Liver International
Special Issue: Proceedings of the 7th Paris Hepatitis Conference International Conference of the Management of Patients with Viral Hepatitis, 13–14 January 2014, Paris, France. Guest Editors: Patrick Marcellin and Tarik Asselah. The publication of this supplement was supported by an unrestricted educational grant from Gilead, Janssen Therapeutics, Janssen, Bristol-Myers Squibb, Roche, Boehringer Ingelheim, Merck, AbbVie, Novartis, Idenix and Alios.
Volume 34, Issue Supplement s1, pages 38–45, February 2014
Review Article
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Vincenzo Boccaccio, Savino Bruno*
Article first published online: 23 DEC 2013
DOI: 10.1111/liv.12391
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Keywords: boceprevir; direct acting antivirals; faldaprevir; HCV-related cirrhosis; hepatitis C virus; simeprevir; sofosbuvir; sustained virological response; telaprevir
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 life-cycle, 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 naïve 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).
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 <10 mmHg), and no varices at endoscopy. In general, these subjects belong to Child-Pugh class A5. However, compensated cirrhosis also includes patients with more severe conditions. Portal hypertension is higher (HVPG ≥10/12 mmHg), esophageal varices may be present on a diagnosis of cirrhosis obtained either by histology or clinically based. Patients can present with thrombo/leukocytopaenia and with low albumin. However, most of these patients can still be classified as Child-Pugh class A (generally A6). Decompensated patients are easier to identify: the MELD score is usually >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 virological 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 Peg-interferon 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 <1log10 decline. In both studies, F3 patients who received PR had SVR rates of 40–50%, while those in the BOC/PR48 arm had higher SVR rates [77% (920/26) in SPRINT-2; 87% (20/23) in RESPOND-2] than patients in the BOC/response guided-therapy (RGT) arm [52% (11/21) and 55% (11/20) respectively]. Baseline viral load appeared to influence the SVR in patients who received BOC and with a <1log10HCV RNA decline at week 4. In SPRINT-2, patients who had a viral load >2 000 000 IU/ml had SVR rates of 5% (1/19); the corresponding SVR rate in RESPOND-2 was 7% (1/14). The SVR in both studies combined was 6% (2/33) of patients, 4% (1/26) with HCV genotype 1a and 14% (1/7) with genotype 1b, respectively, corresponding to a negative predictive value (NPV) of 94%. Conversely, SVR rates were 43% (3/7) in the SPRINT-2 and 60% (3/5) in the RESPOND-2 trials in patients with a <1log10 HCV RNA decline at week 4 but baseline viral load ≤2 000 000 IU/ml. Two of the six patients who achieved SVR were genotype 1a (both in SPRINT-2) and four genotype 1b (1 in SPRINT-2; 3 in RESPOND-2). In the BOC/RGT groups of both studies the duration of therapy was based on a pre-established decision that patients with undetectable HCV RNA at week 8 were eligible for shorter therapy. In patients with advanced fibrosis/cirrhosis, treatment week 8 (TW8) was used to define ‘early responders’ (HCV RNA undetectable at week 8) and ‘late responders’ (HCV RNA detectable at week 8). In both studies in patients with advanced fibrosis/cirrhosis, SVR rates in early responders were more than three times higher than in late responders and were comparable to SVR rates in patients without advanced liver disease. SVR rates were also examined according to the historical response to treatment (i.e., prior non-response vs prior relapse) in patients in the RESPOND-2 study. Patients with advanced fibrosis/cirrhosis with a prior non-response had SVR rates of 0% (0/5), 30% (3/10) and 46% (6/13) in the PR48, BOC/RGT and BOC/PR48 arms respectively. The corresponding SVR rates in those with prior relapse were 20% (2/10), 50% (11/22) and 83% (15/18) in the PR48, BOC/RGT and BOC/PR48 arms respectively. An analysis of SVR rates by IL-28 genotype was limited because of the small number of patients. In SPRINT-2, only five patients with cirrhosis had a favourable CC genotype (2 PR, 1 BOC/RGT and 2 BOC/PR48) and each of these patients achieved SVR. The CT genotype was the most common, and SVR rates were 17% (PR48, 1/6), 33% (BOC/RGT, 2/6) and 0% (BOC/PR48, 0/4) respectively. Eight patients had the less favourable TT genotype (1 PR, 3 BOC/RGT and 4 BOC/PR48) and the corresponding SVR rates were 100% (1/1), 0% (0/3) and 50% (2/4). In the RESPOND-2 trial, eight patients with cirrhosis had the CC genotype (0 PR, 4 BOC/RGT and 4 BOC/PR48) and the SVR rate was 75% in each of the BOC arms. SVR rates for patients with cirrhosis with the CT genotype were 0% (PR48, 0/5), 33% (BOC/RGT, 2/6) and 86% (BOC/PR48, 6/7). Ten patients had the less favourable TT genotype (2 PR; 2 BOC/RGT; 6 BOC/PR48) and the corresponding SVR rates were 0% (0/2), 50% (1/2) and 67% (2/6) respectively.
Thus, an SVR was more likely in patients who had >1.0 log10 decline in HCV RNA at week 4, and in patients with undetectable HCV RNA at week 8. As previously reported, the clearest benefit of adding BOC to PEG-IFN was found in patients with previous treatment failure; SVR rates in patients with cirrhosis who received BOC/PR were 35–77%, compared with 0% for PR alone. SVR rates in patients with advanced fibrosis/cirrhosis and >1 log10 decline in HCV RNA after 4 weeks 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 meta-analysis 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 HCV-RNA 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.
Figure 1. (A) The importance of TW 8 HCV-RNA decline in patients with cirrhosis (F4 Metavir) during BOC-therapy; (B) Proposed Treatment Algorithm for Cirrhotic (F4) and F3 Patients Treated with BOC/P/R. 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. Because no F3 or F4 patients (0/22; 95% CI = 0, 13) with a detectable HCV-RNA and <3 log10 decline in viral load from baseline at Week 8 achieved SVR, stopping therapy in these patients should be considered. Because treatment-naïve F3 and F4 patients with undetectable viral load at treatment week 8 and thereafter achieved similar SVR rates with durations of treatment between 28 and 40 weeks compared with ≥40 weeks, therapy of treatment-naive cirrhotic patients might be stopped after week 28 if the regimen is poorly tolerated [23]. * Consider stopping based on low chance of SVR in F3 and F4 patients with detectable HCV-RNA and <3 log10 decline in HCV-RNA from baseline [SVR = 0/22; 0%; 95% CI (0, 13)].† Consider stopping treatment of treatment-naïve patients after TW28 if undetectable HCV RNA from TW8 through TW24.
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 <3 log10 decline in viral load at TW8 achieved SVR, stopping therapy in these patients should be considered. Furthermore, if F3 or F4 patients with detectable HCV-RNA and <3 log10 decline in viral load from baseline to TW8 are not tolerating treatment, stopping therapy should also be considered. Based on the upper limit of a 95% CI, it is possible that up to 13% of F3 or F4 patients with a <3 log10 decline in viral load can still achieve SVR. Because treatment-naïve F3 and F4 patients with an undetectable viral load at TW8 achieved similar SVR rates with between 28 and 40 weeks of treatment (87%) compared with ≥40 weeks (92%), therapy in treatment-naive and experienced patients with cirrhosis could be stopped after week 28 if the regimen is poorly tolerated. In conclusion, predictors of SVR in F3 and F4 patients include male gender, low baseline viral load and on-treatment viral responses at weeks 4 and 8. These factors can help clinicians to identify patients who will probably achieve SVR. The on-treatment response at TW8 was especially helpful in identifying patients with a high likelihood of response and, on the other hand, could be the earliest stopping point because of a very low probability of response. The frequency of SAEs, transfusions, anaemia and thrombocytopaenia (grade 4) were higher in F4 patients treated with BOC/PR than in F0–F2 patients. Overall, tolerance to BOC/PR in patients with cirrhosis was manageable but closer attention should be paid to the management of anaemia [23].
Compassionate Use of Protease Inhibitors in Viral C Cirrhosis (CUPIC) was established prior to the licensing of TVR and BOC in France to provide early access to triple therapy with new drugs to patients with hepatitis C who are considered to be in urgent need of treatment. Early access use of either TVR or BOC was permitted for treatment-experienced patients with compensated cirrhosis, HCV genotype-1 infection. Of the 292 patients treated with TVR, HCV-RNA was undetectable in 161 (55.1%) 236 (80.5%), 230 (78.8%) and 196 (67.1%) at weeks 4, 8, 12, 16 respectively. At week 16, the response rate was significantly higher in relapsers (74.8%) than in partial responders (66.2%) or null responders (45.8%). A virological response was achieved in patients treated with BOC in 2.4% (5 of 205), 37.6% (77 of 205), 54.6% (112 of 205) and 58.0% (118 of 205) of cases, at weeks 4, 8, 12, 16 respectively. At week 16, the response rate was significantly higher in relapse patients (69.0%) than in partial responders (50.0%) and null responders (22.2%).
In the CUPIC study, the safety profile was poor for treatment regimens including both PIs, mainly because of a high number of SAEs and the occurrence of death and severe complications, such as severe infection or hepatic decompensation in 6.4% of patients. These severe complications have not been previously reported in treatment-experienced patients with cirrhosis included in phase III clinical trials. This could be explained at least in part by the different clinical characteristics of patients included in this real-life cohort and those enrolled in phase III clinical trials. In 31.2 and 43.3% of the cases CUPIC patients treated with BOC had at least one exclusion criterion for the REALIZE and RESPOND-2 studies, respectively, while the patients in the TVR group were older, with lower mean haemoglobin (Hb) levels and platelet count compared with the cirrhotic patients enrolled in REALIZE. Thus, many patients treated in CUPIC did not meet inclusion criteria for the TVR or BOC pivotal trials.
In multivariate analysis, two baseline predictors of severe complications were identified: platelet count <100 000/mm3 and serum albumin <35 g/L. The combination of both conditions defined a subgroup of patients at a high risk (44.1%) of severe complications. Authors have therefore suggested that this subset of individuals should not be treated with triple therapy with BOC or TVR [24].
In this observational study, several cases of renal impairment were also observed for the first time. This aspect was recently emphasized by a subanalysis of another real-life survey, the PAN-study, a non-interventional investigation conducted by the Association of German Gastroenterologists in Private Practice, enrolling patients treated with PR with or without TVR or BOC. In this large cohort, about 5% of patients on triple therapy with BOC or TVR developed stage 3 renal insufficiency, some temporarily. However, a substantial proportion of these patients had risk factors for renal impairment at inclusion, such as older age, arterial hypertension or diabetes mellitus. As expected, all these variables were associated with a marked decrease in eGFR to <60 ml/min on univariate analysis. However, it is important to note that treatment with TVR or BOC was found to be independently associated with the development of renal failure on multiple logistic regression analysis. This is reversible in most patients treated with TVR. The improvement of renal function after discontinuation of PIs strongly suggests a causal relationship [25].
SVR data in the CUPIC study are not yet fully known. Partial results presented at the 2013 EASL meeting, showed that overall SVR12 rates were: 79/190 (41%) for BOC, 118/295 (40%) for TVR; in relapsers 43/85 (51%) for BOC, 61/116 (53%) for TVR; in partial responders 32/80 (40%) for BOC, 43/135 (32%) for TVR; in null responders 1/9 (11%) for BOC, 8/28 (29%) for TVR [26].
The Open Label Early Access Program (EAP) for TVR in adult patients with HCV genotype 1 was an international real life study in which 1587 patients, both naïve and treatment-experienced (genotype 1a/1b: 22%/74%) were treated with triple therapy including TVR. Patients enrolled had persistent compensated bridging fibrosis (752) or cirrhosis (835), ≥3.5 g/dl albumin, ≥90 000 platelets, ≥1500 neutrophils, Hb>12 g/dl (women) or >13 g/dl (men). 321 patients (20%) were naïve, 436 (27%) prior null responders, 531 (33%) relapsers, 49 (3%) had a previous viral breakthrough, 47 (3%) were classified as non-responders (unspecified response). The most relevant grade 2–4 AEs that developed during treatment were: anaemia (44%), rash (13%), thrombocytopaenia (8%), pruritus (6%), asthenia (6%), nausea (4%) and anorectal disorders (4%). Seven patients (six with cirrhosis) experienced AEs with a fatal outcome: four died because of severe infections, two of hepatic failure and one of variceal bleeding. No data are available on SVR [27]. Assessment of data from another very large real-life study of BOC (The Italian and Spanish Name Patient Program) is still ongoing.
Figure 2. Differences between clinical trials and real-world studies.
More than 40 new NS3/4A, NS5A, or NS5B inhibitors are under development. Sofosbuvir (formerly GS 7977, an NS5B polymerase nucleotidic inhibitor), faldaprevir and simeprevir (both NS3 protease inhibitors), are in phase III development and almost ready for marketing distribution.
In particular, clinical studies have shown that sofosbuvir (SOF) has a strong and excellent antiviral activity, with broad HCV genotype coverage, a high genetic barrier to resistance, and is safe and well-tolerated. SOF has been tested both in interferon-based and in interferon-free regimens. The NEUTRINO trial enrolled 327 naïve patients with genotypes 1, 4, 5 or 6 HCV infection (17% with cirrhosis), who received SOF+PR for 12 weeks. SVR12 rates were high in all genotypes, including 89% in genotype 1, 96% in genotype 4 and 100% in genotypes 5 and 6. The SVR12 rate in patients with cirrhosis was 80% [28].
In a non-inferiority trial (FISSION), 499 treatment-naïve patients with genotype 2 or 3 were randomly assigned to receive SOF+ribavirin (RBV) for 12 weeks or PR for 24 weeks. There were 20–21% of patients with cirrhosis. The SVR12 rate in patients with cirrhosis and genotype 2 was 91% vs 61%, respectively, while in those with genotype 3 it was 34% vs 30% respectively [28].
The POSITRON trial compared 12 weeks of treatment with SOF and RBV with matching placebo patients with genotype 2 and 3 who were unwilling, intolerant or ineligible for IFN therapy. Approximately 20% of included patients had evidence of compensated cirrhosis at screening. The SVR12 rate was 94% and 21% in patients with genotype 2 and genotype 3 with cirrhosis respectively [29].
The FUSION study included treatment-experienced patients with genotypes 2 and 3, who received SOF and RBV for 12 or 16 weeks. Approximately 33–35% of the patients enrolled had compensated cirrhosis. SVR12 was achieved by 78% vs 60% of cirrhotic patients with genotype 2 (16 vs 12 weeks of treatment) and by 61% vs 19% in genotype 3 [29].
The most promising study is the phase II LONESTAR trial which evaluated 8-and 12-week courses of therapy with the once-daily fixed-dose combination of SOF and ledipasvir with and without RBV. In this study, 40 patients (half with documented compensated cirrhosis) who had previously failed therapy with an HCV specific PI-based regimen were included. 95% of patients in both arms achieved SVR4, one patient with cirrhosis in the SOF and ledipasvir arm relapsed and one patient in the SOF and ledipasvir plus RBV arm was lost to follow-up [30].
Finally, two other ongoing phase III studies are examining all-oral HCV therapy with SOF and ledipasvir. ION-1 and ION-2 are testing 12- and 24-week courses of the fixed-dose combination with and without RBV in treatment-naïve and treatment-experienced genotype 1 HCV patients, including those with compensated cirrhosis. Based on the results of the LONESTAR trial, Gilead has amended ION-2 to shorten the duration of therapy in one of the two fixed-dose combination arms without RBV from 24 to 12 weeks [30].
Simeprevir (SMV) is an NS3/4A PI with potent antiviral activity against multiple genotypes in preclinical studies and with once-a day dosing.
ASPIRE was a phase IIb trial which included treatment-experienced patients with genotype 1 and F3/F4. Patients received PR alone (for 48 weeks) or in combination with SMV for 12, 24 or 48 weeks. SVR24 in F3/F4 patients treated with SMV was 65% in relapsers, 67% in partial-responders and 33% in null responders [31].
Two additional phase III trials, QUEST-1 and QUEST-2, evaluated the safety and efficacy of SMV plus PR in naïve patients with HCV genotype 1 infection. These two trials differed for the percentage of patients with cirrhosis and with genotypes 1a or 1b in this study: in QUEST-1 there were 56–57% of patients with genotype 1a and 12–13% of patients with cirrhosis; in QUEST-2 there were 58% of patients with genotype 1b and 7–11% with cirrhosis. The addition of SMV to PR in treatment-naive patients with HCV genotype 1 infection was associated with a significant improvement in efficacy over PR alone in both trials, with an overall SVR12 of about 80–81% and 50% respectively. In QUEST-1, the SVR12 rate for patients with cirrhosis was 58% in the SMV arm vs 29% in the PR arm. In QUEST-2, the SVR12 rate for patients with cirrhosis was 65% in the SMV arm vs 40% in the PR one. Response to therapy was also more rapid in patients treated with SMV; the rapid virological response (RVR) rate was 80% vs 12% with placebo. SMV was generally well-tolerated and was only associated with transient, mild elevations in bilirubin levels [32, 33].
The COSMOS trial is now evaluating a combination of SMV and SOF with or without RBV in treatment-naïve patients and non-responders, both without cirrhosis (cohort 1) and with cirrhosis (cohort 2). Treatment for 12 weeks with SMV and SOF, with or without RBV, led to SVR4 rates of 96% and 100%, respectively, in cohort 2, including 90 treatment-naïve or previous null responders [34].
Faldaprevir (FDV) is a potent PI that has been developed in combination with interferon or in all-oral therapeutic regimens. The phase III STARTVerso1 trial has suggested that the response rate to PR in naïve patients with genotype 1 (6% of patients with cirrhosis) can be improved by adding FDV. In fact, the overall SVR12 rate was significantly higher in patients receiving triple therapy (79–80%) than in the placebo group (52%). The SVR12 rate in F3 patients treated with FDV was 67% and 56% in F4 [35].
FDV was also administered, in the phase IIb SOUND-C2 trial, in combination with a non-nucleoside polymerase inhibitor (deleobuvir) with or without RBV in naïve genotype 1 patients (9% with cirrhosis). In patients with cirrhosis SVR12 rates ranged from 36 to 76% depending upon the dosage and duration of therapy. Rashes, photosensitivity, nausea, vomiting, diarrhoea and transient hyperbilirubinaemia were the most common AEs [36].
The results of some trials carried out with second generation DAAs in patients with cirrhosis are shown in Figure 3.
Figure 3. Results of some trials carried out with second generation DAA in cirrhotic patients: (A) Lonestar, (B) Quest-1, (C) Quest-2 [30, 32, 33].
Even more promising third generation DAAs are in phase II of development. Very high cure rates can be obtained with these DAAs when combined with PR, in a triple or quadruple therapeutic regimen (add-on strategy) and, at the same time, clinical results are promising when they are administered in all-oral regimens (combining drugs with different viral targets).
In conclusion, despite not conclusive, the available results suggest that patients with early stage compensated cirrhosis should be treated now with first generation PIs. However, these molecules should be cautiously used in patients with signs of more severe portal hypertension. Baseline characteristics can help to select individuals to be treated while newer on-treatment stopping rules, if validated, could optimize/maximize the treatment schedule, reduce costs and avoid AEs.
Future research must define well-tolerated and cost-effective DAA combinations that provide the highest rates of viral eradication in all patients (including those with advanced liver disease or waiting for OLT, as well as HIV-coinfected patients), the broadest spectrum of action on viral genotypes showing minimal or no clinical resistance, and the shortest treatment duration.
Acknowledgement
Conflict of interest: V. Boccaccio does not have any discosure to report. S. Bruno: advisory board MSD; speaker bureau MSD and Roche.
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