You are here

  • Home
  • Archive
  • Volume 64, Issue 6
  • Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection: a randomised study

Article Text

Article menu
Hepatology
Original article
Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection: a randomised study
  1. Christophe Hézode1,
  2. Gideon M Hirschfield2,
  3. Wayne Ghesquiere3,
  4. William Sievert4,
  5. Maribel Rodriguez-Torres5,
  6. Stephen D Shafran6,
  7. Paul J Thuluvath7,
  8. Harvey A Tatum8,
  9. Imam Waked9,
  10. Gamal Esmat10,
  11. Eric J Lawitz11,
  12. Vinod K Rustgi12,
  13. Stanislas Pol13,
  14. Nina Weis14,
  15. Paul J Pockros15,
  16. Marc Bourlière16,
  17. Lawrence Serfaty17,
  18. John M Vierling18,
  19. Michael W Fried19,
  20. Ola Weiland20,
  21. Maurizia R Brunetto21,
  22. Gregory T Everson22,
  23. Stefan Zeuzem23,
  24. Paul Y Kwo24,
  25. Mark Sulkowski25,
  26. Norbert Bräu26,
  27. Dennis Hernandez27,
  28. Fiona McPhee27,
  29. Megan Wind-Rotolo28,
  30. Zhaohui Liu29,
  31. Stephanie Noviello28,
  32. Eric A Hughes28,
  33. Philip D Yin27,
  34. Steven Schnittman27
  1. 1Hôpital Henri Mondor, AP-HP, Université Paris-Est, Inserm U955, Créteil, France
  2. 2Centre for Liver Research and NIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK
  3. 3Vancouver Island Health Authority & University of British Columbia, Victoria, British Columbia, Canada
  4. 4Monash University and Monash Health, Melbourne, Australia
  5. 5Fundacion De Investigacion, San Juan Bautista School of Medicine, San Juan, Puerto Rico
  6. 6University of Alberta Hospital, Edmonton, Canada
  7. 7Mercy Medical Center, Baltimore, Maryland, USA
  8. 8Options Health Research, LLC, Tulsa, Oklahoma, USA
  9. 9National Liver Institute, Shebin Elkom, Egypt
  10. 10Endemic Medicine and Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
  11. 11Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas, USA
  12. 12Metropolitan Research, Fairfax, Virginia, USA
  13. 13Inserm U1016 and Liver Unit, Université Paris Descartes, Hôpital Cochin, Paris, France
  14. 14Copenhagen University Hospital, Hvidovre, Denmark
  15. 15Scripps Clinic, La Jolla, California, USA
  16. 16Hôpital Saint Joseph, Marseille, France
  17. 17Hôpital Saint-Antoine, Paris, France
  18. 18Baylor College of Medicine, Houston, Texas, USA
  19. 19University of North Carolina, Chapel Hill, North Carolina, USA
  20. 20Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
  21. 21Hepatology Unit, University Hospital of Pisa, Pisa, Italy
  22. 22University of Colorado Denver, Aurora, Colorado, USA
  23. 23Goethe University, Frankfurt, Germany
  24. 24Indiana University, Indianapolis, Indiana, USA
  25. 25Johns Hopkins University, Baltimore, Maryland, USA
  26. 26James J. Peters VA Medical Center, Bronx, New York, USA
  27. 27Bristol-Myers Squibb, Clinical Research and Development, Wallingford, Connecticut, USA
  28. 28Bristol-Myers Squibb, Research and Development, Princeton, New Jersey, USA
  29. 29Bristol-Myers Squibb Research and Development, Hopewell, New Jersey, USA
  1. Correspondence to Dr Christophe Hézode, CHU Henri Mondor Service Hépato-Gastroentérologie, Unité C 13ème étage, 51 avenue du Maréchal de Lattre de Tassigny, Creteil Cedex 94010, France; christophe.hezode{at}hmn.aphp.fr

Abstract

Objective To evaluate the safety and efficacy of daclatasvir, an HCV NS5A inhibitor with pangenotypic activity, administered with peginterferon-alfa-2a/ribavirin.

Design In this Phase 2b double-blind, placebo-controlled study, treatment-naive adults with HCV genotype 1 (N=365) or 4 (N=30) infection were randomly assigned (2:2:1) to daclatasvir 20 mg or 60 mg, or placebo once daily plus weekly peginterferon-alfa-2a and twice-daily ribavirin. Daclatasvir recipients achieving protocol-defined response (PDR; HCV-RNA<lower limit of quantitation at Week 4 and undetectable at Week 10) were rerandomised at Week 12 to continue daclatasvir/peginterferon-alfa-2a/ribavirin for 24 weeks total duration or to placebo/peginterferon-alfa-2a/ribavirin for another 12 weeks. Patients without PDR and placebo patients continued peginterferon-alfa/ribavirin through Week 48. Primary efficacy endpoints were undetectable HCV-RNA at Weeks 4 and 12 (extended rapid virologic response, eRVR) and at 24 weeks post-treatment (sustained virologic response, SVR24) among genotype 1-infected patients.

Results Overall, eRVR was achieved by 54.4% (80/147) of genotype 1-infected patients receiving daclatasvir 20 mg, 54.1% (79/146) receiving 60 mg versus 13.9% (10/72) receiving placebo. SVR24 was achieved among 87 (59.2%), 87 (59.6%), and 27 (37.5%) patients in these groups, respectively. Higher proportions of genotype 4-infected patients receiving daclatasvir 20 mg (66.7%; 8/12) or 60 mg (100.0%; 12/12) achieved SVR24 versus placebo (50.0%; 3/6). A majority of daclatasvir-treated patients achieved PDR and experienced less virologic failure and higher SVR24 rates with a shortened 24-week treatment duration. Adverse events occurred with similar frequency across all treatment groups.

Conclusions The combination of daclatasvir/peginterferon-alfa/ribavirin was generally well tolerated and achieved higher SVR24 rates compared with placebo/peginterferon-alfa/ribavirin among patients infected with HCV genotype 1 or 4.

Trial registration number NCT01125189.

https://doi.org/10.1136/gutjnl-2014-307498

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Significance of this study

    What is already known on this subject?

    • Addition of a direct-acting antiviral agent to peginterferon and ribavirin improves rates of sustained virologic response among patients with chronic HCV infection.

    • Daclatasvir is an HCV NS5A inhibitor with picomolar potency and broad genotypic coverage.

    What are the new findings?

    • Daclatasvir combined with peginterferon and ribavirin increased sustained virologic response rates in patients infected with HCV genotype 1 and 4 compared with placebo plus peginterferon/ribavirin.

    • A high proportion of daclatasvir-treated patients with an early virologic response achieved sustained virologic response with a shortened 24-week treatment duration.

    • Daclatasvir was well tolerated with a similar adverse event profile to placebo.

    How might it impact on clinical practice in the foreseeable future?

    • Improve understanding of the efficacy and tolerability profile of daclatasvir in combination with peginterferon/ribavirin.

    • Supports further development of daclatasvir as a component of direct-acting antiviral-only regimens.

    Introduction

    It is estimated that up to 170 million individuals globally have chronic HCV infection,1–3 which is a common cause of chronic progressive liver disease and hepatocellular carcinoma.4 ,5 HCV has six main genotypes, of which genotype 1 is the most prevalent worldwide,1 ,6–8 while genotype 4 accounts for approximately 20% of infections.1 ,7 ,9 Genotype, together with viral load, patient demographics, disease history, and host genetics, is a key factor that influences treatment response; as such, individuals infected with genotype 1 are generally the most difficult to treat.8 ,10 ,11

    Treatments for chronic HCV infection are evolving; the current standard of care for genotype 1 chronic HCV infection comprises the protease inhibitor simeprevir, or the nucleotide NS5B polymerase inhibitor sofosbuvir, in combination with pegylated interferon (pegIFN) alfa and ribavirin (RBV).12–15 However, some challenges for physicians and patients remain, including the increased incidence of adverse events observed with these pegIFN alfa-based regimens. The recommended treatment for those infected with HCV genotype 4 is sofosbuvir plus pegIFN alfa/RBV.13–15

    The phosphoprotein, NS5A, plays an essential role in HCV replication, and is thus a key target for the development of direct-acting antiviral (DAA) agents. The high potency of NS5A inhibitors and their apparent multiple mechanisms of action, which do not overlap with other DAAs currently in development, suggest that they will be an important component of future HCV treatment regimens. Daclatasvir (BMS-790052) is an HCV NS5A inhibitor with picomolar potency, a pharmacokinetic profile that supports once-daily dosing, and broad genotypic coverage in vitro.16–18 Studies have demonstrated that daclatasvir exerts antiviral activity by blocking NS3 protease-mediated cleavage of the viral polyprotein; altering the subcellular localisation of NS5A; preventing NS5A hyperphosphorylation; and inhibiting the formation of viral replication complexes.17 ,19 ,20 Daclatasvir has demonstrated EC50 values in vitro of 50 pM and 9 pM against HCV genotype 1a and 1b replicons, respectively, and an EC50 of 12 pM against genotype 4.21

    A recent Phase 2a study, conducted in treatment-naive HCV genotype 1-infected patients, examined the efficacy and safety of daclatasvir (3, 10, or 60 mg) compared with placebo once daily, both in combination with pegIFN-alfa/RBV.22 High rates of extended rapid virologic response (eRVR) were observed in those individuals who received daclatasvir 10 and 60 mg doses (≈80% vs 8% with placebo). This translated into high rates of sustained virologic response (SVR), which were achieved by 83% of patients treated with daclatasvir 10 and 60 mg compared with 25% of patients receiving placebo.22 Daclatasvir plus pegIFN-alfa/RBV was well tolerated with an adverse event profile comparable to that of pegIFN-alfa/RBV alone.22 Although the efficacy of the 10 mg and 60 mg daclatasvir doses were comparable in this study, exposures in the 10 mg group overlapped with the subtherapeutic 3 mg group; thus, a 20 mg daclatasvir dose was selected for further evaluation.

    This Phase 2b clinical study (COMMAND-1) was designed to evaluate the safety and efficacy of daclatasvir administered in combination with pegIFN-alfa-2a/RBV to previously untreated patients infected with HCV genotypes 1 or 4.

    Methods

    Study design and patients

    This was a randomised, double-blind, placebo-controlled, Phase 2b clinical study of daclatasvir or placebo, in combination with pegIFN-alfa-2a/RBV, conducted in treatment-naive patients aged 18–70 years who had chronic HCV genotype 1 or 4 infection (ClinicalTrials.gov number, NCT01125189). Compensated cirrhotic patients infected with HCV genotype 1, and patients infected with HCV genotype 4, were each capped at 10% of randomised patients. Cirrhosis was confirmed by biopsy at any time prior to randomisation. For non-cirrhotic patients, a liver biopsy must have been obtained within 24 months prior to randomisation. Additional inclusion criteria included HCV-RNA ≥100 000 IU/mL and alanine aminotransferase (ALT) levels <5×upper limit of normal. Exclusion criteria included a history or evidence of hepatic decompensation, prior exposure to any agent with potential anti-HCV activity, coinfection with HBV or HIV, or evidence of chronic liver disease other than HCV.

    Patients were randomised 2:2:1 to receive either oral daclatasvir 20 mg or 60 mg or placebo once daily; all patients received pegIFN-alfa-2a administered subcutaneously at a dose of 180 µg per week and twice-daily RBV dosed orally according to bodyweight (<75 kg, 1000 mg daily; ≥75 kg, 1200 mg daily) (figure 1). At Week 12, all patients who received daclatasvir and achieved a protocol-defined response (PDR; HCV-RNA <lower limit of quantitation (LLOQ) at Week 4 and undetectable at Week 10) were rerandomised to continue daclatasvir plus pegIFN-alfa-2a/RBV at the previously assigned daclatasvir dose for a total duration of 24 weeks or to continue therapy with placebo in combination with pegIFN-alfa-2a/RBV for an additional 12 weeks. Patients who did not achieve a PDR received placebo plus pegIFN-alfa-2a/RBV between Weeks 12 and 24, and those initially assigned to placebo, received placebo plus pegIFN-alfa-2a/RBV until Week 24; both these populations then received an additional 24 weeks of pegIFN-alfa-2a/RBV alone, receiving a total of 48 weeks of therapy.

    Figure 1
    Figure 1

    Study design. Protocol-defined response (PDR), protocol-defined response: HCV-RNA <lower limit of quantitation at Week 4 and undetectable at Week 10. P/R, peginterferon alfa-2a and ribavirin.

    Patients were enrolled at 64 centres in North and Central America, Australia, North Africa and Europe, and were randomised during the screening period using a randomised block design stratified by HCV genotype 1 or 4 via an interactive voice response system (IVRS). At the Week 12 call, the IVRS determined whether the patient met PDR criteria, and rerandomised the patient, if appropriate. HCV-RNA values were blinded to patients and study sites. Patient randomisation was blinded to the study site and patient until the completion of the post-treatment Week 24 analyses. The sponsor was blinded to treatment assignment until the Week 12 interim analysis.

    The study was designed and conducted by the sponsor (Bristol-Myers Squibb) in collaboration with the principal investigators, was approved by the institutional review board at each participating site, and was conducted in compliance with the Declaration of Helsinki, Good Clinical Practice guidelines, and local regulatory requirements. Written informed consent was obtained from all patients. The sponsor collected the data, monitored study conduct, and performed the statistical analyses. All authors had access to the study data and have reviewed and approved the final manuscript.

    Efficacy assessments

    Plasma HCV-RNA was assessed using Roche COBAS TaqMan (LLOQ: 25 IU/mL; limit of detection: ≈10 IU/mL for genotype 1) and HCV genotype was determined by line probe assay (Siemens Versant HCV Genotype 2.0 Assay). IL28B genotype (rs12979860 single-nucleotide polymorphism) was determined using a Taqman genotyping assay (Applied Biosystems, Carlsbad, California, USA) for those patients who consented to a separate pharmacogenomics analysis.

    The coprimary efficacy endpoints were the proportion of HCV genotype 1-infected patients with eRVR (undetectable HCV-RNA at Weeks 4 and 12) and with SVR at post-treatment Week 24 (SVR24; undetectable HCV-RNA at post-treatment Week 24). Secondary efficacy endpoints included rapid virologic response (RVR; undetectable HCV-RNA at Week 4), complete early virologic response (cEVR; undetectable HCV-RNA at Week 12), end-of-treatment response (EOTR; undetectable HCV-RNA at end of treatment), and SVR at post-treatment Week 12 (SVR12: undetectable HCV-RNA at post-treatment Week 12).

    Patients discontinued study treatment for futility based on one of four criteria. Patients who experienced virologic breakthrough (>1 log10 increase in HCV-RNA over nadir level, or HCV-RNA ≥LLOQ after confirmed undetectable HCV-RNA), or those who had a <1 log10 decrease in HCV-RNA from baseline at Week 4, discontinued placebo/daclatasvir but could continue pegIFN-alfa-2a/RBV for a total of 48 weeks at the discretion of the investigator. Patients who failed to achieve early virologic response (<2 log10 decrease in HCV-RNA and ≥LLOQ at Week 12) or had HCV-RNA ≥LLOQ at Week 24 discontinued all study therapy.

    Resistance analyses were performed on all baseline samples and all on-treatment or follow-up samples with HCV-RNA ≥1000 IU/mL. Consensus sequences of the NS5A region were generated from clinical samples and compared with reference strains. Clonal analyses (≥20 clones) were performed to determine minority species and confirm linkage.

    Safety assessments

    The safety of daclatasvir was assessed by the frequencies of adverse events, serious adverse events, and discontinuations due to adverse events, which were monitored through post-treatment Week 4. Serious adverse events considered to be related to study therapy were monitored up to the end of the study. Vital signs and clinical laboratory abnormalities were recorded throughout the treatment period to post-treatment Week 4. Electrocardiogram assessments were made at screening, Weeks 4 and 12, and at the end of treatment.

    Statistical analysis

    Efficacy analyses were provided separately for HCV genotypes 1 and 4. The proportions of patients with antiviral efficacy endpoints were summarised by treatment regimen using a modified intention-to-treat (mITT) analysis, where the denominator equals the number of all treated patients, and observed values where the denominator was based on patients with available measurements at the analysis week. Response rates and 80% CIs were presented by treatment regimen using mITT and observed values, with CIs based on the normal approximation to the binomial distribution. Safety analyses combined data across HCV genotypes 1 and 4.

    A target sample size of 160 patients per daclatasvir treatment arm was calculated to detect, with 80% probability, a safety event occurring at an incident rate of 1%. A target sample size of 144 genotype-1 patients per daclatasvir arm and 72 patients in the placebo arm was estimated to provide 90% power to infer that at least 1 dose of daclatasvir had antiviral activity 35% greater than placebo, as assessed by the proportion of subjects with eRVR; this is inferred if the lower bound of the 80% CI for the difference (daclatasvir–placebo) is >35%. The target sample size also provides 82% power to infer that at least one dose of daclatasvir is superior to placebo as assessed by SVR24; superiority is inferred if the lower bound of the 80% CI for the difference (daclatasvir–placebo) is >0%.

    Results

    Patient disposition and demographics

    A total of 558 patients were assessed for eligibility. Of these, 395 were randomly assigned to one of three treatment groups and received at least one dose of study drug between July 2010 and the end of the study in August 2012, comprising the intention-to-treat population (see online supplementary figure S1). Following randomisation, 159 patients were assigned to the daclatasvir 20 mg group, 158 patients to the daclatasvir 60 mg group, and 78 patients to the placebo group.

    Baseline characteristics were similar across all treatment groups (table 1), with patients in all groups being predominantly white and male, with a median age of approximately 50 years. The majority of HCV genotype 1-infected patients were subtype 1a (72–78%); 7–8% of patients were infected with HCV genotype 4. Approximately two-thirds of patients had a non-CC IL28B genotype, which has been associated with decreased SVR rates with pegIFN-alfa/RBV-based regimens.23 Patients with compensated cirrhosis accounted for 5–10% of each arm.

    View this table:
    Table 1

    Baseline demographic and disease characteristics

    One hundred and twelve patients (70%) receiving daclatasvir 20 mg, and 116 patients (73%) receiving daclatasvir 60 mg, achieved a PDR. In accordance with the study design, these patients were rerandomised 1:1 to receive a total of 24 weeks’ therapy. Among the 228 daclatasvir-treated patients who achieved a PDR and were rerandomised, 215 (94%) completed treatment; whereas, among the 89 patients who did not achieve PDR, 36 (40%) completed treatment. Reasons for treatment discontinuation among patients achieving PDR were adverse events (8 patients), loss to follow-up (2 patients), poor adherence, patient request, or other (1 patient each). For patients not achieving PDR, most discontinuations were related to lack of efficacy (33 patients), adverse events (7 patients), withdrawn consent (4 patients), or patient requests (3 patients). Of the 78 patients who received placebo, 37 (47%) completed treatment; common reasons for treatment discontinuation included lack of efficacy (25 patients), adverse events (8 patients), and patient request (4 patients).

    HCV genotype 1-infected patients

    Virologic response

    For the coprimary efficacy endpoint of eRVR, higher response rates were achieved in patients receiving both daclatasvir doses in combination with pegIFN-alfa/RBV compared with patients who received placebo plus pegIFN-alfa/RBV, although statistical significance was not reached (table 2 and figure 2A). SVR24 was achieved by 59% and 60% of patients in the daclatasvir 20 mg and 60 mg arms, respectively, compared with 38% of patients in the placebo arm. SVR24 rates with both doses of daclatasvir were superior to placebo as the lower bound of the 80% CIs for the difference (daclatasvir–placebo) was >0%. A higher proportion of daclatasvir-treated patients also achieved the secondary endpoints of RVR, cEVR, EOTR and SVR12 when compared with patients who received placebo. All response rates were comparable between the 20 mg and 60 mg daclatasvir doses. SVR24 based on <LLOQ versus undetectable HCV-RNA were slightly higher among patients receiving daclatasvir 60 mg (62% vs 59%; figure 2A); no differences were noted for the other treatment groups. A consistently higher proportion of patients infected with genotype 1b achieved SVR24 compared with those infected with genotype 1a—SVR24 rates among daclatasvir-treated genotype-1b patients were 76–77% compared with 55–57% for genotype-1a patients (figure 2A). Similarly, a PDR was achieved by a greater proportion of genotype-1b patients receiving daclatasvir (85% (61/72) vs 67% (147/219) for genotype 1a; table 3); however, SVR24 rates among patients achieving a PDR were high (approximately 75%) and comparable, regardless of the duration of daclatasvir therapy or subtype (genotype 1a: 73% (107/147) vs genotype 1b: 79% (48/61); table 3). Among patients who did not achieve PDR, SVR24 rates were 24% (10/42) in those initially receiving daclatasvir 20 mg and 20% (8/41) in those receiving daclatasvir 60 mg. In genotype 1-infected patients with viral load ≥800 000 IU/mL at baseline, SVR24 was achieved by 57% (72/127) of patients in the daclatasvir 20 mg cohort, and 56% (67/120) in the 60 mg daclatasvir group, compared with 31% (18/58) of patients receiving pegIFN-alfa/RBV; SVR24 rates for those with baseline HCV-RNA levels <800 000 were 75% (15/20), 77% (20/26), and 64% (9/14), respectively. Among the small number of patients with cirrhosis at baseline, SVR24 was achieved by approximately 60% of patients who received daclatasvir 20 mg (8/13) or 60 mg (5/8) compared with 3 of 8 (38%) patients treated with pegIFN-alfa/RBV. SVR24 rates in cirrhotic patients who achieved PDR (12/16; 75%) were similar to those without baseline cirrhosis who achieved PDR. Patients treated with the combination of daclatasvir and pegIFN-alfa/RBV had higher SVR24 rates than those receiving pegIFN-alfa/RBV alone across all IL28B genotypes (CC, CT, or TT) regardless of viral subtype (figure 2B), although as observed with other pegIFN-alfa-based regimens, SVR24 was higher among those with IL28B genotype CC compared with CT or TT.

    View this table:
    Table 2

    Virologic endpoints (mITT) among patients with HCV genotype 1 and genotype 4 infections

    View this table:
    Table 3

    Rates of protocol-defined response among patients with HCV genotype 1 infection and effect on SVR24 rates

    Figure 2
    Figure 2

    Rates of sustained virologic response at post-treatment Week 24 (A) among HCV genotype 1-infected and 4-infected patients (modified intention-to-treat). Genotype 1 subtypes include all randomised patients with an available subtype determination. Solid bars represent sustained virologic response at post-treatment Week 24 (SVR24) rates based on undetectable HCV-RNA levels. Hashed bars (and numerical values above each bar) represent SVR24 rates based on <lower limit of quantitation (25 IU/mL). (B) Among genotype 1-infected patients by IL28B genotype (rs12979860). Numbers represent patients with available IL28B genotype data. DCV, daclatasvir; GT, genotype; P/R, peginterferon alfa and ribavirin.

    Concordance between SVR12 and SVR24 was evaluated for patients with available HCV-RNA measurements at follow-up Weeks 12 and 24 (based on HCV-RNA <LLOQ or undetectable) and was 99% and 97% for the daclatasvir 20 mg and 60 mg groups, respectively. All 5 patients who were not concordant were confirmed as relapsers.

    Virologic failure and resistance

    Among HCV genotype 1-infected patients receiving daclatasvir, 119 (41%) experienced treatment failure due to virologic breakthrough, on-treatment failure (other than viral breakthrough), relapse, or various other reasons (table 4). These other reasons included loss to follow-up, withdrawal of consent, death, or patients with no on-treatment HCV-RNA measurements; the majority of these patients (21/22) had undetectable HCV-RNA levels when treatment was discontinued. Failure rates were higher in patients treated with placebo compared with patients who received daclatasvir (20 mg or 60 mg), with similar failure rates observed between the daclatasvir 20 mg and 60 mg treatment groups. Treatment failure rates were also lower among patients who achieved PDR. Among daclatasvir-treated patients, on-treatment failure was observed more frequently among genotype-1a patients compared with genotype-1b patients (daclatasvir 20 mg: 1a 20% (21/106) vs 1b 12% (5/41); daclatasvir 60 mg: 1a 23% (26/113) vs 1b 3% (1/31); placebo: 1a 38% (21/56) vs 1b 50% (8/16)); primarily due to the higher rates of virologic breakthrough observed among genotype-1a patients. IL28B non-CC genotype was associated with virologic failure across all treatment arms—among those with an available genotype result, 77% (99/129) genotype-1a patients and 94% (30/32) genotype-1b patients who experienced virologic failure were non-CC.

    View this table:
    Table 4

    Treatment failures in genotype-1 patients through post-treatment Week 24

    NS5A polymorphisms associated with daclatasvir resistance (L31M/V and/or Y93H/N/S) were observed in 12 genotype-1a patients and 10 genotype-1b patients at baseline. Of these patients, 8 genotype-1a (L31M/V and Y93H/N/S) and 2 genotype-1b (Y93H) failed to achieve SVR24. All daclatasvir-treated genotype-1 patients who experienced virologic breakthrough, or post-treatment relapse, had detectable daclatasvir-associated resistant variants around the time of failure; Q30 variants (58 of 76 patients with an available NS5A sequence) were most frequently detected among genotype-1a patients, whereas L31I/M/V–Y93H variants were most frequently observed in genotype-1b patients (7 of 10 patients with an available NS5A sequence).

    HCV genotype 4-infected patients

    Virologic response

    As observed in patients with genotype 1 infection, higher rates of eRVR and SVR24 were observed in genotype 4-infected patients treated with daclatasvir (20 mg and 60 mg doses) in combination with pegIFN-alfa/RBV compared with patients receiving pegIFN-alfa/RBV control (table 2 and figure 2A). All patients (12/12) treated with 60 mg daclatasvir achieved a PDR, stopped therapy at Week 24, and reached SVR24; PDR and SVR24 were achieved in 67% (8/12) of patients treated with 20 mg daclatasvir. Three of the 6 patients who received placebo plus pegIFN-alfa/RBV achieved SVR24.

    Virologic failure and resistance

    Four patients in the daclatasvir 20 mg group experienced treatment failure due to virologic breakthrough (2 patients) or relapse (2 patients). Analysis of samples from 3 patients with sufficient post-treatment HCV-RNA levels revealed the emergence of L28M-L30H (1 patient) and L28M-L30S (2 patients; >10 000-fold resistance in vitro) resistance-associated variants, which were not present during baseline sequence analysis.

    Safety and tolerability

    The adverse event profile in patients treated with daclatasvir and pegIFN-alfa/RBV was comparable with that observed in patients who received pegIFN-alfa/RBV alone (table 5), with changes in laboratory parameters similar across the daclatasvir and placebo groups. The most commonly reported adverse events across all treatment groups were fatigue, headache, pruritus, insomnia, rash, and nausea. Adverse events of special interest for HCV-infected patients, including ALT elevations, anaemia, increased total bilirubin, and rash, were comparable among all groups. Patients who received daclatasvir (both doses) reported higher incidences (≥10% difference between treatment arms) of dry skin, influenza-like illness, and nausea, compared with patients receiving placebo. The type and frequency of adverse events were comparable between the treatment arms regardless of the dose of daclatasvir received (20 mg or 60 mg) or the duration of daclatasvir dosing.

    View this table:
    Table 5

    On-treatment adverse events, discontinuations, and laboratory abnormalities

    Serious adverse events, Grade 3/4 adverse events, and adverse events leading to discontinuation were comparable across all treatment groups and consistent with rates typically observed in patients treated with pegIFN-alfa/RBV alone (table 5). No Grade 3/4 ALT elevations were observed in the daclatasvir 20 mg group compared with 3.8% of patients receiving daclatasvir 60 mg and 1.3% of patients receiving placebo; however, no concomitant bilirubin elevations were observed in any patient. Two deaths occurred during the treatment/follow-up period; both patients were in the 20 mg daclatasvir cohort. One death occurred in a patient with multiple comorbidities (hypertension, diabetes mellitus, hyperlipidaemia, and sleep apnea) who died during Week 4, from an unknown cause, which was not considered related to study therapy by the investigator. The second patient died during Week 12 of the post-treatment period, as a result of cardiopulmonary disease/asthma that was not considered related to the study drug.

    Discussion

    We assessed the efficacy and tolerability of two doses of daclatasvir versus placebo in combination with pegIFN-alfa/RBV in treatment-naive patients infected with HCV genotypes 1 or 4. SVR24 rates among genotype 1-infected patients were superior for the 20 mg and 60 mg once-daily doses of daclatasvir in combination with pegIFN-alfa/RBV compared with placebo and pegIFN-alfa/RBV.

    High SVR rates were observed among genotype 4-infected patients; although sample sizes were small within these groups, these are the first clinical data demonstrating that daclatasvir plus pegIFN-alfa/RBV is efficacious in the genotype 4-infected patient population, which currently has more limited treatment options. Comparable SVR rates have been observed in the small number of genotype 4 patients treated with sofosbuvir plus pegIFN-alfa/RBV (96%; 27/28) and simeprevir plus pegIFN-alfa/RBV (83%; 29/35).24 ,25

    This study also examined the effect of shortened treatment duration on virologic outcome. At Week 12, patients who had HCV-RNA levels <LLOQ at Week 4 and undetectable HCV-RNA at Week 10 received either an additional 12 weeks of daclatasvir plus pegIFN-alfa/RBV or an additional 12 weeks of pegIFN-alfa/RBV alone. The high proportion of patients (approximately 75%) who achieved SVR following only 24 weeks’ treatment indicates that a shortened duration is possible with both daclatasvir regimens evaluated in this study. IL28B genotype predicted response, with higher rates of SVR observed among patients with a CC genotype compared with those with a non-CC genotype regardless of therapy. Together with HCV genotype, IL28B genotype could be used to identify patients with a higher chance of achieving SVR; for example, genotype-1a patients with a CC genotype achieved comparable SVR rates to genotype-1b patients with a less interferon responsive CT or TT genotype.

    Differences in SVR and virologic failure rates were observed between genotype 1a and 1b for both daclatasvir doses in this study, as observed with boceprevir-based, telaprevir-based and simeprevir-based regimens.26–28 Genotype-1a patients had lower rates of SVR and higher rates of virologic failure compared with genotype-1b patients; this outcome is consistent with in vitro findings that demonstrate that daclatasvir is approximately fivefold more potent against genotype 1b versus 1a.21 This difference in potency against genotype 1b versus 1a is observed with other NS5A inhibitors, including ledipasvir, PPI-446, GSK2336805 and ombitasvir.29

    Although only small numbers of cirrhotic patients were enrolled in this study, cirrhosis did not markedly affect response to daclatasvir plus pegIFN-alfa/RBV. The observed SVR rates with pegIFN-alfa/RBV in this patient population are relatively low30; in our study, only 38% of genotype 1 cirrhotic patients treated with pegIFN-alfa/RBV achieved SVR. By comparison, 62% and 63% of cirrhotic patients who received daclatasvir 20 or 60 mg, respectively, achieved SVR, a finding similar to results observed in cirrhotic patients treated with simeprevir, telaprevir, or boceprevir in combination with pegIFN-alfa/RBV.27 ,28 ,31 ,32

    Daclatasvir was well tolerated in this study, and was associated with an adverse event profile that was comparable with earlier studies of daclatasvir plus pegIFN-alfa/RBV and to pegIFN-alfa/RBV alone. Since daclatasvir did not contribute any additional safety or tolerability concerns over pegIFN-alfa/RBV alone, it is likely to offer improved safety and tolerability over telaprevir-containing and boceprevir-containing regimens; both of which are associated with a number of additional adverse events compared with pegIFN-alfa/RBV alone including rash, anaemia, dysgeusia, pruritus and anorectal symptoms.33 ,34 Furthermore, when daclatasvir is combined with other DAAs, it is unlikely to contribute any additional safety or tolerability issues to those regimens.35 ,36

    The efficacy and tolerability of the 20 mg and 60 mg daclatasvir doses were comparable in this study; however, based on the results of a dose selection analysis, the 60 mg once-daily dose was selected for future Phases 2 and 3 studies. This higher dose will provide additional benefit by mitigating for food effects, acid modifiers, CYP3A4 inducers, and suboptimal adherence.37 In addition, the 60 mg dose is predicted to maximise antiviral response in more difficult-to-treat populations, such as cirrhotic patients, or those with genotype 1a infection, a high baseline viral load, or a non-CC IL28B genotype.37

    This study clearly demonstrates that the antiviral efficacy of pegIFN-alfa/RBV is increased by the addition of daclatasvir, although SVR24 rates were lower among patients infected with genotype 1a compared with genotypes 1b and 4. Similarly, the addition of simeprevir to pegIFN-alfa/RBV increased SVR rates to 80% compared with 50% with placebo plus pegIFN-alfa/RBV; higher SVR rates were also observed among genotype 1b-infected patients (90% vs 71% with genotype 1a).28 SVR12 rates with 12 weeks of sofosbuvir plus pegIFN-alfa/RBV therapy were 89%.24 Recent clinical studies have demonstrated that the combination of DAAs can increase SVR rates and shorten treatment duration. Combining daclatasvir with other DAAs (asunaprevir+BMS-791325 or sofosbuvir±RBV) can provide SVR rates of up to 100% among treatment-naive patients infected with HCV genotype 1, 2, or 3.35 ,36 Furthermore, the combination of daclatasvir and sofosbuvir±RBV has been shown to be highly efficacious in patients who have previously failed treatment with telaprevir or boceprevir.35

    In conclusion, the combination of daclatasvir with pegIFN-alfa/RBV in previously untreated HCV genotype 1- and 4-infected patients resulted in a higher SVR rate than pegIFN-alfa/RBV alone and was well tolerated. This study demonstrates that the combination of daclatasvir and pegIFN-alfa/RBV is likely to provide benefit over pegIFN-alfa/RBV for patients without access to all-oral therapies. The results also support the further development of daclatasvir in combination with other DAA agents.

    Acknowledgments

    Editorial assistance was provided by Andrew Street, PhD, of Articulate Science and was funded by Bristol-Myers Squibb.

    References

    1. ↵
      1. Negro F,
      2. Alberti A
      . The global health burden of hepatitis C virus infection. Liver Int 2011;31(Suppl 2):1–3.
      OpenUrlCrossRefPubMed
    2. ↵
      1. Lavanchy D
      . The global burden of hepatitis C. Liver Int 2009;29(Suppl 1):74–81.
      OpenUrl
    3. ↵
      World Health Organization. Hepatitis C key facts. WHO factsheet No 164. July 2012. 2012; http://www.who.int/mediacentre/factsheets/fs164/en/ (accessed 19 Mar 2014).
    4. ↵
      1. Armstrong GL,
      2. Wasley A,
      3. Simard EP
      et al. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med 2006;144:705–14.
      OpenUrlCrossRefPubMedWeb of Science
    5. ↵
      World Health Organization. Global Alert and Response (GAR)—Hepatitis C. 2012. http://www.who.int/csr/disease/hepatitis/whocdscsrlyo2003/en/index4.html (accessed 19 Mar 2014).
    6. ↵
      1. Sievert W,
      2. Altraif I,
      3. Razavi HA,
      4. et al
      . A systematic review of hepatitis C virus epidemiology in Asia, Australia and Egypt. Liver Int 2011;31(Suppl 2):61–80.
      OpenUrlCrossRefPubMedWeb of Science
    7. ↵
      1. Cornberg M,
      2. Razavi HA,
      3. Alberti A,
      4. et al
      . A systematic review of hepatitis C virus epidemiology in Europe, Canada and Israel. Liver Int 2011;31(Suppl 2):30–60.
      OpenUrlCrossRefPubMedWeb of Science
    8. ↵
      1. Ghany MG,
      2. Strader DB,
      3. Thomas DL
      et al. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009;49:1335–74.
      OpenUrlCrossRefPubMedWeb of Science
    9. ↵
      1. Kamal SM
      . Hepatitis C virus genotype 4 therapy: progress and challenges. Liver Int 2011;31(Suppl 1):45–52.
      OpenUrlCrossRefPubMed
    10. ↵
      1. Thompson AJ,
      2. Muir AJ,
      3. Sulkowski MS
      et al. Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology 2010;139:120–9.
      OpenUrlCrossRefPubMedWeb of Science
    11. ↵
      1. Ochi H,
      2. Maekawa T,
      3. Abe H
      et al. ITPA polymorphism affects ribavirin-induced anemia and outcomes of therapy—a genome-wide study of Japanese HCV virus patients. Gastroenterology 2010;139:1190–7.
      OpenUrlCrossRefPubMedWeb of Science
    12. ↵
      Janssen Therapeutics. OLYSIO™ (simeprevir) Prescribing Information. 2014.
    13. ↵
      Gilead Sciences Inc. SOVALDITM (sofosbuvir) Prescribing Information. 2014.
    14. ↵
      European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatitis C virus infection. J Hepatol 2014;60:392–420.
      OpenUrlCrossRefPubMedWeb of Science
    15. ↵
      American Association for the Study of Liver Diseases, Infectious Diseases Society of America. Recommendations for testing, managing, and treating hepatitis C. 2014. http://www.hcvguidelines.org/ (accessed 29 May 2014).
    16. ↵
      1. Wang C,
      2. Jia L,
      3. Huang H,
      4. et al
      . In vitro activity of BMS-790052 on hepatitis C virus genotype 4 NS5A. Antimicrob Agents Chemother 2012;56:1588–90.
      OpenUrlAbstract/FREE Full Text
    17. ↵
      1. Fridell RA,
      2. Qiu D,
      3. Valera L
      et al. Distinct functions of NS5A in hepatitis C virus RNA replication uncovered by studies with the NS5A inhibitor BMS-790052. J Virol 2011;85:7312–20.
      OpenUrlAbstract/FREE Full Text
    18. ↵
      1. Nettles RE,
      2. Gao M,
      3. Bifano M
      et al. Multiple ascending dose study of BMS-790052, an NS5A replication complex inhibitor, in patients infected with hepatitis C virus genotype 1. Hepatology 2011;54:1956–65.
      OpenUrlCrossRefPubMedWeb of Science
    19. ↵
      1. Qiu D,
      2. Lemm JA,
      3. O'Boyle DR II.
      et al. The effects of NS5A inhibitors on NS5A phosphorylation, polyprotein processing and localization. J Gen Virol 2011;92:2502–11.
      OpenUrlAbstract/FREE Full Text
    20. ↵
      1. Lee C,
      2. Ma H,
      3. Hang JQ
      et al. The hepatitis C virus NS5A inhibitor (BMS-790052) alters the subcellular localization of the NS5A non-structural viral protein. Virology 2011;414:10–18.
      OpenUrlCrossRefPubMed
    21. ↵
      1. Gao M,
      2. Nettles RE,
      3. Belema M
      et al. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 2010;465:96–100.
      OpenUrlCrossRefPubMedWeb of Science
    22. ↵
      1. Pol S,
      2. Ghalib RH,
      3. 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;12:671–7.
      OpenUrlCrossRefPubMedWeb of Science
    23. ↵
      1. Ge D,
      2. Fellay J,
      3. Thompson AJ
      et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009;461:399–401.
      OpenUrlCrossRefPubMedWeb of Science
    24. ↵
      1. Lawitz E,
      2. Mangia A,
      3. Wyles D
      et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013;368:1878–87.
      OpenUrlCrossRefPubMedWeb of Science
    25. ↵
      1. Moreno C,
      2. Hezode C,
      3. Marcellin P,
      4. et al
      . Once-daily simeprevir (TMC435) with peginterferon/ribavirin in treatment-naïve or treatment-experienced chronic HCV genotype 4-infected patients: final results of a phase III trial [Abstract]. J Hepatol 2014;60(Suppl 1):S535.
      OpenUrl
    26. ↵
      1. Kwo PY,
      2. Lawitz EJ,
      3. McCone J
      et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet 2010;376:705–16.
      OpenUrlCrossRefPubMedWeb of Science
    27. ↵
      1. Jacobson IM,
      2. McHutchison JG,
      3. Dusheiko G
      et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011;364:2405–16.
      OpenUrlCrossRefPubMedWeb of Science
    28. ↵
      1. Jacobson I,
      2. Dore GJ,
      3. Foster GR,
      4. et al
      . Simeprevir (TMC435) with peginterferon/ribavirin for chronic HCV genotype-1 infection in treatment-naive patients: Results from QUEST-1, a phase III trial [Abstract]. J Hepatol 2013;58(Suppl 1):S574.
      OpenUrlCrossRef
    29. ↵
      1. Belda O,
      2. Targett-Adams P
      . Small molecule inhibitors of the hepatitis C virus-encoded NS5A protein. Virus Res 2012;170:1–14.
      OpenUrlCrossRefPubMedWeb of Science
    30. ↵
      1. Vezali E,
      2. Aghemo A,
      3. Colombo M
      . A review of the treatment of chronic hepatitis C virus infection in cirrhosis. Clin Ther 2010;32:2117–38.
      OpenUrlCrossRefPubMed
    31. ↵
      1. Manns M,
      2. Marcellin P,
      3. Fred Poordad FP
      et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype-1 infection in treatment-naive patients: Results from QUEST-2, a phase III trial [Abstract]. J Hepatol 2013;58(Suppl 1):S568.
      OpenUrlCrossRef
    32. ↵
      1. Lawitz E,
      2. Zeuzem S,
      3. Nyberg LM
      et al. Boceprevir (BOC) Combined with Peginterferon alfa-2b/ribavirin (P/RBV) in Treatment-Naïve Chronic HCV Genotype 1 Patients with Compensated Cirrhosis: Sustained Virologic Response (SVR) and Safety Subanalyses from the Anemia Management Study [Abstract]. Hepatology 2012;56(Suppl):216A.
      OpenUrl
    33. ↵
      Vertex Pharmaceuticals Inc. INCIVEK™ (telaprevir) Prescribing Information. 2014.
    34. ↵
      Merck & Co. Inc. VICTRELISTM (boceprevir) Prescribing Information. 2014.
    35. ↵
      1. Sulkowski MS,
      2. Gardiner DF,
      3. Rodriguez-Torres M
      et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014;370:211–21.
      OpenUrlCrossRefPubMedWeb of Science
    36. ↵
      1. Everson GT,
      2. Sims KD,
      3. Rodriguez-Torres M
      et al. Efficacy of an interferon- and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 in treatment-naive patients with HCV genotype 1 infection. Gastroenterology 2014;146:420–9.
      OpenUrlCrossRefPubMedWeb of Science
    37. ↵
      1. Chan P,
      2. Tafoya E,
      3. Bifano M
      et al. Exposure-response analysis of daclatasvir in patients with genotype 1 chronic HCV infection: dose selection for phase 3 clinical trials [Abstract]. Rev Antiviral Ther Infect Dis. 2012;6:14.
      OpenUrl
    View Abstract

    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

      Files in this Data Supplement:

    Footnotes

    • Contributors All authors approved the final version of the manuscript. CH, GMH, WG, WS, MR-T, SDS, PJT, HAT, IW, GE, EJL, VKR, SP, NW, PJP, MB, LS, JMV, MWF, OW, MRB, GTE, SZ, PYK, MS and NB participated in study design, data acquisition, analysis and interpretation, manuscript preparation and critical review of the manuscript. DH, FM and MW-R participated in study data acquisition and critical review of the manuscript. ZL participated in study design, conducted statistical analyses and reviewed the manuscript. SN, EAH, PDY and SS participated in study concept and design, administration, technical support, manuscript preparation and critical review of the manuscript.

    • Funding This study was funded by Bristol-Myers Squibb.

    • Competing interests CH has been a speaker and/or consultant for AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Merck, and Roche. WS has been a speaker and/or consultant for Bristol-Myers Squibb, Gilead, Janssen and Merck. MR-T has been a consultant and/or received grant support from Abbott, Akros, Anadys, Beckman Coulter, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead, GlaxoSmithKline, Human Genome Sciences, Idenix, Idera, Inhibitex, Janssen, Johnson & Johnson, Merck, Mochida, Novartis, Pfizer, Pharmasset, Santaris, Scynexis, Siemens Healthcare Diagnostics, Vertex and Zymogenetics. SDS has received grant support and/or personal fees from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Idenix, Janssen, Merck, Pfizer, Roche and Vertex. PJT has been a consultant and/or received grant support from Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Gilead, Janssen, Novartis, Onyx, Salix and Vertex. HAT has been a speaker and/or advisor for AbbVie, Gilead, Merck, and Vertex. IW has been an investigator, speaker and/or consultant for Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Merck, Minapharm and Roche. EJL has been a consultant, research grant recipient, and/or speaker for AbbVie, Achillion, BioCryst, Biotica, Boehringer Ingelheim, Bristol-Myers Squibb, Enanta, Gilead, GlaxoSmithKline, Idenix, Intercept, Janssen, Kadmon, Medtronic, Merck, Novartis, Presidio, Roche, Santaris, Theravance, and Vertex. VKR has been a speaker and/or research grant recipient from Abbott, Achillion, Bristol-Myers Squibb, Genentech, Gilead, Merck and Vertex. SP has been a speaker, consultant and/or research grant recipient from Abbot/AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck, Novartis, Roche, Sanofi, Tibotec and Vertex. NW has been an investigator, consultant and/or speaker for Bristol-Myers Squibb, GlaxoSmithKline, Gilead, Janssen, Merck, and Roche. PJP has received grant support from Scripps Clinical Research and been a consultant for Bristol-Myers Squibb. MB has received personal fees from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen, Merck, Roche and Vertex. JMV has been a consultant and/or research grant recipient from AbbVie, Bristol-Myers Squibb, Conatus, Gilead, GlaxoSmithKline, Globeimmune, Idenix, Janssen, Merck, Novartis, Pfizer, Pharmasset, Roche, Vertex and Zymogenetics. MWF has been a consultant and/or received research grant support from Abbott, Bristol-Myers Squibb, Genentech, Gilead, Janssen, Merck, Roche and Vertex. OW has been a speaker, consultant, investigator and/or research grant recipient from AbbVie, Bristol-Myers Squibb, Gilead, Merck, Novartis and Roche. MRB has been a speaker for Abbott, Bristol-Myers Squibb, Gilead, Janssen, Merck, Novartis and Roche. GTE has been a consultant and/or research grant recipient from AbbVie, Bristol-Myers Squibb, Eisai, Gilead, Janssen, NIH-NIDDK and Novartis; and holds a patent (licensed to HepQuant LLC) with the University of Colorado. SZ has been a consultant for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Idenix, Janssen, Merck, Novartis, Roche, Santaris and Vertex. PYK has been a speaker and/or consultant and/or research grant recipient from AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Merck, Novartis and Vertex. MS has received research grant support and/or personal fees from AbbVie, BIPI, Bristol-Myers Squibb, Gilead, Janssen, Merck and Vertex. NB has received research grants from Bristol-Myers Squibb, Gilead and Vertex. DH, FM, MW-R, ZL, SN, EAH, PDY and SS are employees of Bristol-Myers Squibb.

    • Patient consent Obtained.

    • Ethics approval The institutional review board at each participating site.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement Any unpublished data from the trial is held by the sponsor, Bristol-Myers Squibb, and was made available to the principal investigators.

    Linked Articles