Summary from EASL 2012 for Hepatitis C
Will there be an interferon-free HCV therapy for all: upcoming reality or just a vision?
Jurgen K. Rockstroh M.D., Professor of Medicine
University of Bonn, Germany
"Interferon free therapy has been shown to work in a whole range of different combinations and treatment schedules clearly making interferon free regimens a very realistic scenario for the upcoming years. Nevertheless the "therapy for all" option has not yet been presented and clearly more challenging patient populations such as cirrhotics and previous interferon null-responders will need at least longer durations of treatment or even more potent combinations."
Prof. Dr. J.K. Rockstroh
Department of Medicine I
University of Bonn
Since the regulatory approval of the first oral HCV protease inhibitors in 2011 for treatment of hepatitis C mono-infection, treatment paradigms for HCV therapy have subsequently changed significantly and promise cure of HCV infection in around two thirds of treatment naïve HCV-genotype-1 infected patients undergoing triple therapy. Not only have sustained virological success rates increased dramatically but in addition shortened treatment durations of only 24-28 weeks have become feasible in the so called early rapid responders (ERVR) (defined as a negative HCV-RNA 4 weeks after starting triple therapy). Now 1 year post-approval the obvious question is how have the new options been utilized in clinical reality and how have the HCV PIs behaved with regard to efficacy and safety in a liver disease with more advanced patient population. Also the use of these new treatment options in more challenging patient populations, such as HIV-coinfected or post-transplant HCV recurrence patients, remains of substantial interest. Finally, after several proof of concept studies demonstrating very clearly the success of interferon-free treatment approaches with either combination of several DAAs +/- ribavirin or DAA + ribavirin in pre-specified patient populations the next obvious big step forward would be the regulatory approval of corresponding additional DAAs allowing such interferon-free strategies in predefined patient groups and then ultimately having an interferon-free treatment approach for any given HCV infected patient regardless of baseline fibrosis, HCV genotype or subtype and IL28b genotype. The excitement around the recent developments in HCV therapy as well as the many open questions around best management of HCV, reflect the difficulties around patient selection, response prediction factors, drug-drug interactions, and treatment of so far understudied patient populations. This altogether has helped to substantially increase attendance rates at the EASL conference in Barcelona to a record of 9415 delegates this year. Indeed almost all burning questions listed above were addressed and plenty of new exciting data was presented. This summary aims at capturing the most relevant studies around management of hepatitis C as well as newest insights into hepatitis C drug development in phase II/III.
News on treatment of acute hepatitis C
Early treatment of acute hepatitis C virus (HCV) infection with interferon alpha mono therapy is highly effective with SVR rates of >90% (1). An alternative strategy might be to delay treatment for 3 months and only to treat those patients who are not able to clear HCV spontaneously. This obviously would help to prevent treating patients who would have cleared infection by themselves. At this meeting the final results of the only prospective treatment trial for therapy of acute HCV was presented (2). The Hep-Net-Acute-HCV-III study was designed in 2004 as a prospective, randomized trial in patients with symptomatic acute hepatitis C comparing the efficacy and safety of immediate PEG-IFNa-2b treatment for 6 months (arm-A) versus delayed treatment with PEG-IFNa-2b plus ribavirin for 6 months starting 12 weeks after randomization in patients who were still HCV-RNA positive (arm-B). All asymptomatic patients were assigned to early treatment with PEG-IFNa-2b (arm-C). In total 132 patients (66% genotype 1, 63% icteric) were recruited by 72 centers. The Intent-to-treat analysis included all patients and the completer analysis was based on all patients who completed 24 weeks of follow-up after treatment or 60 weeks of observation (arm B), thereby allowing assessing the on-treatment efficacy of the regimens studied. In the intention-to-treat analyses sustained virological response rates were 76% in the early treatment arm-A (n=49), 54% in the delayed treatment arm-B (n=52; p=0.023 vs. arm A) and 75% in arm C (n=24). The completer analysis showed SVRs of 90% in arm-A (37/41), 90% in arm-B (28/31) and 95% in arm-C (18/19). In arm B, sustained spontaneous HCV clearance could be documented for 11 out of 52 patients (21%). Female gender and HCV-genotype 1 infection but not IL28B-genotype was associated with HCV-RNA negativity at week 12 in the observation arm B. The lower ITT-SVR in arm-B was mainly due to drop-outs during the first 12 weeks observation period. However, delayed PEG-IFNa-2b and ribavirin treatment remained highly effective as all arm-B patients who completed treatment and follow-up achieved a SVR (n=14).
The results of this prospective treatment trial in acute hepatitis C underline that early treatment with PEG-IFNa-2b alone is highly effective in both symptomatic and asymptomatic patients. Delayed PEG-IFNa + ribavirin treatment resulted in lower overall response rates in this real-life treatment setting due to high lost-to-follow-up rates. However, if adherence can be assured and treatment is eventually administered delayed combination therapy seems to be of similar efficacy in symptomatic patients. These findings strengthen the early treatment intervention with PEG-IFN monotherapy but also reassure that waiting for 12 weeks has no negative impact on overall treatment outcome at least if combination HCV therapy is administered.
EASL: Early versus delayed treatment of acute hepatitis C: The German HEP - NET Acute HCV - III Study-a randomized controlled trial - (05/04/12)
Efficacy and safety of boceprevir and telaprevir in clinical reality
The availability of the French early access program for boceprevir and Telaprevir in cirrhotic previous non-responders allowed studying efficacy and safety of the 2 new oral HCV protease inhibitors in a probably much more typical patient population seen in clinics today than in the more restricted clinical phase III trials (3). Only 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 (3). Overall 296 patients received Telaprevir based HCV therapy 159 boceprevir-based therapy. 68% of patients were male, mean age was 57 years. Mean haemoglobin at baseline was 14.4-14.8 mg/dl and mean neutrophils (109/mm3)3.3 and 3.2 for the 2 patient groups, respectively. Mean platelets were 150.000/μl in both groups. With regard to HCV disease characteristics genotype 1b/1a distribution was approximately 60% 1a and 40 1b. The mean baseline HCV RNA was 6.5 log10 IU/mL. 15-16% of the included patients had esophageal varices indicating more advanced liver fibrosis stages. With regard to prior HCV treatment history 52%/49% in the 2 treatment groups (Telaprevir or boceprevir) were partial responders, 40%/48% relapsers and only 8%/3% prior null responder. The safety findings of this study are summarized in table 1:
Although the rate of hepatic decompensations is low with 4.4.% it is clearly a potential risk and suggests that careful monitoring is warranted. Looking at the laboratory findings it is important to mention that anaemia was very frequent with grade 2 anaemia (defined as Hb <8,0 g/dl) occurring in 19.6% of the Telaprevir treated patients and 22.6 % in the boceprevir treated patients. Between 57 and 66% of patients received EPO and between 11-15% blood transfusions. Grade III thrombopenia (25000 -<50.000) was noted in 6.3% of the boceprevir treated patients and 11.8% of Telaprevir treated subjects.
In conclusion it needs to be stressed that the safety profile of TVR or BOC with PEG-IFN/RBV in cirrhotic patients is poor and is 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 patients with liver cirrhosis.
EASL: CUPIC: French Early Access Program - Compassionate Use of Protease Inhibitors in Viral C Cirrhosis - (04/26/12)
Anaemia management: what is new?
As seen in the French EAP study above anaemia represents a common adverse event associated with peginterferon/ribavirin (PR) therapy for chronic hepatitis C, which appears to be even increased with addition of hepatitis C virus (HCV) protease inhibitors. Ribavirin (RBV) dose reduction (DR) and erythropoietin (EPO) are the standard anaemia management strategies in clinical use today. As obviously EPO is associated with quite some considerable additional costs but ribavirin reduction on the other hand may impact overall cure rates, so a controlled anaemia management strategy study was of great clinical interest. In the study presented at EASL by Poordad and colleagues EPO use versus RBV DR was compared as a primary anaemia management strategy in patients receiving boceprevir (BOC)/PR (4). In this very large trial 687 treatment-naive HCV genotype 1 patients with baseline haemoglobin (Hb) between 12-15 g/dL (female) or 13-15 g/dL (male) were enrolled. Patients received PEG2b/RBV (600-1400 mg/d) for 4 weeks, then BOC (800 mg three times daily)/PR for 24 or 44 weeks (according to HCV-RNA at treatment week 8). Investigators could use a secondary management strategy such as EPO, RBV DR, or transfusion in patients with Hb ≤8.5 g/dL to prevent study discontinuation. The primary endpoint was the comparison of sustained virologic response (SVR) between arms. A total of 500 patients developed anaemia (Hb ≤10 g/dL or were expected to reach that nadir before next visit) and were randomized to receive RBV DR (by 200-400 mg/d) or EPO (40,000 units/wk subcutaneously). End-of-treatment response, relapse, and SVR (71% for both intervention groups) were comparable between RBV DR and EPO arms highlighting that indeed reduction of ribavirin dose had no negative impact on overall viral cure rates. In RBV DR and EPO arms, discontinuation was, respectively, 11% and 13% due to any AE, and 2.0% and 2.4% due to anaemia. The rates of influenza-like symptoms, fatigue, depression/anxiety, dyspnoea, and cardiovascular events were similar between arms.
In conclusion these data support ribavirin dose reduction for primary anaemia management. This is of particular importance for countries were no health insurance coverage for erythropoietin therapy exists during HCV therapy. Noteworthy, safety profiles were similar regardless of anaemia management strategy.
A RANDOMIZED TRIAL COMPARING RIBAVIRIN DOSE REDUCTION VERSUS ERYTHROPOIETIN FOR ANEMIA MANAGEMENT IN PREVIOUSLY UNTREATED PATIENTS WITH CHRONIC HEPATITIS C RECEIVING BOCEPREVIR PLUS PEGINTERFERON/RIBAVIRIN - (04/23/12)
Ribavirin Dose Modification in Treatment-naïve and Previously Treated Patients Who Received Telaprevir Combination Treatment: No Impact on Sustained Virologic Response in Phase 3 Studies - (05/04/12)
Licensed DAAs in special populations
Efficacy and safety of boceprevir in HIV/HCV coinfection
Results of the first pilot trial with boceprevir in HIV/HCV coinfected patients were presented as an oral at the EASL meeting (5). The same dataset had been presented earlier at CROI in March this year in Seattle. Within this multi-center, double-blinded, international trial, 100 patients with untreated HCV genotype 1 infections and HIV RNA <50 copies/mL were randomized in a 2:1 ratio to receive peg-IFN-2b 1.5 mg/kg/wk)+RBV (600 to 1400 mg/day, according to weight) + boceprevir (BOC) 800 mg 3 times daily, or peg-IFN+RBV+placebo for 44 weeks (3). All had a 4-week lead-in of peg-IFN+RBV. ARV regimens that included NNRTI, zidovudine, or didanosine were not permitted. Most patients were on a boosted PI based ART regimen (84% in the boceprevir arm and 91% in the placebo arm. Few patients (11 in the boceprevir arm and 4 in the placebo arm) received raltegravir; one patient in each of the arms was on a maraviroc based ART. Patients were stratified by: cirrhosis/fibrosis (yes vs no) and baseline HCV RNA (<800,000 IU/mL vs ≥800,000 IU/mL). The majority of patients included however were non-cirrhotic (95%), white (82%), male (69%) with a median age of ~43 years. Most study participants had a high baseline HCV RNA (88%) and a HCV genotype 1a (65%). Almost all patients (97%) had a baseline HIV-RNA <50 copies/ml. The median CD4 count was 577/μl in the boceprevir arm and 586/μl in the placebo arm. The primary efficacy endpoint was the achievement of sustained virologic response, undetectable plasma HCV RNA 24 weeks after the end of treatment. Secondary endpoints and planned interim analyses included proportion of subjects with undetectable HCV RNA at treatment week 4, 8, 12, 24, and treatment week 48 (end of treatment). Of the 100 patients enrolled into the study 2 patients in the BOC arm did not receive medication; thus, 34 control and 64 experimental patients were treated. The virological response rates over time are depicted in figure 1.
Looking at the delta of 34% in SVR rates between patients receiving triple therapy versus just PEG-IFN/RBV alone, again underlines the dramatic increase in cure rates which can be achieved with the addition of an HCV protease inhibitor. Discontinuation due to adverse events occurred in 20% and 9% in the BOC and control groups, respectively. There were 9% and 53% HCV treatment failures in the BOC and control groups respectively. Compared to the control group, BOC patients were more likely to have decreased appetite, pyrexia, dysgeusia, vomiting, asthenia, anaemia, and neutropenia. Anaemia being among the most important side effects observed in HCV mono-infection studies was noted in 41% of boceprevir treated patients versus 26% of patients in the control arm. Use of erythropoietin was noted in 38% of boceprevir treated patients and 21% in the placebo arm. 6% of patients in both arms respectively received blood transfusions during HCV therapy. Under particular consideration of recently forwarded dear Dr-letters as well as FDA and EMA press releases highlighting clinically relevant drug-drug interactions between HIV boosted protease inhibitors and boceprevir the main safety concern was whether the drug interactions potentially would have influenced HIV replication control in this study. By week 48, 3 and 4 patients in the BOC and control groups, respectively, had HIV RNA virologic failure, mostly near the end of HCV therapy or even after ending treatment. Therefore, no signal of a higher rate of HIV breakthroughs in boceprevir treated patients was found in this study contrasting the observed significant drug-drug interactions which are summarized and discussed in the next section.
In summary, in this first pilot trial on efficacy and safety of the oral HCV protease inhibitor boceprevir in combination with PEGG/RBV significantly higher SVR12 cure rates could be observed in HIV/HCV coinfected patients with triple therapy. Preliminary safety data of B/PR in co-infected patients showed a profile consistent with that observed in mono-infected patients and does not suggest increased toxicity in HIV/HCV coinfected patients.
Similar improved SVR rate for triple therapy including telaprevir were reported earlier this year at CROI in Seattle (6).
Boceprevir Plus Peginterferon/Ribavirin for the Treatment of HCV/HIV Co-Infected Patients - (03/7/12)
Efficacy and safety of protease inhibitors for sever hepatitis C recurrence after liver transplantation: a first multicentre experience
HCV recurrence after OLTX represents probably the most challenging clinical complication after liver transplantation and has contributed to a shortened post-transplant survival rate in HCV-infected individuals undergoing liver transplantation. As in addition so far response rates to HCV therapy in the post-transplant setting have been poor, new strategies and DAAs in particular have been eagerly awaited in this difficult-to-treat patient population. One limitation though are the potential drug-drug interactions with calcineurin inhibitors (CNI) commonly used after transplantation for immunosuppression and prevention of organ rejection which mainly inhibit the CYP 3A4. Indeed, the administration of telaprevir in healthy volunteers increased cyclosporine exposure 4.6-fold and tacrolimus exposure 70-fold (7). The administration of boceprevir in healthy volunteers increased cyclosporine exposure 2.7-fold and tacrolimus exposure 9.9-fold. At EASL first treatment experiences were reported from 5 transplant centers in France which analysed 28 patients (8). Inclusion criteria were: active genotype 1 HCV chronic hepatitis HCV recurrence, ≥ F2 (n=20) or cholestatic hepatitis (n=8), a steady-state of immunosuppressive regimen and no contraindication for protease inhibitors. The first virological response rates are depicted in figure 2.
At week 4 rapid virological response (RVR+) was defined as a reduction of <2log of HCV viral load, complete rapid virological response (cRVR+) was defined as undetectable HCV RNA. At week 8 virological response was defined as VR+: reduction of <2log of HCV viral load and cVR+ as undetectable. Overall, tolerability was acceptable; main adverse event was myelotoxicity with 55-71% of patients having anaemia with an Hb <10g/dl. 90% of patients were treated with EPO. Overall efficacy was good. CNI dosage reduction was constantly required: 1.3 fold with cyclosporine and 5 fold with tacrolimus, in boceprevir group and 4 fold with cyclosporine and 35 fold with tacrolimus, in telaprevir group.
In summary this first data is very encouraging promising much better virological efficacy with HCV PI based triple therapy over historical data from dual therapy in treatment of HCV recurrence following liver transplantation. Nevertheless, increased adverse event rates and drug-drug interactions make this management wise a real challenge and requires extensive monitoring and adverse event management.
Use of Telaprevir Plus Peg Interferon/Ribavirin for Null Responders Post OLT With Advanced Fibrosis/Cholestatic Hepatitis C - (05/04/12) (a different study)
New DAAs in clinical development in combination with pegylated interferon and ribavirin
New HCV protease inhibitors in combination with PEG-IFN/RBV
The second wave HCV protease inhibitor TMC-435 in combination with pegylated interferon and ribavirin was investigated with different durations of triple therapy in the Aspire trial (9). The Study design is shown in figure 3:
Patients were chronically-infected with HCV genotype 1, with documented evidence of null-response (< 2 log10 reduction Week 12), or partial response (≥2 log10 reduction Week 12; detectable end-of-treatment) or relapse (undetectable end-of-treatment; detectable within 24 weeks post-treatment) following ≥1 course of P/R therapy. Patients were randomised to one of seven treatment arms: TMC435 (100 or 150mg once-daily) for 12, 24 or 48 weeks in combination with 48 weeks of P/R, or placebo with P/R for 48 weeks. Of 462 patients enrolled, 19% had Metavir score F3 and 18% F4, 41% were infected with genotype 1a and 58% 1b. Overall, in TMC435-treated patients SVR24 rates were higher (61-80%) compared with control (23%). In addition SVR24 rates were also higher in the most difficult-to-treat group of F4 prior null-responders with 31-46% response versus 0% in the control group. In TMC435 groups, discontinuation due to viral breakthrough or lack of on-treatment response was 9-17% (control 53%), and viral relapse occurred in 6-18% (control 44%). Incidence of adverse events leading to treatment discontinuation and serious adverse events was similar across all groups. Mild, transient, asymptomatic bilirubin increases were observed with TMC435, with no significant differences between 100mg and 150mg doses.
In summary in HCV genotype 1 patients who previously failed PegIFN/RBV treatment, once-daily TMC435 administered with PegIFN/RBV was significantly more effective than PegIFN/RBV/placebo. With TMC435 150 mg in combination with PegIFN/RBV:
· 85% of prior relapsers achieved SVR24
· 75% of prior partial responders achieved SVR24
· 51% of prior null responders achieved SVR24
· 31-82% in patients with cirrhosis
Once-daily TMC435 was well tolerated in this population and 12 weeks of potent PI appeared to be adequate.
TMC435 with peginterferon and ribavirin in treatment-experienced HCV genotype 1 patients: the ASPIRE study, a randomised Phase IIb trial - (04/19/12)
TMC435 in patients infected with HCV genotype 1 who have failed previous pegylated interferon / ribavirin treatment: Virologic analyses of the ASPIRE trial - (04/19/12)
New nucleotides in combination with PEG-IFN/RBV
PSI-7977 is a potent uridine nucleotide analog which was studied in the ATOMIC trial to assess a 12-week regimen of once-daily PSI-7977 400 mg + PEG/RBV (10). Treatment-naïve, non-cirrhotic HCV genotype 1patients were randomized 1:2:3 into 1 of 3 open-label arms (see figure 4). Patients were stratified upon inclusion into the study by IL28B genotype (CC vs. non-CC) and HCV RNA at screening (≤ vs. >800,000 IU/mL).
316 subjects with HCV GT1, 11 with GT4, and 5 with GT6 were enrolled: mean age 50 years, mean BMI 28, 65% male, 10% Black, 20% Hispanic. Mean baseline HCV RNA 6.4 log10 IU/mL and 18% subjects had IL28B genotype TT. PSI-7977+PEG/RBV was well-tolerated, with 20 overall discontinuations [14/332 (4%) due to AEs]. Frequency and severity of AEs were consistent with the historical safety profile of PEG/RBV. Arm C subjects who received PSI-7977/PEG/RBV x 12 wks and were then re-randomized to PSI-7977+/-RBV demonstrated almost immediate return to baseline values in hemoglobin and absolute neutrophil count, confirming the predominant effect of PEG in hematologic abnormalities. The virologic responses are shown in figure 5.
GS-7977 + PEG/RBV provided rapid viral suppression with 97% RVR and no virologic breakthrough in treatment-naïve genotype 1 HCV patients. SVR4 rates ≥ 92% were observed in genotype 1 patients receiving 12 to 24 weeks of treatment with
GS-7977 + PEG/RBV. In ITT analyses 12 weeks of a GS-7977 + PEG/RBV regimen resulted
in a SVR12 rate of 90%. Treatment with the combination of GS-7977 + PEG/RBV was safe and well tolerated for up to 24 weeks. Reassuringly no S282T resistance mutation has been detected to date underlining the high genetic barrier of this particular DAA.
In summary combination of GS-7977 with PEG-IFN and ribavirin should be able to cure almost all HCV infections at least in treatment-naïve non-cirrhotic patients. This study however, does not answer whether efficacy would be the same in more challenging to treat patient groups such as previous IFN non-responders or cirrhotics. This however, represents the patients group in highest need for further improvements in HCV treatment success rates yet these are exactly the patients which are usually not included into clinical trials thereby limiting the impressive success rate under these new combinations to easy-to-treat patient populations.
GS-7977 + PEG/RBV in HCV Genotype 1: The ATOMIC Trial An End To Response-Guided Therapy - (04/20/12)
New non-nucleoside polymerase inhibitors in combination with PEG-IFN/RBV
In a randomized, blinded dose-ranging study the safety and efficacy of ABT-072 (dosed 100, 300, or 600 mg once-daily, QD), or ABT-333 (dosed 400 or 800 mg twice-daily, BID) both being new non-nucleoside HCV NS5B polymerase inhibitors was assessed and compared to placebo given alone for 3 days, followed by combination peginterferon alpha-2a 180 μg/week + weight-based ribavirin 1000-1200 mg/day (P/R) for 12 weeks (11). After week 12, subjects received P/R alone for 36 weeks and are followed post-treatment for 24 weeks. Eligibility criteria included plasma HCV RNA ≥100,000 IU/mL at screening and liver biopsy within the past 3 years with histology consistent with HCV-induced liver damage, but no evidence of cirrhosis. Overall 50 subjects were randomized to ABT-072 (n=23), ABT-333 (n=16), or placebo (n=11); 8 (16%) subjects were female, 6 (12%) black, and 10 (20%) Latino. Baseline characteristics including mean age 50 years, mean BMI 28.3 kg/m2, mean HCV RNA 6.7 log10 IU/mL and 36 (72%) genotype 1a infection, were comparable across groups. Subjects taking ABT-072 or ABT-333 had significantly greater maximum HCV-RNA decreases from baseline than those patients on placebo. The mean maximum decrease in HCV-RNA from baseline was between 1.07 and 1,57 log10IU/mL for the 3 different ABT-072 dose groups and between 0.95 and 1.08 log10IU/mL for the 2 ABT-333 dose groups compared to 0.36 log10IU/mL for the placebo group. SVR24 was achieved in 50%, 25% and 86% of subjects receiving PEG-IFN/RBV + ABT-072 at 100, 300, or 600mg, respectively. 63% in both ABT-333 dose groups achieved SVR24 whereas in the placebo group only 9% cleared HCV infection successfully. There were no ABT-333- or ABT-072-related serious or severe adverse events (AEs), and no subjects discontinued ABT-072 or ABT-333 due to AEs. Laboratory abnormalities and AEs were generally similar in the placebo, ABT-333, and ABT-072 treatment groups and were consistent with the safety profile of P/R.
In summary the non-nucleoside compounds ABT-072 and ABT-333 were well tolerated and demonstrated potent antiviral activity in treatment-naïve subjects when combined with PEG-IFN/RBV. The ABT-333 400 mg BID dose was selected for further development.
ABT-450/ritonavir (ABT-450/r) Combined With Pegylated Interferon Alpha-2a/Ribavirin (P/R) After 3-Day Monotherapy in HCV Genotype 1 (GT1)-Infected Treatment-Naïve Subjects: 12-Week Sustained Virologic Response (SVR12) and Safety Results - (04/27/12)
What new data was presented around interferon-free regimens
The SOUND-C2 trial
The SOUND-C2 is an open label, randomized, phase IIb study with 5 treatment arms evaluating the efficacy and safety of interferon-free combination regimens of BI201335, an HCV protease inhibitor and BI207127, a non-nucleoside RNA polymerase inhibitor, +/- ribavirin (R) for up to 40W, in HCV GT1 infected patients (12). Overall, 362 treatment-naïve (TN) patients (including 10% compensated cirrhotics) were randomized and treated in 5 arms: 120mg QD BI201335 (1335QD) + 600mg TID BI207127 (7127TID) + R for 16W (A), 28W (B), or 40W (C); 1335QD + 600mg BID BI207127 (7127BID) + R for 28W (D); 1335 + 7127TID (no R) for 28W (E). Randomization was stratified by HCV subtype (1a vs. 1b) and IL28B genotype. The SVR rates for all 5 arms are shown in figure 6.
Clearly response was lowest in the arm without ribavirin again highlighting the added value of ribavirin in this interferon-free combination therapy. Further subanalyses showed quite remarkable differences in SVR rates based on HCV genotype 1 subtype with 1a patients performing on average much less favourable than 1b patients. Similarly quite some differences were seen in the subanalyses stratified by IL28b genotype with CC patients outperforming the other patient groups with regard to successful SVR rates.
In summary, the IFN-free combination of BI 201335 + BI 207127 + RBV demonstrated high efficacy and a good safety profile but combination with ribavirin remains necessary. The BID (for BI 207127) regimen demonstrated the most favourable safety and tolerability profile
with a low rate of adverse event related study discontinuations. HCV genotype and IL28b genotype remain prognostically important.
SVR4 and SVR12 with an interferon-free regimen of BI 201335 AND BI 207127, +/- ribavirin, in treatment-naïve patients with chronic genotype-1 HCV infection: Interim results of SOUND-C2 - (04/22/12)
The ELECTRON studies
Indeed there were ground-breaking results from a first interferon free therapy with the nucleotide PSI-7977 in combination with ribavirin for treatment of HCV treatment-naïve genotype 1 patients (13). PSI-7977 is a potent uridine nucleotide analogue in phase 3 development. Previously at AASLD in November 2011, results from the ELECTRON study, evaluating PSI-7977/RBV for 12 weeks without PEG demonstrated 100% SVR in HCV GT2/3 patients (14). In order to evaluate the response of this pegIFN-free regimen in patients infected with HCV GT1, 2 additional cohorts were enrolled in the ELECTRON study-GT1 treatment-naïve patients and GT1 prior null responders (defined as <2 log10 reduction in HCV RNA at week 12 of a pegIFN/RBV regimen). SVR4 Results for the non-responders was presented at this year CROI (15). 78% of GT1 null responders and 71% GT1 treatment-naïve patients were < LOD (limit of detection 15 IU/mL) at 2 weeks (compared to 80% of treatment-naïve GT2/3 patients). All patients in both cohorts were < LOD at week 4 (i.e., 100% RVR) or last available time point. Within 4 weeks after stopping therapy all but one patient from the previous null responder patient group relapsed demonstrating that most likely 12 weeks of this combination are too short to achieve cure from genotype 1 infection in this challenging to treat group of previous non-responders. The only patient who remained undetectable was a female patient with an IL28B genotype with little fibrosis at baseline. Here at EASL for the first time the SVR4 rates for the group of HCV treatment-naïve patients was reported. Indeed 88% (22/25) patients remained HCV-RNA negative 4 weeks after stopping HCV therapy suggesting that interferon-free therapy with PSI-7977 and ribavirin may be feasible in a sub-group of HCV genotype 1 patients. Overall, PSI-7977/RBV was generally well tolerated, with no treatment-related SAE, discontinuations, or Grade 3/4 laboratory abnormalities.
In summary, these results strongly suggest that in genotype 1 patient's different durations of HCV therapy or even different potent combinations of DAAs may be needed in the more challenging HCV GT1 patients such as previous null-responders. Patients with more favourable HCV treatment prediction factors however may well be treatable with interferon-free therapy for only 12 weeks.
Once Daily GS-7977 Plus Ribavirin in HCV Genotypes 1-3: The ELECTRON Trial - (04/21/12)
The ABBOTT studies
ABT-450 is a potent NS3 HCV protease inhibitor identified as a lead compound by Abbott and Enanta (boosted with low-dose ritonavir, ABT-450/r), and ABT-333 is a non-nucleoside NS5B polymerase inhibitor. In this exploratory study ABT-450/r QD + ABT-333 BID + weight-based ribavirin administered twice daily (1000-1200 mg total daily dose) was studied in HCV genotype-1, non-cirrhotic subject (16). Both treatment-naïve subjects and treatment-experienced subjects were assessed. The study design is shown in figure 7.
The majority of patients (88%) were subtype 1a. One subject in Arm 1 discontinued due to isolated ALT/AST elevations at week 2, 1 subject in Arm 2 discontinued due to noncompliance during week 1. All remaining subjects in Arms 1 and 2 completed treatment and achieved SVR12. The virological response rates are shown in figure 8.
In the arm 3 with previous PEG-IFN/RBV non- responders, 6 subjects experienced viral breakthrough while on treatment, and 3 subjects relapsed at post-treatment week 2. Virologic responses appear to be independent of ABT-450/r dose and IL28B genotype in treatment-naïve subjects.
There were no deaths or serious adverse events (AEs). The most common AEs were fatigue (42%), nausea (22%), and headache (20%). Most AEs were mild or moderate; 4 subjects experienced severe AEs (fatigue, pain, hyperbilirubinemia [maximum value: 106 mcmol/L, 6.2 mg/dL], and vomiting); none resulted in study drug interruption or discontinuation.
In summary an interferon-free 12-week regimen of ABT-450/r+ABT-333+RBV was well tolerated and achieved SVR12 in 93-95% of treatment-naïve and 47% of previous non-responder subjects infected with HCV genotype-1. Interestingly in comparison to some of the other IFN-free studies no remaining impact of IL28B on treatment success rates in naïve patients was noted.
In a second small pilot trial 11 treatment-naïve, non-cirrhotic HCV Genotype-1 (GT-1) infected subjects with IL28B rs12979860 genotype CC were enrolled in an open-label study assessing the safety, tolerability, pharmacokinetics, and antiviral activity of ABT-450/r 150/100 mg once-daily (QD) + ABT-072 400 mg QD + weight-based ribavirin 1000-1200 mg/day dosed twice-daily for 12 weeks (17). All 11 subjects completed 12 weeks of treatment and were followed for 24 weeks post-treatment. A rapid decrease in HCV RNA level was observed with treatment and all subjects had HCV RNA levels < 25 IU/mL by week 3. All subjects maintained HCV RNA < 25 IU/mL from weeks 4 through 12 of treatment, and all had undetectable HCV RNA from week 5 to the end of treatment. Viral load rebounded in 1 patient 8 weeks after the completion of treatment, but in the others it remained suppressed below the lower limit of quantification at week 24 (SVR24). A second patient experienced viral breakthrough by 36 weeks post-treatment, leading to a SVR36 rate of 81%. Analysis of resistance variants in the subject who relapsed is currently being performed. There were no deaths, serious or severe adverse events (AEs), or premature discontinuations. Most reported AEs were mild in severity; the most common were headache, fatigue, nausea, and dry skin.
In summary ABT-450/r + ABT-072 + RBV is well tolerated and achieves SVR36 in 81% of treatment-naïve, non-cirrhotic HCV GT1-infected subjects with IL28B CC genotype after 12 weeks of treatment. The late relapse is worrisome and suggests that indeed longer follow-up periods for monitoring of late relapse may be needed in all oral interferon free DAA combination regimens.
ABT-450/ritonavir (ABT-450/r) Combined With Pegylated Interferon Alpha-2a/Ribavirin (P/R) After 3-Day Monotherapy in HCV Genotype 1 (GT1)-Infected Treatment-Naïve Subjects: 12-Week Sustained Virologic Response (SVR12) and Safety Results - (04/27/12)
A 12-Week Interferon-Free Regimen of ABT-450/r + ABT-333 + Ribavirin Achieved SVR12 in More Than 90% of Treatment-Naïve HCV Genotype-1-Infected Subjects and 47% of Previous Non-Responders - (04/23/12)
A 12-Week Interferon-Free Regimen of ABT-450/r, ABT-072, and Ribavirin was Well Tolerated and Achieved Sustained Virologic Response in 91% Treatment-Naïve HCV IL28B-CC Genotype-1-Infected Subjects - (04/19/12)
The BMS studies
In 2011 at AASLD a first study demonstrated very high cure rates for the interferon and ribavirin free therapy with the NS5A replication complex inhibitor daclatasvir and the HCV-PI asunaprevir in noncirrhotic Japanese adults with HCV genotype 1b infection who had previously failed to respond to peginterferon/ribavirin therapy (18). Here at EASL again another Japanese study on the combination of daclatasvir and asunaprevir in patients with peg-alfa/RBV intolerance or prior null response to peg-alfa/RBV was presented (19). This open-label study enrolled 21 null responders (< 2 log10 HCV RNA reduction after 12 weeks of peg-alfa/RBV; group A) and 22 patients ineligible for interferon-containing regimens for medical reasons or who discontinued peg-alfa/RBV after < 12 weeks due to intolerance (group B). Patients received daclatasvir 60mg QD and asunaprevir 200mg BID (initially 600mg BID in 10/21 subjects in group A) for 24 weeks. Addition of peg-alfa/RBV was permitted for Group A patients with virologic failure. All 43 enrolled patients were Japanese with HCV genotype 1b. Baseline characteristics were similar other than a higher proportion of IL28B genotype CC (rs 12979860) in group B vs A (73% vs 14%). HCV RNA was undetectable at Week 12 (cEVR) in approximately 90% of patients in both groups. SVR12 was achieved by 90% and 64% of patients in groups A and B, respectively. Three patients discontinued prematurely for adverse events, 1 for lack of efficacy, 2 due to patient request, and 1 (group A) for lack of efficacy requiring addition of peg-alfa/RBV. Three patients had viral breakthrough, 1 before week 12; HCV variants associated with asunaprevir and daclatasvir resistance were identified.
In summary the dual oral DAA combination of daclatasvir and asunaprevir, without peg-alfa/RBV, may offer a needed therapeutic alternative to peg-alfa/RBV-containing regimens. Interestingly patients who were ineligible for PEG-IFN/RBV therapy also responded more poorly than previous non-responders suggesting that intolerance to IFN may be a poor prognostic factor for overall cure chance.
Another exciting study was AI-444040 as it investigated the combination of 2 DAAs from different companies (BMS and Gilead) (20). Clearly this appears very attractive in order to allow the evaluation of the combination of the most potent compounds of different classes. In AI-444040 the combination of daclatasvir 60mg QD (DCV; BMS-790052) with GS-7977 (PSI-7977) 400mg QD was studied with or without ribavirin, in treatment-naïve patients. Overall, 44 noncirrhotic patients with HCV GT1 and 44 noncirrhotics with HCV GT2/3 were randomized (1:1:1) to: (i) GS-7977 for 7 days then DCV + GS-7977 for 23 weeks; or (ii) DCV + GS-7977 for 24 weeks; or (iii) DCV +GS-7977 + ribavirin for 24 weeks. GT1 patients were 73% GT1a and 27% GT1b; GT2/3 patients were 59% GT2 and 41% GT3. The virological results of the study are shown in figure 9.
HCV RNA was < LLOQ at week 4 in 100% of patients. Bars not reaching 100% after week 4 reflect missing values. Virologic breakthrough occurred in one GT3 patient who had Peg-IFN/RBV added for confirmed detectable HCV RNA < LLOQ after week 8. Inclusion of ribavirin did not increase on-treatment virologic response. The most frequent AEs (≥25% overall) were fatigue, headache, and nausea.
In summary the once-daily combination of DCV and GS-7977 was generally well tolerated and achieved high rates of early virologic suppression in treatment-naïve patients infected with HCV genotypes 1a, 1b, 2, or 3.
Potent Viral Suppression With the All-Oral Combination of Daclatasvir (NS5A Inhibitor) and GS-7977 (Nucleotide NS5B Inhibitor), +/- Ribavirin, in Treatment-Naive Patients With Chronic HCV GT1, 2, or 3 (100% SVR gt1, 91% gt2) - (04/19/12)
Dual Oral Therapy with NS5A Inhibitor Daclatasvir (BMS-790052) and NS3 Protease Inhibitor Asunaprevir (BMS-650032) in HCV Genotype 1b-Infected Null Responders or Patients Ineligible/Intolerant to Peginterferon/Ribavirin - (04/19/12)
The QUAD study
The efficacy and safety of an all-oral regimen of the NS5a inhibitor GS-5885, non-nucleoside NS5b inhibitor tegobuvir, NS3 protease inhibitor GS-9451, and ribavirin for 12 or 24 weeks were assessed in chronic HCV genotype (GT) 1-infected patients (21). 141 treatment-naïve patients were randomized 1:2 to receive GS-5885 30mg/day (Arm 1; n=47) or GS-5885 90mg/day (Arm 2; n=94); patients in both arms received tegobuvir 30mg BID + GS-9451 200mg QD + ribavirin 1000-1200mg/day. Patients not achieving HCV RNA < 25 IU/mL at Week 2 were switched to peginterferon-containing rescue therapy. Arm 2 patients who achieved vRVR and remained undetectable were re-randomized (1:1) at Week 12 to stop therapy immediately or continue for an additional 12 weeks (total duration, 24 weeks). Overall in arm 2, 74 achieved vRVR and 64 were eligible for re-randomization at Week 12. 27/33 patients who stopped therapy at Week 12 have reached post-treatment Week 4. Of these, 26 (96%) achieved SVR4 (18/19 [95%] of the GT1a patients and all 8 GT1b patients). Viral breakthrough occurred only in GT1a patients (8/55). Two patients terminated early: 1 due to alcohol abuse and 1 withdrew consent. IL28B status did not appear to correlate with SVR4 or breakthrough. The most frequently reported AEs were headache (21%), fatigue (16%), diarrhea (14%), nausea (13%), and rash (11%). No WBC or platelet reductions were observed. No patients were discontinued from all-oral therapy due to a drug-related adverse event.
In summary high SVR rates were observed with this well-tolerated, 12-week, interferon-free, all-oral quad regimen in HCV GT1a and 1b patients who achieved vRVR and remained undetectable during 12 weeks of therapy. Viral breakthrough and relapse were limited to GT1a-infected patients.
Gilead: Interim Sustained Virologic Response Rates in Treatment-Naïve HCV Genotype 1a and 1b Patients Treated for 12 or 24 Weeks with an Interferon-Free All-Oral Quad Regimen - (04/21/12)
The cyclophyilin inhibitors
Alisporivir (ALV) is a host targeting antiviral (HTA) with pan-genotypic anti-HCV activity and high barrier to viral resistance. At EASL in the late-breaker session results from the VITAL-1 trial were presented publically for the first time (22). The VITAL-1 trial is an international, multicentre trial in HCV GT2/3 patients aiming to investigate rates of HCV clearance with interferon-free treatment - ALV alone or ALV plus ribavirin (RBV) and with delayed add-on peginterferon (Peg) to ALV/RBV. Overall 340 treatment-naïve HCV GT2 or GT3 patients (ratio 3:7) were randomized to 5 arms: i) ALV-1000mg QD monotherapy [ALV1000, n=83], ii) ALV-600mg QD+RBV [ALV600/RBV, n=84], iii) ALV-800mg QD+RBV [ALV800/RBV, n=94], iv) ALV-600 mg QD+Peg [ALV/Peg, n=39], or v) Peg/RBV, n=40. Patients in ALV-containing arms that achieved RVR (week 4 undetectable HCVRNA< 25 IU/mL) continued on the initial treatment for 24 weeks, while those with detectable HCVRNA continued with ALV+Peg/RBV triple therapy from week 6 to week 24.
Virological treatment responses for SVR 12 for all treatment groups in intent-to-treat analyses are presented in figure 10.
Clearly, ALV mono therapy and ALV/RBV achieved higher SVR12 rates than standard PEG-IFN/RBV therapy. RVR rates were 29% in the 1000 mg alisporivir monotherapy group, 37% with 600 mg alisporivir/ribavirin and 42% with 800 mg alisporivir/ribavirin. In these 3 groups 12%, 17%, and 10%, respectively, experienced primary non-response, defined as < 1 log reduction from baseline levels. Logistic regression analysis identified baseline viral load, ALV exposure and RBV mg/kg dose as significant determinants for RVR with ALV-based, interferon-free treatment. There was no difference in GT2 and GT3 responses to ALV-treatment. ALV-treatments were well tolerated with lower discontinuation rates and markedly lower flu-like symptoms compared with Peg/RBV. Transient hyperbilirubinaemia (>5xULN) with ALT normalization was observed in 6 (2%) ALV-treated patients.
In summary alisporivir plus Ribavirin represents an effective interferon-free option in HCV GT2/3 patients, achieving high SVR rates. Alone or with RBV, ALV maintains on-treatment HCV control, confirming ALV high barrier to resistance. At the end of the presentation it was announced that the US Food and Drug Administration recently put a hold on further development of alisporivir after a small number of patients -- 6 out of approximately 1800 people who have received the drug in various studies -- experienced pancreatitis, leading to 1 death. Importantly no case of pancreatitis was note in this particular trial, nevertheless the future of the drug at this point seems at least uncertain before the pancreatitis cases are worked up and a better understanding of these severe complications has come across.
Alisporivir (ALV) plus Peg-interferon/Ribavirin (PR) in HCV G1 Treatment-experienced Patients Achieves Primary Endpoint with Superior Efficacy at Treatment Week 12 Compared to Retreatment with PR - (04/22/12)
Alisporivir plus ribavirin is highly effective as interferon-free or interferon-add-on regimen in previously untreated HCV-G2 or G3 patients: SVR12 results from VITAL-1 Phase 2b study - (04/22/12)
Anything else in HCV?
At EASL first SVR rates were reported for a possibly better tolerated interferon lambda in the subset of genotype 2,3 patients who entered the EMERGE trial (23). The EMERGE study is an ongoing phase 2b study comparing the efficacy and safety of Lambda with peginterferon alfa-2a (alfa), each combined with RBV, in treatment-naive patients with chronic hepatitis C. Lambda interferon exerts antiviral effects through a unique receptor with limited distribution outside the liver and is expected to have an improved tolerability profile versus interferon alfa. Overall, 118 non-cirrhotic, treatment-naïve patients infected with HCV G2 (n=60) or G3 (n=58) received ribavirin (RBV) and weekly Lambda (120, 180 or 240μg) or alfa for up to 24 weeks. HCV RNA and safety were assessed through Week 48 (SVR24). Lambda compared to alfa interferon was associated with numerically greater SVR24 rate in patients with HCV G2, 3. Indeed there was a more rapid time to virological response in the lambda treated patients and a suggestion of more favorable response in the more difficult-to-treat HCV G3 patients. With regard to tolerability and safety the use of lambda interferon was associated with a reduced RBV and IFN dose-reduction rate compared to alfa interferon as well as less fatigue and fewer musculoskeletal and flu-like symptoms and also less hematological abnormalities. In conclusion lambda interferon may offer some advantages with regard to interferon specific side effects over interferon alfa. How this however, will play out in a potentially increasingly interferon-free HCV treatment future remains unclear.
Thrombocytopenia limits the ability to initiate and maintain peginterferon + ribavirin therapy in patients with cirrhosis due to hepatitis C. Indeed low platelets can formally represent a contraindication for HCV therapy at least according to the package insert of commercially available interferon treatment. Eltrombopag is an oral thrombopoietin receptor agonist that can increase platelet count and has been demonstrated previously to improve SVR rates in ENABLE 1 (PEG-2a/ribavirin). ENABLE 2 was a second study to evaluate the ability of eltrombopag to increase platelet counts, providing patients with pre-existing thrombocytopenia the opportunity to initiate PEG-2b and achieve SVR (24). In Part 1, patients with HCV and platelets < 75Gi/L received eltrombopag 25mg, increased to 50, 75, or 100mg daily until platelets reached ≥100Gi/L to enter Part 2. In Part 2, patients' eligible for PEG-2b (1.5μg/kg/week) and ribavirin (weight-based dosing) were randomized 2:1 to eltrombopag or placebo. Treatment was administered for 24 weeks or 48 weeks according to genotype. The primary endpoint was SVR. The main findings of the study which were presented at EASL was that use of eltrombopag elevated platelet counts to a level enabling introduction of antiviral therapy in 94% of patients. In addition the eltrombopag treated group showed statistically significant and clinically meaningful improvement in SVR versus placebo although overall SVR rates remained constrained by lack of interferon efficacy in patients with advanced disease. The somewhat higher SVR rate in eltrombopag treated patients can be partially explained by delaying and reducing the number of PEG-2b dose reductions, particularly in the early phase of treatment. With regard to tolerability and safety however an unexplained higher rate of thromboembolic events in the eltrombopag arm was noted (this had not been noted in ENABLE 1). This clearly requires evaluation of risk-benefit in patients at risk of disease progression.
· Early treatment of acute hepatitis C with PEG-IFNa-2b alone is highly effective in both symptomatic and asymptomatic patients. Delayed PEG-IFNa + ribavirin treatment results in lower overall response due to high lost-to-follow-up rates. However, if adherence can be assured and treatment is eventually administered delayed combination therapy seems to be of similar efficacy in symptomatic patients. These findings strengthen the early treatment intervention with PEG-IFN monotherapy for therapy of acute HCV but also reassure that waiting for 12 weeks has no negative impact on overall treatment outcome at least if combination HCV therapy is administered.
· First data from HCV protease inhibitor based treatment of HCV patients with more advanced liver fibrosis from a more "real world" clinical treatment scenario underline that the safety profile of TVR or BOC with PEG-IFN/RBV in cirrhotic patients is poor and is 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 patients with liver cirrhosis.
· Anemia seems to be one of the more frequent adverse events when treating HCV infected patients with more advanced fibrosis stages with DAA based therapy. When EPO use versus ribavirin dose reduction was compared as a primary anaemia management strategy in patients no difference in outcome was noted between the 2 strategies. Therefore, for cost effectiveness reasons ribavirin dose reductions in anemic patients under HCV triple therapy appears to be the way forward.
· Studies on the efficacy and safety with the HCV protease inhibitors boceprevir or telaprevir in HCV genotype 1 HIV co-infected individuals have clearly demonstrated substantial higher HCV treatment cure rates under triple therapy compared to just pegylated interferon/ribavirin combination therapy alone allowing for cure of hepatitis C in about two thirds of treated patients; increased toxicities including higher anaemia rates and higher rash rates have been reported although overall discontinuation rates due to adverse events remain low and no discontinuation due to rash has occurred in the studies reported so far.
· First data on treatment of HCV recurrence in HCV-infected patients undergoing liver transplantation with triple therapy is very encouraging promising much better virological efficacy with HCV PI based triple therapy over historical data from dual therapy. Nevertheless, increased adverse event rates and drug-drug interactions complicate management of HCV recurrence following liver transplantation. Clearly extensive monitoring and diligent adverse event management is required.
· New HCV protease inhibitors such as TMC-435 promise similarly improved SVR rates as with triple therapy containing first generation HCV protease inhibitors but with simplified and better tolerated HCV therapy.
· Interferon free therapy has been shown to work in a whole range of different combinations and treatment schedules clearly making interferon free regimens a very realistic scenario for the upcoming years. Nevertheless the "therapy for all" option has not yet been presented and clearly more challenging patient populations such as cirrhotics and previous interferon null-responders will need at least longer durations of treatment or even more potent combinations.
· It appears that in many interferon-free studies the addition of ribavirin still appears to be essential to maximize overall cure rates and prevent relapse rates.
· In an ABBOTT interferon-free trial a late relapse at week 36 was reported that potentially follow-up in interferon-free regimens may need to be longer than in interferon-based regimens where usually no relapse is noted after SVR24.
· The US Food and Drug Administration recently put a hold on further development of alisporivir after a small number of patients -- 6 out of approximately 1800 people who have received the drug in various studies -- experienced pancreatitis, leading to 1 death.
· Use of eltrombopag in cirrhotics to increase platelet counts helps to delay and reduce the number of PEG-IFN dose reductions in this special patient group, particularly in the early phase of treatment. This has been demonstrated to significantly improve SVR rates in this overall difficult to treat patient population. The observed higher rate of thromboembolic events in the eltrombopag arm however, requires evaluation of risk-benefit in patients at risk of disease progression.
1. Jaeckel E, Cornberg M, Wedemeyer H, Santantonio T, Mayer J, Zankel M, Pastore G, Dietrich M, Trautwein C, Manns MP; German Acute Hepatitis C Therapy Group. Treatment of acute hepatitis C with interferon alfa-2b. N Engl J Med. 2001;345:1452-7.
2. Deterding K, Gruner N, Buggisch P, Wiegand J, Galle P, Spengler U, Hinrichsen H, Berg T, Potthoff A, Malek N, Diepolder N, Feyerabend S, Cornberg M, Jung MC, Manns MP, Wedemeyer H, The Hep-Net Acute HCV-Study group. Early versus delayed treatment of acute hepatitis C: Final results of the randomized controlled German HEP-NET acute HCV-III study. 47th Annual Meeting of the European Association for the Study of the Liver, April 18-22, 2012, Barcelona, Spain; abstract 48
3. Hezode C, Dorival C, Zoulim F, Poynard T, Mathurin P, Pol S, Larrey D, Cacoub P, de Ledinghen V, Bourliere M, Bernard PH, Riachi1 G, Alric L, Samuel D, Barthe Y, Fontaine H, Carrat F, Bronowicki JP, ANRS CO20 CUPIC study group. 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) 47th Annual Meeting of the European Association for the Study of the Liver, April 18-22, 2012, Barcelona, Spain; abstract 8
4. Poordad FF, Lawitz EJ, Reddy KR, Afdhal NH, Hézode C, Zeuzem S, Lee SS, Calleja LJ, Brown RS, Jr, Craxi A, Wedemeyer H, Deng W, Koury K, Boparai N, Pedicone LD, Burroughs M, Wahl J, Brass CA, A Albrecht JK, Sulkowski MS. Randomized trial comparing ribavirin dose reduction versus erythrpoeitin for anemia management in previously untreated patients with chronic hepatitis C receiving Boceprevir plus Peginterferon/Riba. 47th Annual Meeting of the European Association for the Study of the Liver, April 18-22, 2012, Barcelona, Spain; abstract 1419
5. Mallolas J, Pol S, Rivero A,. Fainboim H, Cooper C, Slim J, Thompson S, Wahl J, Greaves W, Sulkowski M. Boceprevir + Pegylated Interferon + Ribavirin for the Treatment of HCV/HIV-co-infected Patients: End of Treatment (Week-48) Interim Results. 47th Annual Meeting of the European Association for the Study of the Liver, April 18-22, 2012, Barcelona, Spain; abstract 47
6. Dieterich DT, Soriano V, Sherman KE, Girard PM, Rockstroh JK, Henshaw J, Rubin R, Bsharat M, Adda N, Sulkowski MS on behalf of the Study 110 Team. Telaprevir in Combination with Peginterferon Alfa-2a/Ribavirin in HCV/HIVCo-infected Patients:SVR12 Interim Analysis. 19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012; abstract 46
7. Garg V, van Heeswijk R, Lee JE, Alves K, Nadkarni P, Luo X. Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus. Hepatology.201l;54(1):20-7.
8. Coilly A, Roche B, Botta-Fridlund D,. Leroy V, Pageaux PG, Si-Ahmed SN, Antonini TM, Samuel D, Duclos-Vallee JC. Efficacy and safety of protease inhibitors for severe hepatitis recurrence after liver transplantation: a first multicentric experience. 47th Annual Meeting of the European Association for the Study of the Liver, April 18-22, 2012, Barcelona, Spain; abstract 47
9. Zeuzem S, Berg T, Gane E, Ferenci P, Foster GR, Fried MW, Hezode C, Hirschfield G, Jacobson I, Nikitin I, Pockros P, Poordad F, Lenz O, Peeters M, Sekar V, De Smedt G, Beumont-Mauviel M. TMC435 in HCV genotype 1 patients who have failed previous pegylated interferon/ribavirin treatment: Final SVR24 results of the ASPIRE trial. 47th Annual Meeting of the European Association for the Study of the Liver, April 18-22, 2012, Barcelona, Spain; abstract 2
10. Kowdley KV, Lawitz E, Crespo I, Hassanein T, Davis M, DeMicco M, Nelson DR, Bernstein D, Afdhal NH, Jacobson I, Vierling J, Gordon S, Anderson JK, Hyland RH, Hindes RG, Baker C, Sorensen R, Albanis E, Symonds WT, Berrey MM, ATOMIC Investigators. ATOMIC: 97% RVR for PSI-7977 + PEG/RBV X 12 week regimen in HCV GT1: An end to response-guided therapy? 47th Annual Meeting of the European Association for the Study of the Liver, April 18-22, 2012, Barcelona, Spain; abstract 1
11. Poordad F, Lawitz E, DeJesus E, Kowdley KV, Gaultier I, Cohen DE, Xie W, Larsen L, Pilot-Matias T, Koev G, Dumas E, Podsadecki T, Bernstein B. ABT-072 or ABT-333 combined with pegylated interferon/ribavirin after 3-day monotherapy in HCV genotype 1 (GT1)-infected treatment-naïve subjects: 12-week sustained virologic response (SVR12) and safety results. 47th Annual Meeting of the European Association for the Study of the Liver, April 18-22, 2012, Barcelona, Spain; abstract 1206
12. Zeuzem S, Soriano V, Asselah T, Bronowicki JP, Lohse A, Mullhaupt B, Schuchmann M, Bourliere M, Buti M, Roberts S, Gane E, Stern JO, Kukolj G, Dai L, Böcher WO, Mensa FJ. SVR4 and SVR12 with an interferon-free regimen of BI201335 and BI207127, +/- ribavirin, in treatment-naïve patients with genotype-1 HCV infection: Interim results of SOUND-C2. 47th Annual Meeting of the European Association for the Study of the Liver, April 18-22, 2012, Barcelona, Spain; abstract 101
13. Gane EJ, Stedman CA, Hyland RH, Sorensen RD, Symonds WT, Hindes RG, Berrey MM. ELECTRON: Once daily PSI-7977 plus RBV in HCV GT1/2/3. 47th Annual Meeting of the European Association for the Study of the Liver, April 18-22, 2012, Barcelona, Spain; abstract 1113
14. Gane EJ, Stedman C, Anderson J, Hyland R, Hindes R, Symonds W, Berrey MM. 100% Rapid Virologic Response for PSI-7977 + Ribavirin in Genotype 1 Null Responders (ELECTRON): Early Viral Decline Similar to that Observed in Genotype 1 and Genotype 2/3 Treatment-naïve Patients. 19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012; abstract 54LB
15. Gane EJ, Stedman CA, Hyland RH, et al. Once Daily PSI-7977 plus RBV: Pegylated interferon-Alfa not required for Complete Rapid viral response in Treatment-naive Patients with HCV GT2 or GT3. 62nd Annual Meeting of the American Association for the Study of Liver Disease (AASLD 2011). San Francisco, November 4-8. 2011. Abstract 34.
16. Poordad F, Lawitz E, Kowdley KV, Everson GT, Freilich B, Cohen D, Siggelkow S, Heckaman M, Menon R, Pilot-Matias T, Podsadecki T, Bernstein B. 12-Week Interferon-Free Regimen of ABT-450/r+ABT-333+Ribavirin Achieved SVR12 in More Than 90% of Treatment-Naïve HCV Genotype-1-Infected Subjects and 47% of Previous Non-Responders. 47th Annual Meeting of the European Association for the Study of the Liver, April 18-22, 2012, Barcelona, Spain; LB abstract 1399
17. Lawitz E, Poordad F, Kowdley KV, Jensen D, Cohen DE, Siggelkow S, Wikstrom K, Larsen L, Menon RM, Podsadecki T, Bernstein B. A 12-Week Interferon-Free Regimen of ABT-450/r, ABT-072, and Ribavirin was Well Tolerated and Achieved Sustained Virologic Response in 91% Treatment-Naïve HCV IL28B-CC Genotype-1-Infected Subject. 47th Annual Meeting of the European Association for the Study of the Liver, April 18-22, 2012, Barcelona, Spain; LB abstract 13
18. Chayama K, Takahashi S, Kawakami Y, et al. Dual Oral Combination Therapy with the NS5A Inhibitor BMS-790052 and the NS3 Protease Inhibitor BMS-650032 Achieved 90% Sustained Virologic Response (SVR12) in HCV Genotype 1b-Infected Null Responders. 62nd Annual Meeting of the American Association for the Study of Liver Diseases. San Francisco, November 4-8. 2011. Abstract LB-4
19. Suzuki F, Ikeda K, Toyota J, Karino Y, Ohmura T, Chayama K, Takahashi S, Kawakami Y, Ishikawa H, Watanabe H, Hu W, McPhee F, Hughes E, Kumada H. Dual oral therapy with the NS5A inhibitor dclatasvir (BMS-790052) and NS3 protease inhibitor asunaprevir (BMS-650032) in HCV genotype 1b-infected null responders or ineligible/intolerant to PEGIFN. 47th Annual Meeting of the European Association for the Study of the Liver, April 18-22, 2012, Barcelona, Spain; LB abstract
20. Sulkowski M, Gardiner D, Lawitz E, Hinestrosa F, Nelson D, Thuluvath P, Rodriguez-Torres M, Lok A, Schwartz H, Reddy KR, Eley T, Wind-Rotolo M, Huang SP, Gao M, McPhee F, Hindes R, Symonds B, Pasquinelli C, Grasela D, AI444040 Study Group. Potent viral suppression with all-oral combination of daclatasvir (NS5A inhibitor) and GS-7977 (NS5B inhibitor), +/-ribavirin, in treatment-naïve patients with chronic HCV GT1, 2, or 3. 47th Annual Meeting of the European Association for the Study of the Liver, April 18-22, 2012, Barcelona, Spain; LB abstract 1422
21. Sulkowski M, Rodriguez-Torres M, Lawitz E, Shiffman M, Pol S, Herring R, McHutchison J, Pang P, Brainard D, Wyles D, Habersetzer F. High sustained virologic response rate in treatment-naïve HCV genotype 1a and 1b patients treated for 12 weeks with an interferon-free all-oral quad regimen: Interim results. 47th Annual Meeting of the European Association for the Study of the Liver, April 18-22, 2012, Barcelona, Spain; LB abstract 1421
22. Pawlotsky JM, Sarin SK, Foster G, Peng CY, Rasenack J, Flisiak R, Piratvisuth T, Wedemeyer H, Chuang WL, Zhang WM, Naoumov NV. Alisporivir plus Ribavirin is highly effective as interferon-free or interferon-add-on regimen in previously untreated HCV-GT2 or GT3 patients: SVR12 results from VITAL-1 Phase 2b study. 47th Annual Meeting of the European Association for the Study of the Liver, April 18-22, 2012, Barcelona, Spain; LB abstract LB 11
23. Zeuzem S, Arora S, Bacon B, Box T, Charlton M, Diago M, Dieterich D, Mur RE, Everson G, Fallon M, Ferenci P, Flisiak R, George J, Ghalib R, Gitlin N, Gladysz A, Gordon S, Greenbloom S, Hassanein T, Jacobson I, Jeffers L, Kowdley K, Lawitz E, Lee SS, Leggett B, Lueth S, Nelson D, Pockros P, Rodriguez-Torres M, Rustgi V, Serfaty L, Sherman M, Shiffman M, Sola R, Sulkowski M, Vargas H, Vierling J, Yoffe B, Ishak L, Fontana D, Xu D, Gray T, Horga A, Hillson J, Lopez-Talavera JC, Muir A, EMERGE Study Group. Peginterferon lambda-1a (LAMBDA) compared to peginterferon alfa-2a (ALFA) in treatment-naïve patients with HCV genotypes (G) 2 or 3: First SVR24 results from EMERGE phase IIB. 47th EASL; 47th Annual Meeting of the European Association for the Study of the Liver, April 18-22, 2012, Barcelona, Spain; LB abstract 1435.
24. Dusheiko G, Afdhal N, Giannini EG, Chen PJ, Han KH, Rodriguez-Torres M, Rugina S, Lawitz E, Streinu-Cercel A, Shiffman ML, Poordad F, Mostafa Kamel Y, Brainsky A, Geib J, Vasey SY, Patwardhan R, Campbell F, Theodore D. Results of ENABLE 2, a phase 3, multicenter study of eltrombopag and peginterferon alfa-2b treatment in patients with hepatitis C and thrombocytopenia. 47th Annual Meeting of the European Association for the Study of the Liver, April 18-22, 2012, Barcelona, Spain; LB abstract 279.