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Long-term maintenance of sustained virological response in liver transplant recipients treated for recurrent hepatitis C
Digestive and Liver Disease 46 (2014) 440–445
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Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Liver, Pancreas and Biliary Tract
Long-term maintenance of sustained virological response in liver transplant recipients treated for recurrent hepatitis C Francesca Romana Ponziani a,∗ , Raffaella Viganò b , Rosa Maria Iemmolo c , Maria Francesca Donato d , Maria Rendina e , Pierluigi Toniutto f , Luisa Pasulo g , Maria Cristina Morelli h , Patrizia Burra i , Lucia Miglioresi j , Manuela Merli k , Daniele Di Paolo l , Stefano Fagiuoli g , Antonio Gasbarrini a , Maurizio Pompili a , on behalf of AISF RECOLT-C Group1 a
Agostino Gemelli Hospital, Rome, Italy Niguarda Ca’ Granda Hospital, Milan, Italy University of Modena, Modena, Italy d IRCCS Foundation Ca’ Granda Maggiore Hospital, Milan, Italy e University of Bari, Bari, Italy f University of Udine, Udine, Italy g Ospedali Riuniti, Bergamo, Italy h Sant’Orsola Malpighi Hospital, Bologna, Italy i University of Padua, Padua, Italy j San Camillo Spallanzani Hospital, Rome, Italy k Sapienza University, Rome, Italy l University of Torvergata, Rome, Italy b c
a r t i c l e
i n f o
Article history: Received 31 July 2013 Accepted 25 January 2014 Available online 11 March 2014 Keywords: HCV antiviral treatment Hepatitis C recurrence Liver transplantation Sustained viral response
a b s t r a c t Background: The recurrence of hepatitis C viral infection is common after liver transplant, and achieving a sustained virological response to antiviral treatment is desirable for reducing the risk of graft loss and improving patients’ survival. Aim: To investigate the long-term maintenance of sustained virological response in liver transplant recipients with hepatitis C recurrence. Methods: 436 Liver transplant recipients (74.1% genotype 1) who underwent combined antiviral therapy for hepatitis C recurrence were retrospectively evaluated. Results: The overall sustained virological response rate was 40% (173/436 patients), and the mean followup after liver transplantation was 11 ± 3.5 years (range, 5–24). Patients with a sustained virological response demonstrated a 5-year survival rate of 97% and a 10-year survival rate of 93%; all but 6 (3%) patients remained hepatitis C virus RNA-negative during follow-up. Genotype non-1 (p = 0.007), treatment duration >80% of the scheduled period (p = 0.027), and early virological response (p = 0.002), were associated with the maintenance of sustained virological response as indicated by univariate analysis. Early virological response was the only independent predictor of sustained virological response maintenance (p = 0.008). Conclusions: Sustained virological response achieved after combined antiviral treatment is maintained in liver transplant patients with recurrent hepatitis C and is associated with an excellent 5-year survival. © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction
∗ Corresponding author at: Department of Internal Medicine, Catholic University of Rome, Largo A. Gemelli 8, 00168 Rome, Italy. Tel.: +39 347 1227242. E-mail address: [email protected] (F.R. Ponziani). 1 See Appendix A for the AISF RECOLT-C Group members.
The hepatitis C virus (HCV) infects more than 200 million people worldwide [1,2] and is one of the leading indications for liver transplantation (LT) [3]. HCV infection recurrence is universal after LT [4], and the course of the disease is accelerated, mainly because of host immunological hypo-reactivity [5]. Therefore, treating HCV infection recurrence after LT is mandatory, at least in patients with moderate to severe fibrosis, to reduce the risk of graft loss and improve patients’ survival rates [6–8].
1590-8658/$36.00 © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.dld.2014.01.157
F.R. Ponziani et al. / Digestive and Liver Disease 46 (2014) 440–445
The goal of antiviral treatment is to maintain an undetectable serum HCV RNA level 24 weeks after treatment completion, which is defined as a sustained virological response (SVR). In immunocompetent patients, this goal can be achieved using a combination of pegylated interferon (PEG-IFN) alpha 2a or 2b plus ribavirin (RBV) (double therapy). This double therapy is successful in 42–46% of patients infected with genotype 1 HCV and in 76–82% infected with genotype 2 or 3 [9]. In both naive and experienced patients with genotype 1 HCV, the rate of SVR is substantially increased by the addition of direct acting antivirals, such as telaprevir or boceprevir (triple therapy), reaching values of 66–75% in naive, 75–88% in relapser, and 29–33% in null responder patients [10–13]. In LT recipients, the effectiveness of double therapy in achieving SVR is worse than that reported in non-LT patients. SVR rates have been reported to range between 30% and 48%, owing to the low tolerance of treatment medications and impaired immune function [7,14–16]. As in the non-LT setting, reported SVR rates are higher in genotype 2/3 than in genotype 1/4 patients. Moreover, the question of whether SVR is really maintained over time in LT recipients is still under investigation. Studies published so far reporting long-term follow-up of LT patients who have undergone HCV antiviral treatment have mainly focused on graft or patients’ survival, and there is only a small amount of data about the maintenance of SVR in LT patients completing successful antiviral treatment [17]. In the present study, we retrospectively investigated the longterm maintenance of SVR following antiviral treatment in a large cohort of LT recipients with recurrent hepatitis C.
2. Patients and methods Data on HCV LT recipients who underwent transplantation in 12 Italian transplant centres between January 1989 and December 2008 were retrospectively analyzed. All patients received antiviral treatment for recurrent HCV hepatitis for a period of 48 weeks, regardless of HCV genotype. Antiviral treatment was started at the time of HCV chronic hepatitis diagnosis, as defined by the concomitant occurrence of detectable serum HCV RNA levels, the persistent increase in serum alanine-aminotransferase (ALT) levels after exclusion of all other causes of liver injury, and histological features of HCV-related hepatitis on liver biopsy. A serum HCV RNA was available before, at the end and 6 months after the end of antiviral treatment; in 417 patients, HCV RNA was also available 12 weeks after the start of antiviral treatment. In all patients, quantitative HCV RNA assays were performed using polymerase chain reaction kits (COBAS AMPLICOR HCV test, Roche Molecular Diagnostics, version commercially available at the time of the assay). In a small number of cases (140/436, 32%, overall and 28/173, 16.2%, of SVR patients), only qualitative HCV RNA assays were available before the beginning of treatment. The treatment consisted of conventional doses of recombinant PEG-IFN alpha2a (180 mcg SC once weekly) or alpha 2b (1.0–1.5 mcg/kg SC once weekly), or standard IFN alpha2b 3 million units subcutaneously three times a week plus ribavirin (RBV), at dosages ranging between 200 and 1200 mg/day, according to the patient’s weight and tolerance. In particular, the overall mean RBV dose in the whole population was 237 ± 115 mg. In total, 163/436 patients (36.4%) received more than or equal to 80% of the intended RBV dose, and 70 (42.9%) were SVR patients. Immunosuppression was managed according to the internal guidelines of each institution participating in this retrospective survey. In the vast majority of the patients, the standard postLT regimen consisted of steroids (usually withdrawn within 3–6 months of LT) and a calcineurin inhibitor. At the beginning of antiviral treatment, the majority of the patients were treated with
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cyclosporine (n = 172) or tacrolimus (n = 246) as the main immunosuppressive agent. A negative HCV RNA at week 12 was defined as a complete early virological response (cEVR), and a reduction in HCV RNA of at least 2 Log was defined a partial early virological response (pEVR). SVR was defined as the absence of detectable HCV RNA at the end of treatment and 6 months later. Patients with SVR were usually followed at 3-month intervals by clinical evaluation and biochemical assay of routine liver function parameters. HCV RNA assessment was performed using commercially available kits at 6 months and then every year after SVR was established. Patient follow-up ended in May 2013, and the last HCV RNA assay for each patient was performed using the Cobas Amplicor HCV test v2.0, Roche, Switzerland (lower limit of detection, 50 IU/mL). The patients who achieved but did not maintain a SVR (detectable serum HCV RNA levels at any time during follow-up) were considered SVR relapsers (SVR-R). SVR-R patients underwent a uniform, specific investigation on possible high-risk behaviours for HCV reinfection after SVR achievement, and most of them underwent genotyping for the IL-28B rs12979860C/T polymorphism using PCR and restriction fragment length polymorphism assays, as previously described [18]. 2.1. Statistical analysis Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS), release 15.0. All data were first analyzed for normality of distribution using the Kolmogorov–Smirnov test. The following variables were included in the analysis: age, sex, body mass index (BMI), genotype non-1, immunosuppressive therapy, months from LT to treatment, HCV RNA ≥800,000 IU/mL, evidence of cirrhosis (Ishak stage 5/6), EVR, use of PEG-IFN, and ≥80% of treatment duration. Continuous variables were expressed as the mean ± standard deviation, categorical variables were reported as frequencies, and the appropriate parametric (ttest) or non-parametric test (Mann–Whitney or Chi-squared test for categorical variables) was used to assess the significance of differences between subgroups. Multivariate logistic regression using a backward-stepwise method to obtain a reduced model was performed to evaluate the relationship between SVR maintenance and clinical and biochemical parameters. Covariates introduced into the model were significantly correlated in the univariate analysis. The coefficients obtained from the logistic regression were expressed in terms of odds ratio with 95% confidence intervals. Survival was computed using Kaplan–Meier curves, and the log-rank test was used to compare groups. All of the tests for statistical significance were two-sided, and a p value of less than 0.05 indicated a statistically significant difference. 3. Results Overall 436 patients received antiviral treatment during the study period; 323 (74.1%) were infected with HCV genotype 1, 59 (13.5%) with genotype 2, 37 (8.4%) with genotype 3, and 17 (3.9%) genotype 4. One hundred seventy three patients (77% males, mean age 53 ± 8 years) obtained SVR and are the focus of this study. The mean follow-up period after SVR achievement was 8 ± 3 years (range 3–18, last data recorded in May 2013 in all cases). The follow-up period after LT was equal to or greater than 5 years in all patients, whereas the follow-up period after completion of antiviral treatment was equal to or greater than 5 years in 156 patients (90.2%). Follow-up after SVR achievement was 4 years in 17 patients who completed antiviral treatment in 2009. During follow-up, 12 patients died, and the cumulative 1-, 3-, 5-, and 10-year survival
Abbreviations: BMI, body mass index (kg/m2 ); LT, liver transplant; HCV, hepatitis C virus; ALT, alanine-aminotransferase; EVR, early virological response; SVR, sustained virological response. a Quantitative assay unavailable.
8 6 14 18 6 6 Yes Yes Yes Yes No No No Yes No NA No No 2004 2004 2000 1993 2002 2003 320 1048 123 120 213 355 220,000 12,200.609 1760.000 Positivea 329,648 67,135 4 3 2 3 1 1 115 77 98 70 47 45 Cyclosporin Tacrolimus Tacrolimus Cyclosporin Tacrolimus Cyclosporin 2001 2001 1996 1991 2000 2001 31 29 25 27 31 21 M M F M F F
Treatment duration >80% EVR Year of treatment Baseline ALT (IU/L) Baseline HCV RNA (IU/mL) Staging pre-treatment (Ishak) Months from LT to treatment Immune suppression
59 60 50 45 56 58
SVR, sustained virological response; HCV, hepatitis C virus; LT, liver transplant; EVR, early virological response; PEG-IFN, pegylated interferon. a Quantitative HCV-RNA unavailable in 28 cases. b Histological staging not specified in 30 cases. c EVR unavailable in 13 cases.
1 2 3 4 5 6
73 (42%) 90 (52%) 6 (3%) 4 (2%) 26 ± 28 (range, 1–175) 88 (61%)a 6 (34%)b 124 (77%)c 138 (80%) 144 (83%)
Year of LT
53 ± 8 134 (77%) 25 ± 3 80 (46%) 55 (32%) 32 (18%) 6 (3%)
BMI
N (%)
Mean age (years) Male gender Mean body mass index (kg/m2 ) Genotype 1 Genotype 2 Genotype 3 Genotype 4 Immunosuppressive therapy Cyclosporin Tacrolimus Other drugs Immunotolerant Mean Time from LT to treatment (months) Baseline HCV RNA ≥800,000 IU/mL Cirrhosis (Ishak stage 5/6) EVR PEG-IFN ≥80% treatment duration
Sex
Parameter
Age (years)
Table 1 Clinical features of 173 liver transplant recipients who achieved a sustained virological response after antiviral treatment for recurrent hepatitis C.
Patient
was 100%, 100%, 97%, and 93%, respectively. The causes of death were liver-related in 5 cases (HCC recurrence in 2 cases, chronic rejection, portal system thrombosis, and decompensated cirrhosis with hyperammonemic coma in 1 case each) and non-liver-related in the remaining 7 cases. The main clinical and laboratory parameters of SVR patients are shown in Table 1. Among 323 genotype 1 patients, 80 (25%) achieved SVR, which was maintained after the end of the treatment in all except 6 cases. These cases were classified as SVR-relapsers (SVR-R), and their main clinical features are reported in Table 2. These patients were observed in 3 of the 12 participating centres. All but 1 showed a normal ALT serum level at the end of the period of antiviral treatment, and the time of serum HCV RNA reappearance ranged between 6 and 18 months after SVR was achieved. Notably, all of the SVR-Rs showed sustained detectability of HCV-RNA during follow-up, and none of them underwent a new course of treatment. None of the patients reported risk factors for de novo HCV re-infection, and the HCV genotype was identical to the one detected before treatment in all cases. One of the 6 SVR-R patients (patient no. 2, Table 2) died from portal and mesenteric vein thrombosis. The other 5 patients were alive at the end of the follow-up; in 3 of these patients, a histological assessment obtained after virological recurrence was available. The Ishak fibrosis score was improved in 1 case (from 3 to 2) and worsened in the other 2 cases (from 2 to 5 and from 4 to 5). Among patients with HCV genotypes 2, 3, and 4, 55 (93%), 32 (86%), and 6 (35%) respectively achieved SVR, which was maintained during the entire follow-up period in all cases. Overall, SVR was maintained in 167/173 patients (96.5%). Factors influencing SVR maintenance were investigated, including genotype, body mass index (BMI), age, sex, pre-LT treatment, immunosuppressive therapy, days from LT to treatment, baseline HCV RNA ≥800,000 IU/mL, histological diagnosis of cirrhosis (Ishak stage 5/6), EVR, use of PEG-IFN, and treatment duration ≥80% of the scheduled period (Table 3). Univariate analysis indicated that genotype non-1, EVR and duration of treatment ≥80% were associated with SVR maintenance. Logistic regression showed that the only factor independently associated with SVR maintenance was EVR (ˇ = 3.099 ± 1.165, p = 0.008, OR 22.18 [2.26–217.6]). The impacts of cEVR and pEVR on SVR maintenance were also analyzed; however, only cEVR was significantly predictive of SVR maintenance after
Months from SVR to HCV RNA recurrence
F.R. Ponziani et al. / Digestive and Liver Disease 46 (2014) 440–445
Table 2 Characteristics of the 6 liver transplant recipients showing hepatitis C virus genotype 1 infection recurrence after achievement of sustained virological response.
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F.R. Ponziani et al. / Digestive and Liver Disease 46 (2014) 440–445 Table 3 Factors associated with long-term maintenance of sustained virological response. Recipient characteristic
Univariate analysis (p value)
Age (years) Sex Body mass index Genotype non-1 Immunosuppressive therapy Months from LT to treatment HCV-RNA ≥800.000 IU/mL Cirrhosis (Ishak stage 5/6) EVR cEVR pEVR PEG-IFN ≥80% treatment duration
0.554 0.101 0.182 0.007 0.929 0.482 0.335 0.634 0.002 0.001 0.493 0.416 0.027
Multivariate analysis (p value)
0.996
0.008 0.003
0.327
SVR, sustained virological response; HCV, hepatitis C virus; EVR, early virological response; cEVR, complete early virological response; pEVR, partial early virological response; PEG-IFN, pegylated interferon.
univariate (p = 0.001) and multivariate analysis (p = 0.003; OR 34.74, 95% CI [3.32–363.61]). Furthermore, univariate and multivariate analyses with EVR as the endpoint using the above mentioned baseline parameters were performed. Genotype non-1 was the only factor that was significantly predictive of higher rates of EVR (p < 0001; OR 4.43, 95% CI [2.55–7.72]), suggesting that the influence of EVR on SVR maintenance might be a by-product of viral genotype. Considering the long time span of our study, we performed a subanalysis by separating patients transplanted during the 1989–1998 period from those transplanted in 1999–2008. No significant differences were noted apart from the higher prevalence of pegylated interferon administration and the shorter interval from LT to treatment in the latter group (Table 4). As expected, SVR appeared to have a great impact on graft and overall long-term survival, as the 5- and 10-year survival rates were 97%, and 93%; among the 12 deceased patients, only 5 died because of liver-related causes. In the cohort of 263 patients not achieving SVR in this series, the 5- and 10-year survival rates were significantly lower (82% and 75.6% respectively; p < 0.0001). Lastly, we investigated the IL-28B gene polymorphism in 5 out of 6 SVR-R patients; interestingly, we detected the favourable CC genotype in only one of them, while the remaining 4 showed the unfavourable genotypes CT (2 cases) or TT (2 cases).
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4. Discussion Recurrence of HCV infection is a major challenge after LT, and at present, for LT recipients with severe hepatitis C recurrence, there is no alternative therapeutic regimen apart from combined antiviral treatment with PEG-IFN plus RBV. The rate of SVR is variable and is lower in patients with HCV genotypes 1 and 4 and noticeably higher for genotypes 2 and 3; the loss of SVR could be a worrisome event. Immunocompetent patients seem to lose SVR in 0–9% of cases, especially if they are treated with standard non-pegylated IFN alone and in the presence of advanced fibrosis or cirrhosis [19–24]. Notably, HCV reinfection due to ongoing risk-taking behaviours is still possible after SVR has been achieved [25], and surveillance for early HCC diagnosis should be maintained, at least in patients with established cirrhosis [20,21,26–30]. Data on LT recipients are scarce, and there is only one retrospective single centre case-series of 29 patients reporting no relapse during a 5-year follow-up period [17]. To our knowledge, the present retrospective study is the largest that has evaluated the maintenance of SVR during a long period of follow-up in LT recipients. We can confirm that, as in immunocompetent patients, SVR is durable over a long period of time and that HCV recurrence is very rare, even in LT patients who are indefinitely treated with immunosuppressive drugs and could theoretically be at an increased risk of infection recurrence. Indeed, in the whole population, SVR was maintained in 96.5% of the cases. Univariate analysis indicated that the administration of less than 80% of the scheduled antiviral treatment, HCV genotype 1 infection, and the absence of complete EVR were linked to the loss of SVR. In particular, recipients with genotype 1 infection were more prone to losing SVR, exhibiting a 7.5% rate of relapse, while no cases of HCV infection recurrence were recorded in patients with other HCV genotypes. Only complete absence of EVR was confirmed to be an independent predictor of SVR loss in the multivariate analysis. All of these factors have been shown to be risk factors for the reduced effectiveness of antiviral treatment in HCV LT recipients with recurrent hepatitis C [8,16,31]. In immunocompetent patients, a possible explanation of SVR loss could be the presence of viral reservoirs in tissues and organs that remain unidentified. It has been suggested that hepatic viral clearance could be a better marker of long-term response to antiviral treatment than clearance of HCV RNA from serum, but this hypothesis has not been confirmed [30,32,33]. Other studies have shown that patients achieving SVR may still have detectable HCV RNA strands in the liver and in peripheral mononuclear cells
Table 4 Clinical features of the overall population and of patients with sustained virological response analyzed by liver transplant era. Parameter
Overall
SVR
1989–1998 (N = 67)
1999–2009 (N = 369)
Genotype 1 Genotype 2 Genotype 3 Genotype 4 Months from LT to treatment Baseline HCV RNA ≥800000 IU/mL Cirrhosis (Ishak stage 5/6) PEG-IFN ≥80% treatment duration EVR pEVR cEVR SVR Maintained SVR
52 (78%) 11 (16%) 2 (3%) 2 (3%) 57 ± 46 25 (66%) 4 (9%) 34 (51%) 43 (64%) 27 (44%) 3 (7%) 24 (39%) 30 (45%) –
271 (73%) 48 (13%) 35 (9%) 15 (4%) 17 ± 16 21 (64%) 9 (30%) 297 (80%) 248 (68%) 183 (56%) 47 (16%) 136 (42%) 143 (39%) –
P 0.306
<0.0001 0.808 0.065 <0.0001 0.525 0.088 0.108 0.730 0.354 –
1989–1998 (N = 30)
1999–2009 (N = 143)
16 (53%) 11 (37%) 2 (7%) 1 (3%) 61 ± 46 10 (59%) 2 (9%) 15 (50%) 23 (77%) 17 (71%) 1 (5%) 16 (67%) – 28 (93%)
64 (45%) 44 (31%) 30 (21%) 5 (3%) 19 ± 15 78 (61%) 4 (33%) 123 (80%) 120 (84%) 107 (86%) 11 (9%) 96 (77%) – 139 (97%)
P 0.332
<0.0001 0.867 0.213 <0.0001 0.297 0.245 0.561 0.646 – 0.292
SVR, sustained virological response; HCV, hepatitis C virus; LT, liver transplant; EVR, early virological response; cEVR, complete early virological response; pEVR, partial early virological response; PEG-IFN, pegylated interferon.
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[34,35]. It is possible that inter-individual differences in drug distribution and bioavailability might play an important role in the persistence of such viral niches of resistance, which can recolonize the liver after the end of antiviral treatment via the bloodstream. The occurrence of this scenario could be favoured by the pharmacologically immunocompromised status of LT patients. The short time to relapse, which ranged between 6 and 18 months (mean 10.4) in our series, further supports this hypothesis. Another interesting possibility demonstrated by the present study is that the likelihood of maintaining SVR could be genetically determined. Indeed, 4 out of 5 SVR-R patients for whom the data were available showed unfavourable IL28B genotypes, which are well-known factors associated with a decreased rate of SVR in LT patients treated after diagnosis of recurrent hepatitis C [36,37]. Whether an unfavourable IL28B genotype might play a negative role in the long-term maintenance of SVR in both immunocompetent and LT patients should be further investigated. This study has some limitations. First, the study has the inherent limitations of retrospective evaluation and some unavoidable selection biases. Second, the HCV RNA serum assays were not centralized, and the large time span during which the viral load determinations were performed may introduce a possible bias into our analysis. Indeed, the sensitivity of HCV RNA assays has improved in recent years, and HCV RNA testing may have been less sensitive in patients treated earlier. However, none of the patients who maintained an SVR showed detectable HCV RNA at present. Third, in 3 patients with HCV RNA reappearance, the assay was positive within 6 months from the achievement of SVR. It is possible that the undetectable HCV RNA at 6 months follow-up might have been a false-negative due to a faulty sample collection or the use of an inadequately sensitive test. However, in these 3 patients, the sensitivity of the HCV RNA test was the same at the moment of SVR achievement and 6 months thereafter. Finally, although none of the SVR-R patients reported any risk-taking behaviour for de novo re-infection, sequencing of the HCV genome to confirm that the patients experienced a relapse rather than a re-infection was not available. In conclusion, SVR is maintained over the long term in the vast majority of LT recipients treated after chronic hepatitis C recurrence. However, HCV recurrence seems to be possible in patients with genotype 1 HCV, especially those treated for a shorter period and who do not achieve complete EVR. Conflict of interest None declared. Acknowledgements The authors thank the colleagues who collaborated with the AISF RECOLT-C group. Appendix A. AISF RECOLT-C group: L. Belli, G.E. Gerunda, M. Marino, R. Montalti, F. Di Benedetto, N. De Ruvo, C. Rigamonti, M. Colombo, G. Rossi, A. Di Leo, L. Lupo, V. Memeo, R. Bringiotti, M. Zappimbulso, D. Bitetto, V. Vero, M. Colpani, E. Fornasiere, A.D. Pinna, M.C. Morelli, V. Bertuzzo, E. De Martin, M. Senzolo, G.M. Ettorre, U. Visco-Comandini, G. Antonucci, M. Angelico, G. Tisone, V. Giannelli, M. Giusto. References [1] Lavanchy D. The global burden of hepatitis C. Liver International 2009;29(Suppl. 1):74–81.
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Liver, Pancreas and Biliary Tract
Long-term maintenance of sustained virological response in liver transplant recipients treated for recurrent hepatitis C Francesca Romana Ponziani a,∗ , Raffaella Viganò b , Rosa Maria Iemmolo c , Maria Francesca Donato d , Maria Rendina e , Pierluigi Toniutto f , Luisa Pasulo g , Maria Cristina Morelli h , Patrizia Burra i , Lucia Miglioresi j , Manuela Merli k , Daniele Di Paolo l , Stefano Fagiuoli g , Antonio Gasbarrini a , Maurizio Pompili a , on behalf of AISF RECOLT-C Group1 a
Agostino Gemelli Hospital, Rome, Italy Niguarda Ca’ Granda Hospital, Milan, Italy University of Modena, Modena, Italy d IRCCS Foundation Ca’ Granda Maggiore Hospital, Milan, Italy e University of Bari, Bari, Italy f University of Udine, Udine, Italy g Ospedali Riuniti, Bergamo, Italy h Sant’Orsola Malpighi Hospital, Bologna, Italy i University of Padua, Padua, Italy j San Camillo Spallanzani Hospital, Rome, Italy k Sapienza University, Rome, Italy l University of Torvergata, Rome, Italy b c
a r t i c l e
i n f o
Article history: Received 31 July 2013 Accepted 25 January 2014 Available online 11 March 2014 Keywords: HCV antiviral treatment Hepatitis C recurrence Liver transplantation Sustained viral response
a b s t r a c t Background: The recurrence of hepatitis C viral infection is common after liver transplant, and achieving a sustained virological response to antiviral treatment is desirable for reducing the risk of graft loss and improving patients’ survival. Aim: To investigate the long-term maintenance of sustained virological response in liver transplant recipients with hepatitis C recurrence. Methods: 436 Liver transplant recipients (74.1% genotype 1) who underwent combined antiviral therapy for hepatitis C recurrence were retrospectively evaluated. Results: The overall sustained virological response rate was 40% (173/436 patients), and the mean followup after liver transplantation was 11 ± 3.5 years (range, 5–24). Patients with a sustained virological response demonstrated a 5-year survival rate of 97% and a 10-year survival rate of 93%; all but 6 (3%) patients remained hepatitis C virus RNA-negative during follow-up. Genotype non-1 (p = 0.007), treatment duration >80% of the scheduled period (p = 0.027), and early virological response (p = 0.002), were associated with the maintenance of sustained virological response as indicated by univariate analysis. Early virological response was the only independent predictor of sustained virological response maintenance (p = 0.008). Conclusions: Sustained virological response achieved after combined antiviral treatment is maintained in liver transplant patients with recurrent hepatitis C and is associated with an excellent 5-year survival. © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction
∗ Corresponding author at: Department of Internal Medicine, Catholic University of Rome, Largo A. Gemelli 8, 00168 Rome, Italy. Tel.: +39 347 1227242. E-mail address: [email protected] (F.R. Ponziani). 1 See Appendix A for the AISF RECOLT-C Group members.
The hepatitis C virus (HCV) infects more than 200 million people worldwide [1,2] and is one of the leading indications for liver transplantation (LT) [3]. HCV infection recurrence is universal after LT [4], and the course of the disease is accelerated, mainly because of host immunological hypo-reactivity [5]. Therefore, treating HCV infection recurrence after LT is mandatory, at least in patients with moderate to severe fibrosis, to reduce the risk of graft loss and improve patients’ survival rates [6–8].
1590-8658/$36.00 © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.dld.2014.01.157
F.R. Ponziani et al. / Digestive and Liver Disease 46 (2014) 440–445
The goal of antiviral treatment is to maintain an undetectable serum HCV RNA level 24 weeks after treatment completion, which is defined as a sustained virological response (SVR). In immunocompetent patients, this goal can be achieved using a combination of pegylated interferon (PEG-IFN) alpha 2a or 2b plus ribavirin (RBV) (double therapy). This double therapy is successful in 42–46% of patients infected with genotype 1 HCV and in 76–82% infected with genotype 2 or 3 [9]. In both naive and experienced patients with genotype 1 HCV, the rate of SVR is substantially increased by the addition of direct acting antivirals, such as telaprevir or boceprevir (triple therapy), reaching values of 66–75% in naive, 75–88% in relapser, and 29–33% in null responder patients [10–13]. In LT recipients, the effectiveness of double therapy in achieving SVR is worse than that reported in non-LT patients. SVR rates have been reported to range between 30% and 48%, owing to the low tolerance of treatment medications and impaired immune function [7,14–16]. As in the non-LT setting, reported SVR rates are higher in genotype 2/3 than in genotype 1/4 patients. Moreover, the question of whether SVR is really maintained over time in LT recipients is still under investigation. Studies published so far reporting long-term follow-up of LT patients who have undergone HCV antiviral treatment have mainly focused on graft or patients’ survival, and there is only a small amount of data about the maintenance of SVR in LT patients completing successful antiviral treatment [17]. In the present study, we retrospectively investigated the longterm maintenance of SVR following antiviral treatment in a large cohort of LT recipients with recurrent hepatitis C.
2. Patients and methods Data on HCV LT recipients who underwent transplantation in 12 Italian transplant centres between January 1989 and December 2008 were retrospectively analyzed. All patients received antiviral treatment for recurrent HCV hepatitis for a period of 48 weeks, regardless of HCV genotype. Antiviral treatment was started at the time of HCV chronic hepatitis diagnosis, as defined by the concomitant occurrence of detectable serum HCV RNA levels, the persistent increase in serum alanine-aminotransferase (ALT) levels after exclusion of all other causes of liver injury, and histological features of HCV-related hepatitis on liver biopsy. A serum HCV RNA was available before, at the end and 6 months after the end of antiviral treatment; in 417 patients, HCV RNA was also available 12 weeks after the start of antiviral treatment. In all patients, quantitative HCV RNA assays were performed using polymerase chain reaction kits (COBAS AMPLICOR HCV test, Roche Molecular Diagnostics, version commercially available at the time of the assay). In a small number of cases (140/436, 32%, overall and 28/173, 16.2%, of SVR patients), only qualitative HCV RNA assays were available before the beginning of treatment. The treatment consisted of conventional doses of recombinant PEG-IFN alpha2a (180 mcg SC once weekly) or alpha 2b (1.0–1.5 mcg/kg SC once weekly), or standard IFN alpha2b 3 million units subcutaneously three times a week plus ribavirin (RBV), at dosages ranging between 200 and 1200 mg/day, according to the patient’s weight and tolerance. In particular, the overall mean RBV dose in the whole population was 237 ± 115 mg. In total, 163/436 patients (36.4%) received more than or equal to 80% of the intended RBV dose, and 70 (42.9%) were SVR patients. Immunosuppression was managed according to the internal guidelines of each institution participating in this retrospective survey. In the vast majority of the patients, the standard postLT regimen consisted of steroids (usually withdrawn within 3–6 months of LT) and a calcineurin inhibitor. At the beginning of antiviral treatment, the majority of the patients were treated with
441
cyclosporine (n = 172) or tacrolimus (n = 246) as the main immunosuppressive agent. A negative HCV RNA at week 12 was defined as a complete early virological response (cEVR), and a reduction in HCV RNA of at least 2 Log was defined a partial early virological response (pEVR). SVR was defined as the absence of detectable HCV RNA at the end of treatment and 6 months later. Patients with SVR were usually followed at 3-month intervals by clinical evaluation and biochemical assay of routine liver function parameters. HCV RNA assessment was performed using commercially available kits at 6 months and then every year after SVR was established. Patient follow-up ended in May 2013, and the last HCV RNA assay for each patient was performed using the Cobas Amplicor HCV test v2.0, Roche, Switzerland (lower limit of detection, 50 IU/mL). The patients who achieved but did not maintain a SVR (detectable serum HCV RNA levels at any time during follow-up) were considered SVR relapsers (SVR-R). SVR-R patients underwent a uniform, specific investigation on possible high-risk behaviours for HCV reinfection after SVR achievement, and most of them underwent genotyping for the IL-28B rs12979860C/T polymorphism using PCR and restriction fragment length polymorphism assays, as previously described [18]. 2.1. Statistical analysis Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS), release 15.0. All data were first analyzed for normality of distribution using the Kolmogorov–Smirnov test. The following variables were included in the analysis: age, sex, body mass index (BMI), genotype non-1, immunosuppressive therapy, months from LT to treatment, HCV RNA ≥800,000 IU/mL, evidence of cirrhosis (Ishak stage 5/6), EVR, use of PEG-IFN, and ≥80% of treatment duration. Continuous variables were expressed as the mean ± standard deviation, categorical variables were reported as frequencies, and the appropriate parametric (ttest) or non-parametric test (Mann–Whitney or Chi-squared test for categorical variables) was used to assess the significance of differences between subgroups. Multivariate logistic regression using a backward-stepwise method to obtain a reduced model was performed to evaluate the relationship between SVR maintenance and clinical and biochemical parameters. Covariates introduced into the model were significantly correlated in the univariate analysis. The coefficients obtained from the logistic regression were expressed in terms of odds ratio with 95% confidence intervals. Survival was computed using Kaplan–Meier curves, and the log-rank test was used to compare groups. All of the tests for statistical significance were two-sided, and a p value of less than 0.05 indicated a statistically significant difference. 3. Results Overall 436 patients received antiviral treatment during the study period; 323 (74.1%) were infected with HCV genotype 1, 59 (13.5%) with genotype 2, 37 (8.4%) with genotype 3, and 17 (3.9%) genotype 4. One hundred seventy three patients (77% males, mean age 53 ± 8 years) obtained SVR and are the focus of this study. The mean follow-up period after SVR achievement was 8 ± 3 years (range 3–18, last data recorded in May 2013 in all cases). The follow-up period after LT was equal to or greater than 5 years in all patients, whereas the follow-up period after completion of antiviral treatment was equal to or greater than 5 years in 156 patients (90.2%). Follow-up after SVR achievement was 4 years in 17 patients who completed antiviral treatment in 2009. During follow-up, 12 patients died, and the cumulative 1-, 3-, 5-, and 10-year survival
Abbreviations: BMI, body mass index (kg/m2 ); LT, liver transplant; HCV, hepatitis C virus; ALT, alanine-aminotransferase; EVR, early virological response; SVR, sustained virological response. a Quantitative assay unavailable.
8 6 14 18 6 6 Yes Yes Yes Yes No No No Yes No NA No No 2004 2004 2000 1993 2002 2003 320 1048 123 120 213 355 220,000 12,200.609 1760.000 Positivea 329,648 67,135 4 3 2 3 1 1 115 77 98 70 47 45 Cyclosporin Tacrolimus Tacrolimus Cyclosporin Tacrolimus Cyclosporin 2001 2001 1996 1991 2000 2001 31 29 25 27 31 21 M M F M F F
Treatment duration >80% EVR Year of treatment Baseline ALT (IU/L) Baseline HCV RNA (IU/mL) Staging pre-treatment (Ishak) Months from LT to treatment Immune suppression
59 60 50 45 56 58
SVR, sustained virological response; HCV, hepatitis C virus; LT, liver transplant; EVR, early virological response; PEG-IFN, pegylated interferon. a Quantitative HCV-RNA unavailable in 28 cases. b Histological staging not specified in 30 cases. c EVR unavailable in 13 cases.
1 2 3 4 5 6
73 (42%) 90 (52%) 6 (3%) 4 (2%) 26 ± 28 (range, 1–175) 88 (61%)a 6 (34%)b 124 (77%)c 138 (80%) 144 (83%)
Year of LT
53 ± 8 134 (77%) 25 ± 3 80 (46%) 55 (32%) 32 (18%) 6 (3%)
BMI
N (%)
Mean age (years) Male gender Mean body mass index (kg/m2 ) Genotype 1 Genotype 2 Genotype 3 Genotype 4 Immunosuppressive therapy Cyclosporin Tacrolimus Other drugs Immunotolerant Mean Time from LT to treatment (months) Baseline HCV RNA ≥800,000 IU/mL Cirrhosis (Ishak stage 5/6) EVR PEG-IFN ≥80% treatment duration
Sex
Parameter
Age (years)
Table 1 Clinical features of 173 liver transplant recipients who achieved a sustained virological response after antiviral treatment for recurrent hepatitis C.
Patient
was 100%, 100%, 97%, and 93%, respectively. The causes of death were liver-related in 5 cases (HCC recurrence in 2 cases, chronic rejection, portal system thrombosis, and decompensated cirrhosis with hyperammonemic coma in 1 case each) and non-liver-related in the remaining 7 cases. The main clinical and laboratory parameters of SVR patients are shown in Table 1. Among 323 genotype 1 patients, 80 (25%) achieved SVR, which was maintained after the end of the treatment in all except 6 cases. These cases were classified as SVR-relapsers (SVR-R), and their main clinical features are reported in Table 2. These patients were observed in 3 of the 12 participating centres. All but 1 showed a normal ALT serum level at the end of the period of antiviral treatment, and the time of serum HCV RNA reappearance ranged between 6 and 18 months after SVR was achieved. Notably, all of the SVR-Rs showed sustained detectability of HCV-RNA during follow-up, and none of them underwent a new course of treatment. None of the patients reported risk factors for de novo HCV re-infection, and the HCV genotype was identical to the one detected before treatment in all cases. One of the 6 SVR-R patients (patient no. 2, Table 2) died from portal and mesenteric vein thrombosis. The other 5 patients were alive at the end of the follow-up; in 3 of these patients, a histological assessment obtained after virological recurrence was available. The Ishak fibrosis score was improved in 1 case (from 3 to 2) and worsened in the other 2 cases (from 2 to 5 and from 4 to 5). Among patients with HCV genotypes 2, 3, and 4, 55 (93%), 32 (86%), and 6 (35%) respectively achieved SVR, which was maintained during the entire follow-up period in all cases. Overall, SVR was maintained in 167/173 patients (96.5%). Factors influencing SVR maintenance were investigated, including genotype, body mass index (BMI), age, sex, pre-LT treatment, immunosuppressive therapy, days from LT to treatment, baseline HCV RNA ≥800,000 IU/mL, histological diagnosis of cirrhosis (Ishak stage 5/6), EVR, use of PEG-IFN, and treatment duration ≥80% of the scheduled period (Table 3). Univariate analysis indicated that genotype non-1, EVR and duration of treatment ≥80% were associated with SVR maintenance. Logistic regression showed that the only factor independently associated with SVR maintenance was EVR (ˇ = 3.099 ± 1.165, p = 0.008, OR 22.18 [2.26–217.6]). The impacts of cEVR and pEVR on SVR maintenance were also analyzed; however, only cEVR was significantly predictive of SVR maintenance after
Months from SVR to HCV RNA recurrence
F.R. Ponziani et al. / Digestive and Liver Disease 46 (2014) 440–445
Table 2 Characteristics of the 6 liver transplant recipients showing hepatitis C virus genotype 1 infection recurrence after achievement of sustained virological response.
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F.R. Ponziani et al. / Digestive and Liver Disease 46 (2014) 440–445 Table 3 Factors associated with long-term maintenance of sustained virological response. Recipient characteristic
Univariate analysis (p value)
Age (years) Sex Body mass index Genotype non-1 Immunosuppressive therapy Months from LT to treatment HCV-RNA ≥800.000 IU/mL Cirrhosis (Ishak stage 5/6) EVR cEVR pEVR PEG-IFN ≥80% treatment duration
0.554 0.101 0.182 0.007 0.929 0.482 0.335 0.634 0.002 0.001 0.493 0.416 0.027
Multivariate analysis (p value)
0.996
0.008 0.003
0.327
SVR, sustained virological response; HCV, hepatitis C virus; EVR, early virological response; cEVR, complete early virological response; pEVR, partial early virological response; PEG-IFN, pegylated interferon.
univariate (p = 0.001) and multivariate analysis (p = 0.003; OR 34.74, 95% CI [3.32–363.61]). Furthermore, univariate and multivariate analyses with EVR as the endpoint using the above mentioned baseline parameters were performed. Genotype non-1 was the only factor that was significantly predictive of higher rates of EVR (p < 0001; OR 4.43, 95% CI [2.55–7.72]), suggesting that the influence of EVR on SVR maintenance might be a by-product of viral genotype. Considering the long time span of our study, we performed a subanalysis by separating patients transplanted during the 1989–1998 period from those transplanted in 1999–2008. No significant differences were noted apart from the higher prevalence of pegylated interferon administration and the shorter interval from LT to treatment in the latter group (Table 4). As expected, SVR appeared to have a great impact on graft and overall long-term survival, as the 5- and 10-year survival rates were 97%, and 93%; among the 12 deceased patients, only 5 died because of liver-related causes. In the cohort of 263 patients not achieving SVR in this series, the 5- and 10-year survival rates were significantly lower (82% and 75.6% respectively; p < 0.0001). Lastly, we investigated the IL-28B gene polymorphism in 5 out of 6 SVR-R patients; interestingly, we detected the favourable CC genotype in only one of them, while the remaining 4 showed the unfavourable genotypes CT (2 cases) or TT (2 cases).
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4. Discussion Recurrence of HCV infection is a major challenge after LT, and at present, for LT recipients with severe hepatitis C recurrence, there is no alternative therapeutic regimen apart from combined antiviral treatment with PEG-IFN plus RBV. The rate of SVR is variable and is lower in patients with HCV genotypes 1 and 4 and noticeably higher for genotypes 2 and 3; the loss of SVR could be a worrisome event. Immunocompetent patients seem to lose SVR in 0–9% of cases, especially if they are treated with standard non-pegylated IFN alone and in the presence of advanced fibrosis or cirrhosis [19–24]. Notably, HCV reinfection due to ongoing risk-taking behaviours is still possible after SVR has been achieved [25], and surveillance for early HCC diagnosis should be maintained, at least in patients with established cirrhosis [20,21,26–30]. Data on LT recipients are scarce, and there is only one retrospective single centre case-series of 29 patients reporting no relapse during a 5-year follow-up period [17]. To our knowledge, the present retrospective study is the largest that has evaluated the maintenance of SVR during a long period of follow-up in LT recipients. We can confirm that, as in immunocompetent patients, SVR is durable over a long period of time and that HCV recurrence is very rare, even in LT patients who are indefinitely treated with immunosuppressive drugs and could theoretically be at an increased risk of infection recurrence. Indeed, in the whole population, SVR was maintained in 96.5% of the cases. Univariate analysis indicated that the administration of less than 80% of the scheduled antiviral treatment, HCV genotype 1 infection, and the absence of complete EVR were linked to the loss of SVR. In particular, recipients with genotype 1 infection were more prone to losing SVR, exhibiting a 7.5% rate of relapse, while no cases of HCV infection recurrence were recorded in patients with other HCV genotypes. Only complete absence of EVR was confirmed to be an independent predictor of SVR loss in the multivariate analysis. All of these factors have been shown to be risk factors for the reduced effectiveness of antiviral treatment in HCV LT recipients with recurrent hepatitis C [8,16,31]. In immunocompetent patients, a possible explanation of SVR loss could be the presence of viral reservoirs in tissues and organs that remain unidentified. It has been suggested that hepatic viral clearance could be a better marker of long-term response to antiviral treatment than clearance of HCV RNA from serum, but this hypothesis has not been confirmed [30,32,33]. Other studies have shown that patients achieving SVR may still have detectable HCV RNA strands in the liver and in peripheral mononuclear cells
Table 4 Clinical features of the overall population and of patients with sustained virological response analyzed by liver transplant era. Parameter
Overall
SVR
1989–1998 (N = 67)
1999–2009 (N = 369)
Genotype 1 Genotype 2 Genotype 3 Genotype 4 Months from LT to treatment Baseline HCV RNA ≥800000 IU/mL Cirrhosis (Ishak stage 5/6) PEG-IFN ≥80% treatment duration EVR pEVR cEVR SVR Maintained SVR
52 (78%) 11 (16%) 2 (3%) 2 (3%) 57 ± 46 25 (66%) 4 (9%) 34 (51%) 43 (64%) 27 (44%) 3 (7%) 24 (39%) 30 (45%) –
271 (73%) 48 (13%) 35 (9%) 15 (4%) 17 ± 16 21 (64%) 9 (30%) 297 (80%) 248 (68%) 183 (56%) 47 (16%) 136 (42%) 143 (39%) –
P 0.306
<0.0001 0.808 0.065 <0.0001 0.525 0.088 0.108 0.730 0.354 –
1989–1998 (N = 30)
1999–2009 (N = 143)
16 (53%) 11 (37%) 2 (7%) 1 (3%) 61 ± 46 10 (59%) 2 (9%) 15 (50%) 23 (77%) 17 (71%) 1 (5%) 16 (67%) – 28 (93%)
64 (45%) 44 (31%) 30 (21%) 5 (3%) 19 ± 15 78 (61%) 4 (33%) 123 (80%) 120 (84%) 107 (86%) 11 (9%) 96 (77%) – 139 (97%)
P 0.332
<0.0001 0.867 0.213 <0.0001 0.297 0.245 0.561 0.646 – 0.292
SVR, sustained virological response; HCV, hepatitis C virus; LT, liver transplant; EVR, early virological response; cEVR, complete early virological response; pEVR, partial early virological response; PEG-IFN, pegylated interferon.
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[34,35]. It is possible that inter-individual differences in drug distribution and bioavailability might play an important role in the persistence of such viral niches of resistance, which can recolonize the liver after the end of antiviral treatment via the bloodstream. The occurrence of this scenario could be favoured by the pharmacologically immunocompromised status of LT patients. The short time to relapse, which ranged between 6 and 18 months (mean 10.4) in our series, further supports this hypothesis. Another interesting possibility demonstrated by the present study is that the likelihood of maintaining SVR could be genetically determined. Indeed, 4 out of 5 SVR-R patients for whom the data were available showed unfavourable IL28B genotypes, which are well-known factors associated with a decreased rate of SVR in LT patients treated after diagnosis of recurrent hepatitis C [36,37]. Whether an unfavourable IL28B genotype might play a negative role in the long-term maintenance of SVR in both immunocompetent and LT patients should be further investigated. This study has some limitations. First, the study has the inherent limitations of retrospective evaluation and some unavoidable selection biases. Second, the HCV RNA serum assays were not centralized, and the large time span during which the viral load determinations were performed may introduce a possible bias into our analysis. Indeed, the sensitivity of HCV RNA assays has improved in recent years, and HCV RNA testing may have been less sensitive in patients treated earlier. However, none of the patients who maintained an SVR showed detectable HCV RNA at present. Third, in 3 patients with HCV RNA reappearance, the assay was positive within 6 months from the achievement of SVR. It is possible that the undetectable HCV RNA at 6 months follow-up might have been a false-negative due to a faulty sample collection or the use of an inadequately sensitive test. However, in these 3 patients, the sensitivity of the HCV RNA test was the same at the moment of SVR achievement and 6 months thereafter. Finally, although none of the SVR-R patients reported any risk-taking behaviour for de novo re-infection, sequencing of the HCV genome to confirm that the patients experienced a relapse rather than a re-infection was not available. In conclusion, SVR is maintained over the long term in the vast majority of LT recipients treated after chronic hepatitis C recurrence. However, HCV recurrence seems to be possible in patients with genotype 1 HCV, especially those treated for a shorter period and who do not achieve complete EVR. Conflict of interest None declared. Acknowledgements The authors thank the colleagues who collaborated with the AISF RECOLT-C group. Appendix A. AISF RECOLT-C group: L. Belli, G.E. Gerunda, M. Marino, R. Montalti, F. Di Benedetto, N. De Ruvo, C. Rigamonti, M. Colombo, G. Rossi, A. Di Leo, L. Lupo, V. Memeo, R. Bringiotti, M. Zappimbulso, D. Bitetto, V. Vero, M. Colpani, E. Fornasiere, A.D. Pinna, M.C. Morelli, V. Bertuzzo, E. De Martin, M. Senzolo, G.M. Ettorre, U. Visco-Comandini, G. Antonucci, M. Angelico, G. Tisone, V. Giannelli, M. Giusto. References [1] Lavanchy D. The global burden of hepatitis C. Liver International 2009;29(Suppl. 1):74–81.
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