Profile of sofosbuvir/velpatasvir/voxilaprevir in the treatment of hepatitis C

Abstract

The treatment of chronic hepatitis C has been revolutionized with the introduction of direct-acting antivirals (DAAs). However, some patients are not cured with first-line treatment. Sofosbuvir/velpatasvir/voxilaprevir is a fixed-dose combination of a polymerase inhibitor, an NS5A inhibitor, and a protease inhibitor with activity against strains of the hepatitis C virus that show resistance to other first-line antiviral regimens. Sofosbuvir/velpatasvir/voxilaprevir has been studied in four Phase III randomized trials: POLARIS-1, −2, −3, and −4, which enrolled both treatment naïve and experienced patients with and without compensated cirrhosis. In these trials, at least 95% of patients treated with sofosbuvir/velpatasvir/voxilaprevir achieved sustained virological response (SVR). This includes favorable treatment outcomes in patients who had previously failed a regimen containing sofosbuvir or an NS5A inhibitor. Patient-reported outcomes also improved during and after treatment with sofosbuvir/velpatasvir/voxilaprevir. Treatment with sofosbuvir/velpatasvir/voxilaprevir is well tolerated, with the most commonly reported adverse events being headache, fatigue, diarrhea, and nausea. The approval of sofosbuvir/velpatasvir/voxilaprevir allows a treatment option for patients who have failed treatment with certain DAA regimens.

Full text

REVIEW
Profile of sofosbuvir/velpatasvir/voxilaprevir in the
treatment of hepatitis C
This article was published in the following Dove Press journal:
Infection and Drug Resistance
Lindsey M Childs-Kean
Natalie A Brumwell
Emma F Lodl
Department of Pharmacotherapy and
Translational Research, University of
Florida College of Pharmacy, Gainesville,
FL, USA
Abstract: The treatment of chronic hepatitis C has been revolutionized with the introduction
of direct-acting antivirals (DAAs). However, some patients are not cured with first-line
treatment. Sofosbuvir/velpatasvir/voxilaprevir is a fixed-dose combination of a polymerase
inhibitor, an NS5A inhibitor, and a protease inhibitor with activity against strains of the
hepatitis C virus that show resistance to other first-line antiviral regimens. Sofosbuvir/velpa-
tasvir/voxilaprevir has been studied in four Phase III randomized trials: POLARIS-1, −2, −3,
and −4, which enrolled both treatment naïve and experienced patients with and without
compensated cirrhosis. In these trials, at least 95% of patients treated with sofosbuvir/velpa-
tasvir/voxilaprevir achieved sustained virological response (SVR). This includes favorable
treatment outcomes in patients who had previously failed a regimen containing sofosbuvir or
an NS5A inhibitor. Patient-reported outcomes also improved during and after treatment with
sofosbuvir/velpatasvir/voxilaprevir. Treatment with sofosbuvir/velpatasvir/voxilaprevir is well
tolerated, with the most commonly reported adverse events being headache, fatigue, diarrhea,
and nausea. The approval of sofosbuvir/velpatasvir/voxilaprevir allows a treatment option for
patients who have failed treatment with certain DAA regimens.
Keywords: hepatitis C, direct-acting antivirals, protease inhibitors, resistance
Introduction
Viral hepatitis remains a public health threat in parts of the world, with 71 million
people estimated to have chronic hepatitis C virus (HCV) infection in 2015.
1
Yearly,
an estimated 1.75 million people are newly diagnosed with HCV worldwide.
1
In the
United States, HCV is the most common blood-borne infection, and about 3.5 million
people (range of 2.5–4.7 million) are currently infected.
2,3
Left untreated, complica-
tions of HCV include cirrhosis, hepatocellular carcinoma (HCC), and eventually
death.
1
HCV is classified into 7 genotypes with 67 different subtypes.
4
Genotype 1
is most common in the United States (75%), followed by Genotypes 2 and 3
(20–25%), and the smallest group includes genotypes 4 through 7.
5
The goal of HCV treatment is to reduce mortality and liver complications through
virologic cure.
6
The surrogate marker for virologic cure is sustained virological
response (SVR), which is an undetectable viral load (serum HCV RNA <15 IU/mL)
at least 12 weeks after completing treatment.
6
Since the development of the direct-
acting antivirals (DAAs) and the movement away from ribavirin and interferon-based
treatment, SVR rates have increased to above 90%, and there has been a reduction in
side effects and treatment duration.
7
The DAAs target various proteins throughout the
HCV replication cycle and include the NS3/4A protease inhibitors, NS5A inhibitors,
nucleoside and nucleotide NS5B polymerase inhibitors, and the non-nucleoside NS5B
Correspondence: Lindsey M Childs-Kean
Department of Pharmacotherapy and
Translational Research, University of
Florida College of Pharmacy, PO Box
100486, Gainesville, FL 32610, USA
Tel +1 352 273 5715
Email lchilds-kean@cop.ufl.edu
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http://doi.org/10.2147/IDR.S171338

polymerase inhibitors.
8
Although there has been increased
success of HCV treatment with DAAs, there is still a concern
for virological failure due to baseline resistance-associated
substitutions (RASs).
6
DAA-resistant viruses can also be
selected for during treatment.
On July 18, 2017, Vosevi
®
(sofosbuvir/velpatasvir/vox-
ilaprevir [SOF/VEL/VOX]) was approved by the Food and
Drug Administration (FDA) for the treatment of chronic
HCV genotypes 1–6 in patients without cirrhosis or with
compensated cirrhosis.
5
SOF/VEL/VOX was the first
treatment approved for patients who had been previously
treated with an NS5A inhibitor.
5
The specific indications
for SOF/VEL/VOX include: (1) genotypes 1 through 6
infection with prior treatment of an NS5A inhibitor or
(2) genotype 1a or 3 infection with prior treatment of
sofosbuvir without an NS5A inhibitor.
9
Soon after,
Vosevi
®
was authorized for use in Europe by the
European Medicines Agency on July 26, 2017.
10
SOF/
VEL/VOX is available as a fixed-dose combination tablet
containing 400 mg sofosbuvir, 100 mg velpatasvir, and
100 mg voxilaprevir.
9
The recommended administration
for all patients is to take one tablet once daily with food
for a duration of 12 weeks.
9
The objective of this review is
to examine the efficacy and safety of SOF/VEL/VOX, and
then to propose considerations for clinical patient use.
Materials and methods
PubMed and Google Scholar were searched (August 2016–
March 2019) using the following terms: “voxilaprevir,”
“Vo s e v i , ”“voxilaprevir resistance,”and “voxilaprevir patient
reported outcomes.”All results in English were reviewed.
Data from Phase III trials and post-marketing studies are
included in this review. Other resources included the Food
andDrugAdministrationAdverseEventReportingSystem
and the drug’s prescribing information.
Efficacy
The efficacy and safety of SOF/VEL/VOX was evaluated in
four Phase III trials: POLARIS-1, −2, −3, and −4.
11,12
A summary of the POLARIS trials can be found in Tabl e 1.
The primary efficacy endpoint for all four trials was achieve-
ment of SVR.
11,12
Exclusion criteria that was applied to all
POLARIS studies included failure of previous DAA therapy
due to ADRs or non-adherence, HBV or HIV co-infection,
HCC, hepatic decompensation, renal impairment (defined as
creatinine clearance <50 mL/min), thrombocytopenia, or
anemia.
11,12
The mean age of patients in all four trials was 56
years, and the majority of patients in all studies were male.
11,12
POLARIS-1 was a randomized, double-blind study that
included adult HCV patients with genotypes 1, 2, 3, 4, 5, or
6 with or without compensated cirrhosis who had received
previous treatment with an NS5A inhibitor-containing
regimen.
11
Patients with genotype 1 were randomized to
12 weeks of SOF/VEL/VOX once daily or placebo.
11
Patients with all other genotypes were assigned to receive
SOF/VEL/VOX.
11
Most patients had genotypes 1a, 1b, or
3, and almost half of the patients had compensated cirrhosis
at baseline.
11
SVR for patients who received treatment was
96%comparedwith0%intheplacebogroup.
11
The 96%
SVR rate was significantly above the prespecified perfor-
mance goal of 85% (p<0.001).
Patients who completed 12 weeks of placebo treatment
in POLARIS-1 had the option to enroll in an open-label
substudy after the completion of POLARIS-1, where they
received 12 weeks of SOF/VEL/VOX treatment.
13
Patients
were excluded from this study if they had any of the
exclusion criteria for enrollment in the POLARIS trials,
did not complete 12 weeks of placebo treatment, or had
new clinically significant illness at post-treatment week
4.
13
Patient characteristics were similar to that of the
POLARIS-1 study except that there was a more narrow
age range.
13
Of the 152 patients who completed treatment
with placebo in the POLARIS-1 trial, 147 completed the
12-week treatment with SOF/VEL/VOX.
13
Of these
patients, 143 (97%; 95% CI 93–99) achieved SVR.
13
POLARIS-2 was a randomized, open-label study that
included adult HCV patients with genotypes 1, 2, 3, 4, 5, or
6 with or without compensated cirrhosis and no prior exposure
to a DAA regimen, excluding patients with genotype 3 and
cirrhosis.
12
Patients were randomized to receive SOF/VEL/
VOX for 8 weeks or sofosbuvir/velpatasvir (SOF/VEL) for 12
weeks.
12
Genotype 1a was the most prevalent genotype in this
study, and 18% of patients had compensated cirrhosis.
12
The
overall SVR rate for patients of any genotype with cirrhosis in
the SOF/VEL/VOX group was 91% compared with 99% in
the SOF/VEL group, for a difference of −3.2% (95% CI −6.2
to −0.4).
12
Because the lower threshold of the 95% CI was less
than the pre-established limit of −5%, 8 weeks of SOF/VEL/
VOX was concluded to be inferior to 12 weeks of SOF/VEL in
this patient population.
12
POLARIS-3 was a randomized, open-label study that
enrolled patients with genotype 3 with compensated
cirrhosis and no prior DAA exposure.
12
Similar to
POLARIS-2, patients were randomized to 8 weeks of
SOF/VEL/VOX or 12 weeks of SOF/VEL.
12
SVR for
both treatment groups was 96%.
12
This was significantly
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Table 1 Summary of POLARIS Phase III clinical trials
POLARIS-1
11
POLARIS-1 Deferred
13
POLARIS-2
12
POLARIS-3
12
POLARIS-4
11
Study design Blinded randomization GT1
patients randomized 1:1. All other
GT received SOF/VEL/VOX
Open-label. All patients
received SOF/VEL/VOX
Open-label randomization. All
patients randomized 1:1
Open-label randomization. All
patients randomized 1:1
Open-label randomization GT1, 2,
3patientsrandomized1:1GT4
patients received SOF/VEL/VOX
Exclusion criteria Basic exclusion criteria* applied
to all POLARIS trials
Basic exclusion criteria* PLUS
new illness at post-treatment
week 4
Basic exclusion criteria* PLUS
patients with GT3 and cirrhosis
Basic exclusion criteria* and
only included patients with GT3
and cirrhosis
Basic exclusion criteria* PLUS
GT5 or GT6
Treatment history Previous DAA therapy with
NS5A inhibitor
Completed 12 weeks of pla-
cebo treatment in POLARIS-1
Treatment naïve or treatment
experienced
Treatment naïve or treatment
experienced
Previous DAA therapy not
including an NS5A inhibitor
Treatment SOF/VEL/VOX
(n=263) for 12
weeks
Placebo
(n=152) for
12 weeks
SOF/VEL/VOX (n=147) for 12
weeks
SOF/VEL/VOX
(n=501) for 8
weeks
SOF/VEL
(n=440) for
12 weeks
SOF/VEL/VOX
(n=110) for 8
weeks
SOF/VEL
(n=109) for
12 weeks
SOF/VEL/VOX
(n=182) for 12
weeks
SOF/VEL
(n=151) for
12 weeks
Patient characteristics
Age, mean (range) 58 (27–84) 59 (29–80) 60 (55–64) 53 (18–78) 55 (19–82) 54 (25–75) 55 (31–69) 57 (24–85) 57 (24–80)
Male, (%) 76 80 79 51 54 67 92 79 75
Genotype (%)
1a 38 77 77 34 39 N/A N/A 30 29
1b 17 20 20 13 13 N/A N/A 13 15
2 2 0 0 13 12 N/A N/A 17 22
3 30 0 0 18 20 100 100 30 34
4 8 0 0 13 13 N/A N/A 10 0
Combined 5,6 2 1 1 10 2 N/A N/A N/A N/A
Cirrhosis (%) 46 34 33 18 19 100 100 0 0
SVR 96 0 97 95 98 96 96 98 90
Notes: *Basic exclusion criteria applied to all POLARIS trials includes elevated liver function tests (>10 times upper limit of normal), bilirubin >1.5 times upper limit of normal, thrombocytopenia (platelets <75,000 cells/µL without
cirrhosis or <50,000 cells/µL with cirrhosis), hemoglobin A1c <8.5%, creatinine clearance <60 mL/min, anemia (hemoglobin <11.0 g/dL in females, <12.0 g/dL in males), albumin <3 g/dL, international normalized ratio >1.5 times upper
limit of normal (exceptions: diagnosed hemophilia or on concomitant anticoagulant), electrocardiogram abnormalities, diagnosis of hepatitis B virus or human immunodeficiency virus, history of hepatic decompensation, organ transplant,
porphyria, or significant pulmonary or cardiac history.
Abbreviations: GT, genotype; GT1, genotype 1; SOF/VEL/VOX, sofosbuvir/velpatasvir/voxilaprevir; GT2, genotype 2; GT3, genotype 3; GT4, genotype 4; GT5, genotype 5; GT6, genotype 6; DAA, direct-acting antiviral; N/A, not
applicable; SVR, sustained virological response.
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above the prespecified performance goal of 83%
(p<0.001 for both groups).
12
POLARIS-4 was a randomized, open-label study that
enrolled adult HCV patients with genotypes 1, 2, 3, or 4
with or without compensated cirrhosis and prior non-NS5A
inhibitor DAA therapy.
11
Genotypes 1a and 3 were most
common, each present in about 30% of patients.
11
There
were no patients in this study with compensated cirrhosis.
11
Patients were randomized to 12 weeks of SOF/VEL/VOX or
SOF/VEL. SVR was 98% for the SOF/VEL/VOX group and
90% for the SOF/VEL group.
11
The SVR for SOF/VEL/
VOX was significantly above the prespecified performance
goal of 85% (p<0.001).
11
Across all POLARIS studies, only thirty-four patients
experienced virological relapse with SOF/VEL/VOX treat-
ment (six in POLARIS-1, four in POLARIS-1 Deferred,
21 in POLARIS-2, two in POLARIS-3, and one in
POLARIS-4).
11–13
Additionally, only one patient experi-
enced virologic breakthrough while assigned to the SOF/
VEL/VOX treatment arm; this was likely due to medica-
tion nonadherence based on evaluation of plasma drug
concentration, although the details of this evaluation
were not included in the publications. No patients experi-
enced nonresponse to SOF/VEL/VOX.
11–13
Patient char-
acteristics associated with virological relapse from
POLARIS-1 and POLARIS-4 were genotype 3a (4/7),
compensated cirrhosis (7/7), and NS3/NS5A RASs at
baseline (5/7).
11–14
Several recent studies have focused on patient-reported
outcome (PRO) data as another measurement of efficacy
for HCV treatment regimens.
15,16
PROs are a useful metric
for determining the impact of an intervention on a patient’s
quality of life and can measure the efficacy of the inter-
vention in terms of functionality (eg, days absent from
work). Available PRO studies included a series of post-
hoc analyses from the POLARIS trials and a cohort study
from France.
15–17
All PRO studies utilized 26 domains
from four validated PRO measurement tools: the Short-
Form-36 (SF-36), the chronic liver disease questionnaire-
HCV Version (CLDQ-HCV), the Functional Assessment
of Chronic Illness Therapy-Fatigue (FACIT-F), and the
work productivity activity index: specific health problem
(WPAI-SHP).
15–17
These tools have also been used in
other studies assessing efficacy of DAA regimens for the
treatment of HCV in adults.
18–20
All four tools were self-
administered to study participants at baseline, at the end of
treatment, and at varying post-treatment intervals (post-
treatment weeks 4 and 12 in the POLARIS post-hoc
studies and post-treatment weeks 4,12, and 24 in the
French cohort study).
15–17
In the POLARIS post-hoc studies, patient data were strati-
fied by treatment regimen and presence or absence of compen-
sated cirrhosis. Cirrhotic patients had an overall lower baseline
PRO score compared to non-cirrhotic patients (p<0.05)
regardless of treatment with SOF/VEL or SOF/VEL/VOX.
Both cirrhotic and non-cirrhotic patients demonstrated
improvements in 25 of 26 PRO domains during and following
treatment with SOF/VEL/VOX for 8 or 12 weeks or SOF/VEL
for 12 weeks (range of improvement +2.7 to +16.7 points on
a universal PRO scale ranging from 0 to 100).
15,16
The
improvement of these scores was similar or greater in cirrhotic
patients compared to non-cirrhotic patients (range of improve-
ment +4.5 to +18.7 points for cirrhotic patients).
15,16
The only
domain that did not improve for both cirrhotic and non-
cirrhotic patients in both analyses was the Absenteeism com-
ponent of the WPAI-SHP.
15,16
There was no difference in
improvement in PROs between patients who received SOF/
VEL/VOX and those who received SOF/VEL (p>0.05forall
measures).
15,16
The other major PRO study was conducted in a French
cohort with matched American controls treated with the
same regimens. French subjects had similar clinicodemo-
graphic characteristics to American subjects but had lower
baseline PRO scores in nearly every category, which did
not affect the outcomes of the study.
17
Since the objective
of the study was to determine differences in PROs between
interferon (IFN)- and ribavirin (RBV)-based treatment
regimens, the data were stratified into the broad categories
of IFN + RBV-containing, IFN-free RBV-containing, IFN-
free RBV-free, and placebo. Patients in the IFN-free RBV-
free group, which included patients on ledipasvir/sofosbu-
vir (n=107), SOF/VEL (n=285), or SOF/VEL/VOX
(n=202), demonstrated improvements in PROs from base-
line that were sustained throughout treatment and post-
treatment.
17
Since there was no stratification by individual
treatment regimen, the true effects of SOF/VEL/VOX on
PROs could not be determined from this study.
17
Ruane et al evaluated the efficacy of SOF/VEL/VOX in
the setting of retreatment for patients who had previously
failed a DAA regimen, including patients who failed on
a previous regimen of SOF/VEL/VOX.
21
This open-label
study included patients with or without compensated cirrho-
sis who were previously enrolled in a POLARIS trial and had
failed to achieve SVR after receiving 12 weeks of SOF/VEL
(11/31) or 8 weeks of SOF/VEL/VOX (17/31), or were
enrolled in another manufacturer-sponsored study and had
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received a DAA-based treatment regimen (3/31).
21
This
study applied the same exclusion criteria as the POLARIS
trials.
11,12,21
The primary efficacy endpoint was the propor-
tion of patients who achieved SVR.
21
Half of the enrollees
had genotype 1a infection, and half had compensated cirrho-
sis present at baseline.
21
The other genotypes present in this
study were genotype 3 (26%), genotype 1b (13%), and all
other genotypes (<10%).
21
Over half (55%) of the study
population had previously failed 8 weeks of SOF/VEL/
VOX, and 35% had failed 12 weeks of SOF/VEL.
21
All
patients enrolled in the study achieved SVR.
21
RASs were
screened at the start of the trial revealing that 32% of the
study population had baseline NS5A RASs and 26% had
baseline NS3 RASs (no patient had both NS5A and NS3
RASs).
21
Resistance
Because SOF/VEL/VOX contains three DAAs, the activity
of the drug could theoretically be diminished if the virus has
resistance to any of the three drug classes: NS5B (SOF),
NS5A (VEL), or NS3/4A (VOX). In cell culture, HCV
replicons with reduced voxilaprevir susceptibility were
selected and NS3/4A PI-resistance-associated positions at
41, 156, and 168 were identified.
9
A >100-fold reduction in
voxilaprevir susceptibility was shown at NS3 sites A156L/T
in genotype 1a, A156T/V in genotype 1b, A156L/V in
genotype 2a, A156T/V in genotype 3a, and A156L/T/V in
genotype 4.
9
Having a combination of substitutions, com-
pared to a single substitution, led to higher reductions in
voxilaprevir susceptibility.
9
However, other studies show
that voxilaprevir has improved coverage against NS3
RASs compared to other NS3/4A protease inhibitors.
22–24
Data from the POLARIS-1 and −4 trials were ana-
lyzed to determine the impact of baseline NS3 and NS5A
RASs on SVR rates in patients who were treated with 12
weeks of SOF/VEL/VOX.
14
RAS testing was conducted
at baseline and at the time of virologic failure for patients
who did not achieve SVR.
14
Patients who did not com-
plete treatment for reasons other than virologic failure
were not included.
14
The rates of NS5A and NS3 RASs
in POLARIS-4 treatment-experienced patients who had
not received an NS5A inhibitor were equivalent (40/169
and 39/169, respectively).
14
Of the total 417 patients who
were treatment-experienced, 39% (164/417) had NS5A
RASs, 12% (48/417) had NS3 RASs, and 18% (76/417)
had both NS3 and NS5A RASs.
14
NS5A RASs were also
the most common type of RAS in patients with genotypes
2, 3, 4, 5, and 6.
14
Among the 248 patients in POLARIS-1 who were
NS5A inhibitor treatment-experienced, 52% (129/248)
exhibited NS5A RASs that conferred 2.5 to 100-fold
reduced susceptibility to VEL and 26.6% (66/248) patients
had NS5A RASs that conferred >100-fold resistance to
VEL.
14
The most common VEL-specific NS5A RAS was
Y93H. Less common RASs included A30K and L31M,
usually in combination with each other or with Y93H. NS3
RASs were more common in patients with genotype 1 (45/
217) which was mainly driven by the high prevalence of
the Q80K RAS in patients with genotype 1a infection. Of
the patients with NS3 RASs, 1.4% (6/417) of patients had
VOX-specific NS3 RASs which were not specified in this
study.
14
Despite the high prevalence of baseline NS3 and
NS5A RASs, there was no significant difference in SVR
between treatment-experienced patients with baseline
RASs and those who did not have these substitutions at
baseline (97.9% and 98.5%, respectively).
14
Similarly,
97% (32/33) of patients with baseline NS5B RASs
achieved SVR. In the POLARIS-1 Deferred Treatment
substudy, 131 patients had baseline NS3 or NS5A RASs,
and 10 patients had baseline NS5B RASs.
13
The four
patients who experienced virological relapse all had geno-
type 1a and baseline RASs: all patients had at least one
NS5A RAS, and three had at least one NS3 RAS.
13
Treatment-emergent RAS development was rare across
all studies. Only one patient in POLARIS-1 and one
patient in POLARIS-2 who experienced virologic failure
on SOF/VEL/VOX developed an additional RAS during
treatment, both associated with NS5A.
11
In POLARIS-1,
a genotype 4 patient with the L30R RAS at baseline
developed the additional Y93H RAS; in POLARIS-2,
a genotype 1a patient with the Q30Q/H RAS at baseline
developed the additional L31M RAS.
11,12
No patients
experiencing treatment failure on SOF/VEL/VOX in
POLARIS-3 or POLARIS-4 developed additional RASs
during treatment.
11,12
In the POLARIS-1 Deferred
Treatment substudy, two of the four patients who had
virological relapse developed RASs during treatment:
one patient developed Y56H and D168A/V NS3 RASs
as well as a L31L/M NS5A RAS; another patient devel-
oped a V36V/A NS3 RAS.
13
Therefore, regardless of duration of treatment with
SOF/VEL/VOX (8 weeks vs 12 weeks), there has been
no significant difference in SVR shown between patients
with baseline RASs and those without the presence of
baseline RASs in the POLARIS trials. The only exception
to this was demonstrated in POLARIS-2, where patients
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treated with 8 weeks of SOF/VEL/VOX who had genotype
1a and Q80K NS5A RAS at baseline achieved lower SVR
compared to patients who did not have the Q80K RAS at
baseline (88% vs 94%, respectively).
12
Wyles et al analyzed the emergence and long-term per-
sistence of NS3 and NS5A RASs in patients who received
treatment with a DAA regimen in a manufacturer-sponsored
study and failed to achieve SVR.
25
Patients were included in
this study if they were enrolled in a follow-up sequence
registry and were exposed to an NS5A or NS3 inhibitor.
25
Patients were discontinued if they were initiated on HCV
treatment or if RASs were no longer detectable.
25
The study
population was divided into non-sofosbuvir-based, sofosbu-
vir-based, and SOF/VEL/VOX treatment groups.
25
The
SOF/VEL/VOX group contained only 10 patients.
25
Only
one patient had NS5A RASs detectable at baseline which
persisted through week 48 of follow-up, indicating that
RASs in SOF/VEL/VOX-treated patients appear to be
rare.
25
There were no treatment-emergent NS3 RASs in
the SOF/VEL/VOX group, and there were no data available
for these patients after week 12 of follow-up.
25
Safety
Adverse events
Overall, treatment with SOF/VEL/VOX is well tole-
rated.
9,11–13
The most common adverse reactions
observed in the POLARIS trials included headache, fati-
gue, diarrhea, and nausea (see Tab le 2).
9,11–13
In the
POLARIS-1 trial, one patient discontinued treatment of
SOF/VEL/VOX due to an adverse event of angioedema
after starting ramipril.
11
No patients discontinued SOF/
VEL/VOX treatment in the other POLARIS trials.
11,12
Results from the Ruane et al study show that none of
the 31 patients who received 12 week SOF/VEL/VOX
retreatment discontinued treatment due to adverse events
(Table 2).
21,26
One 63-year-old male patient with a history
of cirrhosis and Dieulafoy lesion was hospitalized with
a Grade 3 serious adverse event of gastrointestinal hemor-
rhage on day 12 of treatment.
21,26
Treatment was inter-
rupted only on days 13 and 17. The patient also had the
Grade 3 serious adverse events of acute respiratory failure,
asthenia, and cellulitis.
21,26
Overall, 61% of patients
experienced adverse events while on treatment.
21,26
The
common (>10% of patients) adverse events were fatigue,
nausea, and headache, similar to what was seen in the
POLARIS trials.
11–13,21,26
A search of the FDA Adverse Event Reporting System
(FAERS) using the search term “voxilaprevir”resulted in
a total of five reports between 2016 and 2018.
27
All five
reports were categorized as serious reaction types, but none
resulted in death.
27
The 2016 report involved a 50-year-old
female taking SOF/VEL/VOX and ribavirin.
27
Alanine ami-
notransferase and aspartate aminotransferase were reported
as increased.
27
In 2017, there was one report for an unre-
ported age/gender patient who was taking SOF/VEL/VOX
and ribavirin with a reaction of lymphocyte count, hemoglo-
bin, and platelet count decreased, and blood glucose and
alanine aminotransferase increased.
27
Three reports were
sent between November and December of 2018, all invol-
ving a 65-year-old male from the same country.
27
These
cases may involve the same patient, with different drug
companies sending in separate reports.
27
The drugs included
sofosbuvir, boceprevir, daclatasvir, ledipasvir, voxilaprevir,
peginterferon alfa-2b, ribavirin, and daclatasvir dihy-
drochloride, and the reactions reported were HCC, asthenia,
upper abdominal pain, nausea, and drug ineffective.
27
Therefore, no additional significant safety signals have
been reported to FAERS since the drug’sapproval.
Table 2 Overview of adverse events
Adverse event POLARIS-1
(n=263)
11
POLARIS-1
Deferred (n=147)
13
POLARIS-2
(n=501)
12
POLARIS-3
(n=110)
12
POLARIS-4
(n=182)
11
Ruane et al
(n=31)
21,26
Any adverse event 206 (78) 112 (76) 361 (72) 83 (75) 140 (77) 19 (61)
Discontinued treatment due
to adverse event
1 (1) 0 0 0 0 0
Serious adverse event 5 (2) 6 (4) 15 (3) 2 (2) 4 (2) 1 (3)
Death 0 0 0 1 (1) 1 (1) 0
Headache 66 (25) 29 (20) 134 (27) 27 (25) 50 (27) 4 (13)
Fatigue 56 (21) 31 (21) 106 (21) 28 (25) 43 (24) 5 (16)
Diarrhea 47 (18) 28 (19) 88 (18) 17 (15) 36 (20) 2 (7)
Nausea 37 (14) 21 (14) 80 (16) 23 (21) 22 (12) 5 (16)
Notes: Data are presented as n (%).
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Drug–drug interactions
There are several important drug interactions to consider
when a patient is going to start treatment with SOF/VEL/
VOX. All three HCV drugs are substrates of p-glycoprotein
(P-gp) and breast cancer resistant protein (BCRP).
9
Voxilaprevir is also a substrate of OATP1B1, OATP1B3,
CYP3A4, CYP1A2, and CYP2C8.
9
Therefore, concomitant
administration with P-gp inducers and/or moderate to potent
CYP inducers (eg, carbamazepine, phenytoin, St. John’s
Wort) will decrease the therapeutic effect of SOF/VEL/
VOX and is not recommended.
9
The concomitant adminis-
tration of rifampin and cyclosporine is not recommended
due to the increased concentration of voxilaprevir.
9
An
important warning to note is the risk for serious sympto-
matic bradycardia when patients take amiodarone with
SOF/VEL/VOX.
9
Due to a potential decrease in absorption
of VEL, antacid and VEL administration times should be
separated by 4 hrs.
9
H
2
-receptor antagonists, at a dose not
exceeding famotidine 40 mg twice daily, and omeprazole
20 mg can be given simultaneously with SOF/VEL/VOX.
9
However, higher doses of omeprazole and other proton-
pump inhibitors have not been studied.
9
There are many antiretroviral drugs that interact with
SOF/VEL/VOX. Atazanavir, fosamprenavir, indinavir, lopi-
navir, and saquinavir should not be coadministered due to
an increase in voxilaprevir plasma concentrations.
28
There
are a lack of coadministration studies with various HIV
drugs, and efavirenz, etravirine, nevirapine, and tipranavir
are not recommended at this time due to potential decreases
in efficacy of the HCV drugs.
28
Special populations
There are no dosage adjustments needed for SOF/VEL/VOX
in mild (eGFR 50–79 mL/min/1.73m
2
) to moderate (eGFR
30–49 mL/min/1.73m
2
) renal impairment.
9
At this time,
there are insufficient data regarding the safety and efficacy
in patients with severe renal impairment (eGFR <30 mL/min/
1.73m
2
) or end-stage renal disease (ESRD) as it has not been
studied in these patients.
9
Sofosbuvir is primarily eliminated
through the kidneys, so an increased exposure to the sofos-
buvir metabolite would occur in severe renal impairment or
ESRD, and use should be avoided.
9
In patients with mild-
hepatic impairment (Child-Pugh A, compensated cirrhosis),
no dosage adjustment is required.
9
In patients with moderate-
severe hepatic impairment (Child-Pugh B or C, decompen-
sated cirrhosis), use of SOF/VEL/VOX is currently not
recommended.
9
Voxilaprevir is mostly eliminated through
biliary excretion; thus, use in patients with decompensated
cirrhosis could lead to increased exposure to voxilaprevir.
9
There is some evidence to support that a transjugular
intrahepatic portosystemic shunt (TIPS) may be a risk
factor for DAA failure due to the impact on pharmacoki-
netic and pharmacodynamic properties. A small retrospec-
tive study found that SVR was achieved in 3/3 patients
treated with SOF/VEL/VOX without a TIPS versus 0/1
patients treated with SOF/VEL/VOX with a TIPS.
29
Post-
transplant patient studies are lacking; however, one case
report showed successful SVR in a post-liver transplant,
DAA-experienced patient with genotype 3 HCV.
30
This
patient was treated for 16 weeks with SOF/VEL/VOX
along with the addition of ribavirin starting at 8 weeks.
30
Further studies are needed to establish safety and efficacy
in this patient population.
In patients with opioid substitution therapy (OST),
there is some evidence to support the use of SOF/VEL/
VOX to achieve SVR without additional safety concerns.
When comparing patients on SOF/VEL/VOX who
received OST or did not receive OST, SVR rates were
similar, 95.9% (47/49) and 95.8% (965/1007),
respectively.
31
Safety and efficacy have not been estab-
lished in pediatric patients, pregnant patients, or lactating
patients.
9
There is a black box warning for risk of
Hepatitis B Virus (HBV) reactivation in patients co-
infected with HCV/HBV while taking SOF/VEL/VOX.
9
Reactivation of HBV has been reported in some patients
who were not on HBV treatment, and some cases led to
fulminant hepatitis, hepatic failure, and death.
9
Therefore,
all patients should be tested for current or prior HBV
infection before initiating treatment with SOF/VEL/VOX.
9
In patients who are co-infected with HCV/HIV, it is impor-
tant to check for interactions with antiretroviral drugs, as
discussed above. Both the European AIDS Clinical Society
(EACS) and the American Association for the Study of Liver
Diseases/Infectious Diseases Society of America (AASLD/
IDSA) guidelines include SOF/VEL/VOX as a treatment
option for HCV/HIV co-infected persons.
6,32
Despite the
lack of supporting data, AASLD/IDSA guidelines state that
this treatment is predicted to have similar response to HCV
mono-infected patients.
6
Similarly, the 2018 US Department
of Health and Human Services (DHHS) HIV Guidelines sug-
gest that DAA regimens are just as effective in HCV/HIV co-
infection as compared to HCV monoinfection.
33
The DHHS
guidelines do not have a specificstatementonSOF/VEL/
VOX; however, this treatment is included in the table of
DAA drugs for HCV treatment in adults with HIV.
33
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Access
Bacon et al examined the accessibility and utilization of SOF/
VEL/VOX in practice, focusing on patients with a history of
treatment failure with an NS5A inhibitor-containing HCV
regimen.
34
Data for this study were acquired from Trio
Health’s disease management program database and included
patients who had initiated treatment with SOF/VEL/VOX
between July and October of 2017.
34
Accessibility was
assessed by determining the proportion of patients who
initiated therapy (termed “starts”), those who were prescribed
therapy but did not initiate therapy (termed “non-starts”), and
those who were prescribed the therapy but did not initiate the
treatment within the study period (termed “pending”). The
majority of patients enrolled in this study were male (99/136)
with compensated cirrhosis (60/136).
34
The mean age was 60,
although the age range was mid-30s to early-80s for all groups
except the non-start group which had a narrower range of age
55–84.
34
Most patients had initiated treatment within the sam-
pling window (83/136), with the second-largest group pending
treatment (41/136) and the smallest percentage having not
initiated treatment (12/136).
34
Themostcommonreasonfor
not starting therapy was insurance denial, 75% of which were
from Medicare and Medicaid, which may have been due to the
patient population and not necessarily the strictness of the
insurance plan.
34
Other reasons for not starting treatment
were physician choice (8%) and patient choice (17%).
34
An
interesting finding from this study was that 34% of patients
with a known treatment status were treatment naïve.
34
However, the reasoning why SOF/VEL/VOX was selected as
initial treatment of HCV in these patients was not described.
34
Treatment-experienced patients tended to have prior exposure
to an NS5A inhibitor-containing regimen (22/26) or a regimen
containing SOF without an NS5A inhibitor (1/26).
34
Place in therapy
The approval of SOF/VEL/VOX made available an evidence-
based DAA regimen for patients who experienced virologic
failure on a previous NS5A or sofosbuvir-containing regimen.
The evidence from the POLARIS trials, as well as the pub-
lications since gaining market approval, illustrate that the
presence of baseline NS3, NS5A, and NS5B RASs that confer
resistance to the individual components of SOF/VEL/VOX do
not appear to have a negative impact on the efficacy of a 12-
week regimen of SOF/VEL/VOX. Therefore, retreatment uti-
lizing a 12-week regimen of SOF/VEL/VOX should be
attempted in DAA-experienced patients with and without
compensated cirrhosis regardless of the presence of baseline
RASs. Patients who should especially be targeted to receive
SOF/VEL/VOX treatment include DAA-experienced patients
with advanced fibrosis or compensated cirrhosis to halt the
deterioration of liver disease. Targeting this patient population
before they reach the point of decompensated cirrhosis is
especially important as treatment options for patients with
decompensated cirrhosis are limited, and there are no high
quality, evidence-based options for DAA-experienced patients
with decompensated cirrhosis. Additionally, treating patients
with compensated cirrhosis will likely improve the patients’
quality of life significantly, as seen for the patients enrolled in
the POLARIS trials.
15,16
Even though SOF/VEL/VOX was studied in some treat-
ment naïve patient populations, its use should be reserved for
DAA-experienced patients. This is owed to the fact that there
are other highly effective and well-tolerated DAA regimens
that include only two DAAs. SOF/VEL/VOX use should
also be avoided in patients with severe renal impairment
and ESRD. Until more data regarding safety are available,
use of SOF/VEL/VOX in pediatric patients and patients who
are pregnant and lactating should be avoided.
Of note, this literature search did not identify any studies
besides the Ruane et al study
21
outlined above that
described how to manage a patient who may fail SOF/
VEL/VOX treatment; additional research is needed in this
area. For those patients who do achieve SVR with SOF/
VEL/VOX, post-treatment monitoring is the same as for
other DAAs: patients without advanced fibrosis should be
followed-up as if they never had HCV, patients with
advanced fibrosis, including cirrhosis, should be screened
for HCC twice per year, and assessing for HCV recurrence
or reinfection is only recommended in patients who have
ongoing risk factors for HCV infection or show unexplained
hepatic dysfunction.
6
Conclusion
Sofosbuvir/velpatasvir/voxilaprevir is a once-daily, fixed-
dose combination tablet for the treatment of HCV in adult
patients with genotypes 1 through 6 who have failed
treatment with an NS5A inhibitor or genotype 1a or 3
who have failed treatment with sofosbuvir without an
NS5A inhibitor. Its approval has added an effective and
safe option for DAA-experienced patients to the extremely
effective group of DAA treatments for chronic HCV.
Disclosure
The authors report no conflicts of interest in this work.
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