Advances in the Treatment of Hepatitis C Virus Infection From AASLD 2012

Fred Poordad, MD

Volume 9, Issue 1, Supplement 1 January 2013

Advances in the Treatment of Hepatitis C Virus Infection From AASLD 2012

The 63rd Annual Meeting of the American Association for the Study of Liver Diseases

November 9–13, 2012 • Boston, Massachusetts

Special Reporting on:

• Timing and Magnitude of Ribavirin Dose Reduction Do Not Impact SVR Rates with Boceprevir Plus Peginterferon α and Ribavirin

• A 12-Week Interferon-Free Treatment Regimen with ABT-450/r, ABT-267, ABT-333, and Ribavirin Achieves High SVR12 Rates

• High Rate of SVR with the All-Oral Combination of Daclatasvir Plus Sofosbuvir with or without Ribavirin

• An Interferon-Free, Ribavirin-Free 12-Week Regimen of Daclatasvir, Asunaprevir, and BMS-791325 Achieved High SVR4 Rates

PLUS  Meeting Abstract Summaries

With Expert Commentary by: 

Fred Poordad, MD

University of San Antonio Health Science Center

San Antonio, Texas

Indexed through the National Library of Medicine (PubMed/Medline), PubMed Central (PMC), and EMBASE 

Disclaimer

Every effort has been made to ensure that drug usage and other information are presented accurately; however, the ultimate responsibility rests with the prescribing physician. Gastro-Hep Communications, Inc., and the participants shall not be held responsible for errors or for any consequences arising from the use of information contained herein. Readers are strongly urged to consult any relevant primary literature. No claims or endorsements are made for any drug or compound at present under clinical investigation.

©2013 Gastro-Hep Communications, Inc. 611 Broadway, Suite 310, New York, NY 10012. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.

 

Timing and Magnitude of Ribavirin Dose Reduction Do Not Impact SVR Rates with Boceprevir Plus Peginterferon α and Ribavirin

The current standard-of-care therapy for patients with genotype 1 chronic hepatitis C virus (HCV) infection is triple therapy consisting of a protease inhibitor (boceprevir or telaprevir) plus peginterferon α and ribavirin. Patients on triple therapy may experience moderate-to-severe treatment-related anemia, which is often managed with ribavirin dose reduction and/or administration of the growth factor erythropoietin. To determine whether these interventions affect the efficacy of HCV therapy, Fred Poordad and colleagues investigated whether the timing and magnitude of ribavirin dose reduction alter sustained virologic response (SVR) rates in patients who are receiving boceprevir plus peginterferon and ribavirin.1 Poordad presented the results of this study at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), which was held November 9–13, 2012, in Boston, Massachusetts.

The Anemia Management Study was a randomized, multicenter, open-label study that assessed ribavirin dose reduction versus erythropoietin for management of anemia. This study enrolled 687 treatment-naïve patients with genotype 1 HCV infection who were at least 18 years of age. Baseline hemoglobin levels were 12–15 g/dL for women and 13–15 g/dL for men, and patients had baseline platelet counts above 100,000 cells/mm3. Liver biopsies were performed to confirm the presence of chronic HCV infection. Patients with compensated cirrhosis were allowed to enroll in this study, but patients with other liver diseases were excluded. Patients who were coinfected with HIV and/or hepatitis B virus (HBV) were also excluded from the study.

The treatment regimen included a 4-week lead-in period during which patients received peginterferon (1.5 µg/kg/week) and weight-based ribavirin (600–1,400 mg/day); patients then received triple therapy with boceprevir (800 mg three times daily) plus peginterferon and ribavirin. The majority of patients received boceprevir plus peginterferon and ribavirin for 25–44 weeks; however, 26% of patients received boceprevir plus peginterferon and ribavirin for a period of 24 weeks or less as part of the study’s response-guided therapy regimen. Hemoglobin levels were measured every 2 weeks for the first 12 weeks of the study, after which they were measured at 24, 28, 34, 40, and 48 weeks. If a patient’s hemoglobin level fell to 10 g/dL or lower, he or she was randomized to receive ribavirin dose reduction (n=249) or erythropoietin (n=251); 187 patients in the study were treated with triple therapy but maintained acceptable hemoglobin levels and did not receive either anemia intervention. Ribavirin was dose-reduced in 3 steps of 200–400 mg/day; erythropoietin was administered at 40,000 units per week, with the dose modified to 20,000 units/week or 60,000 units/week at the physician’s discretion. Patients with hemoglobin levels at or below 8.5 g/dL received a secondary anemia intervention (whichever treatment was not used as the primary intervention), and HCV therapy was discontinued if hemoglobin levels fell to 7.5 g/dL or lower. The primary endpoint of the study was SVR 24 weeks after the end of treatment (SVR24).

As was previously reported at the 2012 meeting of the European Association for the Study of the Liver, SVR was achieved in 71% of patients on triple therapy, regardless of the anemia management strategy that was employed. In addition, the number of patients who relapsed was the same in the ribavirin dose-reduction group (10%; 19/196 patients) and the erythropoietin group (10%; 19/197 patients). Patients with undetectable levels of HCV RNA at the time of ribavirin dose reduction or erythropoietin administration had higher SVR rates compared to patients who had detectable levels of HCV RNA at the time of their anemia intervention (86% vs 56%). Which primary anemia management strategy was employed did not alter this result: Among patients with undetectable HCV RNA levels, SVR rates were 86% for the ribavirin dose-reduction group (111/129 patients) versus 86% for the erythropoietin group (107/124 patients); among patients with detectable HCV RNA levels, SVR rates were 56% (67/120 patients) versus 56% (71/127 patients), respectively.

The timing of the first ribavirin dose reduction did not significantly alter SVR rates: <4 weeks, 70%; >4–8 weeks, 64%; >8–12 weeks, 79%; >12–16 weeks, 82%; >16 weeks, 71%. In addition, SVR rates were similar for patients in the ribavirin dose-reduction arm who received 1–7 steps of ribavirin dose reduction, with SVR rates of 64–83%. When SVR rates were analyzed according to the average daily dose of ribavirin, the data showed that patients who received less than 10 mg/kg/day of ribavirin had an SVR rate of 76% (84/110 patients). Similarly, SVR rates were 69% (36/52 patients) for patients who received a ribavirin dose of 10–11 mg/kg/day, 74% (29/39 patients) for patients who received 11–12 mg/kg/day, 65% (20/31 patients) for patients who received 12–13 mg/kg/day, and 53% (9/17 patients) for patients who received more than 13 mg/kg/day. There was no significant difference in SVR rates between patients whose lowest ribavirin dose was less than 10 mg/kg/day for a minimum of 7 days and those whose lowest ribavirin dose was greater than 10 mg/kg/day (74% vs 68%). However, patients who received less than 50% of the assigned dose of ribavirin over the entire treatment period had significantly lower SVR rates compared to patients who received at least 50% of their assigned dose (18% vs 74–92%).

Since variants in the inosine triphosphatase (ITPA) gene have been shown to protect against ribavirin-induced anemia, this study also assessed anemia rates and SVR rates by ITPA activity and genotype. Low ITPA activity was associated with an anemia rate of 50% (90/180 patients) and an SVR rate of 69% (125/180 patients). Patients with normal ITPA activity had an anemia rate of 70% (264/379 patients) and an SVR rate of 62% (234/379 patients). Patients with ITPA genotype C/C had the lowest rate of anemia (44%) compared to patients with the A/A or A/C genotypes (68% and 57%, respectively); patients with the C/C genotype also had the lowest SVR rate (C/C: 59%; A/A: 63%; A/C: 69%). In addition, the risk of developing anemia was increased in patients with normal ITPA activity (odds ratio [OR], 1.96; 95% confidence interval [CI], 1.28–3.00; P<.0019), age greater than 40 years (OR, 1.98; 95% CI, 1.19–3.28; P=.0084), and/or grade 3/4 fibrosis (OR, 2.02; 95% CI, 1.03–3.98; P=.0421).

Poordad concluded by stating that the timing of ribavirin dose reduction, the average daily ribavirin dose, and the lowest ribavirin dose received did not significantly affect SVR rates in treatment-naïve patients who received triple therapy with boceprevir, peginterferon, and ribavirin. While the SVR rate was significantly affected by whether HCV RNA levels were detectable at the time of anemia intervention, the strategy that was employed to manage anemia (ribavirin dose reduction vs erythropoietin) did not affect the SVR rate. However, SVR rates were lower if patients received less than 50% of their assigned dose of ribavirin.

Reference

1. Poordad F, Lawitz E, Reddy K, et al. Timing and magnitude of ribavirin dose reduction (RBV DR) do not impact sustained virologic response (SVR) rates with boceprevir (BOC) + peginterferon alfa-2b / ribavirin (P/RBV) in the Anemia Management Study in chronic HCV genotype 1 patients. Presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases; November 9–13, 2012; Boston, Massachusetts. Abstract #154.

 

ABSTRACT SUMMARY A Clinical Decision Tool for Predicting Treatment Response and SVR in Patients Treated with Boceprevir Plus Peginterferon and Ribavirin 

Triple therapy comprised of boceprevir plus peginterferon and ribavirin is an efficacious treatment option for many patients with HCV infection. However, a number of factors can influence patient response. To further explore these factors and their impact on HCV therapy, Scott Devine and colleagues sought to develop clinical decision tools for predicting HCV undetectability at treatment Week 8 and SVR. An accurate predictive model could inform clinical decision-making about duration and success of treatment. The results of this study were presented as a poster at the 2012 AASLD meeting.1

Devine and coauthors built logistic regression models to predict HCV undetectability at treatment Week 8 and SVR. The analysis used data from 1,227 patients in the SPRINT-2, RESPOND-2, and PROVIDE studies of boceprevir. The factors used in these models included prior treatment with peginterferon and ribavirin, interleukin (IL)-28B genotype, HCV genotype 1 subtype, initial ribavirin dose, age, race, sex, HCV RNA level after 4 weeks of peginterferon and ribavirin therapy, log10 reduction in HCV RNA level from baseline to treatment Week 4, and baseline characteristics (weight, body mass index [BMI], hemoglobin level, fibrosis score, the ratio between alanine aminotransferase [ALT] level and the upper limit of normal, platelet count, statin use, steatosis score, and HCV RNA level).

Nomograms were not developed for the baseline-only prediction models because of their poor ability to predict treatment Week 8 response and SVR (C-statistics, 0.76 and 0.69, respectively). Instead, final models that included baseline variables plus HCV RNA level at treatment Week 4 were developed to predict response at treatment Week 8 (n=856 patients) and SVR (n=522 patients). Both models included treatment-naïve patients, relapsers, and partial and prior nonresponders. IL-28B genotype was not included in the analysis.

A step-down approach was used to reduce the final number of predictors. In the model to predict treatment Week 8 response, the final variables were race, initial ribavirin dose, platelet count, log10 reduction in HCV RNA level from baseline to treatment Week 4, and HCV RNA level at treatment Week 4. In the SVR model, the final factors were sex, BMI, ribavirin use, platelet count, HCV genotype 1 subtype, and HCV RNA level at treatment Week 4. The final model calibration curves were presented and had good discrimination abilities for both the treatment Week 8 response model and the SVR model (C-statistics, 0.89 and 0.83, respectively). In addition to successfully predicting treatment Week 8 response and SVR without invasive testing, these nomograms could also be useful for clinical decision-making about the initiation and maintenance of therapy.

Reference

1. Devine S, Kattan M, Muir A, et al. Clinical decision tool for predicting treatment week eight response and sustained virologic response in patients treated with boceprevir (BOC) plus peginterferon alfa and ribavirin (PR). Presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases; November 9–13, 2012; Boston, Massachusetts. Abstract #1842.

 

A 12-Week Interferon-Free Treatment Regimen with ABT-450/r, ABT-267, ABT-333, and Ribavirin Achieves High SVR12 Rates

The HCV NS3/4A protease inhibitor ABT-450 has been identified as a potentially efficacious treatment option for HCV infection when it is administered in conjunction with 100 mg of ritonavir (ABT-450/r). In prior exploratory studies, patients with genotype 1 HCV infection achieved high SVR rates (>90%) when they were treated with an interferon-free regimen containing ABT-450/r. At the 2012 AASLD meeting, Kris V. Kowdley presented the results of an ongoing study that is evaluating the safety and efficacy of regimens containing ABT-450/r, ribavirin, and 1 or 2 other direct-acting antiviral agents: ABT-267, an NS5A inhibitor, and/or ABT-333, a non-nucleoside polymerase inhibitor.1 This study enrolled noncirrhotic, treatment-naïve patients and prior null responders, and its goal was to determine which combination of these direct-acting antiviral agents was optimal for the treatment of genotype 1 HCV infection.

The key eligibility criteria for this study were age 18–70 years, chronic genotype 1 HCV infection, no cirrhosis, HCV RNA level greater than 50,000 IU/mL, and no HIV or HBV coinfection. Null responders had received at least 12 weeks of peginterferon and ribavirin therapy but did not achieve a 2 log10 IU/mL decrease in HCV RNA levels. Patients were treated with various combinations of ABT-450/r (100–200 mg/100 mg daily), ABT-267 (25 mg daily), ABT-333 (400 mg twice daily), and/or weight-based ribavirin; treatment was administered for 8, 12, or 24 weeks. The primary efficacy endpoint of this study is SVR24; however, the data presented at the 2012 AASLD meeting were from an interim analysis, so only SVR12 rates were available at this time, and only patients receiving 8 or 12 weeks of treatment were assessed for the interim analysis.

A total of 571 patients (438 treatment-naïve patients and 133 prior null responders) received at least 1 dose of study medication. In the 8-week and 12-week treatment groups, the majority of patients were white, 44% of patients were women, the mean age was 50 years, the mean BMI was 27.1 kg/m2, and one third of patients had genotype 1a HCV infection. The mean baseline HCV RNA level was approximately 6.6 log10 IU/mL.

The highest SVR12 rates were achieved in patients who were treated with all 3 direct-acting antiviral agents plus ribavirin for 12 weeks. In this treatment arm, SVR12 rates were 97.5% (77/79 patients) in treatment-naïve patients and 93.3% (42/45 patients) in prior null responders. In all other treatment regimens, SVR12 rates were 85.4–89.9%. When the data were analyzed according to HCV subtype, the SVR12 rate for patients with genotype 1b HCV infection who received all 3 direct-acting antiviral agents plus ribavirin was 100% for both treatment-naïve patients and null responders. Patients with genotype 1a HCV infection who were treated with this regimen had slightly lower SVR12 rates (96% in treatment-naïve patients and 89% in null responders). In an analysis of IL-28B genotypes, treatment with all 3 direct-acting antiviral agents plus ribavirin again resulted in the highest SVR12 rates for both treatment-naïve patients and null responders (treatment-naïve patients: 100% for IL-28B genotype CC vs 97% for IL-28B genotype non-CC; null responders: 100% for IL-28B genotype CC vs 93% for IL-28B genotype non-CC).

Among patients who were treated for 8 or 12 weeks with all 3 direct-acting antiviral agents plus ribavirin, viral breakthrough was not observed in any of the treatment-naïve patients, but breakthrough did occur in 3 null responders. Among patients who were treated with all 3 direct-acting antiviral agents plus ribavirin, relapse occurred in 9 treatment-naïve patients in the 8-week treatment group, 1 treatment-naïve patient in the 12-week treatment group, and 0 of the null responders. Among the patients in the 8-week treatment arm who relapsed, treatment-emergent resistance variants were detected in 3 of 9 patients. In the 12-week treatment groups, samples from patients with viral breakthrough or relapse showed the presence of resistance variants known to be selected by ABT-450, ABT-267, or ABT-333.

In terms of safety, Kowdley noted that all 8-week and 12-week treatment regimens were well tolerated. Overall, only 2 of 448 patients discontinued treatment due to adverse events. In addition, there were 5 serious adverse events (1%), 1 of which (arthralgia) occurred in the 24-week treatment group and may have been related to the study drugs. The most common grade 3/4 laboratory anomaly was an elevated level of indirect bilirubin (≥2× the upper limit of normal), which occurred in 24 treatment-naïve patients (6.7%) and 11 null responders (2.2%); when such elevations occurred, they were transient and asymptomatic. The most common adverse events included fatigue, headache, insomnia, and nausea. Kowdley noted that the investigators did not detect any new safety issues when patients received combination therapy with 2 or 3 of the direct-acting antiviral agents evaluated in this study.

As has been observed with ribavirin monotherapy, the ribavirin-containing treatment regimens in this study were associated with declines in hemoglobin levels. Patients who received 3 direct-acting antiviral agents without ribavirin had a lower incidence of hemoglobin levels below 10 g/dL. There was also a trend toward fewer events of anemia, insomnia, nausea, and cough in patients whose treatment did not include ribavirin. Kowdley indicated that these data provide some justification for further evaluation of ribavirin-sparing regimens in future studies.

The study investigators concluded that treatment with ABT-450/r, ABT-267, and ABT-333 plus ribavirin for 12 weeks was well tolerated. In addition, both treatment-naïve patients and null responders in this treatment arm achieved high SVR12 rates. Importantly, SVR was achieved even in patients who had predictors of poor response (genotype 1a infection, non-CC IL-28B genotype, and/or prior null response). Given these promising results, the combination of ABT-450/r, ABT-267, and ABT-333—with or without ribavirin—will be studied in planned phase III trials.

Reference

1. Kowdley K, Lawitz E, Poordad F, et al. A 12-week interferon-free treatment regimen with ABT-450/r, ABT-267, ABT-333 and ribavirin achieves SVR12 rates (observed data) of 99% in treatment-naïve patients and 93% in prior null responders with HCV genotype1 infection. Presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases; November 9–13, 2012; Boston, Massachusetts. Abstract #LB-1.

 

ABSTRACT SUMMARY Assessment of Boceprevir Pharmacokinetic/Pharmacodynamic Relationships for SVR and Anemia in HCV/HIV Coinfected and HCV Monoinfected Patients

Administration of ritonavir-boosted HIV protease inhibitors reduces boceprevir concentrations in healthy volunteers. To further explore this interaction, Larissa A. Wenning and colleagues conducted a study that assessed boceprevir pharmacokinetics in HCV/HIV coinfected patients.1 In addition, this study evaluated the relationships among boceprevir pharmacokinetics/pharmacodynamics, SVR, and anemia. These data were presented in a poster at the 2012 AASLD meeting.

This study included data from 3 clinical trials: a phase II HCV/HIV coinfection study, the phase III SPRINT-2 study, and the phase III RESPOND-2 study. Boceprevir-related pharmacokinetic data were available for 51 patients in the coinfection study, 105 patients in SPRINT-2, and 84 patients in RESPOND-2. A population pharmacokinetic model was used to estimate pharmacokinetic parameters. For the study arms that contained boceprevir, the OR was estimated using a linear regression model for SVR or anemia in which boceprevir pharmacokinetics (area under the curve from 0–8 hours [AUC0-8hr] or concentration at 8 hours [C8hr]) were used as predictors.

The cross-study comparison of boceprevir pharmacokinetics found that the boceprevir AUC0-8hr was approximately 20% lower in the HCV/HIV coinfection study than in the studies of HCV monoinfected patients. In addition, the C8hr was approximately 27% lower in the coinfection study compared to the monoinfection studies. The SVR and anemia pharmacokinetic/pharmacodynamic results were similar for both boceprevir AUC0-8hr and C8hr. Thus, Wenning and coauthors were unable to determine whether AUC0-8hr or C8hr was a better predictor of efficacy or safety. In addition, the study found no significant relationship between boceprevir pharmacokinetics and SVR rates. However, there was a lower probability of anemia (hemoglobin level of 8.5–10 g/dL) with decreasing boceprevir pharmacokinetics, although this result was not significant for the coinfection study data alone.

The investigators concluded that overall boceprevir exposure was reduced in HCV/HIV coinfected patients compared to HCV monoinfected patients. However, reduced boceprevir exposure is unlikely to adversely influence the efficacy of treatment, given that the relationship between boceprevir pharmacokinetics and SVR rates was not significant. While reduced boceprevir exposure was associated with a reduced probability of anemia, ribavirin pharmacokinetic data were not collected in the coinfection study; for this reason, ribavirin cannot be eliminated as a confounding factor in the analysis. However, the coinfection study showed no relationship between boceprevir pharmacokinetics and ribavirin dose.

Reference

1. Wenning LA, Flexner C, Liu R, et al. Assessment of boceprevir (VICTRELIS™) pharmacokinetic/pharmacodynamic relationships for sustained viral response (SVR) and occurrence of anemia: results in HCV/HIV co-infected patients and in combined mono- and co-infected patients. Presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases; November 9–13, 2012; Boston, Massachusetts. Abstract #770.

 

ABSTRACT SUMMARY The Second-Generation HCV NS3/4a Protease Inhibitor MK5172 Retains Potent In Vitro Activity Against Boceprevir-Resistant Genotype 1 HCV Isolates

The second-generation HCV NS3/4A protease inhibitor MK5172 has demonstrated activity against multiple HCV genotypes and has been shown to significantly reduce HCV viral load in patients with genotype 1 HCV infection. At the 2012 AASLD meeting, a poster by Robert A. Ogert and coauthors presented data from a study that sought to confirm the activity of MK5172 against HCV isolates from patients who were clinically resistant to boceprevir.1 In this study, investigators amplified the NS3 gene of 13 different clinical isolates from patients who failed therapy with boceprevir plus peginterferon and ribavirin. The amplified NS3 genes were then tested against MK5172 using an in vitro, replicon-based, phenotypic assay. The resistant isolates were also tested against boceprevir, telaprevir, and simeprevir.

Six genotype 1a isolates and 8 genotype 1b isolates with boceprevir resistance-associated variants were grouped according to virologic response; there were 8 isolates from patients with incomplete virologic response (3 genotype1a, 5 genotype 1b), 4 isolates from patients who experienced virologic breakthrough (1 genotype 1a, 3 genotype 1b), 1 relapser (genotype 1a), and 1 nonresponder (genotype 1a). Viral load plots that indicated the presence of resistance-associated variants were presented based on these groupings.

Among patients with incomplete virologic response, the resistance-associated variants in genotype 1a isolates were V36M, T54S, R155K, R155K/T, and A156S, while the variants in genotype 1b isolates were T54A/S, T54A, V170A, T54S, and R155K. Among patients who experienced virologic breakthrough, the resistance-associated variant in the genotype 1a isolate was R155T, and the resistance-associated variants in the genotype 1b isolates were V55A, T54A, V170A, and M175L. The variants present in the genotype 1a patient who relapsed were T54S and R155K, while the patient who was a nonresponder had V36M and R155K variants.

The isolates from genotype 1a patients who failed boceprevir-based therapy were resistant to boceprevir, telaprevir, and simeprevir in vitro. As compared to baseline isolates, there
was an 8–13-fold (boceprevir), 18–36-fold (telaprevir), and greater than 10-fold (simeprevir) shift in IC50 from baseline. However, the boceprevir failure genotype 1a isolates that were resistant to boceprevir, telaprevir, and simeprevir were responsive to MK5172 (IC50, 0.6 nM–4.4 nM).

The isolates from genotype 1b patients who failed boceprevir were resistant to boceprevir (2.7-fold shift in IC50) and telaprevir (2.8-fold shift in IC50) compared to baseline isolates. In contrast to the boceprevir failure genotype 1a isolates, the majority of genotype 1b isolates remained sensitive to simeprevir. Similar to the boceprevir failure genotype 1a isolates, the boceprevir failure genotype 1b isolates were sensitive to MK5172 (IC50, 0.04 nM–0.25 nM) and had a greater than 2-fold shift in IC50 from baseline. The investigators noted that further studies are under way, including a clonal sequence analysis and deep sequencing of select patient samples.

Reference

1. Ogert RA, Black S, Chase R, et al. MK5172, a potent second-generation HCV NS3/4A protease inhibitor, retains potent in vitro activity against a panel of boceprevir-resistant HCV G1A and G1B patient isolates. Presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases; November 9–13, 2012; Boston, Massachusetts. Abstract #1724.

 

ABSTRACT SUMMARY OPTIMIZE Trial Shows Noninferiority of Twice-Daily Telaprevir Compared to 3-Times-Daily Administration 

At the 2012 AASLD meeting, Maria Buti and associates presented the results of the OPTIMIZE trial, the first phase III clinical trial comparing twice-daily administration of telaprevir versus administration every 8 hours.1 The primary endpoint of the study was noninferiority in SVR12 rates for twice-daily versus every-8-hour dosing of telaprevir in combination with peginterferon and ribavirin.

A total of 740 treatment-naïve patients with genotype 1 HCV infection were randomized to receive 12 weeks of peginterferon (180 µg/week) and ribavirin (1,000–1,200 mg/day) plus telaprevir at 1 of 2 doses: either 750 mg every 8 hours or 1,125 mg every 12 hours. All patients then received peginterferon and ribavirin without telaprevir for an additional 12 or 36 weeks; the total treatment duration was 24 or 48 weeks. Administration of telaprevir was halted if HCV RNA levels were greater than 1,000 IU/mL at Week 4 or if HCV RNA levels were at or above 25 IU/mL at Weeks 12, 24, 32, or 40. Patients were followed until Week 72.

In terms of efficacy, twice-daily telaprevir was found to be noninferior to telaprevir administered every 8 hours (SVR12, 74% vs 73%, respectively; 95% CI, –4.9 to 12). A subgroup analysis according to liver fibrosis status and IL-28B genotype also demonstrated similar SVR12 rates for both dosing regimens. Among cirrhotic patients, SVR12 rates were 54% for patients who received telaprevir at a dose of 1,125 mg twice daily versus 49% for those who received telaprevir at a dose of 750 mg every 8 hours. In noncirrhotic patients, SVR12 rates were 78% and 77% for twice-daily versus every-8-hour dosing of telaprevir, respectively. In addition, rapid virologic response (RVR) rates were similar for both dosing regimens (69% and 67%, respectively). In patients who achieved RVR, SVR rates were 86% and 85% for twice-daily versus every-8-hour dosing of telaprevir; in patients who did not achieve RVR, the SVR rate was 47% with either dosing regimen. Relapse rates were 8% for patients who received 1,125 mg of telaprevir twice daily and 7% for patients who received 750 mg of telaprevir every 8 hours. Both dosing regimens had an on-treatment virologic failure rate of 10%.

The safety and tolerability of telaprevir were similar for patients dosed at 1,125 mg twice daily versus 750 mg every 8 hours. The most common adverse events in both groups were fatigue, pruritus, anemia, nausea, rash, and headache. Serious adverse events occurred in 8–9% of patients. Treatment discontinuation due to adverse events occurred in 15% of patients who received 1,125 mg of telaprevir twice daily and 19% of patients who received 750 mg of telaprevir every 8 hours. Since the safety profiles and SVR rates were similar for both treatment arms, Buti and colleagues concluded that telaprevir dosed at 1,125 mg twice daily plus peginterferon and ribavirin could offer a safe, effective, and simplified treatment option for patients with genotype 1 HCV infection.

Reference

1. Buti M, Agarwal K, Horsmans Y, et al. OPTIMIZE trial: noninferiority of twice daily telaprevir versus administration every 8 hours in treatment-naïve, genotype-1 HCV-infected patients. Presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases; November 9–13, 2012; Boston, Massachusetts. Abstract #LB-8.

 

ABSTRACT SUMMARY Treatment of Genotype 1 HCV–Infected Patients with Severe Fibrosis or Compensated Cirrhosis: The International Telaprevir Early Access Program

HEP3002 is an ongoing, international, early-access program for genotype 1HCV–infected patients with severe fibrosis or compensated cirrhosis. At the 2012 AASLD meeting, Massimo Colombo and coworkers presented a poster with interim results from this study.1 Overall, the study has enrolled more than 1,900 telaprevir-treated patients from 16 countries; the first 609 patients were included in this interim analysis.

Enrollment criteria included genotype 1 HCV infection, severe fibrosis or compensated cirrhosis (Metavir score of F3 or F4), and a platelet count over 90,000 cells/mm3. The mean age of the patients was 53.5 years, 66.5% of the patients were male, and 97.7% were white. In addition, 66% of patients had HCV RNA levels of at least 800,000 IU/mL, 45% of patients had severe fibrosis, 55% had cirrhosis, and 28% had genotype 1a HCV infection. At baseline, 20% of patients were treatment-naïve, 28% were prior relapsers, 15% were partial prior responders, 29% were prior null responders, 3% were nonresponders for unspecified reasons, and 5% had prior viral breakthrough.

Patients were treated with telaprevir (750 mg every 8 hours) plus peginterferon and ribavirin for 12 weeks. Peginterferon and ribavirin were then administered for an additional 12–36 weeks using a response-guided treatment paradigm. At Week 4, 54% of patients had undetectable HCV RNA levels. By Week 12, 79% of patients had undetectable HCV RNA levels. The percentage of patients who showed an HCV RNA response at Week 12 was lower for prior null responders (73%) than for prior relapsers or treatment-naïve patients (85% for both groups).

Grade 1–4 anemia developed in 59% of patients (n=359), with 31% of patients experiencing severe anemia. Grade 1–4 rash developed in 42% of patients, with severe rash occurring in 4% of patients. Discontinuation due to adverse events occurred in 14% of patients (11.7% of patients with F3 fibrosis and 15.8% of patients with F4 fibrosis). Reasons for discontinuation included rash (4.9%), anemia (3.1%), asthenia (1.1%), abdominal pain (1.0%), nausea (1%), pruritus (1%), and vomiting (1%). The investigators noted that the rates of discontinuation for rash and anemia were similar to those observed in the phase III registration trials for telaprevir. Three cirrhotic patients (0.5%) died during the peginterferon and ribavirin phase of therapy due to hepatic failure/ischemic colitis and multiorgan failure; 1 of these deaths was deemed to be treatment-related, and 1 death was possibly treatment-related.

Reference

1. Colombo M, Fernandez I, Abdurakhmanov D, et al. Treatment of hepatitis C genotype 1 patients with severe fibrosis or compensated cirrhosis: the international telaprevir early access program. Presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases; November 9–13, 2012; Boston, Massachusetts. Abstract #LB-15.

 

High Rate of SVR with the All-Oral Combination of Daclatasvir Plus Sofosbuvir with or without Ribavirin

The introduction of oral agents that can effectively treat HCV infection will offer new treatment options for patients. The first-in-class NS5A replication complex inhibitor daclatasvir and the nucleotide analogue NS5B inhibitor sofosbuvir are direct-acting antiviral agents that can be administered orally.1-4 Previous studies have shown that administration of daclatasvir and sofosbuvir in combination with peginterferon and ribavirin can achieve high SVR rates in treatment-naïve patients with genotype 1 HCV infection.5,6 In a late-breaking abstract presented at the 2012 AASLD meeting, Mark S. Sulkowski presented the results of a parallel-group, open-label study that investigated interferon-free regimens consisting of daclatasvir plus sofosbuvir with and without ribavirin in treatment-naïve patients with chronic HCV infection.7

This study enrolled a total of 88 HCV-infected patients without cirrhosis: 44 patients were infected with genotype 1 HCV (73% genotype 1a), and 44 patients were infected with genotype 2 or 3 HCV (52% genotype 2 and 41% genotype 3). The mean HCV RNA level was at least 6.2 log10 IU/mL in all treatment groups. Patients’ mean age was 50–56 years, 54% of patients were male, 32% had IL-28B genotype CC, and 65% had a Metavir score of F2 or greater.

Patients were randomized 1:1:1 to receive 1 of 3 regimens: (1) sofosbuvir for 7 days, followed by daclatasvir and sofosbuvir for 23 weeks; (2) daclatasvir and sofosbuvir for 24 weeks; or (3) daclatasvir and sofosbuvir plus ribavirin for 24 weeks. During the study, the protocol was amended to include an additional 82 patients with genotype 1 HCV infection who received daclatasvir and sofosbuvir with or without ribavirin for 12 weeks. Daclatasvir (60 mg) and sofosbuvir (400 mg) were administered orally. Patients with genotype 1 HCV infection received 1,000–1,200 mg/day of ribavirin, while patients with genotype 2 or 3 HCV infection received 800 mg/day of ribavirin. The primary endpoint of the study was SVR12, which was defined as an HCV RNA level less than 25 IU/mL 12 weeks after the end of treatment. SVR4 rates were also assessed.

Plasma HCV RNA levels were measured using the Roche COBAS TaqMan Version 2.0, which has a lower limit of quantitation of 25 IU/mL and a limit of detection less than 10 IU/mL. Population sequencing was used to evaluate resistance-associated variants. Viral breakthrough was confirmed by an HCV RNA increase of at least 1 log10 IU/mL from nadir or an HCV RNA level at or above the lower limit of quantitation at Week 8.

Analysis of patients with genotype 2 or 3 HCV infection showed that both SVR4 and SVR12 were achieved by 91% of patients (40/44). Among the 4 patients infected with genotype 2 or 3 HCV who did not achieve SVR12, 1 patient relapsed at post-treatment Week 4 due to a pre-existing NS5A-A30K polymorphism, 2 patients were lost to follow-up, and 1 patient added peginterferon and ribavirin according to the protocol.

Among the 82 patients with genotype 1 HCV infection who were treated with daclatasvir and sofosbuvir with or without ribavirin for 12 weeks, 95–98% had confirmed undetectable levels of HCV RNA. At the time of this AASLD presentation, 68 of the 82 patients had reached post-treatment Week 12, and all had achieved SVR12. There were no confirmed virologic relapses in the 12-week treatment arm at either post-treatment Week 4 or post-treatment Week 12.

Among patients with genotype 1 HCV infection who were in the 24-week treatment arms, all 44 patients had undetectable HCV RNA levels at the end of treatment (100% SVR4 and 100% SVR12). Forty-three of these 44 patients (93%) achieved SVR24. One patient who had a history of injection drug use developed viremia at SVR24, but further analysis of the patient’s clinical history and physical examination and a comparison of viral sequences between baseline and post-treatment Week 24 suggested that this viremia was due to reinfection rather than a viral relapse. Almost all of the patients who reached post-treatment Week 24 achieved SVR24 (39/40 of genotype 1 patients and 41/43 of genotype 2 or 3 patients). The investigators did not detect a difference in response due to genotype 1 HCV subtype, IL-28B genotype, or the presence/absence of ribavirin in the treatment regimen.

The most common adverse events observed in this study were fatigue (range, 29–50%), headache (range, 16–38%), and nausea (range, 16–32%). Grade 3/4 adverse events occurred in 0% of patients in the group treated with a sofosbuvir lead-in followed by 23 weeks of daclatasvir and sofosbuvir, 14% of patients treated for 24 weeks with daclatasvir and sofosbuvir, 7% of patients treated for 24 weeks with daclatasvir and sofosbuvir plus ribavirin, 2% of patients treated for 12 weeks with daclatasvir and sofosbuvir, and 2% of patients treated for 12 weeks with daclatasvir and sofosbuvir plus ribavirin. Anemia was the most common grade 3/4 laboratory anomaly, but it only occurred in patients treated with ribavirin (n=6 patients [21%] in the 24-week daclatasvir and sofosbuvir plus ribavirin group; n=5 patients [12%] in the 12-week daclatasvir and sofosbuvir plus ribavirin group). One patient in the 24-week daclatasvir and sofosbuvir group and 1 patient in the 24-week daclatasvir and sofosbuvir plus ribavirin group discontinued treatment due to adverse events.

In summary, patients treated with daclatasvir and sofosbuvir achieved high SVR rates regardless of HCV genotype or whether ribavirin was included in the treatment regimen. Genotype 1 HCV–infected patients treated for 12 weeks achieved an SVR4 rate of 96%, and genotype 1 HCV–infected patients treated for 24 weeks achieved an SVR24 rate of 98%. Patients infected with genotype 2 or 3 HCV achieved an SVR24 rate of 93%. Patient responses did not change with genotype 1 HCV subtype, IL-28B genotype, or the addition of ribavirin. Overall, this treatment regimen was well tolerated, with low hemoglobin levels observed only in patients who were treated with ribavirin.

References

1. Gao M, Nettles RE, Belema M, et al. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature. 2010;465:96-100.

2. Nettles RE, Gao M, Bifano M, et al. Multiple ascending dose study of BMS-790052, a nonstructural protein 5A replication complex inhibitor, in patients infected with hepatitis C virus genotype 1. Hepatology. 2011;54:1956-1965.

3. Sofia MJ, Bao D, Chang W, et al. Discovery of a β-d-2’-deoxy-2’-α-fluoro-2’-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus. J Med Chem. 2010;53:7202-7218.

4. Lam AM, Espiritu C, Bansal S, et al. Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus. Antimicro Agents Chemother. 2012;56:3359-3368.

5. Kowdley K, Lawitz E, Crespo I, et al. 1 ATOMIC: 97% RVR for PSI-7977 + PEG/RBV × 12 week regimen in HCV GT1: an end to response-guided therapy? J Hepatol. 2012;56 (Suppl 2):S1.

6. Pol S, Ghalib RH, Rustgi VK, et al. Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: a randomised, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial. Lancet Infect Dis. 2012;12:671-677.

7. Sulkowski M, Gardiner DF, Rodriguez-Torres M, et al. High rate of sustained virologic response with the all-oral combination of daclatasvir (NS5A inhibitor) plus sofosbuvir (nucleotide NS5B inhibitor), with or without ribavirin, in treatment-naïve patients chronically infected with HCV genotype 1, 2, or 3. Presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases; November 9–13, 2012; Boston, Massachusetts. Abstract #LB-2.

 

An Interferon-Free, Ribavirin-Free 12-Week Regimen of Daclatasvir, Asunaprevir, and BMS-791325 Achieved High SVR4 Rates

Previous preliminary studies revealed that 24 weeks of treatment with daclatasvir (an NS5A replication complex inhibitor) and asunaprevir (an NS3 protease inhibitor) is an effective treatment option for prior null responders who are infected with genotype 1b HCV but not for those infected with genotype 1a HCV.1,2 In an effort to enhance virologic response, improve efficacy in difficult-to-treat patient populations, and shorten treatment durations, Gregory T. Everson and colleagues assessed a peginterferon-free, ribavirin-free regimen of 3 direct-acting antiviral agents with different mechanisms of action: daclatasvir, asunaprevir, and BMS-791325 (a selective non-nucleoside NS5B polymerase inhibitor).3

This phase IIa, open-label study enrolled noncirrhotic treatment-naïve patients who were infected with genotype 1 HCV and had baseline HCV RNA levels above 105 IU/mL. In part 1 of the study, 32 patients were randomized 1:1 to receive asunaprevir (200 mg twice daily), daclatasvir (60 mg once daily), and BMS-791325 (75 mg twice daily) for either 24 weeks (group 1) or 12 weeks (group 2). In part 2 of the study, patients were randomized to the same treatment regimens but received a higher dose of BMS-791325 (150 mg twice daily). Part 1 and part 2 of the study were sequentially enrolled, with enrollment in part 2 being delayed until data were collected from part 1 of the study. The primary endpoint of the study was an undetectable level of HCV RNA (below the lower limit of quantitation of 25 IU/mL) at post-treatment Week 12.

At the 2012 AASLD meeting, Everson presented interim data from part 1 of this study; endpoints for this interim analysis were SVR4 rates for patients who received 24 weeks of treatment and SVR12 rates for those who received 12 weeks of treatment.4 Baseline patient characteristics were similar for patients in the 12-week and 24-week treatment arms in part 1 of the study. The median age of the 32 patients in part 1 of the study was 48 years, 53% of patients were male, 75% were white, and the mean baseline HCV RNA level was 6.26 log10 IU/mL. By study design, 75% of these patients were infected with genotype 1a HCV. The majority of patients (72%) had a non-CC IL-28B genotype. Half the patients in this group had a Metavir fibrosis score of F0/F1, 44% had a score of F2/F3, and 6% had a score above F3; patients in the latter group were found to be noncirrhotic by liver biopsy.

In terms of viral kinetics, all patients in the 24-week treatment group showed a rapid decline in HCV viral load. By Week 4 of treatment, all patients (32/32) had HCV RNA levels below the lower limit of quantitation. HCV RNA levels remained undetectable through post-treatment Week 4. Similarly, patients in the 12-week treatment arm experienced a sharp decline in HCV RNA levels, and all patients in this group had viral loads below the limit of detection at post-treatment Week 12.

At treatment Week 12, 94% of patients in the 24-week treatment arm and 88% of patients in the 12-week treatment arm had undetectable HCV RNA levels. At the end of therapy, these rates were 94% and 100%, respectively. The SVR4 rate was 94% for both the 24-week and 12-week treatment arms. The SVR12 rate in the 12-week treatment arm was also 94%. In a subgroup analysis of patients with genotype 1a HCV infection, 92% of patients in the 24-week treatment arm and 100% of patients in the 12-week treatment arm achieved SVR4. Everson highlighted the fact that a high SVR rate was achieved even though many of the patients in this study had a non-CC IL-28B genotype and/or a high viral load.

Overall, treatment with daclatasvir, asunaprevir, and BMS-791325 was well tolerated. No patients discontinued treatment due to adverse events. The most common adverse events were headache (31%), diarrhea (25%), and asthenia (16%). There was 1 serious adverse event (renal calculus), but it was found to be unrelated to the treatment regimen. One patient in the 12-week treatment group experienced a grade 3/4 headache, which resolved, and 1 patient had grade 3/4 lymphopenia at a single study visit, which occurred at a time when the patient had influenza. There were no grade 3/4 elevations in ALT, aspartate aminotransferase, or bilirubin levels.

Based on the interim data presented at the 2012 AASLD meeting, Everson and associates concluded that 12 weeks of therapy with the direct-acting antiviral agents daclatasvir, asunaprevir, and BMS-791325 was well tolerated. In addition, both 12 weeks and 24 weeks of treatment resulted in high SVR rates for patients infected with genotype 1 HCV, including patients with high viral loads and/or non-CC IL-28B genotypes. Everson noted that this treatment is promising and will continue to be evaluated in the future. This trial is currently being expanded to include null responders, treatment-experienced patients, and patients with advanced fibrosis.

References

1. Gao M, Nettles RE, Belema M, et al. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature. 2010;465:96-100.

2. McPhee F, Sheaffer AK, Friborg J, et al. Preclinical profile and characterization of the hepatitis C virus NS3 protease inhibitor asunaprevir (BMS-650032). Antimicrob Agents Chemother. 2012;56:5387-5396.

3. Kadow JF, Gentles R, Ding M, et al. Discovery of BMS-791325, an allosteric NS5B replicase inhibitor for the treatment of hepatitis C. Presented at the 243rd American Chemical Society National Meeting; March 25–29, 2012; San Diego, California. MEDI 23.

4. Everson G, Sims KD, Rodriguez-Torres M, et al. An interferon-free, ribavirin-free 12-week regimen of daclatasvir (DCV), asunaprevir (ASV), and BMS-791325 yielded SVR4 of 94% in treatment-naïve patients with genotype (GT) 1 chronic hepatitis C virus (HCV) infection. Presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases; November 9–13, 2012; Boston, Massachusetts. Abstract #LB-3.

 

Commentary

Fred Poordad, MD 

University of San Antonio Health Science Center

San Antonio, Texas

Several presentations at the 2012 meeting of the American Association for the Study of Liver Diseases (AASLD) focused on the management of hepatitis C virus (HCV) infection. Multiple treatment options are coming to the forefront.

Poordad, et al presented results from the Anemia Management Study, which examined whether sustained virologic response (SVR) rates are affected by the timing and magnitude of ribavirin dose reduction in HCV patients receiving boceprevir plus peginterferon and ribavirin.1 Management of anemia was attempted through ribavirin dose reduction or erythropoietin (EPO). The importance of this study is that it is the only prospective randomized trial to assess the effect of EPO on SVR using a protease inhibitor. It conclusively showed that there was no benefit to using EPO over ribavirin dose reduction as the initial management strategy. Moreover, it suggested that there are potential safety signals, with 11 thromboembolic events in the EPO arm compared to 1 event in the ribavirin dose-reduction arm. This study also highlights the fact that when patients are anemic, ribavirin can be dose-adjusted to whatever degree is necessary, as long as there is maintenance of at least 50% of the overall dose throughout the duration of treatment in order to not impact SVR.

One of the most important abstracts at this year’s AASLD meeting has set a new bar for expectations in treating null responders. Kowdley, et al reported results from a 12-week trial of different combinations of 4 drugs: ritonavir-boosted ABT-450, a protease inhibitor; ABT-267, an NS5A inhibitor; ABT-333, a non-nucleoside polymerase inhibitor; and ribavirin.2 In only 12 weeks, the various combinations of these agents achieved an SVR of up to 98% in treatment-naïve patients and of 93% in a null responder population. This SVR rate is the highest achieved in a null responder population using an all-oral regimen, and it has established the expectation that it is possible to achieve greater than 90% SVR rates in both treatment-naïve and treatment-experienced patients using an all-oral regimen. The limitation to this finding is that there were no cirrhotic patients in this study, and therefore their response to these regimens is unknown.

Sulkowski, et al presented results from a trial that examined daclatasvir, a first-in-class NS5A replication complex inhibitor, combined with the nucleotide analogue NS5B inhibitor sofosbuvir.3 Both the 12-week and 24-week regimens of this combination achieved very high SVR rates in patients with HCV genotypes 1, 2, or 3. Although development of the daclatasvir/sofosbuvir combination will likely not proceed due to industry complications, this study provides a good proof of principle that the combination of a nucleoside analogue with an NS5A inhibitor can led to very high sustained response rates in a multigenotypic patient population. In so doing, this study sets the stage for the development of combinations using other drugs from these classes, such as GS-5885.

The combination of daclatasvir; asunaprevir, an NS3 protease inhibitor; and the relative newcomer BMS-791325, a selective non-nucleoside NS5B inhibitor in patients infected with genotype 1 HCV, was examined in a phase IIa study reported by Everson, et al.4 The combination was well tolerated and resulted in high SVR rates after 12 weeks and 24 weeks of treatment. This trial provided perhaps the most surprising data that emerged from the AASLD meeting because non-nucleoside agents are conventionally thought to have weak antiviral activity and yet BMS-791325 boosted sustained response rates up to 94%.

Poster presentations on HCV reported some interesting data. Wenning, et al presented results of a study that assessed boceprevir pharmacokinetics in patients coinfected with HCV and human immunodeficiency virus (HIV). Boceprevir exposure was reduced in patients with HCV and HIV compared to patients with HCV alone.5 The OPTIMIZE trial showed that twice-daily administration of telaprevir was as effective as administration 3 times daily among treatment-naïve patients with genotype 1 HCV infection.6

The Future of Hepatitis C Therapy

These trials give clinicians a snapshot of the future landscape, when there will be multiple all-oral regimens available with very high response rates that will allow treatment of a larger volume and breadth of patients. Patients who have failed interferon-based therapies or who are reluctant to receive them may now have other alternatives. These studies have the potential to broaden the range of patient types that can be treated in the future. In addition, phase III trials are examining regimens such as sofosbuvir and GS-5885 with or without ribavirin7 and ABT-450 with ritonavir, ABT-267, ABT-333, and ribavirin.8 Two new protease inhibitors, simeprevir and faldaprevir, are nearing the completion of phase III trials and will be coming to market in 2014.9,10 Clinicians may choose to delay initiation of treatment in certain patients as they anticipate the arrival of future therapies.

It should be noted, however, that research in this field is still early. Some of these regimens have not been tested in large enough numbers, and toxicities may derail some of the development programs. We need to be cautiously optimistic, but not declare that the game is over until it is truly over. Future research to improve the understanding of HCV therapy should focus on the response of the cirrhotic patient. A larger percentage of our population is developing advanced cirrhosis. We need to understand how drugs perform in these patients and determine whether different toxicities or increased resistance may arise. Research should also focus on patients who are considered nonresponsive to interferon, in order to ensure that we understand why it is that some regimens are apparently more effective than others.

The future of hepatitis C therapy is very bright, with multiple treatment options coming to the forefront. These choices will add to the complexity of selecting the best course of management for these patients. Every 6 months, there seems to be a substantial amount of new information that changes our understanding of hepatitis C therapy and propels treatment forward. Clinicians should keep an eye toward the future and the next major international meeting, where our focus may be somewhat readjusted as we fine-tune our understanding of this therapeutic area.

References

1. Poordad F, Lawitz E, Reddy K, et al. Timing and magnitude of ribavirin dose reduction (RBV DR) do not impact sustained virologic response (SVR) rates with boceprevir (BOC) + peginterferon alfa-2b / ribavirin (P/RBV) in the Anemia Management Study in chronic HCV genotype 1 patients. Presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases; November 9–13, 2012; Boston, Massachusetts. Abstract #154.

2. Kowdley K, Lawitz E, Poordad F, et al. A 12-week interferon-free treatment regimen with ABT-450/r, ABT-267, ABT-333 and ribavirin achieves SVR12 rates (observed data) of 99% in treatment-naïve patients and 93% in prior null responders with HCV genotype1 infection. Presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases; November 9–13, 2012; Boston, Massachusetts. Abstract #LB-1.

3. Sulkowski M, Gardiner DF, Rodriguez-Torres M, et al. High rate of sustained virologic response with the all-oral combination of daclatasvir (NS5A inhibitor) plus sofosbuvir (nucleotide NS5B inhibitor), with or without ribavirin, in treatment-naïve patients chronically infected with HCV genotype 1, 2, or 3. Presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases; November 9–13, 2012; Boston, Massachusetts. Abstract #LB-2.

4. Everson G, Sims KD, Rodriguez-Torres M, et al. An interferon-free, ribavirin-free 12-week regimen of daclatasvir (DCV), asunaprevir (ASV), and BMS-791325 yielded SVR4 of 94% in treatment-naïve patients with genotype (GT) 1 chronic hepatitis C virus (HCV) infection. Presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases; November 9–13, 2012; Boston, Massachusetts. Abstract #LB-3.

5. Wenning LA, Flexner C, Liu R, et al. Assessment of boceprevir (VICTRELIS™) pharmacokinetic/pharmacodynamic relationships for sustained viral response (SVR) and occurrence of anemia: results in HCV/HIV co-infected patients and in combined mono- and co-infected patients. Presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases; November 9–13, 2012; Boston, Massachusetts. Abstract #770.

6. Buti M, Agarwal K, Horsmans Y, et al. OPTIMIZE trial: noninferiority of twice daily telaprevir versus administration every 8 hours in treatment-naïve, genotype-1 HCV-infected patients. Presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases; November 9–13, 2012; Boston, Massachusetts. Abstract #LB-8.

7. www.ClinicalTrials.gov. Safety and efficacy of sofosbuvir/GS-5885 fixed-dose combination (FDC) +/-ribavirin for the treatment of HCV. http://www.clinicaltrials.gov/ct2/show/NCT01701401?term=sofosbuvir+and+GS-5885&rank=2. Identifier: NCT01701401.

8. www.ClinicalTrials.gov. A study of ABT-450 with ritonavir and ABT-267 and/or ABT-333 with and without ribavirin in genotype 1 HCV infected subjects. http://www.clinicaltrials.gov/ct2/show/NCT01464827?term=direct+acting+antivirals+with+and+without+ribavirin&rank=3. Identifier: NCT01464827.

9. www.ClinicalTrials.gov. TMC435-TiDP16-C216 – phase III trial of TMC435 in treatment-naive, genotype 1 hepatitis C-infected patients (QUEST-2). http://www.clinicaltrials.gov/ct2/show/NCT01290679?term=TMC435+phase+III&rank=2. Identifier: NCT01290679.

10. www.ClinicalTrials.gov. Efficacy and safety of BI 201335 (faldaprevir) in combination with pegylated interferon-alpha and ribavirin in treatment-naïve genotype 1 hepatitis C infected patients (STARTverso 2). http://www.clinicaltrials.gov/ct2/show/NCT01343888?term=BI+201335+phase+III&rank=4. Identifier: NCT01343888.

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