VIRAL HEPATITIS
Concordance of Sustained Virological Response 4, 12,
and 24 Weeks Post-Treatment With SofosbuvirContaining Regimens for Hepatitis C Virus
Eric M. Yoshida,1 Mark S. Sulkowski,2 Edward J. Gane,3 Robert W. Herring, Jr.,4 Vlad Ratziu,5 Xiao Ding,6
Jing Wang,6 Shu-Min Chuang,6 Julie Ma,6 John McNally,6 Luisa M. Stamm,6 Diana M. Brainard,6
William T. Symonds,6 John G. McHutchison,6 Kimberly L. Beavers,7 Ira M. Jacobson,8
K. Rajender Reddy,9 and Eric Lawitz10
Historically, clinical trials of regimens to treat chronic infection with hepatitis C virus
(HCV) have used, as their primary efficacy endpoint, a sustained virological response
(SVR)—defined as HCV RNA levels below a designated threshold of quantification—24
weeks after the end of treatment (SVR24). More recently, regulatory authorities have begun
to accept SVR at 12 weeks post-treatment (SVR12) as a valid efficacy endpoint because of its
high rate of concordance with SVR24. However, the concordance between SVR12 and
SVR24 has not been systematically assessed with new regimens of recently approved directacting antiviral agents. The aim of this study was to assess the concordance between SVR at
various post-treatment time points in phase III clinical trials of sofosbuvir (SOF)-containing
regimens. We conducted a retrospective analysis of five trials enrolling 863 patients infected
with HCV genotypes 1-6. The concordance between SVR at 4 weeks post-treatment (SVR4)
and SVR12, and between SVR12 and SVR24, were determined, as well as positive predictive
values (PPVs) and negative predictive values (NPVs). Overall, 779 of 796 patients (98.0%)
with an SVR4 also achieved an SVR12, making the PPV of SVR4 for SVR12 98% and the
NPV 100%. Of the 779 patients with an SVR12, 777 (99.7%) also achieved an SVR24, making the PPV of SVR12 for SVR24 >99% and the NPV 100%. Of patients who relapsed posttherapy, 77.6% did so within 4 weeks of completing therapy. Conclusion: Data from phase
III studies demonstrate that with SOF-based regimens, with or without interferon, SVR12
and SVR24 correlate closely. Thus, SVR12 can be used effectively to determine “cure” rates
in trials and in clinical practice. (HEPATOLOGY 2015;61:41-45)
C
hronic infection with hepatitis C virus (HCV)
is a curable disease, and the absence of detectable virus in the blood 6 months after completion of treatment is widely regarded as being indicative
of cure. In the interferon (IFN) era, clinical studies of
HCV treatment have, by convention, used a 24-week
sustained virological response (SVR24)—defined as
absence of HCV RNA 24 weeks after completion of
treatment—as a primary efficacy endpoint. Achievement of SVR24 has been associated with a reduced
risk of developing complications of liver disease
(including hepatocellular carcinoma [HCC]), as well as
a reduction in overall mortality, and has been used historically as a regulatory endpoint for approval.1,2
More recently, SVR 12 weeks after the end of treatment (SVR12) has been established as an appropriate
Abbreviations: HCC, hepatocellular carcinoma; HCV, hepatitis C virus; IFN, interferon; LLOQ, lower limit of quantification; NPV, negative predictive value;
Peg-IFN, pegylated interferon; PPV, positive predictive value; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virological response (SVR); SVR4, SVR at 4 weeks
after treatment end; SVR12, SVR at 12 weeks after treatment end; SVR24, SVR at 24 weeks after treatment end.
From the 1University of British Columbia, Vancouver, Canada; 2Viral Hepatitis Center, Johns Hopkins University School of Medicine, Baltimore, MD; 3New
Zealand Liver Transplant Unit, Auckland, New Zealand; 4Quality Medical Research, PLLC, Nashville, TN; 5University Pierre et Marie Curie, Paris, France;
6
Gilead Sciences, Inc., Foster City, CA; 7Asheville Gastroenterology Associates, Asheville, PA; 8Cornell University School of Medicine, New York, NY; 9University of
Pennsylvania School of Medicine, Philadelphia, PA; 10Texas Liver Institute, University of Texas Health Sciences Center, San Antonio, TX.
Received June 25, 2014; accepted August 12, 2014.
Additional Supporting Information may be found at onlinelibrary.wiley.com/doi/10.1002/hep.27366/suppinfo.
This analysis was supported by Gilead Sciences, Inc. (Foster City, CA).
41
42
YOSHIDA ET AL.
endpoint for demonstrating efficacy in trials containing
regimens that include pegylated interferon (Peg-IFN)
with a protease inhibitor for 24-48 weeks of treatment.3 Sofosbuvir (SOF; Gilead Sciences, Inc., Foster
City, CA)—an oral, HCV-specific, nucleotide polymerase inhibitor with clinical efficacy in patients with
HCV genotypes 1-6—is approved currently for use in
combination with other agents for treatment of
chronic HCV infection.4-7 The present analysis
assessed the concordance between SVR 4 weeks posttreatment (SVR4) and SVR12, and between SVR12
and SVR24 in patients with chronic HCV who
received SOF-containing regimens with and without
Peg-IFN in SOF phase III trials.
Patients and Methods
Patients with HCV genotype 1 or 4-6 receiving
SOF in combination with Peg-IFN and ribavirin
(RBV) for 12 weeks, patients with HCV genotype 2
receiving SOF in combination with RBV for 12 weeks,
and patients with genotype 3 receiving SOF in combination with RBV for 24 weeks in SOF phase III trials
who had a virological outcome of SVR4, SVR12,
SVR24, breakthrough, or relapse were included in this
analysis (Fig. 1 and Supporting Fig. 1).4-6 SOF was
administered at 400 mg once-daily, and RBV dose was
based on body weight (1,000 mg/day for <75 kg and
1,200 mg/day for 75 kg in a divided dose) in all
patients; all patients with genotype 1 or 4-6 also
received Peg-IFN-2a 180 mg once-weekly.
All patients with HCV genotype 1 or 4-6 included
in this analysis were enrolled in the NEUTRINO trial
(ClinicalTrials.gov identifier: NCT01641640); all
patients with genotype 2 were enrolled in the FISSION
HEPATOLOGY, January 2014
(NCT01497366), POSITRON (NCT01542788), FUSION (NCT01604850), or VALENCE (NCT01682720)
trial, and all patients with genotype 3 were enrolled in
the VALENCE trial (Fig. 1 and Supporting Fig. 1).4-6
NEUTRINO was an open-label, single-arm trial in
which 327 treatment-na€ıve patients with genotype 1 or
4-6 (98% with genotype 1 or 4) received 12 weeks of
SOF plus Peg-IFN/RBV.6 FISSION was an open-label
noninferiority trial in which 499 patients with genotype 2 or 3 were randomized to receive SOF plus RBV
for 12 weeks (n 5 256; 73 enrolled as genotype 2) or
Peg-IFN/RBV for 24 weeks (n 5 243).6 POSITRON
was a blinded trial in which 278 patients with genotype 2 or 3 in whom Peg-IFN therapy was not an
option were randomized to receive SOF plus RBV
(n 5 207; 109 with genotype 2) or placebo (n 5 71)
for 12 weeks.5 FUSION was a blinded trial in which
201 patients with genotype 2 or 3 previously treated
with Peg-IFN were randomized to receive SOF plus
RBV for 12 (n 5 103; 39 enrolled as genotype 2) or
16 weeks (n 5 98).5 VALENCE was a double-blind
trial in which 419 treatment-experienced (58%) or na€ıve patients with genotype 2 or 3 were initially
randomized to receive SOF plus RBV (n 5 334) or
placebo (n 5 85) for 12 weeks.4 After emerging data
suggested that patients with genotype 3 benefited from
>12 weeks of treatment, the trial was amended to
extend SOF plus RBV treatment to 24 weeks in
patients with genotype 3 (n 5 250) and to offer treatment in an alternative protocol to patients randomized
to placebo. (An additional 11 patients with genotype 3
had completed treatment before their treatment could
be extended; for safety analyses, they were included
with patients with genotype 2, but were analyzed separately for efficacy.) A total of 73 patients with genotype
Address reprint requests to: Eric M. Yoshida, M.D., F.R.C.P. (C.), Division of Gastroenterology, Vancouver General Hospital, Diamond Health Care Center, 5th
Floor, 2775 Laurel Street, Vancouver, British Columbia V5Z 1M9, Canada. E-mail: [email protected]; fax 604-875-5447.
C 2014 The Authors. HEPATOLOGY published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases. This is an
Copyright V
open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium,
provided the original work is properly cited, the use is noncommercial and no modifications or adaptations are made.
View this article online at wileyonlinelibrary.com.
DOI 10.1002/hep.27366
Potential conflict of interest: Dr. Yoshida received grants, lecture fees, and/or speaker honoraria from Hoffman LaRoche, Vertex, Gilead, Merck, Schering,
Astellas, Pfizer, Boehringer Ingleheim, Janssen, and Novartis. Dr. Sulkowski consults, advises, and received grants from AbbVie, Bristol-Myers Squibb, Gilead,
Janssen, Merck, Idenix, and Tobira. Prof. Gane advises and is on the speakers’ bureau for Gilead and Novartis. He advises Merck, Idenix, and Achillion and is on
the speakers’ bureau for Janssen. Dr. Reddy advises and received grants from Gilead, Bristol-Myers Squibb, Vertex, Janssen, Merck, and AbbVie. Dr. Beavers
advises, is on the speakers’ bureau for, and received grants from Gilead; she advises and is on the speakers’ bureau for Janssen and Genentech; she is on the speakers’
bureau and received grants from Vertex; she received grants from Bristol-Myers Squibb, GlaxoSmithKline (GSK), Roche, and Idenix. Dr. Lawitz advises, is on the
speaker’s bureau for, and received grants from Gilead, Janssen, Merck, and Vertex; he advises and received grants from AbbVie, Achillion, Idenix, Novartis, and
Santaris; he advises BioCryst, Biotica, Enanta, and Theravance; he is on the speakers’ bureau for Kadmon; he received grants from Boehringer Ingleheim,
Bristol-Myers Squibb, GSK, Presidio, and Roche. Dr. Jacobson consults, advises, is on the speakers’ bureau for, and received grants from Bristol-Myers Squibb,
Gilead, Genentech, Janssen, and Vertex; he consults and received grants from AbbVie, Boehringer Ingelheim, and Merck; he consults for Achillion and Idenix; he
received grants from Novartis. Drs. McNally, Symonds, Brainard, Wang, McHutchison, Ma, Stamm, Chuang, and Ding own stock in and are employed by
Gilead.
HEPATOLOGY, Vol. 61, No. 1, 2014
YOSHIDA ET AL.
43
Fig. 1. Patient analysis flow
chart by HCV genotype (GT) and
study. *Includes 3 patients subsequently found to have GT 1.
2 received SOF plus RBV for 12 weeks. In all trials,
the primary endpoint was SVR12.
The analyses for concordance included all patients
with known virological outcomes (e.g., SVR4, SVR12,
and SVR24 on-treatment virological failure or relapse)
in the studies. Thus, patients were excluded if they
were lost to follow-up during treatment or in the
follow-up period, or if they discontinued treatment
before HCV RNA suppression (Fig. 1). This analysis
included 324 treatment-na€ıve patients with HCV
genotype 1 or 4-6 receiving SOF plus Peg-IFN/RBV
for 12 weeks (all from NEUTRINO), 291 treatmentna€ıve and -experienced patients with genotype 2
receiving SOF plus RBV for 12 weeks, and 248
treatment-na€ıve and -experienced patients with genotype 3 receiving SOF plus RBV for 24 weeks (all from
VALENCE). For the calculation of final SVR rates,
any patient who received a dose of study drug was
included, resulting in more patients for analysis: genotype 1 or 4-6, n 5 327; genotype 2, n 5 294; and
genotype 3, n 5 250.
In all trials, HCV RNA levels were measured by the
COBAS AmpliPrep/COBAS TaqMan HCV Test
(v2.0) for use with the High Pure System (Roche
Molecular Systems, Pleasanton, CA), with a lower
limit of quantification (LLOQ) of 25 IU/mL, and
HCV genotype was determined by the VERSANT
HCV Genotype 2.0 Assay Line Probe Assay (Siemens
AG, Erlangen, Germany).4-6
SVR24 rates were 92.4%, 90.5%, and 90.5%, respectively; for patients with genotype 2 treated with SOF
plus RBV for 12 weeks, the corresponding rates were
94.2%, 91.8%, and 91.8%, and for patients with
genotype 3 treated with SOF plus RBV for 24 weeks,
the rates were 87.2%, 85.2%, and 84.4%.
Concordance of SVR4 and SVR12. Concordance
of SVR4 and SVR12, and positive predictive value
(PPV) and negative predictive value (NPV) of SVR4
for SVR12 are shown in Table 1. Similar concordance
was observed across all HCV genotypes. Overall,
SVR12 was achieved in 779 of 796 patients (98.0%)
with SVR4, including 296 of 302 (98.0%) with HCV
genotype 1 or 4-6, 270 of 276 (97.8%) with genotype
2, and 213 of 218 (97.7%) with genotype 3. The
PPV of SVR4 for SVR12 was 98.0% and the NPV
was 100%.
Concordance of SVR12 and SVR24. Concordance of SVR12 and SVR24, and PPV and NPV of
Results
SVR by HCV Genotype. SVR4, SVR12, and
SVR24 rates by HCV genotype are shown in Fig. 2.
For patients with genotype 1 or 4-6 treated with SOF
plus Peg-IFN/RBV for 12 weeks, SVR4, SVR12, and
Fig. 2. SVR rates 4 (SVR4), 12 (SVR12), and 24 (SVR24) weeks
after treatment end according to genotype (GT). Treatments for each
GT are those for which SOF is approved: for GT 1 or 4-6, SOF plus
Peg-IFN/RBV for 12 weeks; for GT 2, SOF plus RBV for 12 weeks; for
GT3, SOF plus RBV for 24 weeks.
44
YOSHIDA ET AL.
HEPATOLOGY, January 2014
Table 1. Concordance of SVR4 and SVR12
SVR12 (n)
Genotype
1, 4-6
2
3
Table 3. Timing of Relapses
Summary (%)
Regimen
SVR4 (n)
Yes
No
PPV
NPV
SOF1PEG/RBV
12 weeks
SOF1RBV
12 weeks
SOF1RBV
24 weeks
Yes
No
Yes
No
Yes
No
296
0
270
0
213
0
6
22
6
15
5
30
98.0
100
97.8
100
97.7
100
Discussion
This post-hoc analysis of data from the SOF phase
III registrational studies supports the use of SVR12 as
the primary efficacy endpoint in SOF-containing regimens with or without Peg-IFN. When SOF combined
with RBV or Peg-IFN/RBV was used according to current indications and dosing recommendations, 98.0%
of patients who achieved SVR4 also achieved SVR12
and 99.7% of those who achieved SVR12 also
Table 2. Concordance of SVR12 and SVR24
1, 4-6
2
3
1, 4-6
2
3
SVR12 for SVR24 are shown in Table 2. Overall,
SVR24 was achieved in 777 of 779 patients (99.7%)
with SVR12, including 296 of 296 (100%) with HCV
genotype 1 or 4-6, 270 of 270 (100%) with genotype
2, and 211 of 213 (99.0%) with genotype 3. The
PPV of SVR12 for SVR24 was 99.7% and the NPV
was 100%.
Timing of Relapses. Relapse was defined as being
negative for HCV RNA at the end of treatment and
subsequently having HCV RNA above the LLOQ. In
all cases, relapse, rather than reinfection, was confirmed with viral sequencing. The timing of relapses in
the post-treatment period in the phase III SOF studies
is shown in Table 3. Overall, a total of 85 of 863
patients experienced virological relapse. Of these
patients, 66 (77.6%) had relapse by post-treatment
week 4, 17 (20.0%) had relapse between weeks 4 and
12, and 2 (2.3%) had relapse between weeks 12 and
24. The 2 patients who relapsed between posttreatment weeks 12 and 24 were both in VALENCE
with HCV genotype 3 and were treatment experienced
without cirrhosis (Supporting Table 1).
Genotype
Genotype
SVR24 (n)
Summary (%)
Regimen
SVR12 (n)
Yes
No
PPV
NPV
SOF1PEG/RBV
12 weeks
SOF1RBV
12 weeks
SOF1RBV
24 weeks
Yes
No
Yes
No
Yes
No
296
0
270
0
211
0
0
28
0
21
2
35
100
100
100
100
99.1
100
Regimen
SOF1PEG/RBV
12 weeks
SOF1RBV
12 weeks
SOF1RBV
24 weeks
Relapses
Between
EOT and FU
Week 4 (n)
Relapses
Between
FU Weeks 4
and 12 (n)
Relapses
Between
FU Weeks 12
and 24 (n)
22
6
0
15
6
0
29
5
2
Abbreviations: EOT, end of treatment; FU, follow-up.
achieved SVR24. This is consistent with the results of
the SPARE trial, in which there was 100% concordance
between SVR12 and SVR 24 in GT1 patients with
unfavorable treatment characteristics who received SOF
and RBV for 24 weeks.8 The high degree of concordance
between SVR12 and SVR24 across HCV genotypes 1-6
confirms that SVR12 is an appropriate endpoint for
assessing efficacy of therapy with SOF-containing regimens. Although most patients (77.6%) who relapsed
did so within the first 4 weeks after treatment was completed, 20.0% of patients who relapsed did so between
post-treatment weeks 4 and 12, indicating that SVR4 is
not a suitable primary endpoint for primary efficacy
analyses. Although it would be of interest to determine
what factors may predict a relapse between weeks 12 and
24, there were not enough patients (only 2.3% relapsing
after achieving SVR12) for any meaningful analysis.
There are a couple of limitations of this analysis which
may affect generalizability of the results. First, there were
relatively few patients with HCV genotypes 4-6 as a
result of the lower prevalence of these genotypes and thus
lower enrollment in the clinical studies. However, the
concordance between SVR12 and SVR24 was 100% for
these patients, suggesting that the high concordance with
SOF-based regimens may also be generalized to these
less-prevalent genotypes. Second, these trials used a
highly sensitive assay to detect HCV RNA and determine
relapse. Commercial assays available in clinical practice
may have higher limits of detection, which could theoretically affect the ability to detect relapse. However, across
the clinical trials included in this analysis, patients who
relapsed after post-treatment week 12 did so with HCV
RNA levels that substantially exceeded the lower limit of
detection of any available assay.
It is important to emphasize that the focus of this
analysis was an assessment of the appropriateness of
SVR12 as a primary efficacy endpoint in clinical trials
and not an assessment of the appropriate duration for
follow-up of patients after HCV treatment in clinical
practice. Although patients who achieve SVR have
improved clinical outcomes, current treatment
HEPATOLOGY, Vol. 61, No. 1, 2014
guidelines recommend continued monitoring for HCC
in patients with cirrhosis who achieve SVR.9 Future
long-term virological outcome follow-up studies in
regimens of shorter duration and in IFN-free protocols
will be important to determine the long-term durability of SVR. To date, of the 480 patients in the SOF
phase III studies who enrolled in the long-term registry
study for patients who achieved SVR24, 435 (91%)
and 90 (19%) have week 24 and 48 data, respectively,
and the virological response was durable in 100%.10
In conclusion, this analysis validates that SVR12 is
an appropriate efficacy endpoint for the evaluation of
regimens containing SOF plus Peg-IFN/RBV and SOF
plus RBV. It is unknown whether new direct-acting
antiviral–based regimens, particularly those with
shorter durations and/or with drugs with lower barriers
to resistance, will demonstrate similar concordance.
Acknowledgment: Editorial assistance was provided
by Matt Stenger and Geoff Marx of BioScience Communications (New York, NY) and was funded by
Gilead Sciences, Inc. (Foster City, CA).
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Supporting Information
Additional Supporting Information may be found at
onlinelibrary.wiley.com/doi/10.1002/hep.27366/suppinfo.