Faldaprevir combined with peginterferon alfa-2a and ribavirin in chronic hepatitis C virus genotype-1 patients with prior nonresponse: SILEN-C2 trial

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Hepatology June 2013

Mark S. Sulkowski,1 Marc Bourlie` re,2 Jean-Pierre Bronowicki,3 Tarik Asselah,4 Jean-Michel Pawlotsky,5 Stephen D. Shafran,6 Stanislas Pol,7 Stefan Mauss,8 Dominique Larrey,9 Yakov Datsenko,10 Jerry O. Stern,11George Kukolj,12 Joseph Scherer,11 Gerhard Nehmiz,10 Gerhard G. Steinmann,10 and Wulf O. Bocher13

Abstract

Faldaprevir (BI 201335) is a potent, hepatitis C virus (HCV) NS3/4A protease inhibitor. In all, 290 noncirrhotic HCV genotype (GT)-1 patients with prior null (<1 log10 viral load [VL] drop at any time on treatment) or partial response (≥1 log10 VL drop but never undetectable on treatment) were randomized 2:1:1 to receive 48 weeks of peginterferon alfa-2a and ribavirin (PegIFN/RBV) in combination with faldaprevir 240 mg once daily (QD) with 3 days PegIFN/RBV lead-in (LI), 240 mg QD without LI, or 240 mg twice daily (BID) with LI.

Patients in the 240 mg QD/LI group achieving maintained rapid virologic response (mRVR; VL <25 IU/mL [Roche TaqMan] at week 4 and undetectable at weeks 8 to 20) were rerandomized to cease all treatment at week 24 or continue PegIFN/RBV up to week 48. Sustained virologic response (SVR) rates were 32%, 50%, and 42% in prior partial responders, and 21%, 35%, and 29% in prior null responders in the faldaprevir 240 mg QD/LI, 240 mg QD, and 240 mg BID/LI groups, respectively. In the 240 mg QD/LI group, a significantly higher proportion of mRVR patients rerandomized to 48 weeks' treatment achieved SVR compared with those assigned to 24 weeks treatment (72% versus 43%; P = 0.035). Rates of gastrointestinal disorders, jaundice, dry skin, and photosensitivity were increased at 240 mg BID compared with the 240 mg QD dose. Faldaprevir discontinuations owing to adverse events occurred in 6%, 4%, and 23% of patients in the 240 mg QD/LI, 240 mg QD, and 240 mg BID/LI groups, respectively. Conclusion: Faldaprevir 240 mg QD with PegIFN/RBV was safe and tolerable and produced substantial SVR rates in prior null and partial responders. The 240 mg QD dose is currently undergoing phase 3 evaluation.

Hepatitis C represents one of the most common chronic infectious diseases, affecting 150 to 170 million people worldwide. Of the described hepatitis C virus (HCV) genotypes (GT), GT-1 is most common in many parts of the world.

Historically, GT-1 has been less responsive to peginterferon alfa (PegIFN) and ribavirin (RBV) treatment, with around 50% to 60% of treatment-naïve patients failing to achieve a sustained virologic response (SVR). Treatment options for these patients were previously limited to a repeated course of PegIFN/RBV, with a low chance of cure (15% SVR).1, 2 Recent approval of the HCV NS3/4A protease inhibitors (PIs) boceprevir and telaprevir has resulted in significantly improved SVR rates in GT-1-infected patients including those who failed to respond to prior PegIFN/RBV treatment.3, 4 However, both agents add significant side effects to those of PegIFN/RBV, including severe skin rashes/pruritus (telaprevir), anal and digestive discomfort (telaprevir), anemia (telaprevir and boceprevir), nausea (telaprevir and boceprevir), and dysgeusia (boceprevir), are dosed thrice-daily, and carry a high pill burden.

Faldaprevir (BI 201335) is a peptidomimetic linear PI which has a long half-life, as demonstrated by preclinical and human pharmacokinetic studies, allowing once-daily (QD) dosing.5 In phase 1b studies, faldaprevir combined with PegIFN/RBV demonstrated strong antiviral responses and was well tolerated in treatment-naïve and treatment-experienced HCV GT-1 patients.6 In a phase 2b study of faldaprevir (SILEN-C1), up to 84% of treatment-naïve GT-1 patients achieved SVR and the safety and tolerability profile of faldaprevir was found to be favorable.7 Moreover, up to 87% of patients achieved the criterion of a maintained rapid virologic response (mRVR; HCV RNA <25 IU/mL at week 4 and undetectable from week 8 to week 20) and qualified for shortened treatment duration with 24 weeks of overall treatment. Here we report the results of a phase 2b multicenter, randomized, double-blind study of faldaprevir in combination with PegIFN/RBV in HCV GT-1-infected patients with nonresponse to prior PegIFN/RBV (SILEN-C2; Safety and antIviraL Effect of faldaprevir iN hepatitis C).

Patients and Methods

Patients
Patients were enrolled at 73 centers in 14 countries (Australia, Austria, Canada, Czech Republic, France, Germany, Republic of Korea, The Netherlands, Portugal, Romania, Spain, Switzerland, United Kingdom, and United States). Eligible patients were 18 to 65 years of age, had chronic HCV GT-1 infection, had previously received at least 12 weeks of combination treatment with an approved dose of PegIFN alfa-2a or alfa-2b combined with RBV, and had detectable HCV RNA at the end of previous treatment. At the time that the protocol was developed and approved, there was no standard definition of null or partial response. Accordingly, virologic failure was defined as either a <1 log10 maximum reduction in HCV RNA at any time during treatment (null response), or a maximal reduction in HCV RNA at any timepoint ≥1 log10 but never having achieved HCV RNA below the level of detection (partial response). Relapsers, who experienced undetectable HCV RNA during and/or at the end of prior HCV treatment followed by viral rebound, were specifically excluded from the trial. Other key inclusion criteria included an HCV viral load (VL) of ≥100,000 IU/mL at screening and a liver biopsy within 24 months prior to enrollment; patients with histologic cirrhosis were excluded. Patients with evidence of other liver disease, HCV of mixed GT, hepatitis B virus, human immunodeficiency virus, decompensated liver disease, contraindication to PegIFN or RBV, or hyperbilirubinemia (>1.5 x upper limit of normal [ULN]) were excluded; patients with Gilbert's polymorphism were accepted. Due to the potential for drug interactions, concomitant treatment with medications that are substrates of P-gp, UGT1A1, CYP3A4 or 2C9, with a narrow therapeutic range, were excluded. All patients provided written informed consent prior to trial participation. The study protocol was reviewed and approved by the appropriate Institutional Ethics Committees and health authorities.

Study Design

This was a phase 2b, multicenter, randomized, double-blind trial (NCT00774397). Eligible treatment-experienced patients were randomized to one of three treatment groups in a 2:1:1 ratio: 240 mg faldaprevir QD combined with PegIFN alfa-2a and RBV for 24 weeks, starting with a 3-day lead-in (LI) phase of placebo plus PegIFN/RBV, and followed by an additional 24 weeks of PegIFN/RBV (240 mg QD/LI); 240 mg faldaprevir QD combined with PegIFN alfa-2a and RBV for 24 weeks, followed by an additional 24 weeks of PegIFN/RBV (240 mg QD); 240 mg faldaprevir twice daily (BID) combined with PegIFN alfa-2a and RBV for 24 weeks, starting with a 3-day LI phase of placebo plus PegIFN/RBV, and followed by an additional 24 weeks of PegIFN/RBV (240 mg BID/LI). The rationale for the 3-day LI phase was that short delay of the first intake of faldaprevir would allow sufficient levels of PegIFN and RBV to be achieved prior to the administration of faldaprevir to prevent the possibility of functional faldaprevir monotherapy.

Three days was thought to be sufficient based on the observation that the antiviral effect of interferon can be observed within 1 to 2 days of dosing.8 For all patients, a loading dose of 480 mg faldaprevir was administered on the morning of the first day of faldaprevir treatment. In the 240 mg QD/LI treatment group, all patients achieving mRVR, defined as HCV VL below the lower limit of quantification (LLOQ) at week 4 (HCV RNA <25 IU/mL) and undetectable from week 8 to week 20 (HCV RNA <17 IU/mL), were rerandomized at week 24, at a ratio of 1:1, to either continue PegIFN/RBV up to week 48 or stop all treatment at week 24. PegIFN alfa-2a was administered subcutaneously at a dose of 180 μg per week, and RBV was given orally at a dose of 1,000 mg/day (body weight <75 kg) or 1,200 mg/day (body weight ≥75 kg) in two divided doses. Faldaprevir and RBV were administered with food. Hematopoietic growth factors were not provided but allowed at the discretion of the investigator for the management of anemia and neutropenia. Stopping criteria for virologic failure were as follows: HCV VL rebound by ≥1,000 IU/mL after previous VL below the lower limit of detection (LLOD), in two consecutive visits at least 2 weeks apart; lack of early virologic response, defined as an absence of drop by ≥2 log10 from baseline VL at week 12; or absence of VL below the LLOD at week 24. There were no protocol-specified laboratory or clinical stopping rules for bilirubin elevations.

Efficacy Assessments

Efficacy Endpoints

The primary efficacy endpoint of the study was SVR, defined as HCV RNA below the LLOD 24 weeks after the end of all anti-HCV therapy. Secondary efficacy endpoints included mRVR (defined in the study design section) and the occurrence of rebound, in particular breakthrough and relapse. End of treatment response (EoTR) was defined as HCV RNA not detected at end of treatment. Rebound was defined as HCV RNA >1 log10 from nadir, or ≥100 IU/mL after previous VL below the LLOD in two consecutive visits at least 2 weeks apart. Breakthrough was defined as HCV RNA rebound during faldaprevir/placebo treatment or subsequent PegIFN/RBV treatment. Relapse was defined as HCV RNA undetectable at the end of treatment but detectable during the follow-up period. Nonresponse was used to define patients who did not achieve SVR, but did not experience a virologic breakthrough or relapse.

Analysis of Plasma HCV RNA and GT

Plasma HCV RNA levels were measured using the Roche COBAS TaqMan HCV/HPS (v. 2.0) assay at a central laboratory, with an LLOQ of 25 IU/mL and an LLOD of 17 IU/mL. HCV GT for screening and randomization was determined using the Trugene HCV assay (Bayer, Leverkusen, Germany); due to the technical limitations of this genotyping assay,9 definitive HCV GTs and subtypes used for all analyses were based on complete NS3/4A sequencing and phylogenetic analyses for all randomized patients.

Genotypic and Phenotypic Resistance Monitoring

Samples for genotyping the HCV NS3/4A protease were collected at all patient visits. Retrospective viral genotyping was performed for all patients at baseline, for patients who discontinued study treatment due to virologic failure or who had VL plateaus above the LLOQ, or VL rebounds during or after the end of treatment. Viral RNA was isolated from plasma using the QiaAmp Viral RNA extraction kit. cDNA was synthesized using Superscript III one-step reverse transcription polymerase chain reaction system with platinum Taq DNA polymerase using GT-specific primers. The length of amplified product potentially limits the detection to samples with VL >103 IU/mL. The NS3/4A protease nucleotide sequence was obtained by direct DNA sequencing of the amplified product using Big Dye Terminator V3.1 and the ABI 3130x1 Genetic Analyzer (Applied Biosystems) detection system that allows for the detection of variants present at ≥30%.

Safety Assessments

A written record of all adverse events (AEs), including time of onset, end time, and intensity of the event, as well as any treatment or action required for the event and its outcome, was kept by each investigator. All AEs, including rash, were graded based on tolerability until the introduction of a rash management plan, defined as follows: mild (localized), moderate (diffuse, 30% to <70% body surface area), or severe (diffuse generalized, >70% body surface area or mucous membrane involvement or organ dysfunction or signs of anaphylaxis or life threatening). The intensity of all other AEs was judged based on a patient's tolerability of the event as being mild (easy to tolerate), moderate (interference with usual activity), or severe (incapacitating or causing inability to work or to perform usual activities). Vital signs and electrocardiograms were also evaluated, as were routine laboratory parameters.

Statistical Assessments

Descriptive statistics for efficacy and safety endpoints were reported. All P-values reported are 2-sided and were calculated using Fisher's exact test. All efficacy and safety results relate to all treated patients (Fig. 1). The sample size in this phase 2 trial was based on an optimization approach for the probability of correctly selecting the most efficacious dose for phase 3.

Results

Patient Disposition and Baseline Characteristics

Of 355 patients enrolled in the trial, 290 patients were randomized to treatment (Fig. 1). Of these, 288 patients received at least one dose of treatment; 192 patients completed treatment with faldaprevir, while 96 patients prematurely discontinued for reasons including AEs (n = 27), lack of efficacy (n = 51), refusal to continue the study medication (n = 11), noncompliance with the protocol (n = 3), and other reasons (n = 4) including one patient lost to follow-up. Following completion of the faldaprevir dosing phase, PegIFN/RBV was continued in 162 patients and completed in 114 patients, while 30 were rerandomized to stop all therapy (Fig. 1).

Baseline characteristics were similar among the three treatment groups (Table 1); 67% of patients were male, mean age was 49 years, 5% of patients were black (Hispanic patients were classed as white), and mean log10 HCV RNA was 6.58 IU/mL. As expected for prior nonresponders, only 4% of patients (among those with available IL28B GT data) had the CC polymorphism (rs12979860) (Table 1). Among all patients, 51% were infected with GT-1a and 47% with GT-1b. The majority of patients were documented null responders (47%; using stringent criteria of <1 log10 reduction in HCV RNA at any time during previous treatment) or prior partial responders (36%) to previous treatment (Table 1).

Efficacy

Overall, SVR was achieved by 28% of patients in the 240 mg QD/LI group, 41% in the 240 mg QD group, and 31% in the 240 mg BID/LI group (Fig. 2A). Compared with patients with prior null response, the rate of SVR was higher in patients with prior partial response (Fig. 2B), as expected. SVR was achieved by 32%, 50%, and 42% of prior partial responders in the 240 mg QD/LI, 240 mg QD, and 240 mg BID/LI treatment groups, respectively; corresponding rates in prior null responders were 21%, 35%, and 29%. SVR rates among patients infected with GT-1a tended to be lower than among patients infected with GT-1b virus.

Protocol-defined mRVR was achieved by 43%, 45%, and 47% of patients in the 240 mg QD/LI, 240 mg QD, and 240 mg BID/LI treatment groups, respectively (Fig. 2A). In the 240 mg QD/LI group, 59 patients who achieved mRVR were rerandomized to complete 24 or 48 weeks of PegIFN/RBV (total duration); the rate of SVR was significantly higher in patients treated for 48 weeks (72%) compared with those treated for 24 weeks (43%; P = 0.035) and virologic relapse was significantly lower in patients treated for 48 weeks (21%) compared with those treated for 24 weeks (57%; P = 0.0073) (Fig. 2C). Relapse occurred in 27% of patients with 240 mg QD/LI, 12% of patients with 240 mg QD, and 20% of patients with 240 mg BID/LI. The higher relapse rate in the 240 mg QD/LI group was mainly driven by frequent relapses in patients who obtained mRVR and were rerandomized to shortened treatment duration.

Breakthrough was observed in 24% of patients on faldaprevir treatment, with GT-1a viruses largely encoding NS3 R155 mutants and GT-1b viruses encoding only D168 changes (Table 2). The median time for faldaprevir breakthrough was 30 days (range 14 to 169). Of note, the viral breakthrough rate was lower in patients treated with 240 mg BID/LI (17%) and substitutions at position 155 were not observed in patients infected with GT-1a. After discontinuation of faldaprevir, virologic breakthrough during PegIFN/RBV therapy occurred in 6% of patients and was mainly associated with R155K mutations. Other nonresponse and relapse within all faldaprevir treatment arms was observed in 33% of patients and was characterized by R155K (37/51) substitutions for GT-1a virus and D168V (23/43) changes for GT-1b. However, in these groups 23% (22/94) had viruses that lacked known resistant mutations.

Safety

The most frequent AEs were those typical of PegIFN/RBV treatment, and in most cases were mild or moderate in intensity. Table 3 lists the most common AEs reported at an incidence of >20% in any group during the 24 weeks of treatment with faldaprevir or placebo and PegIFN/RBV. Based on prior studies, gastrointestinal disorders (nausea, diarrhea, and vomiting), skin events (rash and photosensitivity), and jaundice associated with elevated unconjugated bilirubin levels were considered to be potentially related to faldaprevir; these events were frequently observed during the initial weeks of therapy (Table 3). The rates of gastrointestinal disorders, jaundice, dry skin, and photosensitivity were higher in the 240 mg BID group compared with the 240 mg QD dose groups, suggestive of a dose-response relationship.

Serious AEs were more common in patients in the 240 mg BID/LI group (19%) compared with those in the 240 mg QD/LI and 240 mg QD groups (7% in both groups) and included anemia (4%, 1%, and 0%, respectively), gastrointestinal disorders (6%, 1%, and 0%, respectively), and skin and subcutaneous tissue disorders (7%, 0%, and 3%, respectively). No deaths were observed. Discontinuations due to AEs were rather frequent in the 240 mg BID/LI group (23%) but low with the 240 mg QD/LI group (6%) and the 240 mg QD group (4%). AEs leading to discontinuation were mainly rash (10%, 0%, and 0%, respectively), asthenia (4%, 0%, and 0%, respectively), nausea (3%, 1%, and 0%, respectively), vomiting (4%, 1%, and 1%, respectively), increased bilirubin (3%, 1%, and 0%, respectively), and jaundice (1%, 1%, and 0%, respectively). Some patients had more than one AE at the time of discontinuation.

Changes in laboratory values were generally consistent with those commonly reported for PegIFN/RBV. Decreases in hemoglobin, platelets, and white blood cell count were observed at frequencies similar to those observed with PegIFN/RBV and descriptive analysis did not reveal any clinically relevant differences between dose groups (no statistical analyses were conducted; Table 4).10 Erythropoietin was received by 6% to 14% of patients (two patients received transfusions; one in the 240 mg QD arm and one in the 240 mg BID/LI arm). Increases in total bilirubin, characterized by predominance of the unconjugated (indirect) fraction, were common during faldaprevir therapy and rapidly returned to pretreatment levels in all patients after faldaprevir was discontinued. Elevations in bilirubin were not associated with increases in serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels, or other markers of liver injury (Supporting Table 1).

Discussion

Treatment with the PI, faldaprevir 240 mg QD, in combination with PegIFN and RBV, led to virologic cure (SVR) in 35% and 50% of HCV GT-1 patients with strictly defined prior null or partial response to PegIFN/RBV. Interestingly, higher SVR rates were not observed in patients treated with 3-day LI of PegIFN/RBV compared with those treated with all three drugs simultaneously from the start. While 240 mg BID/LI was associated with lower rates of virologic breakthrough, the SVR rate achieved with this regimen was lower than the rate achieved with 240 mg QD, largely due to higher rates of treatment discontinuation due to AEs.

This trial excluded patients with liver cirrhosis and used a more stringent definition of null (<1 log10 reduction in HCV RNA at any time during previous treatment) and partial response (≥1 log10 reduction in VL but never undetectable on treatment) than clinical trials with other HCV PIs plus PegIFN/RBV in treatment-experienced patients.3, 4, 11 The manner in which prior HCV treatment response was collected in this study did not permit retrospective analysis of the current definitions of null (<2 log10 reduction in HCV RNA at week 12) and partial response (≥2 log10 reduction in HCV RNA at week 12 but with detectable HCV RNA at week 24). Accordingly, cross-study comparison of these data with other published studies is not possible.12 A phase 3 trial of faldaprevir plus PegIFN/RBV in treatment-experienced patients classified according to current definitions of null and partial response is ongoing. Prior relapsers are also being assessed in the phase 3 study. While these data are not yet available, this study suggests that, similar to other HCV PIs, prior PegIFN/RBV treatment response impacts the likelihood of response to retreatment with faldaprevir plus PegIFN/RBV.

For telaprevir and boceprevir, shortened response-guided therapy (RGT) provided to patients with rapid virologic response is the standard approach for treatment-naïve patients and prior relapsers (telaprevir). In the US, prior partial responders with RVR are eligible for shortened therapy with boceprevir regimens (but this is not included in the EU label); however, RGT has not been assessed in prior null responders. In this study, virologic relapse occurred in 60% of prior partial and null responders treated with 240 mg QD/LI who achieved mRVR, and were randomly assigned to stop treatment after 24 weeks. Although it is possible that RGT may have been more effective in patients treated with faldaprevir 240 mg QD without the PegIFN/RBV 3-day LI, we believe that these data provide convincing evidence that RGT should not be considered in this difficult-to-cure patient population. Thus, this concept was abandoned for previous null and partial responders in the ongoing phase 3 clinical trial program.

Importantly, even with longer PegIFN/RBV therapy, SVR rates were lower in patients with prior null response compared with those with prior partial response. In addition, the rate of virologic failure with HCV variants resistant to faldaprevir was higher in null responders, likely reflecting the inability of PegIFN/RBV to eradicate variants with decreased susceptibility to faldaprevir. This finding is consistent with those in clinical trials of boceprevir and telaprevir.3, 4 However, some differences in patterns of resistant variants detected in patients failing faldaprevir were observed compared with those previously reported in patients who failed to respond to telaprevir and boceprevir. Most cases of breakthrough and relapse were due to selection of the well-described resistance mutations R155K (GT-1a) and D168V (GT-1b).

Interestingly, a lower breakthrough rate was observed (17%, 12/70) with 240 mg BID/LI, where both GT-1a and GT-1b breakthrough virus encoded D168 mutants exclusively, indicating that the sensitivity shifts of R155K mutants might partially be covered by the increased faldaprevir exposure at this dose level; however, overall efficacy was offset by a higher discontinuation rate in the BID dose group. Wild-type sequence without detectable resistant mutants was found in 23% of nonresponders other than breakthrough (relapsers, other non-SVR) across all arms.

HCV PIs are known to rapidly select for resistant variants when administered as monotherapy.6, 13 Based on the rationale that a short delay in the first intake of a PI may prevent the possibility of functional monotherapy, the effect of a 3-day PegIFN/RBV LI period before initiation of faldaprevir therapy was assessed for the 240 mg QD dose. Consistent with phase 2 results reported in treatment-naïve patients,7, administration of a 3-day LI with PegIFN/RBV prior to faldaprevir treatment resulted in SVR rates around 10% lower than when the same dose of faldaprevir and PegIFN/RBV were initiated simultaneously. This observation remained valid after sensitivity analysis, which involved the removal of the 30 patients with mRVR who were rerandomized to what was found to be a suboptimal treatment duration (24 weeks). The finding that initiation of PegIFN/RBV prior to HCV PI had a negative effect was unexpected. Interestingly, in two randomized controlled trials (one with boceprevir; one with telaprevir), addition of HCV PI after 4 weeks of PegIFN/RBV therapy (LI) was not associated with a decrease or increase in the proportion of patients achieving SVR. The underlying mechanism for impaired viral response with the 3-day LI in our study is not known; further investigation is ongoing. Given the observed negative effect of 3-day PegIFN/RBV LI, simultaneous start of faldaprevir and PegIFN/RBV will be incorporated into current and future studies of this agent.

Faldaprevir was well tolerated at the 240 mg QD dose. At this dose, the main faldaprevir-related AEs were mild-to-moderate skin rash, photosensitivity reactions, and gastrointestinal events, which tended to occur during the first weeks after faldaprevir initiation up to week 12. Only 6% and 4% of patients discontinued faldaprevir due to AEs in the 240 mg QD/LI and 240 mg QD treatment groups, respectively. However, a much higher rate of discontinuation due to AEs was observed with the 240 mg BID dose (23%) without improved efficacy; thus, this dose will not be investigated in phase 3 studies.

Faldaprevir is associated with incidences of jaundice related to increases in unconjugated bilirubin. Similar to some other HCV PIs in development,14 faldaprevir-mediated inhibition of normal bilirubin uptake (OATP-1), processing (UGT1A1), and elimination (MRP-2) appear to drive this event.15 Jaundice was rapidly reversible after cessation of faldaprevir and was not associated with increases in serum ALT, AST, or other markers of liver injury; only three patients discontinued the trial due to jaundice and indirect bilirubin elevation. Skin rash in the 240 mg QD dose groups was mainly mild to moderate and managed without treatment modifications in most instances. In the 240 mg QD dose groups, only one patient discontinued treatment due to rash; however, 10 patients discontinued treatment with the 240 mg BID dose because of rash. In conclusion, addition of 240 mg QD faldaprevir for 24 weeks to 48-week PegIFN/RBV therapy was safe and tolerable and produced SVR rates of up to 50% in even the hardest-to-cure patients, i.e., GT-1 patients with null or partial response to prior PegIFN/RBV. Phase 3 trials testing 120 mg and 240 mg QD faldaprevir without LI, in combination with PegIFN/RBV, for treatment-naïve patients and patients with prior treatment failure are ongoing.

Source

Treatment failure may lead to accelerated fibrosis progression in patients with chronic hepatitis C

Journal of Viral Hepatitis

Early View (Online Version of Record published before inclusion in an issue)

Original Article

B. Baran¹, M. Gulluoglu², O. M. Soyer¹, A. C. Ormeci¹, S. Gokturk¹, S. Evirgen¹, S. Yesil², F. Akyuz¹, C. Karaca¹, K. Demir¹, S. Kaymakoglu¹, F. Besisik^1,*

Article first published online: 27 AUG 2013

DOI: 10.1111/jvh.12127

© 2013 John Wiley & Sons Ltd

Abstract

Keywords: fibrosis progression; gamma-glutamyl transferase; hepatitis C; nonresponder; treatment failure

Summary

Chronic hepatitis C (CHC) patients with treatment failure (TF) remain at risk of continuing fibrosis progression. However, it has not been investigated whether there is an increased risk of accelerated fibrosis progression after failed interferon-based therapy. We aimed to investigate long-term influence of TF on fibrosis progression compared with untreated patients with CHC. We studied 125 patients with CHC who underwent paired liver biopsies from 1994 to 2012. Patients with advanced fibrosis were excluded from the analysis. Sixty-three patients had TF, and 62 patients were treatment-naïve (TN). Annual fibrosis progression rate (FPR) was calculated, and significant fibrosis progression (SFP) was defined as ≥2 stage increase in fibrosis during follow-up. Multiple regression analyses were performed to find out independent predictors of FPR and SFP. Demographic characteristics and duration between paired liver biopsies were similar in TF and TN groups. Baseline alanine aminotransferase and gamma-glutamyl transferase (GGT) levels (71 ± 31 vs 47 ± 22, P < 0.001 and 49 ± 39 vs 36 ± 28, P = 0.027, respectively), baseline mean fibrosis stage (2.2 ± 0.7 vs 1.9 ± 0.7, P = 0.018) and histologic activity index (6.3 ± 1.9 vs 4.3 ± 1.6, P < 0.001) were higher in the TF group compared with the TN group. In regression analyses, the strongest independent predictor of fibrosis progression was the GGT level (OR: 1.03, 95%CI 1.01–1.5, P < 0.001). Treatment experience (OR: 5.97, 95%CI 1.81–19.7, P = 0.003) also appeared as an independent predictor of both FPR and SFP. Failed interferon-based CHC treatment may lead to accelerated FPR in the long-term compared with the natural course.

Source

Primary efficacy and safety data from four phase III Japanese studies of Simeprevir presented at The Japan Society of Hepatology

06-Jun-13 Stockholm, Sweden — Medivir AB (OMX: MVIR) reports that its partner Janssen Pharmaceutical R&D Ireland (Janssen) today announced primary efficacy and safety results from four Japanese phase III clinical studies demonstrating that the use of the investigational NS3/4A protease inhibitor simeprevir (TMC435) led to sustained virologic response 12 weeks after the end of treatment (SVR12) in patients with genotype 1 hepatitis C, when administered once daily with pegylated interferon and ribavirin. The four studies examined the use of simeprevir in genotype 1 chronic hepatitis C patients who were treatment naïve, as well as patients who were non-responders to prior therapy or relapsed following treatment with pegylated interferon with or without ribavirin.

The data were presented today at The Japan Society of Hepatology’s 49th Annual Meeting in Tokyo. The CONCERTO studies supported the new drug application for simeprevir, which was submitted to Japanese regulatory authorities in February 2013.

Janssen’s phase III clinical program for simeprevir in Japan consists of four studies in patients with genotype 1 HCV: CONCERTO-1 in treatment-naïve patients, CONCERTO-2 and -3 in prior non-responders or patients who relapsed after prior interferon-based treatment, and CONCERTO-4 using different pegylated interferon treatments (pegylated interferon alfa-2b) in a broad patient population.

More information about the study design could be found at www.clinicaltrials.gov.

+--------+----------+---------------------+------------------+
| SVR12 in |
| the |
| CONCERTO |
| Trials |
+--------+----------+---------------------+------------------+
| Trial | Patient |Treatment + pegylated| Proportion of |
| | Type | interferon and |Patients Achieving|
| | | ribavirin | SVR12 (%) |
+--------+----------+---------------------+------------------+
|CONCERTO|Treatment |Simeprevir (12 weeks)| 89 |
| -1 | -naïve | | |
+--------+----------+---------------------+------------------+
| | | Placebo (12 weeks) | 62 |
+--------+----------+---------------------+------------------+
|CONCERTO|Prior Non |Simeprevir (12 weeks)| 53 |
| -2 |-responder| | |
| | | | |
+--------+----------+---------------------+------------------+
| | |Simeprevir (24 weeks)| 36 |
+--------+----------+---------------------+------------------+
|CONCERTO| Prior |Simeprevir (12 weeks)| 96 |
| -3 | Relapser | | |
+--------+----------+---------------------+------------------+
|CONCERTO|Treatment |Simeprevir (12 weeks)| 92 |
| -4 | -naïve | | |
+--------+----------+---------------------+------------------+
| | Prior |Simeprevir (12 weeks)| 100 |
| | Relapser | | |
+--------+----------+---------------------+------------------+
| |Prior Non |Simeprevir (12 weeks)| 39 |
| |-responder| | |
| | | | |
+--------+----------+---------------------+------------------+

The most common adverse events seen in patients receiving simeprevir plus pegylated interferon and ribavirin in CONCERTO-1 were similar to those observed with pegylated interferon and ribavirin alone and were also similar in the other studies (decreased white blood cell count, fever, anemia, decreased neutrophil count, malaise, headache and rash). Treatment discontinuation rates due to an adverse event in CONCERTO-1 were five percent in the simeprevir arm and 8 percent in the placebo arm, four percent in CONCERTO-2, four percent in CONCERTO-3 and one percent in CONCERTO-4.

For more information please contact:
Rein Piir, EVP Corporate Affairs & IR
Mobile: +46 708 537 292

About Simeprevir
Simeprevir is a new generation NS3/4A protease inhibitor jointly developed by Medivir and Janssen for the treatment of chronic hepatitis C in adult patients with compensated liver disease.

For additional information about simeprevir clinical trials, please visit www.clinicaltrials.gov.

About Hepatitis C
Hepatitis C, a blood-borne infectious disease of the liver and a leading cause of chronic liver disease and liver transplants, is a rapidly evolving treatment area with a clear need for innovative treatments. Approximately 150 million people are infected with hepatitis C worldwide, and about 350,000 people per year die from the disease.

About Medivir
Medivir is an emerging research-based pharmaceutical company focused on infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company’s key pipeline asset is simeprevir, a novel protease inhibitor in late phase III clinical development for hepatitis C that is being developed in collaboration with Janssen R&D Ireland. Medivir has also a broad product portfolio with prescription pharmaceuticals in the Nordics.

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Medivir is a collaborative and agile pharmaceutical company with an R&D focus on infectious diseases and a leading position in hepatitis C. We are passionate and uncompromising in our mission to develop and commercialize innovative pharmaceuticals that improve people’s lives.

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Sofosbuvir Works for Patients Who Cannot Take Peginterferon

Published in Journal Watch Gastroenterology May 24, 2013

Two phase III studies confirm the efficacy of a sofosbuvir and ribavirin therapy in patients with HCV genotype 2 or 3 infection for whom peginterferon is not an option.

In patients infected with hepatitis C virus (HCV) genotype 2 or 3, treatment with peginterferon plus ribavirin has a sustained virologic response (SVR) of 70% to 85%. However, adverse effects of peginterferon are a barrier to treatment for many patients. Now, two industry-funded, phase III trials have evaluated the efficacy of sofosbuvir (400 mg daily) plus ribavirin (1000 mg–1200 mg daily) in these patients.

In a blinded, placebo-controlled trial, investigators randomized 280 patients for whom peginterferon therapy was not an option (e.g., adverse effects, contraindications for interferons, and patient refusal) to receive sofosbuvir/ribavirin or matching placebo for 12 weeks. In a blinded, active-control trial, researchers randomized 202 patients with prior nonresponse to peginterferon therapy to receive 12 or 16 weeks of sofosbuvir/ribavirin. The primary endpoint in both studies was SVR at 12 weeks after therapy ended.

In patients for whom peginterferon therapy was not an option, SVR was 78% for treatment with sofosbuvir/ribavirin compared with 0% for placebo (P<0.001). In previously treated patients, SVR was 50% for 12 weeks of therapy versus 73% for 16 weeks (P<0.001). SVR rates were lower for patients with genotype 3 versus genotype 2 in both treatment-naive patients (61% vs. 93%) and treatment-experienced patients who received therapy for 12 weeks (30% vs. 86%) or 16 weeks (62% vs. 94%).

SVR rates were lower in patients with cirrhosis than without, both in treatment-naive patients (overall, 61% vs. 81%; genotype 3 vs. 2, 21% vs. 94%) and treatment-experienced patients (overall, 66% vs. 76%; genotype 3 vs. 2 in 16-week group, 61% vs. 78%). In both studies, investigators found no evidence of resistance development, and discontinuation rates were low (1%–2%).

Comment: Oral sofosbuvir plus ribavirin is effective in patients with HCV genotypes 2 or 3 for whom peginterferon-based therapy is not an option or was previously ineffective. Of note, these sustained virologic response rates for sofosbuvir plus ribavirin are comparable to or higher than those previously reported for therapy with peginterferon plus ribavirin in this population.

— Atif Zaman, MD, MPH

Citation(s):

Jacobson IM et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 2013 May 16; 368:1867. (http://dx.doi.org/10.1056/NEJMoa1214854)

Medline abstract (Free)

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Nonresponse to Interferon-α Based Treatment for Chronic Hepatitis C Infection Is Associated with Increased Hazard of Cirrhosis

PLoS One. 2013 Apr 25;8(4):e61568. doi: 10.1371/journal.pone.0061568. Print 2013.

Cozen ML, Ryan JC, Shen H, Lerrigo R, Yee RM, Sheen E, Wu R, Monto A.

Department of Medicine, Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, United States of America.

Abstract

BACKGROUND: The long-term consequences of unsuccessful interferon-α based hepatitis C treatment on liver disease progression and survival have not been fully explored.

METHODS AND FINDINGS: We performed retrospective analyses to assess long-term clinical outcomes among treated and untreated patients with hepatitis C virus in two independent cohorts from a United States Veterans Affairs Medical Center and a University Teaching Hospital. Eligible patients underwent liver biopsy during consideration for interferon-α based treatment between 1992 and 2007. They were assessed for the probability of developing cirrhosis and of dying during follow-up using Cox proportional hazards models, stratified by pretreatment liver fibrosis stage and adjusted for known risk factors for cirrhosis and characteristics affecting treatment selection. The major predictor was a time-dependent covariate for treatment outcome among four patient groups: 1) patients with sustained virological response to treatment; 2) treatment relapsers; 3) treatment nonresponders; and 4) never treated patients. Treatment nonresponders in both cohorts had a statistically significantly increased hazard of cirrhosis compared to never treated patients, as stratified by pretreatment liver fibrosis stage and adjusted for clinical and psychosocial risk factors that disproportionately affect patients who were ineligible for treatment (Veterans Affairs HR = 2.35, CI 1.18-4.69, mean follow-up 10 years, and University Hospital HR = 5.90, CI 1.50-23.24, mean follow-up 7.7 years). Despite their increased risk for liver disease progression, the overall survival of nonresponders in both cohorts was not significantly different from that of never treated patients.

CONCLUSION: These unexpected findings suggest that patients who receive interferon-α based therapies but fail to clear the hepatitis C virus may have an increased hazard of cirrhosis compared to untreated patients.

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Free Full Text Article

Triple Therapy Can Help in Advanced Hep C

By Michael Smith, North American Correspondent, MedPage Today

Published: April 28, 2013

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco

AMSTERDAM -- About 40% of people with advanced hepatitis C (HCV) can benefit from triple therapy even if they have cirrhosis and previous treatment failures, a researcher said here.

An interim analysis of a large cohort of patients in France found that benefit following treatment with one of the recently approved HCV protease inhibitors, telaprevir (Incivek) or boceprevir (Victrelis), when each was combined with pegylated interferon and ribavirin, according to Helene Fontaine, MD, of Cochin Hospital AP-HP in Paris.

But the benefit was counterbalanced by a high risk of serious adverse events, Fontaine reported at the meeting of the European Association for the Study of the Liver (EASL).

Triple therapy has been shown to improve outcomes for most HCV patients, commented Laurent Castera, MD, PhD, of Centre Hospitalier Universitaire in Bordeaux, France, who was not involved in the study but who moderated an EASL press conference.

But it's not well understood how very sick patients will respond to treatment because they have been largely left out of clinical trials, he said, and those who have been treated have generally had poor outcomes.

"The paradox is that for the patients who most need treatment – patients with cirrhosis and treatment-experienced patients – results have been pretty disappointing," he said.

The current study, which is from the French early access program, may go some way toward clarifying what can be expected from triple therapy in very sick patients, he said.

The CUPIC study (for Compassionate Use of Protease Inhibitors in viral C Cirrhosis) now includes some 674 cirrhotic or treatment-experienced patients treated at 56 sites from Feb. 15, 2011 to April 12, 2013.

The primary endpoint is the rate of undetectable HCV RNA 24 weeks after the end of the therapy (SVR₂₄). But since many patients have not reached that mark, Fontaine reported SVR₁₂ data for 485 patients, or 72% of the cohort.

In that subgroup, 295 patients were treated with telaprevir (Incivek) and 190 with boceprevir (Victrelis), both combined with pegylated interferon and ribavirin, Fontaine said. The study is observational, with no randomization, and the treatment choice is left to the patient and his or her doctor, she noted.

Response rates – defined as undetectable HCV viremia -- in the telaprevir patients reached a high of 81% at week 12 of treatment, but then tailed off to 56% at week 48, the end of treatment, Fontaine said.

Twelve weeks later, 40% of patients still had undetectable HCV RNA and had achieved an SVR₁₂.

The pattern among the boceprevir patients was "not different," Fontaine said – the response rates peaked during therapy, fell to 57% at the end of treatment, and 41% of patients achieved SVR₁₂.

In either case, patients who had previously responded to treatment pegylated interferon and ribavirin but then relapsed did better, with SVR₁₂ rates of 53% for telaprevir and 51% for boceprevir, than those who had never responded or had a partial response.

In addition, patients with the HCV 1a genotype did worse than those with genotype 1b, regardless of the protease inhibitor.

A multivariate analysis found that patients who relapsed had an odds ratio for SVR₁₂ of 2.03 (95% CI 1.38 to 3.0) compared with null or partial responders (P=0.0003).

The analysis also showed that genotype 1b patients had an OR for SVR₁₂ of 1.92 (95% CI 1.3 to 2.84) compared with genotype 1a (P=0.0011).

On the other hand, Fontaine said, rates of serious adverse events were high in both groups.

Among telaprevir patients, there were 535 serious adverse events among 160 patients while 63 patients stopped treatment because of serious adverse events. There were seven deaths.

The researchers noted that 9.1% of patients had severe infections and 12.9% had severe anemia. Anemia of 8 g/dL or blood transfusion was reported in 17.8% of cases.

Among boceprevir patients, the pattern was similar: There were 321 serious adverse events among 97 patients and 27 patients stopped treatment because of serious adverse events. There were three deaths.

Also, 4.2% of patients had severe infections and 10% had severe anemia. Anemia of less than 8 g/dL or blood transfusion was reported in 8.7% of cases.

She concluded that while some patients – especially those who had relapsed after previous therapy and those with genotype 1b disease – can do well on triple therapy, the benefit "should be balanced" with the risks of serious adverse events.

The study was supported by ANRS. Fontaine reported financial links with Jannsen, BMS, MSD, Roche, and Gilead.

Castera reported financial links with BMS, Merck, Gilead, and Echosens.

Primary source: European Association for the Study of the Liver
Source reference:
Fontaine H, et al. "SVR12 Rates and Safety of Triple Therapy Including Telaprevir or Boceprevir in 221 Cirrhotic Non-Responders Treated in the Frent Early Access Program (ANRS CO20-CUPIC)." EASL 20113;abstract 60.

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Standardization of Terminology of Virological Response in the Treatment of Chronic Hepatitis C

From Journal of Viral Hepatitis

Panel Recommendations

M. Jacobson; F. Poordad; R. S. Brown Jr; P. Y. Kwo; K. R. Reddy; E. Schiff

Posted: 05/03/2012; J Viral Hepat. 2012;19(4):236-243. © 2012 Blackwell Publishing

Abstract and Introduction

Abstract

Summary. The treatment paradigm for hepatitis C virus (HCV) infection is at a critical point in its evolution. The addition of a protease inhibitor to peginterferon plus ribavirin has become the new standard-of-care treatment for most patients. Data from clinical trials of new antivirals have been difficult to interpret and compare, partly because of heterogeneity in trial design, and partly because of inconsistencies in terminology used to define viral responses and the populations evaluated. Present definitions of viral responses for treatment with peginterferon and ribavirin are insufficient for novel treatment paradigms. Further, categorization of prior patient treatment experience in clinical trials, particularly of nonresponders to prior therapy, is inconsistent. Existing terms and definitions must be updated, standardized and/or redefined for easier interpretation of data and effective communication among clinicians. A panel of experts in HCV infection treatment met on 3 December 2009. Goals of the panel were to evaluate terms and definitions used traditionally in treatment with peginterferon and ribavirin, to refine and clarify definitions of existing terms that have varying meanings and to propose new terms and definitions appropriate for novel treatment paradigms emerging with development of new agents. A number of recommendations were accepted unanimously by the panel. Adoption of these terms would improve communication among investigators, enhance comparability among clinical trials, facilitate development of therapeutic guidelines and provide a standardized terminology for use in clinical practice.

Introduction

Over the past decade, the standard of care for the treatment of infection with HCV – 48 weeks of peginterferon alfa-2a or 2b plus ribavirin – yielded overall sustained virological response (SVR) rates of 42–46%.^[1,2] The recent approval of direct-acting antiviral agents (DAA), such as the protease inhibitors telaprevir and boceprevir, represent a new standard of care for treatment-naïve and experienced patients. Many other DAAs are in development as well.

Not unexpectedly, these new agents have brought with them novel study designs, patient categorizations and treatment paradigms, which has led to some confusion over the terminology used at scientific meetings and in published articles, especially for terms relating to on-treatment virological response. The desirability of a standardized set of terms to allow comparisons between clinical trials led to the roundtable discussion among the investigators described herein. The purpose of the discussion was to evaluate, refine and standardize the definitions of existing terminology and to propose, where necessary, new terms and definitions appropriate for the novel treatment paradigms resulting from the next generation of antiviral agents.

Diagnostic Precision of Hepatitis C Virus RNA Assays

When seeking to apply standardized terminology that focuses on the presence, absence or degree of virological response experienced in patients with HCV, it is important to consider the diagnostic tests used to detect and quantify viral load. Previous qualitative HCV assays (e.g. Roche HCV Amplicor 2.0, Pleasanton, CA, USA) that measured viral load using endpoint polymerase chain reaction (PCR) have been replaced by quantitative assays that utilize real-time PCR (e.g. Roche COBAS TaqMan, Pleasanton, CA, USA; Abbott Realtime HCV RNA, Des Plaines, IA, USA) and transcription-mediated amplification technology (Quest Diagnostics Heptimax, Madison, NJ, USA). These newer commercial assays allow for the more accurate representation of HCV RNA levels given their high sensitivity, broad dynamic range and improved lower limits of detection (Table 1).^[3–7] Given these differences, it is important to consider which HCV RNA assay is being used when utilizing the nomenclature or making cross-study comparisons of efficacy.

Table 1. Commercially available diagnostic assays for HCV^3–7

 

Diagnostic assay*	Lower limit of detection (IU/mL)	Dynamic range of quantitation (IU/mL)
Roche HCV Amplicor 2.0	50	600–500 000
Roche COBAS TaqMan 2.0 HCV	10	25–390 000 000
Abbott Realtime HCV RNA	12	12–100 000 000 begin_of_the_skype_highlighting 12–100 000 000 end_of_the_skype_highlighting
Quest Diagnostics Heptimax	5	5–69 000 000

HCV, hepatitis C virus. *The COBAS Ampliprep is often used for sample preparation (i.e. automated vs manual RNA extraction) in conjunction with the listed diagnostic assays.

Current Terminology in the Context of Novel Therapies

In the two decades since the advent of interferon-based therapy for hepatitis C, investigators have developed terminology to characterize patient response to treatment. The term 'SVR' has been defined as being HCV RNA negative 6 months following treatment cessation. This became the standard endpoint for clinical trials and, given exceedingly low rates of relapse after that time point, has been interpreted as a 'cure'.^[8] Other terms are associated with specific milestones in viral response that have been shown to be predictive of eventual SVR and are listed in Table 2.^[8]

Table 2. Current definitions for virological response⁸

 

Virological response	Definition	Clinical utility
Rapid virological response (RVR)	HCV RNA negative at treatment week 4 by a sensitive PCR-based quantitative assay	May allow shortening of course for genotype 2 and 3 and possibly genotype 1 with low viral load
Early virological response (EVR)	≥2 log reduction in HCV RNA level compared with baseline HCV RNA level (partial EVR) or HCV RNA negative at treatment week 12 (complete EVR)	Predicts lack of SVR
End-of-treatment response (ETR)	HCV RNA negative by a sensitive test at the end of 24 or 48 weeks of treatment
Sustained virological response (SVR)	HCV RNA negative 24 weeks after cessation of treatment	Sustained clearance or cure
Breakthrough	Reappearance of HCV RNA in serum while still on therapy
Relapse	Reappearance of HCV RNA in serum after therapy is discontinued
Nonresponder	Failure to clear HCV RNA from serum after 24 weeks of therapy
Null responder	Failure to decrease HCV RNA by >1 log10 at 4 weeks or >2 log10 at 12 weeks of therapy
Partial responder	2-log10 decrease in HCV RNA, but still HCV RNA positive at week 24

HCV, hepatitis C virus; PCR, polymerase chain reaction.

The existing terminology has, for the most part, proved adequate for use in the development of study designs, communication of results and patient management in the context of peginterferon and ribavirin treatment. However, with new treatment paradigms and the introduction of new terms in recent studies of novel drugs, limitations of the current terminology have become apparent.

One example of this new terminology involves phase 3 studies of the protease inhibitor telaprevir, in which treatment-naïve patients evaluated response-guided therapy, with HCV RNA levels measured at weeks 4 and 12 (Fig. 1a,b). Patients with undetectable levels at each time point were said to have achieved 'extended rapid viral response' (eRVR),^[9,10] which was required to stop therapy after a 24-week course instead of the 48-week course non-eRVR patients received.

Figure 1. (a) ADVANCE and (b) ILLUMINATE study design. eRVR, extended rapid viral response (undetectable hepatitis C virus RNA at week 4 and week 12); PEG, peginterferon alfa-2a; RBV, ribavirin; TVR, telaprevir.

Lead-in dosing with peginterferon and ribavirin, used in the phase 3 development programme for boceprevir and incorporated into its approved treatment regimen, also poses particular terminological challenges because of potential ambiguity in designating response at various time points (Fig. 2a,b).^[11,12] In the phase 3 SPRINT-2 trial, rapid virological response (RVR) criteria differed from the standard used in peginterferon/ribavirin trials: HCV RNA negativity by PCR after 4 weeks of peginterferon plus ribavirin treatment.^[12] Instead, the SPRINT-2 trial criterion for the equivalent of 'RVR' was HCV RNA negativity at week 4 of boceprevir treatment, which was overall treatment week 8. For patients who achieved this milestone and remained negative at treatment week 24, all therapy was stopped. Meanwhile, patients with detectable HCV RNA at week 4 of boceprevir treatment to week 20, yet had undetectable HCV RNA at week 24, continued to receive peginterferon plus ribavirin alone for a total treatment duration of 48 weeks (Fig. 2b).^[12] Thus, referring to response at week 4 of boceprevir as RVR may be confusing because that term refers to response at week 4 of treatment overall.

Figure 2. (a) SPRINT-1 and (b) SPRINT-2 study design.^11,12 Patients in all arms were followed for 24 weeks after the end of treatment. Lead-in = peginterferon alfa-2b (1.5 μg/kg/week) + ribavirin (800–1400 mg/day) for 4 weeks. BOC, boceprevir; PEG, peginterferon alfa-2b; RBV, ribavirin; TID, 3 times daily; 4/24/48, 4-week/24-week/48-week treatment duration; TW, treatment week.

With such challenges in mind, the panel proposed recommendations for terminology to be used in the reporting of clinical data pertaining to the treatment of chronic HCV infection, particularly data generated from studies of the new antiviral agents

Recommendations

Terminology for New Treatment Paradigms in Development

Two general terms have been widely used to describe new antiviral agents for the treatment of HCV infection. One is 'specifically targeted antiviral therapy for hepatitis C' (STAT-C), and the other is 'DAAs'. While STAT-C has appeal from the standpoint of pronunciation and specificity for the context of HCV therapy, the term 'DAA' has been adopted by the European Medicines Agency (EMEA) as its term of choice.^[13] The US Food and Drug Administration has also used 'DAA' in the HIV arena and, more recently, in the HCV arena.^[14] In recognition of the need to align with the terminology that appears likely to be adopted by regulatory agencies and others, the panel supports the future use of 'DAA'.

Terminology Relating to Treatment Experience

While the panel agreed that the term 'treatment naïve' is clear, 'treatment failure' was the subject of some debate. First, it does not adequately describe patients who stop therapy for reasons other than lack of response, such as discontinuation of treatment because of adverse events. Second, patient advocates argue that the word 'failure' should be avoided because of its pejorative connotations. While an alternative term 'treatment experienced' was discussed by the panel, it was decided to be too vague with regard to prior treatment success/failure. Therefore, the panel recommended that the term 'treatment failure' be retained but that physicians remain aware that this term may be perceived to have a negative connotation by patients or their families.

Recommendation 1: The terms 'treatment naïve' and 'treatment failure' should be retained in their current usages. The term 'treatment failure' may be refined with specific information about the nature of the failure (e.g. the regimen on which the patient failed and the nature of the failure – relapse, nonresponse and premature discontinuation for adverse events).

Definitions of Response

Sustained Virological Response The most common primary endpoint for clinical trials is SVR, which is defined as undetectable HCV RNA at 24 weeks after the end of treatment. Panel members felt that adding a number to the end of the acronym to represent the time of last-confirmed viral negativity, as has already been adopted in some presentations, would provide added clarity (e.g. SVR12 would stand for viral negativity at week 12 post-treatment). This may be important as the duration of therapy continues to shorten and late relapse may be seen beyond 24 weeks. The panel believes that a minimum follow-up period of 12 weeks is required before any terminology related to 'SVR' is used.

Recommendation 2: SVR is defined as undetectable HCV RNA levels at 24 weeks post-treatment. The term may be modified by adding a number to the end to indicate the time of the last documented negative HCV RNA result (e.g. SVR12 would mean negative HCV RNA levels at 12 weeks post-treatment).

End-of-treatment Response End-of-treatment response has been defined previously as HCV RNA negativity at the completion of treatment. The panel supported the continued use of this definition and agreed that the abbreviation 'end-of-treatment response' (ETR) is most appropriate.

Recommendation 3: An ETR is defined as undetectable HCV RNA levels at the end of treatment regardless of treatment duration.

Rapid Virological Response and Complete Early Virological Response Rapid virological response is generally defined as undetectable HCV RNA using a sensitive PCR assay at week 4 of therapy, while a complete early virological response (EVR) is defined as undetectable HCV RNA at week 12 of therapy. To simplify the nomenclature, the panel suggested that a new term be established: complete virological response (CVR), defined as an undetectable level of HCV RNA while the patient is still on treatment. To clarify the time point at which a patient achieves CVR, a number can be added to indicate the week of treatment (e.g. CVR4 and CVR12). Under this scheme, the term RVR will be replaced by CVR4, and complete EVR will be replaced by CVR12. These new terms will be very relevant to clinical studies of the DAAs, because in many trials complete viral suppression within a certain time frame will be required to allow continuation of therapy. Given the central role accorded 'extended' RVR (eRVR, attainment of RVR with maintenance of HCV RNA undetectability at subsequent time points) in studying response-guided therapy in major DAA trials to date, the term CVR allows for greater precision because it may be followed by a designation of the weeks at which HCV undetectability is required to have been demonstrated. Thus, HCV RNA undetectability at weeks 4 and 12 would be designated 'CVR4,12', while its undetectability at multiple time points, for example, weeks 4, 12, 16, 20, could be designated 'CVR4–20'.

Recommendation 4: A complete virological response (CVR#) is defined as an undetectable HCV RNA level during treatment, where # is the total treatment week at which time a negative HCV RNA level is first documented. CVR4 should thus replace the term 'RVR', and CVR12 should replace the term 'complete EVR'. The term eRVR should be replaced by CVR at the intended time points, starting with the first time point at which HCV RNA became undetectable.

Partial Early Viral Response and Partial Responder The panel agreed that that the term partial EVR has been a useful clinical tool. Clinicians have typically stopped peginterferon/ribavirin treatment for patients who fail to achieve at least a partial EVR because their likelihood of achieving an SVR is extremely low, but patients who do achieve a partial EVR still have a chance for SVR and may benefit from an extended treatment period. A partial responder has usually been defined as a patient who achieves at least a 2-log₁₀ decline in HCV RNA level at treatment week 12 but who does not achieve an undetectable viral level by the end of treatment. However, this does not specify the duration of therapy to which the term applies. The panel proposed that the terms 'partial EVR' and 'partial responder' be supplanted by the more precise term 'partial virological response' (PVR), defined as a 2-log₁₀ decline in HCV RNA level with detectable viraemia at a given treatment week. A number can be added to indicate the first or any subsequent treatment week at which the latest HCV RNA level was documented (e.g. PVR12). Using this nomenclature, the term 'partial EVR' is replaced by 'PVR12'. A partial response that persists to a subsequent time point can be designated by the addition of a second number, for example, a partial response that occurred at week 12 and persisted to week 24 could be designated as PVR12, 24. Note that the designation of PVR# can be adapted to novel treatment regimens using other criteria for degree of viral decline that may be more suitable in the context of such therapies.

Recommendation 5: A partial response (PVR#) is defined as a ≥ 2-log₁₀ decrease in HCV RNA level but with detectable viraemia at treatment week #. A 'partial EVR' on peginterferon and ribavirin should be referred to as a PVR12.

Slow responder The term 'slow responder' has been used to describe a patient with detectable viraemia at treatment week 12 (generally with at least a 2-log₁₀ decline) and whose HCV RNA level is undetectable at treatment week 24. Studies have suggested that extending therapy to 72 weeks can increase the chance of SVR in such patients.^[15–17] However, some studies evaluating prolongation of extended therapy have used different criteria, such as failure to attain HCV RNA undetectability by week 4^[18] or initial undetectability at week 12 after HCV RNA was positive at week 8.^[19] The panellists decided there was no need for a term that is open to various interpretations when the time point can be specified in the term itself. The proposed term CVR24 clearly indicates that the first documentation of an undetectable HCV RNA level occurred at treatment week 24. In this context, a 'slow responder' would be referred to as 'PVR12, CVR24'. This terminology can be readily adapted to the study of other time points for initial HCV RNA undetectability as a determinant of treatment duration.

Recommendation 6: Use the term 'CVR24' to indicate the initial attainment of a complete response by treatment week 24 instead of 'slow responder'.

Nonresponder The panel agreed that the term should be defined as a patient who never achieved an undetectable (i.e. CVR) level of HCV RNA during or at the end of treatment.

Recommendation 7: A nonresponder is defined as any patient who never achieved undetectable serum HCV RNA level on treatment or at the end of treatment.

Null Responder The historical definition of a null responder has been either a patient who achieves less than a 1-log₁₀ decline in HCV RNA level at treatment week 4 or one who achieves less than a 2-log₁₀ decline in HCV RNA at treatment week 12. The panel proposed using the term 'null response' (NuR) followed by a number indicating the last time point of evaluation, with the following definitions:

Recommendation 8: NuR is defined as:

• NuR4 = <1-log₁₀ decline in HCV RNA level at treatment week 4.
• NuR12 = <2-log₁₀ decline in HCV RNA level at treatment week 12.

The patient should be categorized by last time point of evaluation. When used in clinical trials on retreatment, study investigators should define patients' degree of exposure to prior treatment. The use of these terms allows for additional refinement of patient groups. Thus, the term NuR4PVR12 denotes a patient with <1-log decline in HCV RNA at treatment week 4 but a ≥ 2-log decline by week 12.

Breakthrough and Viral Rebound The panel noted that there has been much confusion about the precise definition of the terms 'breakthrough' and 'viral rebound'. In the past, both 'breakthrough' and 'viral rebound' have been defined as greater than a 1-log₁₀ increase in HCV RNA from nadir and a minimum level of 1000 IU/mL. Others have used the term 'breakthrough' to indicate at least a 2-log₁₀ increase in HCV RNA level from nadir and a minimum level of 50 000 IU/mL. Still another definition of 'breakthrough' has been a greater than 1-log₁₀ increase in HCV RNA from nadir or an increase to >100 IU/mL, provided that the HCV RNA level had been undetectable at some point during treatment. The panel suggested that the key difference between the terms 'breakthrough' and 'rebound' is whether the patient has achieved HCV RNA negativity (a CVR) at any point on treatment. A patient who has had a CVR on treatment but then becomes viraemic would fall into the category of breakthrough, but a patient who has had a decline in HCV RNA levels that stops short of a CVR and then experiences a rise in HCV RNA level would fall into the category of viral rebound.

Recommendation 9: Breakthrough is defined as the on-treatment presence of detectable HCV RNA on 2 consecutive serum tests conducted after a previous on-treatment serum test showed an undetectable level of HCV RNA with a real-time quantitative PCR or similarly sensitive test. The HCV RNA level must be at least 100 IU/mL on the second positive serum test.

Recommendation 10: Viral rebound is defined as an on-treatment 1-log₁₀ increase in HCV RNA level from nadir and an absolute level of at least 1000 IU/mL in a patient who has not achieved an undetectable HCV RNA level during the current treatment regimen.

Terminology for Agents Utilizing the Lead-in Strategy

There was much discussion among the panel members about clarifying the terminology for the lead-in strategy. There was a consensus that the language must facilitate comparisons of clinical trial results among various agents, both those that are dosed with and without a lead-in strategy of peginterferon and ribavirin alone. Further, it was unanimously agreed that the new terminology should not create the misperception that treatment begins with the initiation of the targeted antiviral; the panel was definitive that treatment begins at the start of the lead-in period. It was agreed that the abbreviation Li4 (lead-in 4) before an abbreviation for response (e.g. Li4-CVR8) would be a clear way to indicate the exact time point during treatment at which the HCV RNA test was conducted. Another example of defining patterns of response using the terminologies proposed in this manuscript would be the term Li4-NuR4 (see 'recommendation 8'). This would indicate that at the end of a 4-week lead-in phase, the patient has had <1 log decline in HCV RNA. To stratify treatment outcomes between patients with intrinsically poor vs better interferon responsiveness, one could apply the terms Li4-NuR4 or Li4-R4, where the latter denotes a ≥ 1 log decline in HCV RNA after 4 weeks of lead-in therapy.

Recommendation 11: The abbreviation Li4 should be added as a prefix to on-treatment response terminology when the clinical study utilizes the lead-in strategy in which patients receive 4 weeks of treatment with peginterferon and ribavirin before the addition of the DAA to the regimen. Under this system, Li4-CVR8 would indicate an undetectable level of HCV RNA at triple therapy week 4 and total treatment week 8. As another example, Li4-CVR8, 24 would indicate an absence of detectable HCV RNA at total treatment weeks 8 and 24 after 4 weeks of lead-in therapy followed by the addition of a protease inhibitor, as is currently required to stop all therapy at total treatment week 28 in a response-guided therapy regime containing boceprevir. Finally, Li4-NuR4 would indicate a failure of HCV RNA to decline by at least 1 log after 4 weeks of lead-in therapy.

A summary of recommended terminology, with definitions, is presented in Table 3.

 

Table 3. Summary of recommendations for updated terminology

Term	Definition
Treatment failure	Patient who failed to achieve sustained virological response
Sustained virological response (SVR)	Undetectable HCV RNA level at 24 weeks post-treatment
End-of-treatment response (ETR)	Undetectable HCV RNA level at end of treatment regardless of treatment duration
Complete virological response (CVR); number at end represents week at which HCV RNA negativity is noted	Undetectable HCV RNA level during treatment CVR4 should replace the old term RVR CVR12 should replace the old term cEVR CVR24 should replace the old term slow responder CVRx,y or x-y should replace the term eRVR
Partial virological response (PVR)	≥2-log10 decrease in HCV RNA level but with detectable viraemia at treatment week no. PR12 should replace the old term pEVR
Nonresponder	Any patient who never achieved undetectable serum HCV RNA level on treatment or at the end of treatment
Null response (NuR)	NuR4 = <1-log10 decline in HCV RNA level at treatment week 4 NuR12 = <2-log10 decline in HCV RNA level at treatment week 12
Breakthrough	On-treatment presence of detectable HCV RNA on two consecutive serum tests conducted after a previous on-treatment serum test showed an undetectable level of HCV RNA with a real-time quantitative PCR or similarly sensitive test. The HCV RNA level must be at least 100 IU/mL on the second positive serum test
Viral rebound	On-treatment 1-log10 increase in HCV RNA level from nadir and an absolute level of at least 1000 IU/mL in a patient who has not achieved an undetectable HCV RNA level during the current treatment regimen
Lead-in 4 (Li4)	The abbreviation Li4 should be added as a prefix to on-treatment response terminology when the clinical study utilizes the lead-in strategy in which patients receive 4 weeks of treatment with peginterferon and ribavirin before the addition of the DAA to the regimen. Li4-CVR8 indicates an undetectable level of HCV RNA at triple therapy week 4 and total treatment week 8

DAA, direct-acting antiviral agent; HCV, hepatitis C virus; PCR, polymerase chain reaction; eRVR, extended rapid viral response.

Conclusions

The changing treatment landscape of HCV infection has highlighted a number of difficulties with the current definitions and terminology used in the standard-of-care HCV treatment paradigm. The authors of this report have presented recommendations that are intended both to clarify historical terminology and introduced new terms. The definitions contained in this report were designed to reflect current and future clinical practice and to standardize clinical trial design. It is of note that unanimous agreement was obtained on all issues in the present report. Although this proposal is not intended to represent guidelines for diagnosis or treatment, it is the hope of the panel that these recommendations will prove valuable for the development of a language common to clinical trials, the dissemination and comparison of clinical trial data, the development of new clinical guidelines, as well as for everyday use in clinical practice. It is very possible that future treatment paradigms will require a further modification of the nomenclature used to describe various scenarios in the treatment of hepatitis C.

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Source

EASL 2012: Safety OF TELAPREVIR or Boceprevir IN COMBINATION WITH Peginterferon alfa/Ribavirin, in CIRRHOTIC NON RESPONDERS.

Abstract

Title
Safety OF TELAPREVIR or Boceprevir IN COMBINATION WITH Peginterferon alfa/Ribavirin, in CIRRHOTIC NON RESPONDERS. FIRST RESULTS OF THE FRENCH EARLY ACCESS PROGRAM (ANRS CO20-CUPIC)

Speaker:
Christophe Hezode

Author:
C. Hezode¹*, C. Dorival², F. Zoulim³, T. Poynard⁴, P. Mathurin⁵, S. Pol⁶, D. Larrey⁷, P. Cacoub⁴, V. de Ledinghen⁸, M. Bourlière⁹, P.H. Bernard¹⁰, G. Riachi¹¹, L. Alric¹², D. Samuel¹³, Y. Barthe², H. Fontaine⁶, F. Carrat², J.-P. Bronowicki¹⁴, ANRS CO20 CUPIC study group

Affiliation:
¹Hôpital Henri Mondor, Inserm U955, Université Paris-Est, Creteil, ²Hôpital Saint-Antoine, Inserm U707, UPMC-Paris6, Paris, ³Hospices Civils de Lyon, Lyon, ⁴Hôpital de la Pitié-Salpêtrière, Paris, ⁵Hôpital Claude Huriez, Lille, ⁶Hôpital Cochin, Inserm U1016, Université Paris Descartes, Paris, ⁷Hôpital Saint-Eloi, Montpellier, ⁸Hôpital Haut-Lévèque, Pessac, ⁹Fondation Hôpital Saint Joseph, Marseille, ¹⁰Hôpital Saint André, Bordeaux, ¹¹Hôpital Charles Nicolle, Rouen, ¹²Hôpital Purpan, Toulouse, ¹³Hôpital Paul Brousse, Villejuif, ¹⁴Hôpital de Brabois, Nancy, France. *christophe.hezode@hmn.aphp.fr

Phase III trials have shown that Telaprevir (TVR) is associated with frequent dermatological disorders and anemia, whereas Boceprevir (BOC) is associated with frequent anemia. However, few cirrhotic patients were included in these trials. We report the safety profiles of TVR or BOC in combination with peginterferon (PEG-IFN) and ribavirin (RBV) in the French Early Access Program for the use of protease inhibitors (PI).

Methods: Patients with compensated child A cirrhosis, HCV genotype 1 infection and prior relapse or partial response to PEG-IFN/RBV regimen were prospectively included to receive either 12 weeks of TVR, PEG-IFN-alfa2a/RBV and 36 weeks of PEG-IFN-alfa2a/RBV, or 4 weeks of PEG-IFN-2b/RBV and 44 weeks of BOC, PEG-IFN-2b/RBV without randomization which precludes any comparison between the two molecules. Safety analysis is restricted to patients with at least 8 weeks of treatment.

Results: Female-to-male ratio was 0.4 and mean age was 57 years in each group. Safety profiles are summarized in the table.

Conclusions: The safety profile of TVR or BOC with PEG-IFN/RBV in cirrhotic patients was poor and associated with increased SAE rates (30% to 51%) compared to those reported in phase III trials (9% to 14%). These data strongly suggest that triple therapy must be administered cautiously with intensive safety monitoring in these patients.

	TVR n=169	BOC n=138
Median treatment / PI duration (days)	112.0 / 85.0	113.0 / 84.0
Serious adverse events (SAE) / Discontinuation(AE)	87 (51%) / 20 (12%)	41 (30%) / 10 (7%)
Death	3 (2%)	1 (1%)
Anemia Grade 2(8.0-<10.0g/dL) / Grade 3-4(<8.0g/dL)	54 (32%) / 23 (14%)	39 (28%) / 8 (6%)
EPO use / Blood transfusion	94 (56%) / 32 (19%)	71 (51%) / 8 (6%)
Neutropenia Grade3-4(<1000/mm3) / G-CSF use	21 (12%) / 5 (3%)	14 (10%) / 7 (5%)
Thrombopenia Grade 3-4(<50000/mm3) / Thrombopoietin use	37 (22%) / 1 (1%)	10 (7%) / 1 (1%)
Rash Grade 3 / SCAR	11 (7%) / 0 (0%)	1 (1%) / 0 (0%)
Grade 3-4 infection / other AEs	4 (2%) / 90 (53%)	1 (1%) / 44 (32%)

[safety profile]

Source