Liver International ISSN 1478-3223
REVIEW ARTICLE
Management of HCV patients with cirrhosis with direct acting antivirals Vincenzo Boccaccio and Savino Bruno Department of Internal Medicine, A.O. Fatebenefratelli e Oftalmico, Milan, Italy
Keywords boceprevir – direct acting antivirals – faldaprevir – HCV-related cirrhosis – hepatitis C virus – simeprevir – sofosbuvir – sustained virological response – telaprevir Abbreviations AEs, adverse events; BOC, boceprevir; DAAs, direct acting antivirals; HCV, hepatitis C virus; HVPG, hepatic venous pressure gradient; NPV, negative predictive value; PIs, protease inhibitors; PR, peg-interferon and ribavirin; RAVs, viral variants with resistance to PI; RBV, ribavirin; RGT, response guided-therapy; RVR, rapid virological response; SAEs, severe adverse events; SOF, sofosbuvir; SVR, sustained virological response; TVR, telaprevir; TW8, treatment week 8. Correspondence Savino Bruno, MD, Department of Internal Medicine, A.O. Fatebenefratelli e Oftalmico, Corso di Porta Nuova, 23, 20121 Milan, Italy Tel: +39 0263632421 Fax: +39 0263632714. e-mail:
[email protected]
Abstract In recent years, several studies have clearly shown that sustained virological response (SVR) achieved by interferon-based therapies may delay or reduce the risk of hepatocellular carcinoma, liver decompensation and all-causes of mortality in all categories of patients with HCV-related cirrhosis, a condition characterized by a wide heterogeneity of clinical features, especially in patients with compensated disease. Unfortunately, the advanced fibrosis stage has been shown to be associated with poor SVR rates and poor tolerance with Peg-interferon and ribavirin. Therefore, on the basis of its risk/efficacy evaluation, most patients are considered to be ineligible for antiviral therapy with these molecules. Recently, improvement in the knowledge of the HCV lifecycle, has resulted in the rapid development of many direct-acting antivirals (DAAs). Two first generation DAAs, boceprevir (BOC) and telaprevir (TVR), have been approved, and more than 40 new small molecules are still in development. However, only a few individuals with compensated cirrhosis were included in the phase III studies assessing the safety and efficacy of BOC or TVR in na€ıve and chronic hepatitis C genotype 1 patients in whom treatment had failed, and patients with either decompensation or end-stage liver disease were excluded. Therefore, the information available in these patients, which have shown significantly lower SVR compared with patients with mild to moderate fibrosis, are not fully reliable. In addition, in real practice, some studies that have not yet been fully published have shown that triple therapy with these two molecules was associated with low SVR and high serious adverse events (SAEs).
DOI:10.1111/liv.12391
Cirrhosis is highly heterogeneous
It is well-known that the prognosis of hepatitis C virus (HCV) infection is mainly linked to the progression of fibrosis (1). Once cirrhosis has developed, many different clinical features can be recognized, ranging from early (compensated) to more severe (decompensated) cirrhosis and terminal end stage liver disease. Compensated cirrhosis can include patients with very early stage disease who are often diagnosed during an incidental assessment of chronic hepatitis by histology (F3 Metavir or F4 Ishak) or by transient elastography (stiffness ≥ 9.5 < 12.5 kPa). There are frequently no clinical signs of significant portal hypertension (Hepatic Venous Pressure Gradient (HVPG) ≥6 mmHg 15 and a number of these patients are on the list for orthotopic liver transplantation (OLT) (2–4). These heterogenous clinical features strongly influence short and long-term disease outcome (5, 6). Sustained viral response
Two studies have clearly shown that the regression of cirrhosis and fibrosis are not infrequent in patients with hepatitis C virus (HCV) who achieved sustained viroLiver International (2014) © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Boccaccio and Bruno
logical response (SVR) after antiviral therapy (7, 8). Moreover, SVR has been shown to be associated with (I) a significant reduction in the development of esophageal varices and (II) a decreased incidence of hepatocellular carcinoma (HCC), liver decompensation and all-causes of mortality in patients with all stages of cirrhosis (9–11). Unfortunately, it is well-known that the stage of disease is a major independent predictor of SVR using Peginterferon and ribavirin (PR) (12–14). Over the past decade, the availability of the HCV replicon has improved knowledge of the HCV life-cycle allowing the development of many direct-acting antivirals (DAAs). These molecules inhibit all HCV structural proteins (NS3/4A protease, NS5A protein, NS5B polymerase) (15). Two first generation NS3/4A protease inhibitors (boceprevir (BOC) and telaprevir (TVR)) have recently been approved. Up to now, five large phase III trials have assessed the safety and efficacy of BOC and TVR in untreated patients and in patients with chronic HCV genotype-1 infection in whom standard PR treatment has failed (16–20). Because of the few patients with cirrhosis included in these phase III studies, available data on the safety and efficacy of both molecules are limited in these patients. A retrospective, post-hoc analysis of the REALIZE trial showed that the stage of liver fibrosis was a determining factor for treatment success with TVR. SVR rates were 58% and 53% (with and without lead-in respectively) in patients with Metavir F3/4 compared with 75% in F0–F2. However, in previous relapse patients, the SVR rate was 84% regardless of the stage of fibrosis; in previous partial and null responders the SVR rates decreased from 72 to 41% in F0–F2 fibrosis, from 56 to 39% in F3 fibrosis and from 34 to 14% (both TVR12 and lead-in arms combined) in F4 respectively (21). More detailed results have been obtained with BOC in a retrospective post-hoc analysis in patients with cirrhosis and/or advanced fibrosis who participated in SPRINT-2 and RESPOND-2 (22). Overall, patients randomized to a BOC-containing regimen had SVR rates ranging from 13% (2/16) to 25% (3/12). Patients with ≥1log10 decline in HCV RNA at week 4 had significantly higher SVR rates than those with 1 log10 decline in HCV RNA after 4 weeks
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Management of HCV patients with cirrhosis
of lead-in were 77–87% after 44 weeks of triple therapy, compared with 50% after 48 weeks of PR alone. Patients with undetectable HCV RNA at week 8 (corresponding to 4 weeks of triple therapy) had SVR rates of 79–80% (BOC/RGT) and 90–93% (BOC/PR48). Thus, early viral kinetics could be used to predict the response to treatment in patients with cirrhosis. Unlike PR therapy, virological failure of protease inhibitor (PI)-based combination therapy may result in the selection of viral variants with resistance to PI (RAVs). This resistance can emerge early during treatment: so it is important to identify which patients have a poor chance of achieving SVR. RAVs were detected in approximately 50% of the patients in the SPRINT-2 and RESPOND-2 trials with advanced fibrosis/cirrhosis, who did not achieve SVR (22). Very recently and not already fully published, a metaanalysis on cirrhotic patients included in all five phase III BOC clinical trials (SPRINT-2, RESPOND-2, PEGASYS study, EPO study, interim data from PROVIDE) was also performed to (I) combine SPRINT-2/ RESPOND-2 results (to create a larger population of patients), to (II) provide predictors of SVR by multiple logistic regression analysis, to (III) evaluate the risk of severe adverse events (SAEs) as suggested by real-life studies, to (IV) develop newer more reliable stopping rules to reduce the cost and risk of therapy, to (V) assess whether short treatment (i.e. 36 weeks) can be applied to a subset of patients. The meta-analysis showed that over one-half of all F4 patients treated with BOC/PR can achieve SVR (SVR rate by meta-analysis = 55%). In addition, the SVR rates were particularly high (89%) in F4 patients with undetectable HCV-RNA at TW8; these patients accounted for 43% of all patients with cirrhosis who were treated. Eighty-two percent of the patients with detectable HCVRNA at TW8 (57% of the total population of patients with cirrhosis) achieved more than 3 log10 decline in HCV-RNA resulting in a SVR rate of 35% while 18% had less than 3 log10 decline and did not achieve SVR (SVR 0%). The importance of the virological response at TW8 is shown in Figure 1A. A potential algorithm for the treatment of F4 and F3 patients was derived from the on-treatment viral responses at weeks 8, 12 and 24 (Fig. 1B). Because none of the F3 or F4 patients with detectable HCV-RNA and
