Journal of Infection and Public Health 11 (2018) 156–164

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Journal of Infection and Public Health

journal homepage: http://www.elsevier.com/locate/jiph

Review

Safety and efficacy of sofosbuvir plus velpatasvir with or without

ribavirin for chronic hepatitis C virus infection: A systematic review
and meta-analysis
Hussien Ahmed a,b,c,∗∗,1 , Abdelrahman I. Abushouk a,d,e,1 , Attia Attia a,f ,
Mohamed Gadelkarim a,g , Mohamed Gabr a,b,c , Ahmed Negida a,b,c ,
Mohamed M. Abdel-Daim h,i,∗
a
Medical Research Group of Egypt, Cairo, Egypt
b
Faculty of Medicine, Zagazig University, Zagazig, El-Sharkia, Egypt
c
Student Research Unit, Zagazig University, Zagazig, El-Sharkia, Egypt
d
Faculty of Medicine, Ain Shams University, Cairo, Egypt
e
NovaMed Medical Research Association, Cairo, Egypt
f
Faculty of Medicine, Al-Azhar University, Cairo, Egypt
g
Faculty of Medicine, Alexandria University, Alexandria, Egypt
h
Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt
i
Department of Ophthalmology and Micro-Technology, Yokohama City University, Yokohama, Japan

a r t i c l e i n f o a b s t r a c t

Article history: Velpatasvir is a newly FDA-approved inhibitor of hepatitis C virus (HCV) NS5A protein. We performed
Received 28 January 2017 this systematic review and meta-analysis to investigate the safety and efficacy of velpatasvir plus sofos-
Received in revised form 8 August 2017 buvir in the treatment of chronic HCV infection. A computerized literature search of PubMed, SCOPUS,
Accepted 9 September 2017
EMBASE, EBSCO, Web of science, and Cochrane CENTRAL was conducted using relevant keywords. Data
from eligible studies were pooled in a fixed effect meta-analysis model, using OpenMeta[Analyst] soft-
Keywords:
ware. Pooled data from six randomized trials (n = 1427 patients) showed that velpatasvir plus sofosbuvir
Sofosbuvir
achieved sustained virological response (SVR12) rates of 98.2% in genotype-1, 99.4% in genotype-2, 94.7%
Velpatasvir
Ribavirin
in genotype-3, 99.6% in genotype-4, 97.1% in genotype-5, and 98.8% in genotype-6 patients. The addition
Hepatitis C Virus of ribavirin did not significantly increase the SVR12 (RR = 0.95, 95%CI [0.88, 1.02]) or decrease relapse
Meta-analysis rates (RR = 2.52, 95% CI [0.49, 12.87]) in HCV genotype-1 patients. However, adding ribavirin significantly
increased SVR12 (RR = 89.5, 95% CI [80.4, 99.5]) in genotype-3 patients. In conclusion, the 12-week reg-
imen of sofosbuvir plus velpatasvir was highly effective in HCV patients, including those with cirrhosis
and former treatment experience. Except for genotype-3, adding ribavirin was not associated with sig-
nificant improvements in SVR12 rates. Further studies should investigate the effect of adding ribavirin
to this regimen, especially in HCV genotype-3 patients.
© 2017 The Authors. Published by Elsevier Limited on behalf of King Saud Bin Abdulaziz University
for Health Sciences. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
Literature search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157

Abbreviations: DAAs, direct antiviral agents; NS5A, non-structural protein 5A; NS5B, non-structural protein 5B; NS3, non-structural protein 3; RAS, resistance-associated
substitutions; SVR, sustained viral response.
∗ Corresponding author at: Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt.
∗∗ Corresponding author at: Faculty of Medicine, Zagazig University, Egypt.
E-mail addresses: Hoseen011232@medicine.zu.edu.eg (H. Ahmed), Abdeldaim.m@vet.suez.edu.eg, Abdeldaim.m@gmail.com (M.M. Abdel-Daim).
1
Both authors contributed equally.

https://doi.org/10.1016/j.jiph.2017.09.004
1876-0341/© 2017 The Authors. Published by Elsevier Limited on behalf of King Saud Bin Abdulaziz University for Health Sciences. This is an open access article under the
CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 H. Ahmed et al. / Journal of Infection and Public Health 11 (2018) 156–164 157

Eligibility criteria and study selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157

Data extraction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .158
Risk of bias assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
Data synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
Literature search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
Characteristics of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
Efficacy endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
SVR12 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Relapse rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Subgroup analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Genotype 1a versus genotype 1b . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Cirrhotic versus non-cirrhotic patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Treatment naïve versus treatment experienced patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Safety analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
Implications for future research and clinical practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
Ethical approval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163

Introduction potent activity against all HCV genotypes [17]. Another integral
component of multiple HCV therapeutic regimens is ribavirin; how-
Up to 71 million individuals worldwide are infected with hep- ever, its efficacy when added to new DAAs remains a matter of
atitis C virus (HCV) [1]. Around 50–80% of patients with acute HCV debate.
infection develop chronicity with viral persistence, increasing the Recently, several randomized controlled trails (RCTs) have eval-
risk of decompensated cirrhosis and hepatocellular carcinoma [2]. uated the efficacy of the combination (sofosbuvir plus velpatasvir)
The 5-year cumulative risk of malignant transformation is more in the treatment of different HCV genotypes [18–22]. Therefore, we
than 17% in patients with HCV-associated cirrhosis [3]. In the USA, performed this systematic review and meta-analysis to investigate
40% of liver transplants are attributed to HCV infection; however, the safety and efficacy of sofosbuvir plus velpatasvir regimen in
in Japan, it is up to 90% [4,5]. Moreover, a wide range of extra- chronic HCV infection and to evaluate the role of ribavirin as an
hepatic manifestations has been reported in these patients, such add-on therapy to this regimen.
as autoimmune/lymphoproliferative and central nervous system
disorders [6,7]. Materials and methods
The aim of HCV therapy is to achieve sustained virological
response (SVR), which is defined as HCV-RNA <15 IU/ml, 12 or 24 We followed the PRISMA statement guidelines during the
weeks after the end of antiviral therapy. Conventionally, SVR was preparation of this systematic review and meta-analysis [23].
estimated after 24 weeks of treatment cessation; however, the new
recommendations support the 12 weeks based estimation due to
the concordance between SVR12 and SVR24 [4,8,9]. Literature search strategy
For decades, the treatment of chronic HCV infection has been
based on the adminstration of pegylated interferon and ribavirin. We searched the following electronic databases: PubMed,
The triple combination, characterized by the addition of first- Cochrane CENTRAL, EBSCO, EMBASE, SCOPUS and Web of science
generation direct-acting antivirals (DAAs), including telaprevir and through March 2016 using the following query: “Sofosbuvir plus
boceprevir, had a relatively short life and was only indicated for Velpatasvir AND HCV”. No restrictions by language or period of pub-
genotype 1 infections [10–12]. Moreover, several adverse events, lication were used. We also scanned the reference list of included
related to the use of interferon, were frequently reported, such studies and potentially relevant reviews for other eligible trials.
as neuropsychiatric problems, seizures, bone marrow suppression
and flu-like symptoms [13]. Eligibility criteria and study selection
The introduction of second-generation DAAs was a remarkable
revolution in the field of HCV therapy. These drugs are classified into We used the following inclusion criteria: (1) population: HCV-
three groups according to their mechanism of action: the first group infected patients (all genotypes) with or without cirrhosis, (2)
is HCV NS3/4A protease inhibitors, the second is HCV NS5B poly- intervention: oral combination of sofosbuvir (400 mg/day) plus
merase inhibitors, and the third is HCV NS5A replication complex velpatasvir (100 mg/day) with ribavirin (1000 mg/day), (3) com-
inhibitor [14]. parator: sofosbuvir plus velpatasvir (control group in double-arm
The NS5B nucleotide inhibitor (sofosbuvir) is effective against analysis) or none in single-arm analysis, (4) outcomes: efficacy out-
all HCV genotypes with a favorable safety profile and a low risk comes including the rates of SVR12 and virological relapse, as well
for development of resistance. The active form of sofosbuvir mim- as the risk of adverse events, and (5) study design: RCTs.
ics the physiological nucleotide and competitively blocks the NS5B We excluded observational studies, trials in which patients were
polymerase, thereby inhibiting HCV-RNA synthesis by RNA chain not randomly allocated to the treatment arms or whose outcomes
termination [15,16]. Velpatasvir (formerly known as GS-5816, were not reported as dichotomous data, and conference abstracts
Gilead Sciences) is an inhibitor of the HCV NS5A protein with a for inability to perform a thorough risk of bias assessment.
158 H. Ahmed et al. / Journal of Infection and Public Health 11 (2018) 156–164
Fig. 1. The PRISMA flow diagram of studies’ screening and selection.
Three independent authors applied the selection criteria. Eligi-
bility screening was performed in two steps: the first step was to
screen abstracts for eligibility to the study objective and in the sec-
ond step, full-text articles of eligible abstracts were retrieved and
screened for eligibility to meta-analysis.
Data extraction
Three authors extracted the data independently and another
author (Ahmed H) resolved disagreements. The extracted data
included the following: (1) criteria of study design, (2) baseline
characteristics of enrolled patients, (3) risk of bias domains, and (4)
study outcomes: sustained virologic response (SVR12) rate, defined
as HCV RNA <15 IU/ml 12 weeks after the end of the antiviral ther-
apy and relapse rate, defined as detectable HCV RNA level during a
12-week follow-up after achieving undetectable levels at the end of
treatment, as well as the incidence of treatment-emergent adverse
events.
Risk of bias assessment
Two authors (Gadelkarim M and Gabr M) independently
assessed the risk of bias in each included study in strict accordance
with the Cochrane handbook for systematic reviews of interven-
tions [24]. We used the risk of bias assessment table provided in
(part 2, Chapter 8.5) of the same book. The Cochrane risk of bias
assessment tool includes the following domains: sequence gener-
ation (selection bias), allocation sequence concealment (selection
bias), blinding of participants and personnel (performance bias),
blinding of outcome assessment (detection bias), incomplete out-
come data (attrition bias), selection outcome reporting (reporting
bias), and other potential sources of bias. The authors’ judgment is
categorized as ‘low risk’, ‘high risk’ or ‘unclear risk’ of bias.
According to Egger et al. [25,26], publication bias assessment
is not reliable for less than 10 pooled studies. Therefore, in the
present study, we could not assess the existence of publication bias
by Egger’s test for funnel plot asymmetry.
Data synthesis
The proportions of SVR12 rates were pooled in a meta-analysis
model, using the Mantel–Haenszel method. Statistical analyses
were performed by OpenMeta[Analyst] software (by Center of Evi-
dence Based Medicine http://www.cebm.brown.edu/open meta/).
In case of significant heterogeneity (Chi-Square p < 0.1), the analy-
sis was conducted under the random effects model; otherwise, the
fixed effect model was adopted.
Results
Literature search strategy
Our search retrieved 51 unique citations. Following title and
abstract screening, twenty full text articles were retrieved and
screened for eligibility. Of them, 15 articles were excluded and five
articles (six RCTs: n = 1427 patients) [18–22] were included in the
final analysis (See PRISMA flow diagram; Fig. 1). Reasons for exclu-
sion of the 15 studies are illustrated in Supplementary file 1 in the
online version at DOI:10.1016/j.jiph.2017.09.004.
Characteristics of included studies
A summary of the design and main findings of included stud-
ies is shown in Table 1 and baseline characteristics of enrolled
patients are shown in Table 2. All included studies were of a low
risk of bias in terms of random sequence generation, attrition and
reporting biases. Except for the study by Feld et al. [21], all included
studies were of a high risk in terms of performance and detection
biases (open-label studies). Only two studies (Everson et al. [18] and
Pianko et al. [19]) adequately reported on their methods of alloca-
tion concealment. A summary of risk of bias assessment domains is
shown in Fig. 2; Authors’ judgments with justifications are shown
in (Supplementary file 2 in the online version at DOI:10.1016/j.jiph.
2017.09.004).
Efficacy endpoints
The double regimen of sofosbuvir and velpatasvir for 12 weeks
achieved SVR12 rates of 98.2% (95% CI [97–99.4%], p < 0.001,
451 patients) in genotype 1 patients, 99.4% (95% CI [98.4–100%],
p < 0.001, 242 patients) in genotype 2 patients, 94.7% (95% CI
[92.5–97%], p < 0.001, 371 patients) in genotype 3 patients, 99.6%
(95% CI [98.4–100%], p < 0.001, 120 patients) in genotype 4 patients,
Table 1
A summary of the design and findings of included studies.
Study ID Study design
Everson et al. [18] Phase II, open label,
randomized trail, openP
Pianko et al. [19] Phase II, open label,
randomized trail
Curry et al. [20] Phase III, open label,
randomized trail
Foster et al. [22] Two Phase III, open label,
randomized trails
Feld et al. [21] Phase III, double blinded,
randomized trail
Abbreviations: GT: genotype, HCV: hepatitis C virus, RBV: ribavirin, SOF: sofosbuvir, SVR: sustained virological response, VEL: velpatasvir.
Sample size (n) Population
337 Naïve, non-cirrhotic
patients with HCV
(genotypes 1–6)
321 Experienced, compensated
cirrhotic or non-cirrhotic
patients with HCV
(genotypes 1 or 3)
267 Naïve or experienced,
decompensated cirrhotic
patients with HCV
(genotypes 1–6).
818 Naïve or experienced,
compensated cirrhotic and
non-cirrhotic patients with
HCV (genotypes 2 or 3)
706 Naïve or experienced,
compensated cirrhotic and
non-cirrhotic patients with
HCV (genotypes 1–6)
Study arms
GT (1–6): SOF 400 mg + VEL
25 mg or 100 mg (12
weeks)
SOF 400 mg + VEL 25 mg or
100 mg (12 weeks)
SOF 400 mg + VEL
100 mg + RBV (12 weeks)
(GT 2, 3) SOF 400 mg/VEL
100 mg (12 weeks)
SOF 400 mg/VEL 100 mg
(12 weeks)
Main finding
GT (1 and 2): SOF GT (1 and 2): SOF Twelve weeks of sofosbuvir
400 mg + VEL 25 or 400 mg + VEL 25 or 100 mg (400 mg) and velpatasvir
100 mg + RBV (8 weeks) (8 weeks) (100 mg) was
well-tolerated and resulted
in high SVR rates in
patients, infected with HCV
(genotypes 1–6)
H. Ahmed et al. / Journal of Infection and Public Health 11 (2018) 156–164
SOF 400 mg + VEL 25 or Twelve weeks of sofosbuvir
100 mg with RBV (12 (400 mg) and velpatasvir
weeks) (100 mg) was
well-tolerated and resulted
in high SVR rates in
treatment experienced
patients, infected with HCV
(genotypes 1 or 3)
SOF 400 mg + VEL 100 mg SOF 400 mg + VEL 100 mg Sofosbuvir (400 mg) and
(12 weeks) (24 weeks) velpatasvir (100 mg) for 12
weeks (with or without
ribavirin) or 24 weeks was
well-tolerated and resulted
in high SVR rates in
decompensated patients,
infected with HCV
(genotypes 1–6)
(GT 2) SOF 400 mg + RBV (GT 3) SOF 400 mg + RBV Twelve weeks of treatment
(12 weeks) (24 weeks) of sofosbuvir (400 mg) and
velpatasvir (100 mg)
resulted in high rates of
SVR that were superior to
those with sofosbuvir and
ribavirin
Placebo Twelve weeks of sofosbuvir
(400 mg) and velpatasvir
(100 mg) was
well-tolerated and resulted
in high SVR rates in
patients infected with HCV
(genotypes 1–6)
159
 160
Table 2
Baseline characteristics of the population of included studies.

Study Treatment No Duration (weeks) Age mean (range) BMI mean (range) Population HCV genotypes HCV RNA − log10 HCV RNA ≥ 800.000
IU/ml (mean ± SD) log10 IU/ml no. (%)

Everson et al. [18] SOF + VEL 25 mg 27 12 28 (20–43) 49 (24–64) Non-cirrhotic Genotype 1 6.4 ± 0.60 23 (85)
SOF + VEL 100 mg 28 12 28 (19–42) 49 (20–68) Non-cirrhotic Genotype 1 6.4 ± 0.74 22 (79)
SOF + VEL 25 mg 27 12 28 (20–75) 52 (25–70) Non-cirrhotic Genotype 3 6.4 ± 1.09 18 (67)
SOF + VEL 100 mg 27 12 27 (20–48) 50 (20–70) Non-cirrhotic Genotype 3 6.2 ± 0.74 21 (78)
SOF + VEL 25 mg 23 12 29 (19–43) 48 (23–78) Non-cirrhotic Genotype 2,4,5,6 6.4 ± 0.70 18 (78)

H. Ahmed et al. / Journal of Infection and Public Health 11 (2018) 156–164

SOF + VEL 100 mg 22 12 27 (20–38) 54 (23–70) Non-cirrhotic Genotype 2,4,5,6 6.4 ± 0.83 16 (73)
SOF + VEL 25 mg 30 8 50 (19–64) 26 (19–64) Non-cirrhotic Genotype 1 6.5 ± 0.69 25 (83)
SOF + VEL 25 mg + RBV 30 8 53 (34–68) 28 (21–44) Non-cirrhotic Genotype 1 6.5 ± 0.63 25 (83)
SOF + VEL 100 mg 29 8 55 (21–67) 28 (20–43) Non-cirrhotic Genotype 1 6.3 ± 0.85 21 (72)
SOF + VEL100 mg + RBV 31 8 52 (18–69) 29 (21–43) Non-cirrhotic Genotype 1 6.6 ± 0.055 28 (90)
SOF + VEL 25 mg 26 8 52 (28–70) 27 (20–42) Non-cirrhotic Genotype 2 6.4 ± 0.87 20 (77)
SOF + VEL 25 mg + RBV 25 8 54 (24–68) 30 (18–45) Non-cirrhotic Genotype 2 6.6 ± 0.80 21 (84)
SOF + VEL 100 mg 26 8 54 (24–71) 29 (20–39) Non-cirrhotic Genotype 2 6.5 ± 0.74 21 (81)
SOF + VEL 100 mg + RBV 26 8 51 (28–67) 30 (22–53) Non-cirrhotic Genotype 2 6.7 ± 0.57 24 (92)

Pianko et al. [19] SOF + VEL 25 mg 26 12 54 (22–69) 27 (20–38) Non-cirrhotic Genotype 3 6.7 ± 0.8 21 (81)
SOF + VEL 25 mg + RBV 28 12 51 (25–67) 28 (20–38) Non-cirrhotic Genotype 3 6.6 ± 0.7 22 (79)
SOF + VEL 100 mg 27 12 55 (32–68) 27 (22–39) Non-cirrhotic Genotype 3 6.6 ± 0.6 25 (93)
SOF + VEL 100 mg + RBV 26 12 56 (42–72) 28 (21–39) Non-cirrhotic Genotype 3 6.7 ± 0.5 24 (92)
SOF 400 mg + VEL 25 mg 26 12 57 (40–68) 27 (20–39) Cirrhotic Genotype 3 6.6 ± 0.5 23 (88)
SOF + VEL 25 mg + RBV 25 12 56 (38–65) 28 (22–45) Cirrhotic Genotype 3 6.2 ± 0.7 18 (72)
SOF + VEL 100 mg 26 12 56 (45–68) 29 (23–44) Cirrhotic Genotype 3 6.4 ± 0.8 19 (73)
SOF + VEL 100 mg + RBV 26 12 54 (44–65) 28 (20–38) Cirrhotic Genotype 3 6.7 ± 0.5 24 (92)
SOF + VEL 25 mg 27 12 55 (25–67) 28 (23–43) Cirrhotic Genotype 1 6.5 ± 0.6 21 (78)
SOF + VEL 25 mg + RBV 29 12 57 (47–67) 30 (21–45) Cirrhotic Genotype 1 6.8 ± 0.4 29 (100)
SOF + VEL 100 mg 27 12 57 (46–67) 30 (20–50) Cirrhotic Genotype 1 6.4 ± 0.5 24 (89)
SOF + VEL 100 mg + RBV 28 12 56 (41–66) 29 (18–37) Cirrhotic Genotype 1 6.5 ± 0.4 25 (89)

Feld et al. [21] Placebo 116 12 53 (25–74) 26 (18–40) Cirrhotic Genotype 1, 2, 4, 5 and 6 6.3 ± 0.58 87 (75)
SOF + VEL 624 12 54 (18–82) 27 (17–57) Cirrhotic Genotype 1, 2, 4, 5 and 6 6.3 ± 0.66 461 (74)

Curry et al. [20] SOF + VEL 90 12 58 (42–73) 31 (17–56) Cirrhotica Genotype 1, 2, 3, 4 and 6 6.0 ± 0.5 59 (66)
SOF + VEL + RBV 87 12 58 (40–71) 30 (20–55) Cirrhotica Genotype 1, 2, 3, 4 and 6 5.8 ± 0.6 45 (52)
SOF + VEL 90 24 58 (46–72) 30 (18–50) Cirrhotica Genotype 1, 2, 3, 4 and 6 5.9 ± 0.6 45 (50)

Foster et al. [22] SOF + VEL 134 12 57 (26–81) 28 (17–45) Cirrhotic Genotype 2 6.5 ± 0.78 111 (83)
SOF + RBV 132 12 57 (23–76) 29 (19–61) Genotype 2 6.4 ± 0.74 101 (77)
SOF + VEL 277 12 49 (21–76) 26 (17–48) Cirrhotic Genotype 3 6.2 ± 0.72 191 (69)
SOF + RBV 275 24 50 (19–74) 27 (17–56) Cirrhotic Genotype 3 6.3 ± 0.71 194 (71)

BMI: body mass index, HCV: hepatitis C virus, RBV: ribavirin, SOF: sofosbuvir, VEL: velpatasvir.
a
Decompensated cirrhosis.
 H. Ahmed et al. / Journal of Infection and Public Health 11 (2018) 156–164
Fig. 2. Risk of bias summary according to Cochrane risk of bias assessment tool.
97.1% (95% CI [91.6–100%], 35 patients) in genotype 5 patients, and
98.8% (95% CI [95.5–100%], 41 patients) in genotype 6 patients;
Fig. 3.
Two randomized clinical trials [19,20] investigated the effect of
adding ribavirin to sofosbuvir and velpatasvir in terms of:
SVR12
The overall effect estimate did not favor the 12 weeks’ regimen
of sofosbuvir plus velpatasvir and ribavirin over the 12 weeks’ reg-
imen of sofosbuvir plus velpatasvir in genotype 1 (RR = 0.95, 95%
CI [0.88, 1.02], p = 0.23, 191 patients), genotype 2 (RR = 1.00, 95% CI
[0.66, 1.51], 8 patients), and genotype 4 patients (RR = 1.08, 95% CI
[0.60, 1.93], 6 patients). However, the ribavirin containing regimen
was superior to the ribavirin free regimen in terms of SVR12 rate
in genotype 3 patients (RR = 0.89, 95% CI [0.80, 0.99], p = 0.04, 132
patients); Fig. 4A.
Relapse rate
The overall effect estimate did not favor the 12 weeks’ regimen
of sofosbuvir plus velpatasvir and ribavirin over the 12 weeks’ reg-
imen of sofosbuvir plus velpatasvir in genotype 1 (RR = 2.52, 95%
CI [0.49, 12.87], p = 0.26, 191 patients) and genotype 3 patients
(RR = 4.27, 95% CI [0.98, 18.47], p = 0.52, 132 patients); Fig. 4B.
Subgroup analysis
Genotype 1a versus genotype 1b
Pooling data from two studies [20,21] (260 genotype 1a and
136 genotype 1b patients) showed that treatment with sofosbuvir
161
(400 mg/day) plus velpatasvir (100 mg/day) achieved SVR12 rates
of 97.7% (95%CI [95.9–99%], p < 0.001) in patients with genotype
1a infection and 99% (95%CI [97.4–100%], p < 0.001) in those with
genotype 1b infection.
Cirrhotic versus non-cirrhotic patients
Pooling data from three studies [18,20,21] (141 cirrhotic and
283 non-cirrhotic patients) showed that treatment of HCV geno-
type 1 infection with sofosbuvir plus velpatasvir achieved SVR12
rates of 97.5% (95% CI [95–100%], p < 0.001) in cirrhotic and 98.5%
(95% CI [97–99.9%], p < 0.001) in non-cirrhotic patients. Moreover,
in cirrhotic patients with HCV genotypes 2–4 infections, sofosbu-
vir plus velpatasvir regimen achieved SVR12 rates of 100% (95%
CI [82.5–100%]), 90.7% (95% CI [85.2–96.2%], p < 0.001), and 100%
(95% CI [93.2–100%]), respectively. In non-cirrhotic patients with
HCV genotypes 2–4 infections, sofosbuvir plus velpatasvir regimen
achieved SVR12 rates of 99.5% (95% CI [98–100%]), 97% (95% CI
[94.9–99.1%], p < 0.001), and 99.4% (95% CI [97.9–100%]), respec-
tively.
Treatment naïve versus treatment experienced patients
Pooling data from two studies [18,19] (28 treatment naïve and
27 treatment experienced patients) showed that treatment of HCV
genotype 1 infection with sofosbuvir plus velpatasvir achieved
SVR12 rates of 100% (95% CI [93–100%]) in treatment naïve and
100% (95% CI [93.2–100%]) in treatment experienced patients.
In patients with genotype 3 patients, sofosbuvir plus velpatasvir
regimen achieved SVR12 rates of 92.3% (95% CI [82.3–100%]) in
treatment naïve and 94.2% (95% CI [88–100%]) in treatment expe-
rienced patients.
Safety analysis
The frequency of adverse events was comparable between both
groups (with or without ribavirin), except for nausea, diarrhea,
insomnia, pruritus, and reduced hemoglobin level <100 g/L, which
were more common in the group receiving the ribavirin-containing
regimen. The pooled RRs for adverse events were as fol-
lows: discontinuation due to adverse events (RR = 3.75, 95% CI
[0.63–22.49], p = 0.15), serious adverse events (RR = 0.83, 95%
CI [0.46–1.50], p = 0.54), nausea (RR = 1.48, 95% CI [1.06–2.06],
p = 0.02), headache (RR = 1.04, 95% CI [0.72–1.52], p = 0.83), diarrhea
(RR = 3.45, 95% CI [2.02–5.89], p < 0.00001), insomnia (RR = 1.90,
95% CI [1.05–3.43], p = 0.03), pruritus (RR = 2.22, 95% CI [1.16–4.25],
p = 0.02), decreased hemoglobin level <100 g/L (RR = 2.85, 95% CI
[1.39–5.88], p = 0.004), and decreased hemoglobin level <85 g/L
(RR = 5.13, 95% CI [0.90–29.08], p = 0.07) (Supplementary file 3 in
the online version at DOI:10.1016/j.jiph.2017.09.004).
Discussion
Our meta-analysis showed that a single-tablet regimen of sofos-
buvir plus velpatasvir is highly effective in chronic HCV (genotypes
1–6) patients, with SVR12 rates >97%, except for genotype 3 (SVR12
rate = 94.7%). Subgroup analysis showed that SVR12 rates were not
affected by former treatment exposure or compensated cirrhotic
state. Adding ribavirin to the dual regimen had no significant bene-
fit on SVR12 rates in all genotypes, except for genotype 3. In terms
of safety, the incidence of all adverse events was comparable in
the ribavirin-containing and ribavirin-free groups, except for nau-
sea, diarrhea, insomnia, pruritus, and decreased hemoglobin level
below 10 g/dl (higher with the ribavirin-containing regimen).
The observed lack of clinical benefit for ribavirin (in most HCV
genotypes) in this analysis is consistent with the results of other
studies on other regimens, such as ledipasvir plus sofosbuvir [27]
and simeprevir plus sofosbuvir [28]. In a pooled analysis of the
162 H. Ahmed et al. / Journal of Infection and Public Health 11 (2018) 156–164
Fig. 3. Forest plots of pooled proportions of SRV rates for sofosbuvir plus velpatasvir in HCV patients.
ASTRAL trials, the effect of baseline resistance associated substi-
tutions (RASs) on SVR12 rates was more pronounced in genotype
3 patients (88% for patients with baseline RASs versus 97% for
patients without baseline RASs), compared to other genotypes [29].
Ribavirin may act by delaying or preventing the emergence of RASs,
which may explain the observed value of adding ribavirin in geno-
type 3 patients in our analysis [30]. Although this theory needs fur-
ther confirmation in larger studies, the American Association for the
Study of Liver Diseases (AASLD) and the Infectious Diseases Society
of America (IDSA) recommend adding ribavirin to sofosbuvir plus
velpatasvir in all genotype 3 patients who are either cirrhotic or
treatment experienced with baseline Y93 substitutions [31].
Due to lack of data, we could not evaluate the efficacy of sofos-
buvir plus velpatasvir regimen in some difficult-to-treat patients,
such as those with decompensated cirrhosis, RASs, and human
immunodeficiency virus (HIV) co-infection. Across the ASTRAL tri-
als, NS5A and NS5B RASs were detected in 1% and 7% of patients at
baseline, respectively. These trials reported SVR12 rates of 100% in
patients with baseline NS5B RASs and 98% in those with NS5A RASs
[29]. In the recently published ASTRAL-5 trial [abstract], sofosbu-
vir plus velpatasvir achieved a SVR12 rate of 95% in patients with
HCV/HIV-1 co-infection, receiving antiretroviral therapy [32].
The ASTRAL-4 study randomized chronic HCV patients with
decompensated cirrhosis to receive either the dual regimen
(sofosbuvir plus velpatasvir) for 12 or 24 weeks or the triple
regimen (with ribavirin) for 12 weeks. These regimens achieved
SVR12 rates of 83%, 86% and 94%, respectively. However, the
ribavirin-free regimen was associated with a lower incidence of
anemia, fatigue, diarrhea, cough and lymphopenia, compared to
the ribavirin-containing regimen [20]. We believe that prolonged
treatment duration (24 weeks) with a higher safety margin (in the
dual regimen) should be preferred in these patients. However, the
2016 guidelines of the AASLD/IDSA, recommend sofosbuvir plus
velpatasvir and ribavirin for treatment of decompensated cirrhotic
patients with HCV infection (genotypes 1–4) [31]. In the USA and
the European Union (EU), a single tablet/once daily administra-
tion of sofosbuvir plus velpatasvir was recently approved for the
treatment of all HCV genotypes in non-cirrhotic and compensated
cirrhotic patients (Child-Pugh class A), or combined with ribavirin
to treat all HCV genotypes in decompensated cirrhotic patients
(Child-Pugh Class B and C) [33].
Several studies investigated the effect of sofosbuvir plus vel-
patasvir regimen over the quality of life parameters and patient
reported outcomes (PROs) in patients of the ASTRAL trials,
using specific questionnaires, such as the Chronic Liver Disease
Questionnaire-HCV version (CLDQ-HCV) and the Work Productiv-
ity Activity Index (WPAI). There was a significant improvement in
most PROs at week 4 of treatment, at the end of treatment, and
after 12 and 24 weeks of follow up in cirrhotic and non-cirrhotic
patients [34–37]. We are aware of an ongoing follow up study (NCT
01457755) that is recruiting patients who achieved a SVR12 in the
ASTRAL trials to follow the maintenance of SVR12 and functional
state of their liver for 5 years. The results of this study are eagerly
awaited and similar long-term follow up studies are recommended
for all HCV therapeutic regimens.
Limitations
The effect estimates for SVR12 rates in genotypes 5 and 6 are
based on a smaller number of patients, compared to other geno-
types; therefore, they should be the focus of future clinical trials.
Lack of data in decompensated patients and those with RASs or HIV
co-infection did not allow us to generate pooled results about the
safety and efficacy of this regimen in these difficult to treat patients.
Implications for future research and clinical practice
Future well-designed clinical trials with a larger sample size are
required to confirm our findings. Owing to the high cost of oral DAAs
[4,38–40], future studies should investigate the cost-effectiveness
 H. Ahmed et al. / Journal of Infection and Public Health 11 (2018) 156–164
Fig. 4. Forest plots of pooled risk ratio comparing sofosbuvir plus velpatasvir with the sofosbuvir plus velpatasvir and RBV in terms of; (A) SVR 12 rates, (B) relapse rates
with 95% CI. RR = risk ratio, CI = confidence interval, RBV = ribavirin.
parameters of using this regimen in HCV patients. Although sofos-
buvir plus velpatasvir regimen achieved a fairly high SVR12 in
HCV genotype 3 patients, therapeutic regimens with higher SVR
rates are needed for this particular genotype. In light of the cur-
rent evidence, ribavirin is no longer recommended as an add-on
therapy for HCV patients (genotypes 1–4) receiving the sofosbuvir
plus velpatasvir regimen. However, further data are needed about
the utility of adding ribavirin to this regimen in patients with HCV
genotype-3 infection.
Conclusion
Sofosbuvir plus velpatasvir therapeutic regimen was highly
effective in HCV patients with genotypes 1–6, including treatment
experienced and cirrhotic patients. Except for genotype 3, adding
ribavirin was not associated with a significant improvement of
SVR12 rates. Further studies should investigate the effect of adding
ribavirin to this regimen in HCV genotype 3 patients.
Funding
No funding sources.
Competing interests
None declared.
163
Ethical approval
Not required.
Acknowledgement
None to declare.
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