Gastroenterology 2016;151:893901

CLINICALLIVER
Efcacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients
With Genotype 1 Hepatitis C Virus Infection in an Open-Label,
Phase 2 Trial
Eric Lawitz,1 Nancy Reau,2 Federico Hinestrosa,3 Mordechai Rabinovitz,4 Eugene Schiff,5
Aasim Sheikh,6 Ziad Younes,7 Robert Herring Jr,8 K. Rajender Reddy,9 Tram Tran,10
Michael Bennett,11 Ronald Nahass,12 Jenny C. Yang,13 Sophia Lu,13 Hadas Dvory-Sobol,13
Luisa M. Stamm,13 Diana M. Brainard,13 John G. McHutchison,13 Brian Pearlman,14
Mitchell Shiffman,15 Trevor Hawkins,16 Michael Curry,17 and Ira Jacobson18

CLINICAL LIVER
1
Texas Liver Institute, University of Texas Health Sciences Center, San Antonio, Texas; 2Rush University Medical Center,
Chicago, Illinois; 3Orlando Immunology Center, Orlando, Florida; 4University of Pittsburgh, Pittsburgh, Pennsylvania;
5
Schiff Center for Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida; 6Gastrointestinal Specialists of
Georgia, Marietta, Georgia; 7GastroOne, Germantown, Tennessee; 8Quality Medical Research Center, Nashville, Tennessee;
9
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; 10Sinai Medical Center, Los Angeles, California;
11
Medical Associates Research Group, Inc, San Diego, California; 12Infectious Disease Care, Hillsborough, New Jersey;
13
Gilead Sciences, Foster City, California; 14Atlanta Medical Center, Atlanta, Georgia; 15The Liver Institute of Virginia,
Richmond, Virginia; 16Southwest CARE Center, Santa Fe, New Mexico; 17Beth Israel Deaconess Medical Center, Boston,
Massachusetts; 18Mount Sinai Beth Israel, New York, New York

safe and effective in patients previously treated with DAAs. The

See editorial on page 795.
BACKGROUND & AIMS: The best regimen to re-treat patients
who do not respond to direct-acting antivirals (DAAs) and the
feasibility of further shortening regimens is unclear. We
assessed the efcacy and safety of the combination of the
nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor
velpatasvir, and the NS3/4A protease inhibitor GS-9857 in
patients with hepatitis C virus genotype 1 infection. METHODS:
We performed an open-label trial at 32 sites in the United States
and at 2 sites in New Zealand of 197 patients with genotype 1
hepatitis C virus infection, with or without compensated
cirrhosis, who were treatment-naive or were treated previously
with a DAA. Between March 2, 2015, and September 1, 2015,
patients received sofosbuvir-velpatasvir (400 mg/100 mg in a
xed-dose combination) plus GS-9857 (100 mg) once daily for
612 weeks, plus ribavirin for 1 treatment group consisting of
treatment-naive patients with cirrhosis. The primary end point
was sustained virologic response 12 weeks after treatment
(SVR12). RESULTS: Among treatment-naive patients without
cirrhosis, 71% (24 of 34; 95% condence interval [CI], 5385)
achieved SVR12 after 6 weeks of treatment and 100% (36 of 36;
95% CI, 90%100%) achieved SVR12 after 8 weeks of treat-
ment. Among treatment-naive patients with cirrhosis, 94%
(31 of 33; 95% CI, 8099) achieved SVR12 after 8 weeks of
treatment and 81% (25 of 31; 95% CI, 6393) achieved SVR12
after 8 weeks of treatment with ribavirin. Among
DAA-experienced patients treated for 12 weeks, 100% without
cirrhosis (31 of 31; 95% CI, 89100) and 100% with cirrhosis
(32 of 32; 95% CI, 89100) achieved SVR12. The most common
adverse events were headache, diarrhea, fatigue, and nausea.
One patient (<1%) discontinued treatment because of adverse
events. CONCLUSIONS: In a phase 2 open-label trial, we found 8
weeks of treatment with sofosbuvir-velpatasvir plus GS-9857 to
be safe and effective in treatment-naive patients; 12 weeks was
combination was safe and effective in patients with or without
compensated cirrhosis. Clinicaltrials.gov no: NCT02378935.
Keywords: Direct-Acting Antiviral Agent; NS5A; NS5B; NS3/4A.
O f the 6 known genotypes of the hepatitis C virus
(HCV), genotype 1 is the most common, affecting
almost half of the estimated 130150 million people with
chronic HCV infection worldwide.1,2 Although genotype 1
HCV was long considered the most difcult to treat HCV
infection, several highly effective and safe regimens involving
combinations of recently approved direct-acting antivirals
(DAAs) now are available for patients with genotype 1 HCV,
regardless of treatment history and stage of liver disease.36
One clinical question that remains unanswered is the iden-
tication of retreatment regimens for patients who do not
achieve sustained virologic response (SVR) with approved
regimens of DAAs in which resistance-associated sub-
stitutions (RASs) may have emerged. Treatment-emergent
RASs, particularly after exposure to NS5A inhibitors, have
the potential to limit re-treatment options.7 There is
Abbreviations used in this paper: ALT, alanine aminotransferase; CI,
condence interval; DAA, direct-acting antiviral agent; HCV, hepatitis C
virus; RAS, resistance-associated substitution; SVR, sustained virologic
response; SVR12, sustained virologic response 12 weeks after treatment;
ULN, upper limit of normal.
Most current article
2016 by the AGA Institute. Published by Elsevier Inc. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.
org/licenses/by-nc-nd/4.0/).
0016-5085
http://dx.doi.org/10.1053/j.gastro.2016.07.039
 894 Lawitz et al
currently no approved regimen for patients who have failed
an HCV regimen including an NS5A inhibitor. Current treat-
ment recommendations for NS5A inhibitor-experienced pa-
tients suggest delaying therapy in those without urgent
indications for treatment and, when treatment is necessary,
long durations with the addition of ribavirin often are
advised on the basis of minimal evidence.8 One possible
strategy to address the need for a salvage regimen is to
combine highly potent DAAs with enhanced activity against
RASs. Such a combination regimen additionally may allow for
shortening of treatment duration in patients who have not
been treated previously for HCV.
Sofosbuvir is a nucleotide analogue inhibitor of the HCV
NS5B polymerase approved for the treatment of genotypes
16 HCV infection in combination with other agents.9,10
CLINICAL LIVER
Velpatasvir is a novel HCV NS5A inhibitor with pan-
genotypic efcacy.11 The combination of sofosbuvir and
velpatasvir has been shown in phase 3 clinical trials to be
highly effective and safe in treatment-naive and previously
treated patients with HCV of all genotypes, including those
with compensated and decompensated cirrhosis.1214
GS-9857 is a novel macrocyclic NS3/4A protease inhibitor
with potent in vitro antiviral activity against genotypes 16
HCV and broad coverage of NS3/4A protease poly-
morphisms, including RASs associated with rst-generation
NS3/4A protease inhibitors.15,16 In a phase 1 trial, admin-
istration of 100 mg of GS-9857 to patients with genotypes
14 HCV resulted in median maximum reductions in
HCV-RNA levels of 3 log10 IU/mL or greater.17
We assessed the efcacy and safety of 612 weeks of
sofosbuvir-velpatasvir plus GS-9857 in treatment-naive
patients and patients previously treated with DAA-
containing regimens with genotype 1 HCV, including those
with compensated cirrhosis.
Materials and Methods
Study Design
This open-label, 2-cohort, phase 2 study was conducted
between March 2, 2015, and September 1, 2015, at 32 sites in
the United States and at 2 sites in New Zealand. Cohort 1
enrolled treatment-naive patients, and cohort 2 enrolled
patients previously treated with regimens that contained an
NS5A inhibitor alone, or 2 or more classes of DAAs.
Cohort 1. At the time the study was initiated, 2 groups of
treatment-naive patients were enrolled in cohort 1: a group of
patients without cirrhosis, who received sofosbuvir-velpatasvir
plus GS-9857 for 6 weeks, and a group of patients with
cirrhosis, who received sofosbuvir-velpatasvir plus GS-9857 for
8 weeks. The protocol specied that if the rate of relapse among
patients with cirrhosis who received 8 weeks of treatment was
10% or less, there was an option that another group could be
enrolled to receive 6 weeks of treatment. This option was not
exercised. Instead, preliminary results from these rst 2
groups prompted us to amend the protocol to add 2 groups to
this cohort: a group of patients without cirrhosis, who
received 8 weeks of sofosbuvir-velpatasvir plus GS-9857, and a
group of patients with cirrhosis, who received 8 weeks of
sofosbuvir-velpatasvir plus GS-9857 with ribavirin.
Gastroenterology Vol. 151, No. 5
Cohort 2. Two groups of DAA-experienced
patientsthose with and without cirrhosiswere enrolled in
cohort 2. Both groups received 12 weeks of sofosbuvir-
velpatasvir plus GS-9857. The protocol specied that if the
rate of relapse in either group was 10% or less, there was an
option that another group of patients could be enrolled to
receive 8 weeks of treatment. This option was not exercised.
Patients. Enrollment was open to patients at least 18 years
of age chronically infected with genotype 1 HCV with serum HCV
levels of at least 10,000 IU/mL. Cirrhosis was dened as any one
of the following: biopsy showing cirrhosis (Metavir score of 4 or
Ishak score of
5), transient elastography (FibroScan; Echosens,
Paris, France) result greater than 12.5 kPa, or a FibroTest
(Biopredictive, Paris, France) score greater than 0.75 together
with an aspartate aminotransferaseto-platelet ratio index
greater than 2 during screening. Exclusion criteria included a
platelet count less than 50,000 cells/mL, hemoglobin level less
than 110 g/L for women and less than 120 g/L for men, albumin
level less than 30 g/L, creatinine clearance less than 60 mL/min as
calculated by the CockcroftGault equation, and prothrombin
time or direct bilirubin greater than 1.5 times the upper limit of
normal. Patients with evidence of decompensation (ie, clinical
ascites, encephalopathy, or variceal hemorrhage) and those with
hepatocellular carcinoma were excluded.
Written informed consent was obtained from all patients
before enrollment and before any study procedures were per-
formed. The study was approved by the institutional review
board or independent ethics committee at all participating sites
and was conducted in accordance with the principles of the
Declaration of Helsinki and Good Clinical Practice. The sponsor
(Gilead Sciences) collected the data, monitored the study
conduct, and performed the statistical analyses. All authors had
access to the study data and reviewed and approved the nal
manuscript.
Procedures
All patients received a xed-dose combination tablet of
sofosbuvir 400 mg and velpatasvir 100 mg once daily, along
with a 100-mg tablet of GS-9857 once daily, taken with food.
Ribavirin was administered 10001200 mg/day (1000 mg for
patients weighing <75 kg and 1200 mg for patients weighing

75 kg) in a divided daily dose. This was an open-label study,
in which patients were enrolled by investigators at the study
centers. No participants or study personnel were blinded to
treatment assignments at any time during the study.
Assessments
Serum HCV-RNA concentrations were measured using the
COBAS AmpliPrep/COBAS TaqMan HCV Test, v2.0 (Roche,
Indianapolis, IN) with a lower limit of quantication for HCV
RNA of less than 15 IU/mL. HCV genotype and subtype were
determined using the Siemens Versant HCV Genotype INNO-
LiPA 2.0 assay (Tarrytown, NY). For all patients, the inter-
leukin 28B genotype was determined by polymerase chain
reaction amplication and sequencing of the rs12979860
single-nucleotide polymorphism.
Deep sequencing of the NS3A, NS5A, and NS5B regions of
the HCV RNA using MiSeq technology (DDL Diagnostic Labo-
ratory, Rijswijk, The Netherlands) was performed at baseline
for all patients and at the time of virologic failure for all
November 2016
patients who did not achieve SVR 12 weeks after treatment
(SVR12). The resulting sequences were compared with refer-
ence sequences or sequences from baseline samples to deter-
mine the prevalence of RASs and the association of RASs with
virologic outcomes. RASs present at greater than 1% and 15%
of sequence reads were reported, unless specied.
Safety was assessed in all patients at all on-treatment visits
and for 30 days after the completion of treatment by physical
examination and review of adverse events and laboratory test
results.
Outcomes
The primary efcacy end point of this study was SVR12
(serum HCV-RNA level <15 IU/mL) in all patients who were
enrolled and received at least 1 dose of study drug. The sec-
ondary efcacy end points included the proportion of patients
with virologic failure. The primary safety end point was any
adverse event leading to the permanent discontinuation of
study treatment.
Statistical Analysis
For this exploratory phase 2 study we did not plan or
conduct any inferential statistics. No formal sample size cal-
culations were used to determine the group size of 30. The
SVR12 rate in each of the treatment groups was calculated with
2-sided 95% exact condence intervals (CIs) based on the
ClopperPearson method.
Role of the Funding Source
The study sponsor oversaw trial management, data collec-
tion, statistical analyses, and the writing and review of the
report. All authors had access to the study data and had
reviewed and approved the nal manuscript.
Results
Of the 247 patients screened, 197 were enrolled and
received treatment: 34 treatment-naive patients without
cirrhosis, 33 treatment-naive patients with cirrhosis, 31
previously treated patients without cirrhosis, and 32 pre-
viously treated patients with cirrhosis (Supplementary
Figure 1). Reasons for screen failure are listed in the
Appendix. Baseline characteristics of patients are shown in
Table 1. The groups were balanced overall with regard to
baseline characteristics. A majority of patients in all groups
were men, of white race, with genotype 1a infection and
non-CC interleukin 28B genotypes. Among the DAA-
experienced patients in cohort 2, 46% previously received
a NS5A inhibitor (ledipasvir, n 7; daclatasvir, n 11;
other, n 11) and 54% previously received a NS3/4A
protease inhibitor and a NS5B polymerase inhibitor
(simeprevir with sofosbuvir, n 25; other, n 9).
By week 4 of treatment, 68 of 70 (97%) treatment-naive
patients without cirrhosis and 60 of 64 (94%) treatment-
naive patients with cirrhosis had HCV-RNA levels less than
15 IU/mL. Among treatment-experienced patients, 29 of 31
(94%) without cirrhosis and 31 of 32 (97%) with cirrhosis
had HCV-RNA levels less than 15 IU/mL by week 4 of
treatment. By week 8 of treatment, all patients receiving at
SOF/VEL Plus GS-9857 in HCV GT 1 895
least 8 weeks of treatment had a HCV-RNA level less than
15 IU/mL. In treatment-naive patients with cirrhosis, the
addition of ribavirin appeared to have no impact on HCV
viral kinetics (Table 2).
Among treatment-naive patients without cirrhosis, rates
of SVR12 were 71% (24 of 34; 95% CI, 5385) in patients
receiving 6 weeks of treatment, and 100% (36 of 36; 95%
CI, 90100) in patients receiving 8 weeks of treatment
(Table 2). Among treatment-naive patients with cirrhosis,
rates of SVR12 were 94% (31 of 33; 95% CI, 8099) in
patients receiving 8 weeks of sofosbuvir-velpatasvir plus
GS-9857 and 81% (25 of 31; 95% CI, 6393) in patients
receiving 8 weeks of sofosbuvir-velpatasvir plus GS-9857
with ribavirin (Table 2). Among patients previously
treated with DAA-containing regimen(s), rates of SVR12
CLINICAL LIVER
were 100% (31 of 31; 95% CI, 89100) in patients without
cirrhosis receiving 12 weeks of treatment, and 100% (32 of
32; 95% CI, 89100) in patients with cirrhosis receiving 12
weeks of treatment. Across the groups, no signicant dif-
ferences in SVR12 rates were observed based on baseline
differences (Appendix). Eighteen patients with virologic
failure relapsed after the end of treatment; no patient had a
virologic breakthrough during treatment (Appendix).
Baseline sequencing was available for 197 of the 197
patients enrolled in the study. Overall, 63% (84 of 134) of
treatment-naive and 83% (52 of 63) of DAA-experienced
patients had baseline class RASs in at least 1 of the 3 target
genes (NS3, NS5A, and NS5B), with a 1% deep sequencing
assay cut-off level (Table 3). Among the DAA-experienced
patients, 93% (27 of 29) of the NS5A inhibitor-experienced
patients had NS5A RASs, as compared with 21% (7 of 34) of
DAA-experienced patients who were not treated previously
with an NS5A inhibitor (data not shown).
Table 3 shows the SVR rates for patients without RASs
and with single and multiclass NS3, NS5A, and NS5B RASs
with a 1% sequencing cut-off level. In treatment-naive pa-
tients, 8 weeks of treatment with sofosbuvir-velpatasvir
plus GS-9857 without ribavirin led to SVR12 in 96% (23
of 24) and 98% (44 of 45) of patients without and with
baseline RASs, respectively. Use of a 15% sequencing cut-off
level led to a similar result (Supplementary Material). All
DAA-experienced patients, regardless of the presence of
single or multiclass RASs, achieved SVR12 after 12 weeks of
treatment with sofosbuvir-velpatasvir plus GS-9857. There
were 12 DAA-experienced patients with the NS5A RAS
Y93H/N at baseline, all of whom achieved SVR12.
Sequencing data were available for all 18 treatment-naive
patients who relapsed. Eleven of 18 patients (61%) had the
same number of or fewer RASs at the time of virologic relapse
than at baseline. Four of 18 patients (22%) had no RASs both
at baseline and at virologic relapse. Only 3 patients had
treatment-emergent RASs, all in the NS3 gene and all at fre-
quencies less than 2% of the viral population. The treatment-
emergent NS3 RASs included V170T, Q41R/A156T, and
V36M. Of these, only A156T resulted in in vitro resistance to
GS-9857 (confers an w500-fold shift in median effective
concentration in genotype 1a and 1b replicon assays).
The most common adverse events were headache,
nausea, fatigue, and diarrhea (Table 4). Overall, 64% of
 CLINICAL LIVER

896
Lawitz et al
Table 1.Baseline Characteristics

Treatment naive DAA experienced

No cirrhosis Cirrhosis No cirrhosis Cirrhosis

SOF-VEL plus SOF-VEL plus SOF-VEL plus SOF-VEL plus SOF-VEL plus SOF-VEL plus
GS-9857 for GS-9857 for GS-9857 for GS-9857 plus RBV GS-9857 for GS-9857 for
6 wk (n 34) 8 wk (n 36) 8 wk (n 33) for 8 wk (n 31) 12 wk (n 31) 12 wk (n 32)

Age, y 53 51 58 59 57 59
Men 23 (68) 21 (58) 19 (58) 19 (61) 23 (74) 26 (81)
Race
White 31 (91) 32 (89) 25 (76) 26 (84) 27 (87) 26 (81)
Black 3 (9) 4 (11) 7 (21) 5 (16) 4 (13) 6 (19)
Hawaiian or Pacic Islander 0 0 1 (3) 0 0 0
Mean BMI, kg/m2 (SD) 26.1 (4.64) 27.4 (5.94) 28.9 (4.64) 29.2 (6.48) 26.4 (3.92) 32.0 (6.07)
HCV RNA level, log10 IU/mL 6.2 (0.51) 6.2 (0.55) 6.0 (0.59) 6.3 (0.47) 6.4 (0.77) 6.0 (0.61)
HCV genotype
1a 27 (79) 28 (78) 26 (79) 25 (81) 27 (87) 24 (75)
1b 7 (21) 8 (22) 7 (21) 6 (19) 4 (13) 8 (25)
IL28b
CC 12 (35) 9 (25) 7 (21) 12 (39) 4 (13) 4 (13)
CT 15 (44) 21 (58) 19 (58) 12 (39) 19 (61) 21 (66)
TT 7 (21) 4 (11) 7 (21) 6 (19) 7 (23) 7 (22)
Missing 0 2 (6) 0 1 (3) 1 (3) 0
Baseline ALT level, U/L (SD) 61 (34.8) 57 (43.6) 97 (49.0) 95 (68.3) 59 (41.4) 84 (54.1)
DAA experience
NS5A inhibitor with or without NA NA NA NA 17(55) 12 (38)
other DAA(s)
Ledipasvir NA NA NA NA 5 (16) 2 (6)
Daclatasvir NA NA NA NA 5 (16) 6 (19)
Other NA NA NA NA 7 (23) 4 (13)
NS3/4A protease NA NA NA NA 14 (45) 20 (62)

Gastroenterology Vol. 151, No. 5

inhibitor and NS5B
polymerase inhibitor
Sofosbuvir-simeprevir NA NA NA NA 8 (26) 17 (53)
Other NA NA NA NA 6 (19) 3 (9)

BMI, body mass index; IL, interleukin; NA, not applicable; RBV, ribavirin; SOF-VEL, sofosbuvir-velpatasvir.
November 2016 SOF/VEL Plus GS-9857 in HCV GT 1 897

patients experienced at least 1 adverse event. Patients in the

12 wk (n 32)
SOF-VEL plus
GS-9857 for
ribavirin-containing group had higher rates of fatigue (32%)
Cirrhosis

32 (100)
32 (100)

94100
20 (63)
31 (97)
and anemia (23%) than patients in the other groups. Two

0
0
Treatment experienced

patients, both in the group of treatment-naive patients with

cirrhosis receiving 8 weeks of treatment without ribavirin,
had treatment-emergent serious adverse events: a 61-year-
old white woman with valvular disease experienced atrial
utter on day 35 of treatment, and a 67-year-old white
woman had vertigo on post-treatment day 26.
12 wk (n 31)
SOF-VEL plus
GS-9857 for
No cirrhosis

One patient discontinued treatment because of adverse

31 (100)
31 (100)

89100
18 (58)
29 (94)
events. This patient, a 50-year-old black woman with

0
0
cirrhosis who was receiving sofosbuvir-velpatasvir plus GS-
9857 with ribavirin, stopped study treatment on day 24
after having conrmed abnormally high levels of alanine
aminotransferase (ALT) (grade 3) and aspartate amino-

CLINICAL LIVER
transferase (grade 2). A single grade 1 increase in total
bilirubin was observed at study treatment week 2, and
GS-9857 plus RBV
for 8 wk (n 31)

remained within normal limits at all other timepoints.

SOF-VEL plus

Aminotransferase levels returned to normal 4 weeks after

25 (81)
17 (55)
30 (97)

27 (87)

6 (19)
6393

stopping the study drug. An evaluation for acute causes of

0

hepatitis was negative. Another patient in the same treat-

ment group discontinued ribavirin after experiencing diar-
rhea, nausea, vomiting, and rib soreness on day 2 of
Cirrhosis

treatment. This patient continued sofosbuvir-velpatasvir

plus GS-9857 without ribavirin and achieved SVR12.
One treatment-naive patient with cirrhosis who received
SOF-VEL plus

8 weeks of treatment died on day 175 of follow-up

8 wk (n 33)
GS-9857 for

evaluation. The cause of death was atypical pneumonia.

31 (94)
21 (64)
30 (91)

31 (94)

8099

2 (6)
Table 2.Patients With HCV-RNA Level Less Than 15 IU/mL During and After Treatment

Overall, 19 patients (10%) had grade 3 laboratory

0
Treatment naive

abnormalities and 2 patients (1%) had grade 4 laboratory

LLOQ, lower limit of quantication; RBV, ribavirin; SOF-VEL, sofosbuvir-velpatasvir.

abnormalities. Grades 3 and 4 laboratory abnormalities

occurred almost exclusively in patients with cirrhosis. There
were 4 patients with cirrhosis who had postbaseline he-
moglobin values less than 10 g/dL; all were receiving
SOF-VEL plus

8 wk (n 36)

ribavirin. One patient (mentioned earlier) had a grade 3 ALT

GS-9857 for

increase (>5  upper limit of normal [ULN]). No patient had

36 (100)
36 (100)

NOTE. Bold type indicates results of the primary efcacy endpoint.

90100
27 (75)
34 (94)

a grade 2 ALT increase (an increase of >2.5 to 5  ULN) and

0
0

2 patients (both cirrhotic) had a grade 1 ALT increase

(increases to 1.252.5  ULN).
No cirrhosis

Discussion
SOF-VEL plus

6 wk (n 34)

The development of oral DAAs represents a major

GS-9857 for

34 (100)

advance in the treatment of HCV in patients of all geno-

5385
24 (71)
27 (79)

30 (88)

10 (29)
0

types. Currently available DAA combination regimens offer

SVR rates well over 90% overall and in most patient sub-
populations. Nevertheless, some patients do not achieve
SVR with existing regimens. Patients who have failed prior
treatment with rst-generation NS3/4A protease inhibitors
(eg, telaprevir, boceprevir, or simeprevir) may be re-treated
Lost to follow-up evaluation

with ledipasvir-sofosbuvir, but patients who have been

treated unsuccessfully with a regimen that includes
HCV RNA <LLOQ, n (%)

an NS5A inhibitor have no approved re-treatment options.

In a previous trial, patients with genotype 1 HCV who
Week 12 (SVR)
During treatment

did not achieve SVR after 8 or 12 weeks of ledipasvir-

Virologic failure
After treatment

sofosbuvirbased regimens and subsequently were

95% CI

Relapse
Week 2
Week 4

Week 4

re-treated with 24 weeks of ledipasvir-sofosbuvir had an

SVR12 rate of only 71%. In this population, the presence of
baseline NS5A RASs was associated with a higher rate of
 898 Lawitz et al Gastroenterology Vol. 151, No. 5

virologic failure.18 In another small trial, 14 of 16 patients

(88%) who previously failed a daclatasvir-containing

2/2 (100)
27/27 (100)

8/8 (100)

19/19 (100)
SOF-VEL plus GS-9857 for 12 weeks

NS5A /-

(n 29)
DAA(s)
regimen achieved SVR12 after re-treatment with
simeprevir-sofosbuvir for 12 weeks. Thirteen of the 16

-
DAA experienced, n/N (%)

patients had NS5A RASs at baseline, and, of these 13, 11

(85%) achieved SVR12. The 2 patients who did not achieve
SVR12 had Q30K and L31M substitutions as the dominant
viral populations at re-treatment baseline.19
In this open-label, phase 2 study, 12 weeks of treatment
with sofosbuvir-velpatasvir plus GS-9857 was safe and
highly effective in patients with HCV genotype 1, with and
Non-NS5A

9/9 (100)
25/25 (100)
17/17 (100)
2/2 (100)

6/6 (100)
without cirrhosis, who did not achieve SVR after prior
(n 34)
DAA(s)

treatment with DAAs, including those who previously

-

received an NS5A inhibitor. In treatment-naive patients, the

8-week regimen was safe and effective, regardless of
CLINICAL LIVER

cirrhosis status. Among the treatment-naive patients who

relapsed, the presence of baseline RASs appeared to have no
impact on treatment outcome. Treatment-emergent RASs by
deep sequencing with a 1% cut-off rate were rare (3 of 18;
17%), and no treatment-emergent RASs among relapsers
for 8 wka (n 31)
GS-9857 RBV
SOF-VEL plus

were detected with the 15% cut-off level. This is consistent

10/11 (91)
15/20 (75)
6/7 (86)
2/4 (50)

7/9 (78)

with the anticipated high barrier of resistance of the com-

-

bination therapy based on in vitro data.20

Treatment-naive patients without cirrhosis treated for 8
weeks achieved a SVR12 rate of 100%, which was higher
Cirrhosis

than results reported in a recent study of combining 3 DAAs

for treatment for the same population and treatment
Table 3.SVR12 for Patients With and Without Baseline RASs: 1% Sequencing Cut-Off Value

duration.21 Treatment-naive patients with cirrhosis treated

for 8 weeks had lower SVR12 rates (81%94%) than pa-
SOF-VEL plus

8 wk (n 33)
GS-9857 for

tients without cirrhosis. Larger studies will determine

(100)
(100)
(100)
(90)
(96)
(94)
Treatment naive, n/N (%)

whether this short duration is adequate for this patient

9/10
22/23
16/17
2/2
1/1
3/3

population.
One unexpected result in our trial was the apparent lack
of benet of the addition of ribavirin to sofosbuvir-
velpatasvir plus GS-9857 for treatment-naive patients with
cirrhosis. Although patients in this group receiving ribavirin
had a numerically lower rate of SVR12 than treatment-naive
SOF-VEL plus

8 wk (n 36)
GS-9857 for

patients with cirrhosis who received sofosbuvir-velpatasvir

(100)
(100)
(100)
(100)
(100)
(100)

plus GS-9857 without ribavirin (81% vs 94%), the con-

14/14
22/22
9/9
4/4
2/2
7/7

dence intervals overlap and it is likely that this reects the

small sample sizes.
Includes 1 patient who did not complete treatment.
No cirrhosis

Factors limiting the interpretation of the results of this

RBV, ribavirin; SOF-VEL, sofosbuvir-velpatasvir.

trial include its small size and the uncontrolled, open-label

design. Although the trial enrolled only patients with ge-
Includes patients with the NS3 RAS Q80K.

notype 1 HCV, another trial of similar design has been

SOF-VEL plus

6 wk (n 34)
GS-9857 for

conducted to assess this combination regimen in patients

(100)
(67)
(74)
(83)
(50)

(50)

with nongenotype 1 HCV.

10/15
14/19
10/12
1/2
1/1
2/4

In conclusion, sofosbuvir-velpatasvir plus GS-9857 for 12

weeks provided a high rate of SVR12 (100%) and was well
tolerated in a group of patients currently without treatment
optionsthose with and without compensated cirrhosis
who have not achieved SVR after previous treatment with a
NS5A inhibitor-containing regimen. The addition of GS-9857
Multiclass RASsb
NS5B RASs only
NS5A RASs only
NS3 RASs onlyb

to sofosbuvir-velpatasvir also was safe in the treatment-

naive population, in whom it was effective in reducing the
treatment duration to 8 weeks while preserving a high rate
Any RASs
No RASs

of SVR12. These 3 potent pangenotypic DAAs have been

co-formulated into a xed-dose combination tablet. The
phase 3 program will evaluate this xed-dose combination
b
a
 November 2016
Table 4.Safety

Treatment naive DAA experienced

No cirrhosis Cirrhosis No cirrhosis Cirrhosis

SOF-VEL plus SOF-VEL plus SOF-VEL plus SOF-VEL plus SOF-VEL plus SOF-VEL plus
GS-9857 for GS-9857 for GS-9857 for GS-9857 plus RBV GS-9857 for GS-9857 for
n (%) 6 wk (n 34) 8 wk (n 36) 8 wk (n 33) for 8 wk (n 31) 12 wk (n 31) 12 wk (n 32)

Any adverse event 21 (62) 24 (68) 24 (73) 24 (77) 15 (48) 16 (50)

AEs leading to discontinuation 0 0 0 1 (3) 0 0
of all treatment
Deaths 0 0 1 (3) 0 0 0
AEs (occurring in
5%
of patients in any cohort)
Headache 11 (32) 7 (19) 7 (21) 9 (29) 4 (13) 5 (16)
Nausea 2 (6) 10 (28) 7 (21) 9 (29) 3 (10) 3 (9)
Fatigue 4 (12) 7 (19) 1 (3) 10 (32) 7 (23) 3 (9)
Diarrhea 4 (12) 6 (17) 2 (6) 3 (10) 3 (10) 3 (9)
Insomnia 5 (15) 1 (3) 0 3 (10) 2 (6) 0
Constipation 0 4 (11) 3 (9) 1 (3) 0 0
Nasopharyngitis 1 (3) 3 (8) 1 (3) 0 2 (6) 0
Anemia 0 0 0 7 (23) 0 0
Cough 1 (3) 3 (8) 0 0 1 (3) 1 (3)
Dizziness 2 (6) 2 (6) 1 (3) 1 (3) 0 0
Laboratory abnormalities
Hemoglobin level, <10.0 g/dL 0 0 0 4 (13) 0 0
Platelets, 25,000 to <50,000/mm3 0 0 1 (3) 0 0 2 (6)
INR, >2.0 to 3.0  ULN 0 0 1 (3) 0 0

SOF/VEL Plus GS-9857 in HCV GT 1

ALT level, >5.00 to 10.00  ULN 0 0 0 1 (3) 0 0
Creatine kinase level, 0 1 (3) 0 0 0 0
10.0 to <20.0  ULN
Hyperglycemia, >250 to 500 mg/dL 0 0 1 (3) 1 (3) 0 2 (6)
Lipase, >5.0  ULN 1 (3) 0 0 4 (12) 0 1 (3)
Hyperbilirubinemia, 0 0 3 (10) 0 1 (3)
> 2.5 to 5.0  ULN

AE, adverse event.

899
CLINICAL LIVER
 900 Lawitz et al
for 8 weeks in treatment-naive patients and for 12 weeks in
DAA-experienced patients, including those who previously
have received an NS5A inhibitor.
Supplementary Material
Note: To access the supplementary material accompanying
this article, visit the online version of Gastroenterology at
www.gastrojournal.org, and at http://dx.doi.org/10.1053/
j.gastro.2016.07.039.
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Received May 23, 2016. Accepted July 26, 2016.
Reprint requests
Address requests for reprints to: Eric Lawitz, MD, Texas Liver Institute, 607
Camden Street, San Antonio, Texas 78215. e-mail: lawitz@txliver.com;
fax: 210-477-1808.
Conicts of interest
These authors disclose the following: Eric J. Lawitz has served as a consultant
for AbbVie, Achillion Pharmaceuticals, Bristol-Myers Squibb, Enanta, Gilead
Sciences, Janssen, Merck & Co, Novartis, Santaris Pharmaceuticals,
Regulus, and Theravance, has received grants from AbbVie, Achillion
Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Enanta
Pharmaceuticals, Gilead Sciences, GlaxoSmithKline, Janssen, Merck & Co,
Roche, Salix, Santaris Pharmaceuticals, Tacere, and Theravance, and has
served as a speaker for AbbVie, Bristol-Myers Squibb, Gilead, Janssen, and
Merck & Co; Nancy Reau has served as a consultant for AbbVie, Bristol-
Myers Squibb, Gilead, and Merck, and has performed research for AbbVie,
Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, and Merck; Federico
Hinestrosa has served on the advisory board for Gilead, has performed
research for Gilead, BMS, and AbbVie, and has served as a speaker for
Gilead, BMS, AbbVie, and Merck; Eugene Schiff has served as a consultant
for Accorda, has performed research for Gilead, Janssen, Merck, AbbVie,
Beckman Coulter, Discovery Life Sciences, MedMira, Orasure, Roche,
Siemens, Conatus, and Bristol-Myers Squibb, and has served as a speaker
for Gilead, Janssen, Merck, Salix, Pzer, and Arrowhead; Aasim Sheikh has
served on the advisory board for BMS, Gilead, Intercept, and AbbVie, has
performed research for BMS, Gilead, Merck, Intercept, Pzer, Genentech,
Actelion, Theravance, and Cubist, has served as a speaker for BMS, Gilead,
and AbbVie, and owns stock in Gilead; Ziad Younes has performed research
for AbbVie, BMS, Gilead, Idenix, Janssen, Merck, and Intercept, and has
served as a speaker for AbbVie and Gilead; K. Rajender Reddy has served
on the advisory board for Gilead, BMS, Merck, AbbVie, and Janssen, and
has performed research for Gilead, BMS, Merck, AbbVie, and Janssen;
Ronald Nahass has served on the advisory board for Gilead, Merck, and
Janssen; has performed research for Gilead, Merck, Janssen, and AbbVie,
and has served as a speaker for Gilead, Janssen, and Merck; Brian
November 2016
Pearlman has served as a consultant, speaker, and on the advisory board for
Gilead, Merck, and J&J, and has performed research for BMS, BI, Gilead,
Merck, and J&J; Mitchell Shiffman has served on the advisory board for
Merck, Gilead, Boehringer-Ingelheim, Bristol-Myers-Squibb, AbbVie,
Janssen, and Achillion, has served as a consultant for Roche/Genentech,
has performed research for Merck, Gilead, Boehringer-Ingelheim, Bristol-
Myers-Squibb, AbbVie, Beckman-Coulter, Achillion, Lumena, Intercept,
Novartis, and Gen-Probe, and has served as a speaker for Roche/
Genentech, Merck, Gilead, AbbVie, Janssen, and Bayer; Trevor Hawkins has
served as a consultant for Bristol-Myers Squibb, and is an employee of and
holds stock interest in Gilead; Michael Curry has served as a consultant for
Gilead, AbbVie, and BMA, and has performed research for Gilead and
Conatus; Ira Jacobson has served as a consultant for AbbVie, Achillion,
SOF/VEL Plus GS-9857 in HCV GT 1 901
Bristol-Myers Squibb, Gilead Sciences, Janssen, and Merck, has performed
research for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck,
and Tobira, and has served as a speaker for Bristol-Myers Squibb, Gilead
Sciences, Janssen, and Merck; and Jenny C. Yang, Sophia Lu, Hadas
Dvory-Sobol, Luisa M. Stamm, Diana M. Brainard, and John G. McHutchison
are employees and/or hold stock interest in Gilead Sciences. The remaining
authors disclose no conicts.
Funding
This study was sponsored by Gilead Sciences. Clinical operations support was
provided by Juan Betular, Jonathan Kong, Nikki Zona, Ken Imamura, Desiree
Varela, and Erin Waller of Gilead Sciences; and writing assistance was
provided by David McNeel and Sandra Chen of Gilead Sciences.
CLINICAL LIVER
901.e1 Lawitz et al Gastroenterology Vol. 151, No. 5

Supplementary Figure 1. Patient disposition. AE, adverse event.