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Deferred treatment with sofosbuvir–velpatasvir–voxilaprevir for patients with chronic hepatitis C virus who were previously treated with an NS5A inhibitor: an open-label substudy of POLARIS-1
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Deferred treatment with sofosbuvir–velpatasvir–voxilaprevir for patients with chronic hepatitis C virus who were previously treated with an NS5A inhibitor: an open-label substudy of POLARIS-1 Marc Bourlière, Stuart C Gordon, Eugene R Schiff, Tram T Tran, Natarajan Ravendhran, Charles S Landis, Robert H Hyland, Luisa M Stamm, Jie Zhang, Hadas Dvory-Sobol, G Mani Subramanian, Diana M Brainard, John G McHutchison, Lawrence Serfaty, Alex J Thompson, Thomas E Sepe, Michael P Curry, K Rajender Reddy, Michael P Manns
Summary
Background Direct-acting antiviral regimens containing NS5A inhibitors are highly effective treatments for chronic hepatitis C virus (HCV) infection, but are not always successful. In the POLARIS-1 phase 3 study, sofosbuvir−velpatasvir−voxilaprevir for 12 weeks was highly effective in the treatment of chronic HCV infection in patients previously treated with a direct-acting antiviral regimen containing an NS5A inhibitor. We aimed to assess the efficacy and safety of sofosbuvir−velpatasvir−voxilaprevir in patients from the deferred treatment group of POLARIS-1, who were initially assigned to masked placebo treatment. Methods This open-label, deferred treatment substudy was done at 73 clinical sites (hospitals and clinics) in the USA, France, Canada, the UK, Germany, Australia, and New Zealand. Patients who received placebo in the primary study and who did not have a new clinically significant illness at the post-treatment week 4 assessment were eligible to enter this substudy. Participants received a combination tablet of sofosbuvir (400 mg), velpatasvir (100 mg), and voxilaprevir (100 mg) once daily for 12 weeks. The primary efficacy outcome was achievement of sustained virological response (defined as HCV RNA concentration below the lower limit of quantification) 12 weeks after the end of treatment (SVR12). The primary safety outcome was the proportion of patients who discontinued treatment due to adverse events. This study is registered with ClinicalTrials.gov, number NCT02607735, and the EU Clinical Trials Register, number 2015-003455-21. Findings 152 patients received placebo in the primary study and were potentially eligible for participation in the open-label substudy, of whom 147 were enrolled from March 30, 2016, to Oct 12, 2016. All 147 patients completed treatment, and 143 (97%; 95% CI 93–99) achieved SVR12. Four (3%) patients had virological relapse; all had HCV genotype 1a infection and one also had compensated cirrhosis. The most common adverse events were fatigue (31 [21%]), headache (29 [20%]), diarrhoea (28 [19%]), and nausea (21 [14%]). No deaths, treatment discontinuations, or treatment-related serious adverse events occurred. Interpretation Supporting the results from the blinded portion of the phase 3 primary study, the single-tablet regimen of sofosbuvir−velpatasvir−voxilaprevir for 12 weeks was safe, well tolerated, and highly effective in patients with chronic HCV infection who had previous treatment failure with NS5A inhibitor-containing regimens. A salvage regimen for this population represents an important advance for patients with limited retreatment options. Funding Gilead Sciences. Copyright © 2018 Elsevier Ltd. All rights reserved.
Introduction Worldwide, a small but growing population of patients with chronic hepatitis C virus (HCV) infection has been unsuccessfully treated with a direct-acting antiviral regimen; most of these patients have received regimens that include an NS5A inhibitor. NS5A inhibitors are the most potent class of direct-acting antivirals but have a relatively low barrier to resistance compared with other classes, such as non-nucleotide HCV NS5B inhibitors. Particularly when administered without an NS5B inhibitor, NS5A resistance at the time of virological
failure is nearly universal in patients who do not respond to treatment with a regimen including an NS5A inhibitor. Furthermore, NS5A resistance-associated substitutions usually persist long term1 and are associated with a reduced response to treatment regimens containing NS5A inhibitors, especially in patients with advanced cirrhosis, HCV genotype 1a or 3 infection, or previous failure of interferon treatment.2–6 To date, the POLARIS-1 study7 has been the only phase 3 study to exclusively enrol patients who did not respond to previous treatment with an NS5A inhibitor. The study
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Lancet Gastroenterol Hepatol 2018 Published Online May 30, 2018 http://dx.doi.org/10.1016/ S2468-1253(18)30118-3 See Online/Comment http://dx.doi.org/10.1016/ S2468-1253(18)30162-6 Hépato-Gastroentérologie, Hôpital Saint Joseph, Marseille, France (M Bourlière MD); Henry Ford Health System, Detroit, MI, USA (S C Gordon MD); Schiff Center for Liver Diseases, University of Miami, Coral Gables, FL, USA (Prof E R Schiff MD); Cedars-Sinai Medical Center, Los Angeles, CA, USA (T T Tran MD); Digestive Disease Associates, Catonsville, MD, USA (N Ravendhran MD); Division of Gastroenterology and Hepatology, Department of Medicine, University of Washington, Seattle, WA, USA (C S Landis MD); Gilead Sciences, Foster City, CA, USA (R H Hyland DPhil, L M Stamm MD, J Zhang PhD, H Dvory-Sobol PhD, G M Subramanian MD, D M Brainard MD, J G McHutchison MD); Service d’Hépatologie, Hôpital Saint-Antoine, Paris, France (L Serfaty MD); St Vincent’s Hospital and the University of Melbourne, Melbourne, Fitzroy, VIC, Australia (A J Thompson MD); Liver Center, University Gastroenterology, Providence, RI, USA (Prof T E Sepe MD); Beth Israel Deaconess Medical Center, Boston, MA, USA (M P Curry MD); Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA (Prof K R Reddy MD); and Medizinischen Hochschule, Hannover, Germany (Prof M P Manns MD)
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Correspondence to: Dr Marc Bourlière, Hépato-Gastroentérologie, Hôpital Saint-Joseph, Marseille 13008, France [email protected]
Research in context Evidence before this study Before the approval of sofosbuvir–velpatasvir–voxilaprevir, no retreatment options were approved for patients with chronic hepatitis C virus infection who had been treated with a direct-acting antiviral regimen containing an NS5A inhibitor. The POLARIS-1 study was the first phase 3 registrational, randomised, placebo-controlled trial to enrol and treat such patients, as we confirmed by a review of PubMed using the search terms, “HCV”, “NS5A treatment-experienced”, “prior DAA experience”, and “salvage therapy”, for clinical trials published by Aug 21, 2015. In the primary study of POLARIS-1, 253 (96%) of 263 patients who received sofosbuvir–velpatasvir–voxilaprevir for 12 weeks achieved sustained virological response. Added value of this study In the current substudy of POLARIS-1, patients with genotype 1 hepatitis C virus infection assigned to the placebo
assessed 12 weeks of therapy with a combination of sofosbuvir (an NS5B inhibitor), velpatasvir (an NS5A inhibitor), and voxilaprevir (an NS3/4A protease inhibitor) versus placebo. Among 263 patients who received sofosbuvir−velpatasvir−voxilaprevir, 253 (96%) achieved sustained virological response, compared with none of the 152 patients who received placebo. On the basis of the results from POLARIS-1, sofosbuvir−velpatasvir− voxilaprevir has been approved in the USA and European Union as a pan-genotypic salvage regimen for patients previously given an NS5A inhibitor.8–10 Patients in POLARIS-1 who were masked to treatment and initially received placebo were eligible for a subsequent open-label substudy in which they would receive sofosbuvir−velpatasvir−voxilaprevir for 12 weeks. We report the safety and efficacy results of the deferred treatment substudy.
Methods
Study design and participants This open-label deferred treatment substudy from the international phase 3, multicentre POLARIS-1 study7 was done at 73 clinical sites (hospitals and clinics) in the USA, France, Canada, the UK, Germany, Australia, and New Zealand. The initial phase of POLARIS-1 was a blinded, randomised study comparing 12 weeks of once-daily treatment with either placebo or a combination tablet containing sofosbuvir, velpatasvir, and voxilaprevir. Assignments were unblinded 4 weeks after treatment. Patients who com pleted 12 weeks of treatment with placebo and did not have a new clinically significant illness at the post-treatment week 4 visit were eligible to enter the deferred treatment substudy. At enrolment for the primary study, eligible patients had chronic HCV infection and had previously been treated with an NS5A inhibitor for at least 4 weeks. Other inclusion 2
group in the primary study of POLARIS-1 were subsequently treated with sofosbuvir–velpatasvir–voxilaprevir for 12 weeks to assess efficacy and safety. The large number of patients (143 [97%] of 147) treated in this deferred treatment substudy who achieved sustained virological response further supports the efficacy and safety of treatment in the primary study. Combined with the results of the primary study of POLARIS-1, 396 (97%) of 410 patients have achieved sustained virological response in clinical trials with sofosbuvir–velpatasvir–voxilaprevir. Implications of all the available evidence These results support the use of sofosbuvir–velpatasvir– voxilaprevir for the treatment of chronic hepatitis C virus infection in patients with NS5A inhibitor experience, regardless of which direct-acting antivirals were used in previous treatments.
criteria included HCV genotype 1 as determined by the Abbott RealTime HCV Genotype II assay (Abbott, Chicago, IL, USA), age 18 years or older, body-mass index of at least 18 kg/m², and plasma HCV RNA concentrations of at least 104 IU/mL. Patients without cirrhosis or with compensated cirrhosis were eligible for participation. The presence of cirrhosis was determined by: liver biopsy with a Metavir score of 4 or Ishak score of 5 or more; a Fibroscan score of more than 12·5 kPa; or a FibroTest score of more than 0·75 and an aspartate aminotransferase:platelet ratio index value of more than 2. Patients were excluded if they had any of the following conditions: platelet count of less than 50 000 per µL, haemoglobin concentration of less than 10 g/dL, alanine aminotransferase or aspartate aminotransferase concentrations of more than 10 × upper limit of normal (ULN), direct bilirubin concentration of more than 1·5 × ULN, glycated haemoglobin A1c concentrations of more than 8·5%, creatinine clearance of less than 50 mL/min (determined using the CockcroftGault equation), albumin concentration of less than 3 g/dL, international normalised ratio of prothrombin time of more than 1·5 × ULN, or infection with hepatitis B or HIV. Patients provided written informed consent for the primary study and the deferred treatment substudy before undergoing any study-related procedures. The study protocol7 was approved by the review board or ethics committee of each institution before study initiation. The study was done in accordance with the International Conference on Harmonization Good Clinical Practice Guidelines and the Declaration of Helsinki.
Procedures Patients received a once-daily combination tablet of sofosbuvir (400 mg), velpatasvir (100 mg), and voxilaprevir (100 mg). After completing 12 weeks of
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treatment, patients underwent follow-up visits at post-treatment weeks 4, 12, and 24. Screening assessments included measurement of plasma HCV RNA concentration and genotyping, IL28B genotyping, and standard laboratory tests (haematology, coagulation, chemistry, and urinalysis) and clinical tests (physical examinations and assessments of vital signs). HCV RNA concentrations were quantified with the COBAS Ampliprep/COBAS TaqMan HCV Test, version 2.0 (Roche Molecular Systems, Branchburg, NJ, USA), which has a lower limit of quantification (LLOQ) of 15 IU/mL. At screening, HCV genotype and subtype were determined using the Abbott RealTime HCV Genotype II assay, which is unable to distinguish genotype 6 from genotype 1. Subsequently, HCV genotype and subtype were determined by analysis of NS3/4A, NS5A, and NS5B sequences obtained by deep sequencing with use of the Basic Local Alignment Search Tool; these results were used in the reported analyses. IL28B genotype was determined by PCR amplification of the single-nucleotide polymorphism rs12979860, with sequence-specific forward and reverse primers and allele-specific fluorescently labelled TaqMan minor groove binder probes at the start of the primary study. Plasma HCV RNA concentrations were evaluated at every study visit, including screening; day 1 of treatment; treatment weeks 1, 2, 4, 8, 10, and 12; and post-treatment weeks 4, 12, and 24. Post-treatment week 12 HCV RNA assessments that were missing were imputed as less than the LLOQ only if preceding and subsequent assessments were less than the LLOQ. Plasma samples for viral sequencing were collected at all treatment and follow-up visits. Deep sequencing of the NS5A, NS3/4A, and NS5B coding regions was done on samples obtained from all patients at baseline of the initial phase of POLARIS-1 (before placebo treatment) and from those with virological failure at the time of treatment failure. Sequences obtained at the time of virological failure were compared with sequences from baseline samples to detect treatment-emergent resistance-associated substitutions. Physical examinations were done at screening, on treatment day 1, and at the final treatment visit. Vital signs, adverse events, concomitant medication intake, and clinical laboratory assessments were collected at screening, every treatment visit, and at the post-treatment week 4 visit, but not up to the week 12 visit. Adverse events were coded using the Medical Dictionary for Regulatory Activities, version 20.0.
Outcomes For this substudy, the primary efficacy outcome was achievement of sustained virological response at post-treatment week 12 (SVR12), defined as HCV RNA concentration below the LLOQ 12 weeks after
discontinuing study drugs. The primary safety outcome was the proportion of patients who discontinued treatment because of adverse events.
Statistical analysis We did not calculate sample size because enrolment into this substudy was conditional on the placebo sample size from the initial phase of the POLARIS-1 study. No statistical hypothesis testing was done for the primary efficacy outcome. For the percentage of patients achieving SVR12, we constructed a two-sided 95% exact CI using the Clopper-Pearson method. We summarised safety results descriptively. We used SAS version 9.4 for statistical analyses. No data monitoring committee was used for this deferred treatment study. Sofosbuvir–velpatasvir– voxilaprevir once daily for 12 weeks (n=147) Age (years)
60 (55–64)
Sex Male Female
116 (79%) 31 (21%)
Race White Black or African American Asian Body-mass index (kg/m²)
121 (82%) 20 (14%) 6 (4%) 28 (25–32)
HCV genotype 1
145 (99%) 1a
113 (77%)
1b
30 (20%)
1 other 6 HCV RNA (log10 IU/mL)
2 (1%) 2 (1%) 6·3 (0·53)
Compensated cirrhosis Yes
49 (33%)
No
98 (67%)
IL28B genotype CC
26 (18%)
CT
89 (61%)
TT
32 (22%)
Previous direct-acting antivirals by class of inhibitor NS5A and NS5B
76 (52%)
NS5A and NS3/4A with or without NS5B
61 (42%)
NS5A with or without other
9 (6%)
NS5B with or without NS3/4A
1 (1%)
Baseline NS3 or NS5A resistance-associated substitutions* None
14 (10%)
NS3 only
10 (7%)
NS5A only
60 (41%)
NS3 and NS5A
61 (41%)
Data are median (IQR), n (%), or mean (SD). HCV=hepatitis C virus. *Complete sequencing data were not available for two patients.
Table 1: Patient demographics and baseline characteristics
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Sofosbuvir–velpatasvir– voxilaprevir once daily for 12 weeks (n=147)
Sofosbuvir–velpatasvir– voxilaprevir once daily for 12 weeks (n=147)
Hepatitis C virus RNA concentration <15 IU/mL
Compensated cirrhosis
On treatment
Yes
48/49 (98%)
Week 1
21 (14%)
No
95/98 (97%)
Week 2
92 (63%)
Hepatitis C virus genotype
Week 4
137 (93%)
Week 8
147 (100%)
1 (all subtypes) 1a
109/113 (97%)
Week 12
147 (100%)
1b
30/30 (100%)
After treatment
1 other
141/145 (97%)
2/2 (100%)
Week 4
145 (99%; 95–100)
6
Week 12 (SVR12)
143 (97%; 93–99)
Previous direct-acting antivirals by class of inhibitor
Virological failure
2/2 (100%)
NS5A and NS5B
73/76 (96%)
On treatment
0
NS5A and NS3/4A with or without NS5B
60/61 (98%)
Relapse
4 (3%)
NS5A with or without other
9/9 (100%)
Data are n (%) or n (%; 95% CI). SVR12=sustained virological response 12 weeks after treatment.
Other
1/1 (100%)
Table 2: Treatment response to sofosbuvir−velpatasvir−voxilaprevir
None
This trial is registered with ClinicalTrials.gov, number NCT02607735 and EudraCT, number 2015-003455-21.
Baseline NS3 or NS5A resistance-associated substitutions* NS3 or NS5A
14/14 (100%) 127/131 (97%)
NS3 only
10/10 (100%)
NS5A only
59/60 (98%)
NS3 and NS5A
58/61 (95%)
Data are n/N (%). *Complete sequencing data were not available for two patients.
Role of the funding source The sponsor (Gilead Sciences) collected the data, monitored study conduct, did the statistical analyses, and interpreted the data. The first draft of the manuscript was prepared by a professional writer funded by the sponsor, with the final version incorporating input from all authors. The corresponding author had full access to all of the data in the study and had the final responsibility to submit for publication.
Results 152 patients received placebo in the primary study and were potentially eligible for participation in the open-label substudy, 147 of whom were enrolled from March 30, 2016, to Oct 12, 2016. Five patients enrolled in the primary study were not eligible for the deferred treatment substudy; three patients had discontinued placebo in the primary study, and two patients developed new clinically significant illnesses (namely, liver decompensation and prostate cancer). The median age for the substudy population was 60 years (IQR 55–64; table 1). 49 (33%) patients had compensated cirrhosis, and 121 (82%) patients had a non-CC IL28B genotype (table 1). Most patients (113 [77%]) had HCV genotype 1a (30 [20%] had genotype 1b, and two had genotype 6; table 1). 76 (52%) patients had previously been treated with an NS5A inhibitor and NS5B inhibitor without an NS3/4A protease inhibitor; all but four of them had received ledipasvir− sofosbuvir (table 1). Ledipasvir was the most commonly received NS5A inhibitor (91 [62%] patients), followed by daclatasvir (27 [18%] patients) and ombitasvir (24 [16%] patients). One patient had not previously been treated 4
Table 3: Sustained virological response 12 weeks after treatment by select subgroups
with an NS5A inhibitor; this patient had received sofosbuvir and simeprevir. NS3 or NS5A resistanceassociated substitutions were present in 131 (89%) patients at baseline (table 1). NS5B nucleotide inhibitor resistance-associated substitutions were detected in ten (7%) of 147 patients at baseline (V321I n=2, M289L n=2, E237G n=2, and L159F n=4). Reported resistanceassociated substitutions were present in more than 15% of the sequence reads. All 147 patients completed sofosbuvir−velpatasvir−voxilaprevir treatment. 143 (97%; 95% CI 93–99) of 147 patients achieved the primary efficacy outcome of SVR12 (table 2). No patients had virological non-response (table 2). All 147 patients had HCV RNA concentrations below the LLOQ at the final treatment visit (table 2). The four patients who did not reach SVR12 relapsed; all had genotype 1a, and one had compensated cirrhosis at study entry. 48 (98%; 89–100) of 49 patients with compensated cirrhosis and 95 (97%; 91–99) of 98 patients without cirrhosis achieved SVR12 (table 3). 73 (96%; 89–99) of 76 patients previously exposed to an NS5A inhibitor and an NS5B inhibitor, and 60 (98%; 91–100) of 61 patients previously exposed to an NS5A inhibitor and an NS3/4A inhibitor with or without an NS5B inhibitor reached SVR12 (table 3). SVR12 was also achieved by 127 (97%; 92–99) of 131 patients with baseline resistance-associated substitutions, 14 (100%; 77–100) of 14 patients without resistance-associated substitutions, and two (100%; 16–100) of two patients
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whose baseline resistance-associated substitutions could not be determined (table 3). All patients with NS5B nucleotide inhibitor resistance-associated substitutions at baseline achieved SVR12. Of the 143 patients with SVR12, 138 (97%) returned for the post-treatment week 24 visit, and all 138 had sustained virological response at that visit. Of the four patients who did not achieve SVR12, all had resistance-associated substitutions at baseline and two developed treatment-emergent resistance (table 4). One patient had treatment-emergent NS3 resistanceassociated substitutions Y56H and D168A/V and the NS5A resistance-associated substitution L31M, and the other patient had treatment-emergent NS3 resistanceassociated sub stitution V36A. The NS3 substitutions V36A, Y56H, and D168A/V exhibited 2–4 times greater change in half maximal effective concentration in response to voxilaprevir in a genotype 1a replicon assay than did the wild-type control. The NS5A substitution L31M exhibited 16 times greater change in half maximal effective concentration in response to velpatasvir in a genotype 1a replicon assay than did the wild-type control. No NS5B nucleotide inhibitor resistance-associated substitutions emerged in any of these patients (table 4). 112 (76%) of 147 patients had at least one adverse event (table 5). The most commonly reported adverse events overall were fatigue (31 [21%]), headache (29 [20%]), diarrhoea (28 [19%]), and nausea (21 [14%]; table 5). Seven serious adverse events were reported among six patients (table 5). The serious adverse events were acute myocardial infarction, generalised tonic-clonic seizure, hepatocellular carcinoma, mesenteric vein thrombosis, and wrist fracture, each occurring in separate individuals, and nephrolithiasis and urosepsis occurring in a single patient. No serious adverse events were considered to be related to study treatment. The patient with hepatocellular carcinoma had compensated cirrhosis at entry into the study. With the exception of hepatocellular carcinoma, all serious adverse events resolved within the study follow-up period. No patients had adverse events leading to premature discontinuation of treatment (table 5). Two patients had sofosbuvir−velpatasvir−voxilaprevir dosing interrupted because of an adverse event. One patient with a history of hypertension and a cerebral haemorrhage more than 10 years before the study had a serious generalised tonic-clonic seizure that led to interruption of study drug from day 6 to day 8 of treatment. The patient initially received lorazapam and midazolam and began chronic treatment for the seizure with levetiracetam; this patient relapsed at the post-treatment week 4 visit. A second patient had their study drug interrupted from days 36 to 44 because of abdominal pain and back pain, and achieved sustained virological response after completing treatment. The only grade 3 or 4 laboratory abnormalities that occurred in more than one patient were elevated lipase (n=9; all asymptomatic with no cases of clinical pancreatitis), hyperglycaemia (n=3; all patients with a medical history of
NS3 resistance-associated substitutions
NS5A resistance-associated substitutions
Baseline
Relapse
Baseline
Relapse
Patient 1
Q80K
Q80K
M28T, Q30H
M28T, Q30H
Patient 2
T54S, V55I
T54S, V55I
Q30Q/L, Y93Y/H
Q30L, Y93H
Patient 3
None
Y56H*, D168A/V*
Y93N
L31L/M*, Y93N
Patient 4
Q80K
V36V/A*, Q80K
M28T, Q30H, H58N
M28T, Q30H, H58N
All patients had genotype 1a hepatitis C virus infection. No NS5B resistance-associated substitutions were observed. *Treatment-emergent resistance-associated substitution.
Table 4: Resistance-associated substitutions of patients who had virological relapse
Sofosbuvir–velpatasvir– voxilaprevir once daily for 12 weeks (n=147) Patients with any adverse event
112 (76%)
Patients with a grade 3 or 4 adverse event
7 (5%)
Patients with a serious adverse event
6 (4%)
Adverse events leading to discontinuation of study drug
0
Deaths
0
Adverse events in ≥5% of patients Fatigue
31 (21%)
Headache
29 (20%)
Diarrhoea
28 (19%)
Nausea
21 (14%)
Arthralgia
9 (6%)
Laboratory abnormalities (grade 3 or worse) Bilirubin (>2·5 to 5·0 × ULN)
2 (1%)
Creatine kinase (≥20·0 × ULN)
1 (1%)
Glucose (>250 to 500 mg/dL)
3 (2%)
Lipase >3·0 to 5·0 × ULN
8 (5%)
>5·0 × ULN
1 (1%)
Lymphocytes (per μL) 350 to 500
1 (1%)
<350
1 (1%)
Data are n (%). ULN=upper limit of normal.
Table 5: Adverse events and laboratory abnormalities
diabetes or glucose elevations while receiving placebo in the primary study), and hyperbilirubinaemia (n=2; both patients with compensated cirrhosis and grade 2 elevations in total bilirubin at baseline; table 5).
Discussion In this open-label substudy of POLARIS-1, once daily sofosbuvir−velpatasvir−voxilaprevir was highly effective in treatment of patients with chronic HCV infection who had a history of treatment failure with an NS5A inhibitorcontaining regimen. The SVR12 rate was 97% overall and 98% in patients previously treated with an NS5A inhibitor and an NS3/4A inhibitor. A substantial proportion of patients (89%) had baseline NS5A or NS3
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resistance-associated substitutions detected by deep sequencing with a 15% assay cutoff, but these had no discernible impact on the primary efficacy outcome. These results are consistent with those reported in the initial phase of POLARIS-1 and add to the confidence of the regimen by considerably increasing the number of patients treated with it. Combining the data in the primary and substudy portions of POLARIS-1, 396 (97%) of 410 patients were considered to be cured. Sofosbuvir−velpatasvir−voxilaprevir was well tolerated, with no treatment discontinuations due to adverse events and no clinically significant laboratory abnormalities. Compared with placebo and active treatment groups during the initial, blinded phase of the POLARIS-1 study, adverse events and serious adverse events observed during active treatment in the current substudy were similar, with 70%, 78%, and 76% of patients having any adverse event, and 5%, 2%, and 4% having serious adverse events, and the most common adverse events in all groups were fatigue (20%, 21%, and 21%), headache (17%, 25%, and 20%), and diarrhoea (13%, 18%, and 19%). The consistency of these efficacy and safety results further shows that sofosbuvir–velpatasvir–voxilaprevir for 12 weeks is a safe, well tolerated, and effective treatment for patients who previously had treatment failure with an NS5A inhibitor-containing direct-acting antiviral regimen, irrespective of the other drugs in the previous treatment regimen, cirrhosis status, or baseline resistance. To date, POLARIS-1 is the only phase 3 registration study dedicated to enrolment of patients who were previously treated with NS5A inhibitors, and there have been few data for retreatment of these patients from other clinical development programmes. An alternative treatment for these patients is combination therapy with the NS3/4A protease inhibitor glecaprevir and the NS5A inhibitor pibrentasvir. In the USA, glecaprevir− pibrentasvir is approved for patients with HCV genotype 1 infection who have received an NS5A inhibitor not in combination with an NS3/4A inhibitor, on the basis of data from 17 patients in the MAGELLAN-1 study.11–13 Glecaprevir–pibrentasvir is not recommended in the European Union for retreatment of patients with previous exposure to NS5A inhibitors or NS3/4A inhibitors.14 Small phase 2 studies15–17 suggest that the combination of sofosbuvir and ribavirin with grazoprevir–elbasvir or ombitasvir–paritaprevir–ritonavir plus dasabuvir is also effective in patients previously exposed to NS5A inhibitors. From a public health perspective, a highly effective and simple retreatment option for patients who do not respond to a direct-acting antiviral regimen is important, especially in efforts to eradicate hepatitis C. In 2016, WHO issued an advocacy brief calling for elimination of hepatitis C by 2030.18 Strategies to achieve this goal have been implemented in many regions, including Georgia, Iceland, and Australia.19 Salvage therapies are a crucial component of large-scale treatment initiatives. 6
One limitation of this study is that most patients were previously treated with the NS5A inhibitor ledipasvir, which was commonly used when the study began; however, other NS5A inhibitors (eg, daclatasvir and ombitasvir) are now increasingly being used. Although patients treated with the NS5A inhibitors daclatasvir and ombitasvir were represented in this study, they each comprised less than 20% of patients. However, the resistance-associated substitutions observed after treat ment with these NS5A inhibitors did not differ substantially from those observed following treatment with ledipasvir. In summary, treatment with sofosbuvir−velpatasvir− voxilaprevir for 12 weeks was highly effective in treatment of patients with chronic HCV genotype 1 infection who previously did not respond to treatment including an NS5A inhibitor. A salvage regimen for this population represents an important advance for individual patients and public health initiatives. Contributors RHH, LMS, GMS, DMB, and JGM contributed to the study design. MB, SCG, ERS, TTT, NR, CSL, LS, AJT, TES, MPC, KRR, and MPM were the investigators in this study. RHH, LMS, JZ (study statistician), and HD-S contributed to data interpretation. All authors contributed to the writing and review of the report. Declaration of interests MB has served on advisory boards for Gilead, AbbVie, Merck Sharp & Dohme (MSD), Janssen, Bristol-Myers Squibb (BMS), Novartis GlaxoSmithKline (GSK), Vertex, and Intercept, and has served as a speaker for Gilead, MSD, Janssen, AbbVie, and Intercept. SCG has served as a consultant for Gilead, AbbVie, Merck, Intercept, and Dova, and has received research grants from Gilead, AbbVie, Merck, Intercept, Shire, Cymba Bay, and Conatus. ERS has served on advisory boards for BMS, Gilead, and Merck, has served as a consultant for Dova Pharmaceutical and Arbutus Biopharma, has served on data monitoring boards for AstraZeneca, has received research grants from Beckman, BMS, Conatus, Discovery Life Sciences, Genfit, Gilead, Intercept, Novartis, Orasure Technologies, Ortho Diagnostics, Roche, Shire, Siemens, Target Pharma Solutions, University of Florida, and Novo Nordisk, and has received royalties from Wiley. TTT has received research grants, and has served on advisory boards, as a speaker, and consultant for Gilead, AbbVie, Merck, and BMS. NR has received research grants from Gilead, AbbVie, Merck, Shire, and Novartis, has served on advisory boards for Gilead and AbbVie, and has served as a speaker for Gilead, AbbVie, Merck, and Allergan. CSL has received research grants from Gilead and AbbVie. RHH, LMS, JZ, HD-S, GMS, DMB, and JGM are employees of Gilead Sciences and hold stock interest in the company. LS has received research grants from AbbVie, Allergan, BMS, Gilead, Intercept, Merck, Novartis, and Sanofi. AJT has served on advisory boards for Gilead, AbbVie, BMS, and Merck, has served as a speaker for Gilead, Merck, BMS, AbbVie, and Roche Diagnostics, has served as a study investigator for Gilead, Merck, AbbVie, BMS, Genfit, Arrowhead, Spring Bank, Sillajen, and Novartis, and has received research and grant support from Gilead, Merck, BMS, AbbVie, and Bayer. TES has received grant support from Gilead, Allergan, Intercept, Conatus, Cirius, and BMS, has served as a speaker for Gilead, AbbVie, Intercept, and Merck, and has served on advisory boards for Gilead, Intercept, and AbbVie. MPC has received financial compensation for consultancy from AbbVie, BMS and Trio Health Analytics, and research grant support from Gilead, Mallinckrodt, and Conatus. KRR has served on advisory boards for Gilead, Merck, BMS, Janssen, and AbbVie, and has received research grants (paid to the University of Pennsylvania) from Merck, Gilead, AbbVie, BMS, Janssen, and Conatus. MPM has received financial compensation for consultancy or lecture activities from AbbVie, Boehringer Ingelheim, BMS, Idenix, Gilead, GSK, Janssen, Merck, Novartis, Roche, and research grants from AbbVie, Boehringer Ingelheim, BMS, Gilead, Janssen Therapeutics, Merck, Novartis, and Roche.
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Acknowledgments We thank the patients and their families as well as the study-site personnel. Writing assistance was provided by Jennifer King (August Editorial; Durham, NC, USA) and was funded by Gilead Sciences. Editorial assistance was provided by Sandra Chen (Gilead Sciences; Foster City, CA, USA). References 1 Yoshimi S, Imamura M, Murakami E, et al. Long term persistence of NS5A inhibitor-resistant hepatitis C virus in patients who failed daclatasvir and asunaprevir therapy. J Med Virol 2015; 87: 1913–20. 2 Kumada H, Suzuki Y, Ikeda K, et al. Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection. Hepatology 2014; 59: 2083–91. 3 Esposito I, Trinks J, Soriano V. Hepatitis C virus resistance to the new direct-acting antivirals. Expert Opin Drug Metab Toxicol 2016; 12: 1197–209. 4 Itakura J, Kurosaki M, Hasebe C, et al. Complex pattern of resistance-associated substitutions of hepatitis C virus after daclatasvir/asunaprevir treatment failure. PLoS One 2016; 11: e0165339. 5 Iio E, Shimada N, Abe H, et al. Efficacy of daclatasvir/asunaprevir according to resistance-associated variants in chronic hepatitis C with genotype 1. J Gastroenterol 2017; 52: 94–103. 6 Carrasco I, Arias A, Benítez-Gutiérrez L, et al. Baseline NS5A resistance associated substitutions may impair DAA response in real-world hepatitis C patients. J Med Virol 2018; 90: 532–36. 7 Bourlière M, Gordon SC, Flamm SL, et al. Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection. N Engl J Med 2017; 376: 2134–46. 8 Struble K, Chan-Tack K, Qi K, Naeger LK, Birnkrant D. Benefit-risk assessment for sofosbuvir/velpatasvir/voxilaprevir based on patient population and hepatitis C virus genotype: U. S. Food and Drug Administration’s evaluation. Hepatology 2017; published online Oct 23. DOI:10.1002/hep.29601. 9 Gilead Sciences, Inc. VOSEVI (sofosbuvir, velpatasvir, and voxilaprevir) prescribing information. Foster City, CA: Gilead Sciences Inc, 2017.
10 Gilead Sciences International Ltd. VOSEVI (sofosbuvir/velpatasvir/ voxilaprevir) summary of product characteristics. Cambridge: Gilead Sciences International Ltd, 2017. 11 AbbVie Inc. MAVYRET (glecaprevir and pibrentasvir) prescribing information. North Chicago, IL; AbbVie Inc, 2017. 12 Poordad F, Felizarta F, Asatryan A, et al. Glecaprevir and pibrentasvir for 12 weeks for hepatitis C virus genotype 1 infection and prior direct-acting antiviral treatment. Hepatology 2017; 66: 389–97. 13 Poordad F, Pol S, Asatryan A, et al. Glecaprevir/pibrentasvir in patients with hepatitis C virus genotype 1 or 4 and past direct-acting antiviral treatment failure. Hepatology 2018; 67: 1253–60. 14 AbbVie Ltd. MAVIRET (glecaprevir/pibrentasvir) summary of product characteristics. Maidenhead: AbbVie Ltd, 2017. 15 Lawitz E, Poordad F, Gutierrez JA, et al. Short-duration treatment with elbasvir/grazoprevir and sofosbuvir for hepatitis C: a randomized trial. Hepatology 2017; 65: 439–50. 16 de Lédinghen V, Laforest C, Hézode C, et al. Retreatment with sofosbuvir plus grazoprevir/elbasvir plus ribavirin of patients with hepatitis C virus genotype 1 or 4 who previously failed a NS5A or NS3-containing regimen: the ANRS HC34 REVENGE study. Clin Infect Dis 2018; 66: 1013–18. 17 Poordad F, Bennett M, Sepe TE, et al. Ombitasvir/paritaprevir/r, dasabuvir, and sofosbuvir treatment of patients with HCV genotype 1-infection who failed a prior course of DAA therapy: the QUARTZ-I study. J Hepatol 2016; 64 (suppl 1): S767–68. 18 WHO. Combating hepatitis B and C to reach elimination by 2030. May, 2016. http://apps.who.int/iris/bitstream/10665/206453/1/ WHO_HIV_2016.04_eng.pdf?ua=1 (accessed Dec 18, 2017). 19 Mitruka K, Tsertsvadze T, Butsashvili M, et al. Launch of a nationwide hepatitis C elimination program—Georgia, April 2015. MMWR Morb Mortal Wkly Rep 2015; 64: 753–57.
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Deferred treatment with sofosbuvir–velpatasvir–voxilaprevir for patients with chronic hepatitis C virus who were previously treated with an NS5A inhibitor: an open-label substudy of POLARIS-1 Marc Bourlière, Stuart C Gordon, Eugene R Schiff, Tram T Tran, Natarajan Ravendhran, Charles S Landis, Robert H Hyland, Luisa M Stamm, Jie Zhang, Hadas Dvory-Sobol, G Mani Subramanian, Diana M Brainard, John G McHutchison, Lawrence Serfaty, Alex J Thompson, Thomas E Sepe, Michael P Curry, K Rajender Reddy, Michael P Manns
Summary
Background Direct-acting antiviral regimens containing NS5A inhibitors are highly effective treatments for chronic hepatitis C virus (HCV) infection, but are not always successful. In the POLARIS-1 phase 3 study, sofosbuvir−velpatasvir−voxilaprevir for 12 weeks was highly effective in the treatment of chronic HCV infection in patients previously treated with a direct-acting antiviral regimen containing an NS5A inhibitor. We aimed to assess the efficacy and safety of sofosbuvir−velpatasvir−voxilaprevir in patients from the deferred treatment group of POLARIS-1, who were initially assigned to masked placebo treatment. Methods This open-label, deferred treatment substudy was done at 73 clinical sites (hospitals and clinics) in the USA, France, Canada, the UK, Germany, Australia, and New Zealand. Patients who received placebo in the primary study and who did not have a new clinically significant illness at the post-treatment week 4 assessment were eligible to enter this substudy. Participants received a combination tablet of sofosbuvir (400 mg), velpatasvir (100 mg), and voxilaprevir (100 mg) once daily for 12 weeks. The primary efficacy outcome was achievement of sustained virological response (defined as HCV RNA concentration below the lower limit of quantification) 12 weeks after the end of treatment (SVR12). The primary safety outcome was the proportion of patients who discontinued treatment due to adverse events. This study is registered with ClinicalTrials.gov, number NCT02607735, and the EU Clinical Trials Register, number 2015-003455-21. Findings 152 patients received placebo in the primary study and were potentially eligible for participation in the open-label substudy, of whom 147 were enrolled from March 30, 2016, to Oct 12, 2016. All 147 patients completed treatment, and 143 (97%; 95% CI 93–99) achieved SVR12. Four (3%) patients had virological relapse; all had HCV genotype 1a infection and one also had compensated cirrhosis. The most common adverse events were fatigue (31 [21%]), headache (29 [20%]), diarrhoea (28 [19%]), and nausea (21 [14%]). No deaths, treatment discontinuations, or treatment-related serious adverse events occurred. Interpretation Supporting the results from the blinded portion of the phase 3 primary study, the single-tablet regimen of sofosbuvir−velpatasvir−voxilaprevir for 12 weeks was safe, well tolerated, and highly effective in patients with chronic HCV infection who had previous treatment failure with NS5A inhibitor-containing regimens. A salvage regimen for this population represents an important advance for patients with limited retreatment options. Funding Gilead Sciences. Copyright © 2018 Elsevier Ltd. All rights reserved.
Introduction Worldwide, a small but growing population of patients with chronic hepatitis C virus (HCV) infection has been unsuccessfully treated with a direct-acting antiviral regimen; most of these patients have received regimens that include an NS5A inhibitor. NS5A inhibitors are the most potent class of direct-acting antivirals but have a relatively low barrier to resistance compared with other classes, such as non-nucleotide HCV NS5B inhibitors. Particularly when administered without an NS5B inhibitor, NS5A resistance at the time of virological
failure is nearly universal in patients who do not respond to treatment with a regimen including an NS5A inhibitor. Furthermore, NS5A resistance-associated substitutions usually persist long term1 and are associated with a reduced response to treatment regimens containing NS5A inhibitors, especially in patients with advanced cirrhosis, HCV genotype 1a or 3 infection, or previous failure of interferon treatment.2–6 To date, the POLARIS-1 study7 has been the only phase 3 study to exclusively enrol patients who did not respond to previous treatment with an NS5A inhibitor. The study
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Lancet Gastroenterol Hepatol 2018 Published Online May 30, 2018 http://dx.doi.org/10.1016/ S2468-1253(18)30118-3 See Online/Comment http://dx.doi.org/10.1016/ S2468-1253(18)30162-6 Hépato-Gastroentérologie, Hôpital Saint Joseph, Marseille, France (M Bourlière MD); Henry Ford Health System, Detroit, MI, USA (S C Gordon MD); Schiff Center for Liver Diseases, University of Miami, Coral Gables, FL, USA (Prof E R Schiff MD); Cedars-Sinai Medical Center, Los Angeles, CA, USA (T T Tran MD); Digestive Disease Associates, Catonsville, MD, USA (N Ravendhran MD); Division of Gastroenterology and Hepatology, Department of Medicine, University of Washington, Seattle, WA, USA (C S Landis MD); Gilead Sciences, Foster City, CA, USA (R H Hyland DPhil, L M Stamm MD, J Zhang PhD, H Dvory-Sobol PhD, G M Subramanian MD, D M Brainard MD, J G McHutchison MD); Service d’Hépatologie, Hôpital Saint-Antoine, Paris, France (L Serfaty MD); St Vincent’s Hospital and the University of Melbourne, Melbourne, Fitzroy, VIC, Australia (A J Thompson MD); Liver Center, University Gastroenterology, Providence, RI, USA (Prof T E Sepe MD); Beth Israel Deaconess Medical Center, Boston, MA, USA (M P Curry MD); Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA (Prof K R Reddy MD); and Medizinischen Hochschule, Hannover, Germany (Prof M P Manns MD)
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Correspondence to: Dr Marc Bourlière, Hépato-Gastroentérologie, Hôpital Saint-Joseph, Marseille 13008, France [email protected]
Research in context Evidence before this study Before the approval of sofosbuvir–velpatasvir–voxilaprevir, no retreatment options were approved for patients with chronic hepatitis C virus infection who had been treated with a direct-acting antiviral regimen containing an NS5A inhibitor. The POLARIS-1 study was the first phase 3 registrational, randomised, placebo-controlled trial to enrol and treat such patients, as we confirmed by a review of PubMed using the search terms, “HCV”, “NS5A treatment-experienced”, “prior DAA experience”, and “salvage therapy”, for clinical trials published by Aug 21, 2015. In the primary study of POLARIS-1, 253 (96%) of 263 patients who received sofosbuvir–velpatasvir–voxilaprevir for 12 weeks achieved sustained virological response. Added value of this study In the current substudy of POLARIS-1, patients with genotype 1 hepatitis C virus infection assigned to the placebo
assessed 12 weeks of therapy with a combination of sofosbuvir (an NS5B inhibitor), velpatasvir (an NS5A inhibitor), and voxilaprevir (an NS3/4A protease inhibitor) versus placebo. Among 263 patients who received sofosbuvir−velpatasvir−voxilaprevir, 253 (96%) achieved sustained virological response, compared with none of the 152 patients who received placebo. On the basis of the results from POLARIS-1, sofosbuvir−velpatasvir− voxilaprevir has been approved in the USA and European Union as a pan-genotypic salvage regimen for patients previously given an NS5A inhibitor.8–10 Patients in POLARIS-1 who were masked to treatment and initially received placebo were eligible for a subsequent open-label substudy in which they would receive sofosbuvir−velpatasvir−voxilaprevir for 12 weeks. We report the safety and efficacy results of the deferred treatment substudy.
Methods
Study design and participants This open-label deferred treatment substudy from the international phase 3, multicentre POLARIS-1 study7 was done at 73 clinical sites (hospitals and clinics) in the USA, France, Canada, the UK, Germany, Australia, and New Zealand. The initial phase of POLARIS-1 was a blinded, randomised study comparing 12 weeks of once-daily treatment with either placebo or a combination tablet containing sofosbuvir, velpatasvir, and voxilaprevir. Assignments were unblinded 4 weeks after treatment. Patients who com pleted 12 weeks of treatment with placebo and did not have a new clinically significant illness at the post-treatment week 4 visit were eligible to enter the deferred treatment substudy. At enrolment for the primary study, eligible patients had chronic HCV infection and had previously been treated with an NS5A inhibitor for at least 4 weeks. Other inclusion 2
group in the primary study of POLARIS-1 were subsequently treated with sofosbuvir–velpatasvir–voxilaprevir for 12 weeks to assess efficacy and safety. The large number of patients (143 [97%] of 147) treated in this deferred treatment substudy who achieved sustained virological response further supports the efficacy and safety of treatment in the primary study. Combined with the results of the primary study of POLARIS-1, 396 (97%) of 410 patients have achieved sustained virological response in clinical trials with sofosbuvir–velpatasvir–voxilaprevir. Implications of all the available evidence These results support the use of sofosbuvir–velpatasvir– voxilaprevir for the treatment of chronic hepatitis C virus infection in patients with NS5A inhibitor experience, regardless of which direct-acting antivirals were used in previous treatments.
criteria included HCV genotype 1 as determined by the Abbott RealTime HCV Genotype II assay (Abbott, Chicago, IL, USA), age 18 years or older, body-mass index of at least 18 kg/m², and plasma HCV RNA concentrations of at least 104 IU/mL. Patients without cirrhosis or with compensated cirrhosis were eligible for participation. The presence of cirrhosis was determined by: liver biopsy with a Metavir score of 4 or Ishak score of 5 or more; a Fibroscan score of more than 12·5 kPa; or a FibroTest score of more than 0·75 and an aspartate aminotransferase:platelet ratio index value of more than 2. Patients were excluded if they had any of the following conditions: platelet count of less than 50 000 per µL, haemoglobin concentration of less than 10 g/dL, alanine aminotransferase or aspartate aminotransferase concentrations of more than 10 × upper limit of normal (ULN), direct bilirubin concentration of more than 1·5 × ULN, glycated haemoglobin A1c concentrations of more than 8·5%, creatinine clearance of less than 50 mL/min (determined using the CockcroftGault equation), albumin concentration of less than 3 g/dL, international normalised ratio of prothrombin time of more than 1·5 × ULN, or infection with hepatitis B or HIV. Patients provided written informed consent for the primary study and the deferred treatment substudy before undergoing any study-related procedures. The study protocol7 was approved by the review board or ethics committee of each institution before study initiation. The study was done in accordance with the International Conference on Harmonization Good Clinical Practice Guidelines and the Declaration of Helsinki.
Procedures Patients received a once-daily combination tablet of sofosbuvir (400 mg), velpatasvir (100 mg), and voxilaprevir (100 mg). After completing 12 weeks of
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treatment, patients underwent follow-up visits at post-treatment weeks 4, 12, and 24. Screening assessments included measurement of plasma HCV RNA concentration and genotyping, IL28B genotyping, and standard laboratory tests (haematology, coagulation, chemistry, and urinalysis) and clinical tests (physical examinations and assessments of vital signs). HCV RNA concentrations were quantified with the COBAS Ampliprep/COBAS TaqMan HCV Test, version 2.0 (Roche Molecular Systems, Branchburg, NJ, USA), which has a lower limit of quantification (LLOQ) of 15 IU/mL. At screening, HCV genotype and subtype were determined using the Abbott RealTime HCV Genotype II assay, which is unable to distinguish genotype 6 from genotype 1. Subsequently, HCV genotype and subtype were determined by analysis of NS3/4A, NS5A, and NS5B sequences obtained by deep sequencing with use of the Basic Local Alignment Search Tool; these results were used in the reported analyses. IL28B genotype was determined by PCR amplification of the single-nucleotide polymorphism rs12979860, with sequence-specific forward and reverse primers and allele-specific fluorescently labelled TaqMan minor groove binder probes at the start of the primary study. Plasma HCV RNA concentrations were evaluated at every study visit, including screening; day 1 of treatment; treatment weeks 1, 2, 4, 8, 10, and 12; and post-treatment weeks 4, 12, and 24. Post-treatment week 12 HCV RNA assessments that were missing were imputed as less than the LLOQ only if preceding and subsequent assessments were less than the LLOQ. Plasma samples for viral sequencing were collected at all treatment and follow-up visits. Deep sequencing of the NS5A, NS3/4A, and NS5B coding regions was done on samples obtained from all patients at baseline of the initial phase of POLARIS-1 (before placebo treatment) and from those with virological failure at the time of treatment failure. Sequences obtained at the time of virological failure were compared with sequences from baseline samples to detect treatment-emergent resistance-associated substitutions. Physical examinations were done at screening, on treatment day 1, and at the final treatment visit. Vital signs, adverse events, concomitant medication intake, and clinical laboratory assessments were collected at screening, every treatment visit, and at the post-treatment week 4 visit, but not up to the week 12 visit. Adverse events were coded using the Medical Dictionary for Regulatory Activities, version 20.0.
Outcomes For this substudy, the primary efficacy outcome was achievement of sustained virological response at post-treatment week 12 (SVR12), defined as HCV RNA concentration below the LLOQ 12 weeks after
discontinuing study drugs. The primary safety outcome was the proportion of patients who discontinued treatment because of adverse events.
Statistical analysis We did not calculate sample size because enrolment into this substudy was conditional on the placebo sample size from the initial phase of the POLARIS-1 study. No statistical hypothesis testing was done for the primary efficacy outcome. For the percentage of patients achieving SVR12, we constructed a two-sided 95% exact CI using the Clopper-Pearson method. We summarised safety results descriptively. We used SAS version 9.4 for statistical analyses. No data monitoring committee was used for this deferred treatment study. Sofosbuvir–velpatasvir– voxilaprevir once daily for 12 weeks (n=147) Age (years)
60 (55–64)
Sex Male Female
116 (79%) 31 (21%)
Race White Black or African American Asian Body-mass index (kg/m²)
121 (82%) 20 (14%) 6 (4%) 28 (25–32)
HCV genotype 1
145 (99%) 1a
113 (77%)
1b
30 (20%)
1 other 6 HCV RNA (log10 IU/mL)
2 (1%) 2 (1%) 6·3 (0·53)
Compensated cirrhosis Yes
49 (33%)
No
98 (67%)
IL28B genotype CC
26 (18%)
CT
89 (61%)
TT
32 (22%)
Previous direct-acting antivirals by class of inhibitor NS5A and NS5B
76 (52%)
NS5A and NS3/4A with or without NS5B
61 (42%)
NS5A with or without other
9 (6%)
NS5B with or without NS3/4A
1 (1%)
Baseline NS3 or NS5A resistance-associated substitutions* None
14 (10%)
NS3 only
10 (7%)
NS5A only
60 (41%)
NS3 and NS5A
61 (41%)
Data are median (IQR), n (%), or mean (SD). HCV=hepatitis C virus. *Complete sequencing data were not available for two patients.
Table 1: Patient demographics and baseline characteristics
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Sofosbuvir–velpatasvir– voxilaprevir once daily for 12 weeks (n=147)
Sofosbuvir–velpatasvir– voxilaprevir once daily for 12 weeks (n=147)
Hepatitis C virus RNA concentration <15 IU/mL
Compensated cirrhosis
On treatment
Yes
48/49 (98%)
Week 1
21 (14%)
No
95/98 (97%)
Week 2
92 (63%)
Hepatitis C virus genotype
Week 4
137 (93%)
Week 8
147 (100%)
1 (all subtypes) 1a
109/113 (97%)
Week 12
147 (100%)
1b
30/30 (100%)
After treatment
1 other
141/145 (97%)
2/2 (100%)
Week 4
145 (99%; 95–100)
6
Week 12 (SVR12)
143 (97%; 93–99)
Previous direct-acting antivirals by class of inhibitor
Virological failure
2/2 (100%)
NS5A and NS5B
73/76 (96%)
On treatment
0
NS5A and NS3/4A with or without NS5B
60/61 (98%)
Relapse
4 (3%)
NS5A with or without other
9/9 (100%)
Data are n (%) or n (%; 95% CI). SVR12=sustained virological response 12 weeks after treatment.
Other
1/1 (100%)
Table 2: Treatment response to sofosbuvir−velpatasvir−voxilaprevir
None
This trial is registered with ClinicalTrials.gov, number NCT02607735 and EudraCT, number 2015-003455-21.
Baseline NS3 or NS5A resistance-associated substitutions* NS3 or NS5A
14/14 (100%) 127/131 (97%)
NS3 only
10/10 (100%)
NS5A only
59/60 (98%)
NS3 and NS5A
58/61 (95%)
Data are n/N (%). *Complete sequencing data were not available for two patients.
Role of the funding source The sponsor (Gilead Sciences) collected the data, monitored study conduct, did the statistical analyses, and interpreted the data. The first draft of the manuscript was prepared by a professional writer funded by the sponsor, with the final version incorporating input from all authors. The corresponding author had full access to all of the data in the study and had the final responsibility to submit for publication.
Results 152 patients received placebo in the primary study and were potentially eligible for participation in the open-label substudy, 147 of whom were enrolled from March 30, 2016, to Oct 12, 2016. Five patients enrolled in the primary study were not eligible for the deferred treatment substudy; three patients had discontinued placebo in the primary study, and two patients developed new clinically significant illnesses (namely, liver decompensation and prostate cancer). The median age for the substudy population was 60 years (IQR 55–64; table 1). 49 (33%) patients had compensated cirrhosis, and 121 (82%) patients had a non-CC IL28B genotype (table 1). Most patients (113 [77%]) had HCV genotype 1a (30 [20%] had genotype 1b, and two had genotype 6; table 1). 76 (52%) patients had previously been treated with an NS5A inhibitor and NS5B inhibitor without an NS3/4A protease inhibitor; all but four of them had received ledipasvir− sofosbuvir (table 1). Ledipasvir was the most commonly received NS5A inhibitor (91 [62%] patients), followed by daclatasvir (27 [18%] patients) and ombitasvir (24 [16%] patients). One patient had not previously been treated 4
Table 3: Sustained virological response 12 weeks after treatment by select subgroups
with an NS5A inhibitor; this patient had received sofosbuvir and simeprevir. NS3 or NS5A resistanceassociated substitutions were present in 131 (89%) patients at baseline (table 1). NS5B nucleotide inhibitor resistance-associated substitutions were detected in ten (7%) of 147 patients at baseline (V321I n=2, M289L n=2, E237G n=2, and L159F n=4). Reported resistanceassociated substitutions were present in more than 15% of the sequence reads. All 147 patients completed sofosbuvir−velpatasvir−voxilaprevir treatment. 143 (97%; 95% CI 93–99) of 147 patients achieved the primary efficacy outcome of SVR12 (table 2). No patients had virological non-response (table 2). All 147 patients had HCV RNA concentrations below the LLOQ at the final treatment visit (table 2). The four patients who did not reach SVR12 relapsed; all had genotype 1a, and one had compensated cirrhosis at study entry. 48 (98%; 89–100) of 49 patients with compensated cirrhosis and 95 (97%; 91–99) of 98 patients without cirrhosis achieved SVR12 (table 3). 73 (96%; 89–99) of 76 patients previously exposed to an NS5A inhibitor and an NS5B inhibitor, and 60 (98%; 91–100) of 61 patients previously exposed to an NS5A inhibitor and an NS3/4A inhibitor with or without an NS5B inhibitor reached SVR12 (table 3). SVR12 was also achieved by 127 (97%; 92–99) of 131 patients with baseline resistance-associated substitutions, 14 (100%; 77–100) of 14 patients without resistance-associated substitutions, and two (100%; 16–100) of two patients
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whose baseline resistance-associated substitutions could not be determined (table 3). All patients with NS5B nucleotide inhibitor resistance-associated substitutions at baseline achieved SVR12. Of the 143 patients with SVR12, 138 (97%) returned for the post-treatment week 24 visit, and all 138 had sustained virological response at that visit. Of the four patients who did not achieve SVR12, all had resistance-associated substitutions at baseline and two developed treatment-emergent resistance (table 4). One patient had treatment-emergent NS3 resistanceassociated substitutions Y56H and D168A/V and the NS5A resistance-associated substitution L31M, and the other patient had treatment-emergent NS3 resistanceassociated sub stitution V36A. The NS3 substitutions V36A, Y56H, and D168A/V exhibited 2–4 times greater change in half maximal effective concentration in response to voxilaprevir in a genotype 1a replicon assay than did the wild-type control. The NS5A substitution L31M exhibited 16 times greater change in half maximal effective concentration in response to velpatasvir in a genotype 1a replicon assay than did the wild-type control. No NS5B nucleotide inhibitor resistance-associated substitutions emerged in any of these patients (table 4). 112 (76%) of 147 patients had at least one adverse event (table 5). The most commonly reported adverse events overall were fatigue (31 [21%]), headache (29 [20%]), diarrhoea (28 [19%]), and nausea (21 [14%]; table 5). Seven serious adverse events were reported among six patients (table 5). The serious adverse events were acute myocardial infarction, generalised tonic-clonic seizure, hepatocellular carcinoma, mesenteric vein thrombosis, and wrist fracture, each occurring in separate individuals, and nephrolithiasis and urosepsis occurring in a single patient. No serious adverse events were considered to be related to study treatment. The patient with hepatocellular carcinoma had compensated cirrhosis at entry into the study. With the exception of hepatocellular carcinoma, all serious adverse events resolved within the study follow-up period. No patients had adverse events leading to premature discontinuation of treatment (table 5). Two patients had sofosbuvir−velpatasvir−voxilaprevir dosing interrupted because of an adverse event. One patient with a history of hypertension and a cerebral haemorrhage more than 10 years before the study had a serious generalised tonic-clonic seizure that led to interruption of study drug from day 6 to day 8 of treatment. The patient initially received lorazapam and midazolam and began chronic treatment for the seizure with levetiracetam; this patient relapsed at the post-treatment week 4 visit. A second patient had their study drug interrupted from days 36 to 44 because of abdominal pain and back pain, and achieved sustained virological response after completing treatment. The only grade 3 or 4 laboratory abnormalities that occurred in more than one patient were elevated lipase (n=9; all asymptomatic with no cases of clinical pancreatitis), hyperglycaemia (n=3; all patients with a medical history of
NS3 resistance-associated substitutions
NS5A resistance-associated substitutions
Baseline
Relapse
Baseline
Relapse
Patient 1
Q80K
Q80K
M28T, Q30H
M28T, Q30H
Patient 2
T54S, V55I
T54S, V55I
Q30Q/L, Y93Y/H
Q30L, Y93H
Patient 3
None
Y56H*, D168A/V*
Y93N
L31L/M*, Y93N
Patient 4
Q80K
V36V/A*, Q80K
M28T, Q30H, H58N
M28T, Q30H, H58N
All patients had genotype 1a hepatitis C virus infection. No NS5B resistance-associated substitutions were observed. *Treatment-emergent resistance-associated substitution.
Table 4: Resistance-associated substitutions of patients who had virological relapse
Sofosbuvir–velpatasvir– voxilaprevir once daily for 12 weeks (n=147) Patients with any adverse event
112 (76%)
Patients with a grade 3 or 4 adverse event
7 (5%)
Patients with a serious adverse event
6 (4%)
Adverse events leading to discontinuation of study drug
0
Deaths
0
Adverse events in ≥5% of patients Fatigue
31 (21%)
Headache
29 (20%)
Diarrhoea
28 (19%)
Nausea
21 (14%)
Arthralgia
9 (6%)
Laboratory abnormalities (grade 3 or worse) Bilirubin (>2·5 to 5·0 × ULN)
2 (1%)
Creatine kinase (≥20·0 × ULN)
1 (1%)
Glucose (>250 to 500 mg/dL)
3 (2%)
Lipase >3·0 to 5·0 × ULN
8 (5%)
>5·0 × ULN
1 (1%)
Lymphocytes (per μL) 350 to 500
1 (1%)
<350
1 (1%)
Data are n (%). ULN=upper limit of normal.
Table 5: Adverse events and laboratory abnormalities
diabetes or glucose elevations while receiving placebo in the primary study), and hyperbilirubinaemia (n=2; both patients with compensated cirrhosis and grade 2 elevations in total bilirubin at baseline; table 5).
Discussion In this open-label substudy of POLARIS-1, once daily sofosbuvir−velpatasvir−voxilaprevir was highly effective in treatment of patients with chronic HCV infection who had a history of treatment failure with an NS5A inhibitorcontaining regimen. The SVR12 rate was 97% overall and 98% in patients previously treated with an NS5A inhibitor and an NS3/4A inhibitor. A substantial proportion of patients (89%) had baseline NS5A or NS3
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resistance-associated substitutions detected by deep sequencing with a 15% assay cutoff, but these had no discernible impact on the primary efficacy outcome. These results are consistent with those reported in the initial phase of POLARIS-1 and add to the confidence of the regimen by considerably increasing the number of patients treated with it. Combining the data in the primary and substudy portions of POLARIS-1, 396 (97%) of 410 patients were considered to be cured. Sofosbuvir−velpatasvir−voxilaprevir was well tolerated, with no treatment discontinuations due to adverse events and no clinically significant laboratory abnormalities. Compared with placebo and active treatment groups during the initial, blinded phase of the POLARIS-1 study, adverse events and serious adverse events observed during active treatment in the current substudy were similar, with 70%, 78%, and 76% of patients having any adverse event, and 5%, 2%, and 4% having serious adverse events, and the most common adverse events in all groups were fatigue (20%, 21%, and 21%), headache (17%, 25%, and 20%), and diarrhoea (13%, 18%, and 19%). The consistency of these efficacy and safety results further shows that sofosbuvir–velpatasvir–voxilaprevir for 12 weeks is a safe, well tolerated, and effective treatment for patients who previously had treatment failure with an NS5A inhibitor-containing direct-acting antiviral regimen, irrespective of the other drugs in the previous treatment regimen, cirrhosis status, or baseline resistance. To date, POLARIS-1 is the only phase 3 registration study dedicated to enrolment of patients who were previously treated with NS5A inhibitors, and there have been few data for retreatment of these patients from other clinical development programmes. An alternative treatment for these patients is combination therapy with the NS3/4A protease inhibitor glecaprevir and the NS5A inhibitor pibrentasvir. In the USA, glecaprevir− pibrentasvir is approved for patients with HCV genotype 1 infection who have received an NS5A inhibitor not in combination with an NS3/4A inhibitor, on the basis of data from 17 patients in the MAGELLAN-1 study.11–13 Glecaprevir–pibrentasvir is not recommended in the European Union for retreatment of patients with previous exposure to NS5A inhibitors or NS3/4A inhibitors.14 Small phase 2 studies15–17 suggest that the combination of sofosbuvir and ribavirin with grazoprevir–elbasvir or ombitasvir–paritaprevir–ritonavir plus dasabuvir is also effective in patients previously exposed to NS5A inhibitors. From a public health perspective, a highly effective and simple retreatment option for patients who do not respond to a direct-acting antiviral regimen is important, especially in efforts to eradicate hepatitis C. In 2016, WHO issued an advocacy brief calling for elimination of hepatitis C by 2030.18 Strategies to achieve this goal have been implemented in many regions, including Georgia, Iceland, and Australia.19 Salvage therapies are a crucial component of large-scale treatment initiatives. 6
One limitation of this study is that most patients were previously treated with the NS5A inhibitor ledipasvir, which was commonly used when the study began; however, other NS5A inhibitors (eg, daclatasvir and ombitasvir) are now increasingly being used. Although patients treated with the NS5A inhibitors daclatasvir and ombitasvir were represented in this study, they each comprised less than 20% of patients. However, the resistance-associated substitutions observed after treat ment with these NS5A inhibitors did not differ substantially from those observed following treatment with ledipasvir. In summary, treatment with sofosbuvir−velpatasvir− voxilaprevir for 12 weeks was highly effective in treatment of patients with chronic HCV genotype 1 infection who previously did not respond to treatment including an NS5A inhibitor. A salvage regimen for this population represents an important advance for individual patients and public health initiatives. Contributors RHH, LMS, GMS, DMB, and JGM contributed to the study design. MB, SCG, ERS, TTT, NR, CSL, LS, AJT, TES, MPC, KRR, and MPM were the investigators in this study. RHH, LMS, JZ (study statistician), and HD-S contributed to data interpretation. All authors contributed to the writing and review of the report. Declaration of interests MB has served on advisory boards for Gilead, AbbVie, Merck Sharp & Dohme (MSD), Janssen, Bristol-Myers Squibb (BMS), Novartis GlaxoSmithKline (GSK), Vertex, and Intercept, and has served as a speaker for Gilead, MSD, Janssen, AbbVie, and Intercept. SCG has served as a consultant for Gilead, AbbVie, Merck, Intercept, and Dova, and has received research grants from Gilead, AbbVie, Merck, Intercept, Shire, Cymba Bay, and Conatus. ERS has served on advisory boards for BMS, Gilead, and Merck, has served as a consultant for Dova Pharmaceutical and Arbutus Biopharma, has served on data monitoring boards for AstraZeneca, has received research grants from Beckman, BMS, Conatus, Discovery Life Sciences, Genfit, Gilead, Intercept, Novartis, Orasure Technologies, Ortho Diagnostics, Roche, Shire, Siemens, Target Pharma Solutions, University of Florida, and Novo Nordisk, and has received royalties from Wiley. TTT has received research grants, and has served on advisory boards, as a speaker, and consultant for Gilead, AbbVie, Merck, and BMS. NR has received research grants from Gilead, AbbVie, Merck, Shire, and Novartis, has served on advisory boards for Gilead and AbbVie, and has served as a speaker for Gilead, AbbVie, Merck, and Allergan. CSL has received research grants from Gilead and AbbVie. RHH, LMS, JZ, HD-S, GMS, DMB, and JGM are employees of Gilead Sciences and hold stock interest in the company. LS has received research grants from AbbVie, Allergan, BMS, Gilead, Intercept, Merck, Novartis, and Sanofi. AJT has served on advisory boards for Gilead, AbbVie, BMS, and Merck, has served as a speaker for Gilead, Merck, BMS, AbbVie, and Roche Diagnostics, has served as a study investigator for Gilead, Merck, AbbVie, BMS, Genfit, Arrowhead, Spring Bank, Sillajen, and Novartis, and has received research and grant support from Gilead, Merck, BMS, AbbVie, and Bayer. TES has received grant support from Gilead, Allergan, Intercept, Conatus, Cirius, and BMS, has served as a speaker for Gilead, AbbVie, Intercept, and Merck, and has served on advisory boards for Gilead, Intercept, and AbbVie. MPC has received financial compensation for consultancy from AbbVie, BMS and Trio Health Analytics, and research grant support from Gilead, Mallinckrodt, and Conatus. KRR has served on advisory boards for Gilead, Merck, BMS, Janssen, and AbbVie, and has received research grants (paid to the University of Pennsylvania) from Merck, Gilead, AbbVie, BMS, Janssen, and Conatus. MPM has received financial compensation for consultancy or lecture activities from AbbVie, Boehringer Ingelheim, BMS, Idenix, Gilead, GSK, Janssen, Merck, Novartis, Roche, and research grants from AbbVie, Boehringer Ingelheim, BMS, Gilead, Janssen Therapeutics, Merck, Novartis, and Roche.
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Acknowledgments We thank the patients and their families as well as the study-site personnel. Writing assistance was provided by Jennifer King (August Editorial; Durham, NC, USA) and was funded by Gilead Sciences. Editorial assistance was provided by Sandra Chen (Gilead Sciences; Foster City, CA, USA). References 1 Yoshimi S, Imamura M, Murakami E, et al. Long term persistence of NS5A inhibitor-resistant hepatitis C virus in patients who failed daclatasvir and asunaprevir therapy. J Med Virol 2015; 87: 1913–20. 2 Kumada H, Suzuki Y, Ikeda K, et al. Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection. Hepatology 2014; 59: 2083–91. 3 Esposito I, Trinks J, Soriano V. Hepatitis C virus resistance to the new direct-acting antivirals. Expert Opin Drug Metab Toxicol 2016; 12: 1197–209. 4 Itakura J, Kurosaki M, Hasebe C, et al. Complex pattern of resistance-associated substitutions of hepatitis C virus after daclatasvir/asunaprevir treatment failure. PLoS One 2016; 11: e0165339. 5 Iio E, Shimada N, Abe H, et al. Efficacy of daclatasvir/asunaprevir according to resistance-associated variants in chronic hepatitis C with genotype 1. J Gastroenterol 2017; 52: 94–103. 6 Carrasco I, Arias A, Benítez-Gutiérrez L, et al. Baseline NS5A resistance associated substitutions may impair DAA response in real-world hepatitis C patients. J Med Virol 2018; 90: 532–36. 7 Bourlière M, Gordon SC, Flamm SL, et al. Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection. N Engl J Med 2017; 376: 2134–46. 8 Struble K, Chan-Tack K, Qi K, Naeger LK, Birnkrant D. Benefit-risk assessment for sofosbuvir/velpatasvir/voxilaprevir based on patient population and hepatitis C virus genotype: U. S. Food and Drug Administration’s evaluation. Hepatology 2017; published online Oct 23. DOI:10.1002/hep.29601. 9 Gilead Sciences, Inc. VOSEVI (sofosbuvir, velpatasvir, and voxilaprevir) prescribing information. Foster City, CA: Gilead Sciences Inc, 2017.
10 Gilead Sciences International Ltd. VOSEVI (sofosbuvir/velpatasvir/ voxilaprevir) summary of product characteristics. Cambridge: Gilead Sciences International Ltd, 2017. 11 AbbVie Inc. MAVYRET (glecaprevir and pibrentasvir) prescribing information. North Chicago, IL; AbbVie Inc, 2017. 12 Poordad F, Felizarta F, Asatryan A, et al. Glecaprevir and pibrentasvir for 12 weeks for hepatitis C virus genotype 1 infection and prior direct-acting antiviral treatment. Hepatology 2017; 66: 389–97. 13 Poordad F, Pol S, Asatryan A, et al. Glecaprevir/pibrentasvir in patients with hepatitis C virus genotype 1 or 4 and past direct-acting antiviral treatment failure. Hepatology 2018; 67: 1253–60. 14 AbbVie Ltd. MAVIRET (glecaprevir/pibrentasvir) summary of product characteristics. Maidenhead: AbbVie Ltd, 2017. 15 Lawitz E, Poordad F, Gutierrez JA, et al. Short-duration treatment with elbasvir/grazoprevir and sofosbuvir for hepatitis C: a randomized trial. Hepatology 2017; 65: 439–50. 16 de Lédinghen V, Laforest C, Hézode C, et al. Retreatment with sofosbuvir plus grazoprevir/elbasvir plus ribavirin of patients with hepatitis C virus genotype 1 or 4 who previously failed a NS5A or NS3-containing regimen: the ANRS HC34 REVENGE study. Clin Infect Dis 2018; 66: 1013–18. 17 Poordad F, Bennett M, Sepe TE, et al. Ombitasvir/paritaprevir/r, dasabuvir, and sofosbuvir treatment of patients with HCV genotype 1-infection who failed a prior course of DAA therapy: the QUARTZ-I study. J Hepatol 2016; 64 (suppl 1): S767–68. 18 WHO. Combating hepatitis B and C to reach elimination by 2030. May, 2016. http://apps.who.int/iris/bitstream/10665/206453/1/ WHO_HIV_2016.04_eng.pdf?ua=1 (accessed Dec 18, 2017). 19 Mitruka K, Tsertsvadze T, Butsashvili M, et al. Launch of a nationwide hepatitis C elimination program—Georgia, April 2015. MMWR Morb Mortal Wkly Rep 2015; 64: 753–57.
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