The French ATU (temporary authorization for use) provides patients who are the most in need with a medicinal product before marketing authorization (MA). The major objective of the ATU was to make first generation PIs available and evaluate their safety. In the telaprevir and boceprevir ATUs, genotype 1, treatment-experienced patients (either relapsers or partial responders to prior PEG-IFN/RBV therapy) with compensated cirrhosis were eligible to receive a 48 weeks of treatment with triple therapy. Between January 2011 and July 2011 for boceprevir and September 2011 for telaprevir, 558 patients were treated with 12 weeks of triple therapy followed by 32 weeks of PR, and 373 patients were treated by a 4 week PEG-IFN/RBV lead-in phase followed by 44 weeks of triple therapy with boceprevir. Moreover, 63 patients were also treated during the same period with a nominative ATU. These patients were mostly (42) –responders. The ATU was not a clinical trial. Only limited data could be collected by the pharmaceutical companies involved and only safety data should be reported by clinicians and could not be monitored by either French health authorities or pharmaceutical companies. Clinicians had no obligation to report any efficacy data. Recently data from telaprevir ATU have been reported after a median follow-up of 18.6 weeks (1.3–36.4 weeks) . Seventy one per cent of the patients were men with a median age of 56 years (range 22–89), 56% were genotype 1b and the median viral load at baseline was 6.05 log10 IU/ml; 54% of patients were partial responders and 43% were relapsers. Ninety-eight per cent of the patients began with 180 μg/week of PEG-IFNalfa-2a and a weight-based dose of RBV with a median dose of 14.3 mg/kg/days. Eighty-nine per cent of the patients had adverse events and 40% experienced serious adverse events, leading to discontinuation of telaprevir in 14%. Three patients died during the treatment period. Haematological disorders were frequent during treatment. Anaemia below 10 g/dl was observed in 36% of the patients despite the use of erythropoietin in 49% of the patients. Transfusions were given to 11% of the patients and a RBV dose reduction was used to manage anaemia in 6.6% of the patients. Grade 4 neutropenia (<500 cells/mm3) was observed in 2% of the patients and grade 4 thrombopenia (<25 000 cells/mm3) was observed in 3% of the patients. Only one severe telaprevir-related rash was reported. A RVR was observed in 70% (157 of 223) of patients, 66% in partial responders, 77% in relapsers, 62% in genotype 1a and 82% in genotype 1b patients. An eRVR was observed in 69% (84 of 122) of the patients, 66% in partial responders, 72% in relapsers, 63% in genotype 1a and 83% in genotype 1b patients. Overall no new adverse events were observed, the safety profile of telaprevir regimen appeared to be compatible with use in clinical practice but close monitoring of haematological parameters is recommended in those with cirrhosis. Preliminary on-treatment virological response appeared to be promising in this population. However, the main drawback of the ATU is the absence of systematic data collection and the absence of data monitoring. Therefore, the data provide by ATU are relatively scarce and may be significantly biased.
To collect reliable data from patients with cirrhosis, we set up a prospective cohort on the use of protease inhibitors in these patients (CUPIC cohort) on behalf of the French national agency for AIDS and viral hepatitis (ANRS). The aim of this cohort was to collect data on the efficacy, safety, resistance, pharmaco-kinetics (PK) and quality of life. All data were monitored as in clinical trials. From February 2011 to April 2012, 674 genotype 1 patients with cirrhosis were included in 55 sites. Recently an interim analysis in 455 patients who had received at least 16 weeks of treatment was reported . Most patients had compensated cirrhosis, had not responded to prior PEG-IFN/RBV and were treated in the French ATU. Although non-responders were theoretically excluded, after the end of ATU the protocol was amended and these patients were included. All patients were treated with a regimen of 48 weeks of treatment recommended by the ATU. The choice of PIs (telaprevir or boceprevir) was left to the physicians and therefore no head-to-head comparison could be obtained from the cohort. Baseline patient's characteristics are given in Table 1. They were similar to patient characteristics in the ATU cohort. Most of the patients were Child Pugh A cirrhosis, however, at least 15% of the patients had oesophageal varices and 26% of the patients in the boceprevir regimen and 34% in the telaprevir regimen had exclusion criteria for phase III trials. Therefore, this cirrhotic population was different from that included in clinical trials and reflected a more real-life population with cirrhosis. Preliminary safety findings for the telaprevir regimen are provided in Table 2. Serious adverse events were more frequent in the CUPIC cohort (48.6%) than in phase 3 trials, leading to premature discontinuation of treatment in 14.5% of the population treated so far. Six deaths (2%) occurred during the early course of treatment, half of them from infection. Grade 3/4 infection occurred in 8.8% of the population and hepatic decompensation (ascites, encephalopathy or variceal bleeding) occurred in 13 patients (4.4%) leading to death in two patients. Severe rash was rare and occurred in two patients. Preliminary safety findings for the boceprevir regimen are given in Table 3. Serious adverse events were more frequent in the CUPIC cohort (38.4%) than in phase 3 trials, leading to premature discontinuation in 7.4% of the population treated so far. Two deaths (1.3%) owing to infection occurred during the lead-in phase. Grade 3/4 infection occurred in 2.5% of the population and hepatic decompensation occurred in seven patients (4.4%). In addition to these findings, haematological disorders were a major issue for patient management (Table 4). Anaemia below 10 g/dl occurred in 29.7% of patients on telaprevir and in 32.7% of patients on boceprevir despite the use of erythropoietin in 56.8 and 66% of the patients respectively. The rate of blood transfusion, 15.2% with the telaprevir regimen and 10.7% with the boceprevir regimen was higher than that reported in phase 3 trials. This was probably due partly to the low frequency of RBV dose reduction in these patients (<5%) and may also be owing to the lower efficacy of erythropoietin in patients with cirrhosis. Recent data from phase III trials have shown that, in naïve and relapse patients treated with telaprevir, a significant (≤600 mg/days) and early RBV dose reduction did not influence the SVR . These data modify our paradigm for the management of anaemia. However, in this difficult-to-treat population with cirrhosis, in the absence of data on SVR, it is still unknown whether significant and early RBV reductions will impair SVR. Moreover, in phase III trials, SVR rates appear to be lower in patients with advanced fibrosis and cirrhosis when RBV is reduced (19 of 33, 58%) than with the use of erythropoietin (26 of 39, 67%) . Grade 4 neutropenia (<500 cells/mm3) is rare with both drugs and observed in less than 1% of the population while GCSF was used in less than 4% of the population. Grade 4 thrombopenia (<25 000 cells/mm3) was also rare with both drugs and observed in less than 2% of the population leading to thrombopoietin use in less than 2% of the population. On-treatment virological response was high with both drugs (Figs 7 and 8) leading to undetectable viral load by week 16 in 86% of patients treated with telaprevir and 71% of patients treated with boceprevir on a per protocol analysis. Overall these data show that in this difficult-to-treat population, the triple regimen is feasible and can result in a good on-treatment virological response. However, serious adverse events are more frequent than previously observed and patients need to be carefully and frequently monitored. The preliminary analysis of the baseline characteristics of patients who died suggest that patients with either a past history of hepatic decompensation (ascites, bleeding or encephalopathy), a baseline Child Pugh score >5 and/or portal hypertension, low platelets levels and diabetes may be at a higher risk of hepatic decompensation or infection and require close follow-up and early intervention. These difficult-to-treat patients also raise the question of prophylactic antibiotics during triple therapy.
In the post-transplant setting, a retrospective study from a single centre has recently been reported. Six non-responder patients to PEG-IFN/RBV after liver transplantation who had developed cirrhosis were treated with a triple regimen with telaprevir . Prior to treatment, all patients were converted to administration of cyclosporin with a trough level of 100 ng/ml. After a 4-week lead-in with PEG-IFN alfa-2b (1 μg/kg/days) and RBV (600–1000 mg/days), patients received telaprevir 750 mg TID. On the first day of telaprevir, patients received 25 mg daily of cyclosporine with trough level titrated to 100 ng/ml. The virological response was promising and two of six patients had undetectable HCV RNA by week 8 and four of six by weeks 12 and 16. Only two patients experienced a breakthrough. However, safety was difficult to manage as all patients required RBV dose reduction due to severe anaemia. Nearly all patients required blood transfusions and erythropoietin. Moreover, nearly all patients required G-CSF and two patients required elthrombopag for platelet levels below 20 000 cells/mm3. Drug-drug interactions between telaprevir and cyclosporine were manageable with cyclosporin dose adjustments. Results of another multicenter study in 28 liver transplant patients including 5 patients with cirrhosis treated with either boceprevir or telaprevir were identical and drug-drug interaction were manageable by major drug dose reduction in calcineurin inhibitors especially when telaprevir was used with tacrolimus.