75 matched untreated controls and, among the treated cases, patients who achieved a SVR with subjects who did not. The authors first demonstrated that all the main measures of outcome (mortality, development of cirrhosis and decompensation) were worse for untreated patients compared to patients who were treated and for NR compared to SVR. Our study confirms the findings of Berenguer et al[7] regarding the positive role of SVR. Moreover, it offers an additional analysis focused on the long-term outcome of the broad and heterogeneous population of untreated patients, which has never been thoroughly investigated.

Our data indicate that the treatment itself was not associated with a better long-term outcome. In fact, we showed that treated and untreated patients had a comparable 10-year survival rate. However, the untreated group comprised a very inhomogeneous population. In particular, the reason for the choice not to start antiviral therapy could also be related to conditions different from a mild disease all having a distinct impact on survival, such as a too severe hepatic condition, a comorbidity (of varying severity) or the lack of compliance.

It should be acknowledged that the design of the study from Berenguer et al[7] was more appropriate as the results emerged from the comparison with a population of matched controls. Indeed, we analyzed a heterogeneous group of untreated patients, which comprised three different subgroups: (1) patients with mild HCV recurrence; (2) patients too sick to be treated; and (3) patients with comorbidities. Interestingly, untreated patients with mild HCV recurrence showed a 10-year survival rate that was comparable to treated patients achieving a SVR (89.3% vs 84.7%, respectively). Notably, patients included in the mild recurrence subgroup had no clinically relevant comorbidities nor graft malfunction and/or complications after LT. In fact, these conditions a priori can affect long-term survival.

Our data confirm that a SVR is an independent predictor of 10-year survival as only two SVR patients of 63 died of an HCV-related cause in the follow-up period. Together with achieving a SVR, our study once again confirms the impact of donor age on the severity of HCV-recurrence, the response to antiviral therapy and survival. In fact, it has been largely reported that older donor age negatively affects the progression of fibrosis in transplanted patients[23-27].

Regarding the treatment of HCV recurrence, it is important to consider the oncoming availability of DAAs. Currently, several reports on first wave PI treatment in the post-LT period are available. Recent studies reporting data on the efficacy and safety of BOC/TVR and PegIFN/RBV[28,29] showed encouraging efficacy results but also a complex side effects profile including infections, hematological and dermatological toxicity, renal failure, diabetes, drug-drug interactions with immunosuppressants and severe forms of plasma-cell hepatitis with occasional fatal outcomes[28-32]. The data on triple BOC/TVR based regimens are of great importance considering that the second/third wave DAA cost issue will continue to produce controversy for a certain amount of time in the future. Sofosbuvir, a pan-genotypic inhibitor of polymerase activity, is reported to have a good virological outcome and favorable safety profile when associated with Daclatasvir[33] or PegIFN ± RBV[18,19,34], and also in the treatment of severe HCV recurrence.

The main limitation of our study is the retrospective design. Nonetheless, this approach is a feasible one to analyze the long-term outcomes of transplanted patients. The most important issue emerging from our data is that the antiviral treatment should be undertaken in patients with moderate-severe disease because of the high risk of progression to recurrent cirrhosis, decompensation and death in the time of a few years[2,3]. Evidence has emerged from our study and many others that clearly indicate that achievement of a SVR may avoid this unfortunate course. On the other hand, our data suggest that patients with mild HCV recurrence have a very favorable long-term outcome even if untreated. Interestingly, a prospective randomized trial conducted in Italy confirms, at least partially, the observations emerging from our retrospective cohort[35]. Notably, it appears mandatory to have, in the first three years after LT, a correct histological classification for patients with HCV recurrence.

Our results can be useful in the complex decision-making process regarding whether and when to start antiviral treatment in LT recipients with HCV recurrence. This is even more important today with the availability of new DAAs, whose inappropriate use can dramatically increase costs, adverse event rates, drug-drug interactions and the risk of a virological resistance outbreak. 

Finally, the results from our cohort reveal that a certain rate of mortality in post-LT HCV recurrence concerns patients with comorbidities that are often considered as contraindications to antiviral treatment. Along with the availability of antiviral agents with a low-toxicity profile, the limitations related to the patients’ eligibility for the treatment are expected to be reassessed. Furthermore, according to recent compassionate program derived results, the antiviral treatment will become increasingly applicable in the so called too sick to be treated population[18]. However, in those cases in whom a severe HCV recurrence is diagnosed, due to the latter’s rapidly progressive nature, the treatment should be started as soon as possible.

Thus, more information from predictive analyses are necessary at this moment because data focused on the long-term effectiveness of antiviral therapy would help with a more feasible guidelines conception, correct clinical approach and rational cost-effectiveness treatment management in the LT population.

In conclusion, awaiting the consolidation of new interferon-free regimens, we suggest that, in carefully selected patients with predictors of long-term favorable outcomes, antiviral treatment might be delayed. Most likely, the development of interferon-free regimens will completely change the approach to HCV in both pre- and post-LT settings. Nevertheless, studies focusing on the mechanisms and factors leading to a mild HCV recurrence will still be extremely useful.

View Full Text: Introduction, Tables, Results and References, here

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