Oral Direct-Acting Agent Therapy for Hepatitis C Virus Infection:
A Systematic Review
Oluwaseun Falade-Nwulia, MBBS, MPH
*
, Catalina Suarez-Cuervo, MD
*
, David R. Nelson,
MD, Michael W. Fried, MD, Jodi B. Segal, MD, MPH, and Mark S. Sulkowski, MD
Johns Hopkins University School of Medicine, Baltimore, Maryland; University of Florida,
Gainesville, Florida; and University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
Abstract
Background—Rapid improvements in hepatitis C virus (HCV) therapy have led to the approval
of multiple oral direct-acting antiviral (DAA) regimens by the U.S. Food and Drug Administration
(FDA) for treatment of chronic HCV infection.
Purpose—To summarize published literature on the efficacy and safety of oral DAAs for
treatment of persons with chronic HCV infection.
Data Sources—MEDLINE and EMBASE from inception through 1 November 2016.
Requests for Single Reprints: Oluwaseun Falade-Nwulia, MBBS, MPH, Department of Medicine, Johns Hopkins University School of
Medicine, 725 North Wolfe Street, Suite 215, Baltimore, MD 21205; ofalade1@jhmi.edu.
*
Drs. Falade-Nwulia and Suarez-Cuervo contributed equally to this work.
Reproducible Research Statement:
Study protocol:
Registered in PROSPERO (CRD42014009711).
Statistical code:
Not applicable.
Data set:
See the Supplement. Additional data are available upon request from Dr. Falade-Nwulia (ofalade1@jhmi.edu) or Dr. Suarez-
Cuervo (csuarez3@jhmi.edu).
Current Author Addresses: Dr. Falade-Nwulia: Department of Medicine, Johns Hopkins University School of Medicine, 725 North
Wolfe Street, Suite 215, Baltimore, MD 21205.
Dr. Suarez-Cuervo: Johns Hopkins Evidence-Based Practice Center, Johns Hopkins University School of Medicine, 624 North
Broadway, Suite 680, Baltimore, MD 21205.
Dr. Nelson: Department of Medicine, University of Florida, 2004 Mowry Road, Gainesville, FL 32611.
Dr. Fried: Department of Medicine, University of North Carolina at Chapel Hill, CB 7584, Room 8015 Burnett-Womack, Chapel Hill,
NC 27514.
Dr. Segal: Department of Medicine, Johns Hopkins University School of Medicine, 624 North Broadway, Room 644, Baltimore, MD
21205.
Dr. Sulkowski: Department of Medicine, Johns Hopkins University School of Medicine, 1830 East Monument Street, Baltimore, MD
21205.
Disclosures: Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M16-2575.
Authors not named here have disclosed no conflicts of interest.
Current author addresses and author contributions are available at Annals.org.
Author Contributions: Conception and design: O. Falade-Nwulia, C. Suarez-Cuervo, D.R. Nelson, M.W. Fried, J.B. Segal, M.S.
Sulkowski.
Analysis and interpretation of the data: O. Falade-Nwulia, C. Suarez-Cuervo, D.R. Nelson, M.W. Fried, J.B. Segal, M.S. Sulkowski.
Drafting of the article: O. Falade-Nwulia, C. Suarez-Cuervo, M.S. Sulkowski.
Critical revision of the article for important intellectual content: O. Falade-Nwulia, C. Suarez-Cuervo, D.R. Nelson, M.W. Fried, J.B.
Segal, M.S. Sulkowski.
Final approval of the article: O. Falade-Nwulia, C. Suarez-Cuervo, D.R. Nelson, M.W. Fried, J.B. Segal, M.S. Sulkowski.
Provision of study materials or patients: C. Suarez-Cuervo.
Statistical expertise: C. Suarez-Cuervo, J.B. Segal.
Obtaining of funding: M.S. Sulkowski.
Administrative, technical, or logistic support: C. Suarez-Cuervo, M.S. Sulkowski.
Collection and assembly of data: O. Falade-Nwulia, C. Suarez-Cuervo, J.B. Segal, M.S. Sulkowski.
HHS Public Access
Author manuscript
Ann Intern Med
. Author manuscript; available in PMC 2018 March 30.
Published in final edited form as:
Ann Intern Med
. 2017 May 02; 166(9): 637–648. doi:10.7326/M16-2575.
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
Study Selection—42 English-language studies from controlled and single-group registered
clinical trials of adults with HCV infection that evaluated at least 8 weeks of an FDA-approved
interferon-free HCV regimen that included at least 2 DAAs.
Data Extraction—Two investigators abstracted data on study design, patient characteristics, and
virologic and safety outcomes sequentially and assessed quality independently.
Data Synthesis—Six DAA regimens showed high sustained virologic response (SVR) rates
(>95%) in patients with HCV genotype 1 infection without cirrhosis, including those with HIV co-
infection. Effective treatments for HCV genotype 3 infection are limited (2 DAA regimens).
Patients with hepatic decompensation, particularly those with Child–Turcotte–Pugh class C
disease, had lower SVR rates (78% to 87%) than other populations. The addition of ribavirin was
associated with increased SVR rates for certain DAA regimens and patient groups. Overall rates of
serious adverse events and treatment discontinuation were low (<10% in the general population);
regimens that included ribavirin had more mild or moderate adverse events than those without.
Limitations—Twenty-three studies had moderate risk of bias (10 were open-label single-group
trials, 11 had limited information on concealment of the allocation scheme, and 5 had selective
outcome reporting). All but 1 of the studies were industry-funded. Heterogeneity of interventions
precluded pooling.
Conclusion—Multiple oral DAA regimens show high rates of safety, tolerability, and efficacy
for treatment of HCV genotype 1 infection, particularly among persons without cirrhosis.
Primary Funding Source—Patient-Centered Outcomes Research Institute. (PROSPERO:
CRD42014009711)
In the United States, 3.2 to 5 million people are chronically infected with hepatitis C virus
(HCV) and are at risk for cirrhosis, liver cancer, and death if untreated (1,2). Infection with
HCV is the primary indication for liver transplantation and causes more deaths than all other
notifiable infectious diseases in the United States combined (3, 4). Cure of this infection,
defined as the absence of detectable HCV RNA in the blood at least 12 weeks after
treatment completion (sustained virologic response [SVR]), is strongly associated with
reduced liver-related morbidity and mortality (5, 6). The development of drugs that directly
inhibit key steps in viral replication has led to availability of several oral HCV treatment
regimens (7). We systematically reviewed the efficacy and safety of oral interferon-free
HCV treatment regimens that have been approved by the U.S. Food and Drug
Administration (FDA) and include at least 2 direct-acting antivirals (DAAs). We also
assessed the effect of ribavirin on rates of SVR and adverse events. We reviewed phase 2 and
3 clinical trial data for patients infected with HCV genotypes 1 to 6 and patients previously
considered difficult to cure with decompensated cirrhosis, HIV infection, renal failure, or
liver transplantation.
Methods
Data Sources and Searches
We developed a protocol for this systematic review and registered it in PROSPERO
(CRD42014009711). We searched MEDLINE and EMBASE for literature published in
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English from inception through 1 November 2016. The search strategy included terms for
HCV infection and the medications of interest (Figure 1). We also searched
ClinicalTrials.gov and hand-searched the reference lists of included articles and related
systematic reviews.
Study Selection
We included English-language, single-group, randomized, controlled trials (RCTs) of adults
with chronic HCV infection that evaluated at least 8 weeks of an FDA-approved interferon-
free HCV regimen that included at least 2 DAAs. We included trials that used DAA
combinations—including inhibitors of HCV NS3 protease (grazoprevir, paritaprevir, and
simeprevir), NS5A (daclatasvir, elbasvir, ledipasvir, ombitasvir, and velpatasvir), and NS5B
polymerase (sofosbuvir and dasabuvir), as well as the oral antiviral ribavirin—and for which
the primary outcome was SVR. We excluded studies published only as abstracts; dose-
finding studies; those in which the primary outcome was pharmacokinetics; or those in
which the regimens included interferon, DAAs that were not FDA-approved, or only 1 DAA
(for example, sofosbuvir plus ribavirin). Trials were included regardless of participants’
cirrhosis, HIV, or liver transplantation status, but trials of limited populations (for example,
DAA-experienced patients or those of a single race) were excluded.
Data Extraction and Quality Assessment
Two reviewers independently screened titles and abstracts and then the full text of
potentially eligible articles to identify studies meeting inclusion criteria. Using standardized
forms, 1 reviewer extracted information from the selected studies about study characteristics,
design, outcomes, and the funding source. A second reviewer confirmed the accuracy of the
extractions. Differences were resolved through consensus. Two reviewers independently
assessed risk of bias for each selected study by using 5 items from the Cochrane risk-of-bias
tools for RCTs and a Cochrane tool for assessment of risk of bias in nonrandomized trials
and observational studies (8, 9).
Data Synthesis and Analysis
Detailed evidence tables were generated, and studies were summarized by outcomes. The
results were organized by genotype and then by the specific population studied. The
heterogeneity of the interventions precluded quantitative pooling of results.
Role of the Funding Source
The Patient-Centered Outcomes Research Institute (PCORI) funded the study and reviewed
the report but did not participate in the formulation of the review’s questions, data searches,
study appraisals, evidence interpretation, or the preparation or approval of the manuscript for
publication.
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Results
Study and Quality Characteristics
Of 1796 citations evaluated, we included 42 studies published in 40 articles (Figure 1). All
but 1 of the studies were funded by industry (10). Ten were open-label, single-group studies
(10–19); 5 had a placebo group with deferred treatment (20–24); 11 evaluated different
durations of therapies and the addition of ribavirin (for example, 8 vs. 12 weeks or 12 vs. 24
weeks of therapy with or without ribavirin) (25–35); 5 evaluated the same duration of
therapy with and without ribavirin (36–39); 6 evaluated different durations with ribavirin
(40–45); and 3 evaluated different durations of therapy without ribavirin (46–48). Only 2
studies had an active comparator group receiving an HCV treatment regimen other than that
being evaluated in the trial (49). Three studies had 48 weeks of posttreatment follow-up,
whereas the remainder had 12 or 24 weeks of follow-up.
Of the 42 studies, 19 had low risk of bias and 23 had moderate risk. Sources of possible bias
included single-group design (
n
= 10), lack of information on sequence generation or
concealment of the allocation scheme (
n
= 11), and selective reporting of outcomes (
n
= 5).
Because SVR is a highly objective outcome measure, lack of blinding was not considered an
important threat to validity. Rates of loss to follow-up were low (<10% for all studies).
HCV Genotype 1 Infection
Thirty-two studies enrolled persons with HCV genotype 1 infection (Table; Figure 2; and
Table 1 of the Supplement, available at Annals.org).
Regimens That Include NS3/4A Protease Inhibitors
Grazoprevir–Elbasvir: Grazoprevir is an NS3 protease inhibitor that is available in a fixed-
dose combination with elbasvir, an NS5A inhibitor. This regimen was studied in 4
multicenter randomized trials published in 6 articles (11, 20, 21, 25–27). Risk of bias was
moderate in 3 of these studies due to lack of a comparator group (
n
= 1) and selective
reporting (
n
= 2). Daily grazoprevir-elbasvir for 12 weeks was associated with SVR rates of
92% and 99% to 100% in treatment-naive and treatment-experienced patients with genotype
1a and 1b infection, respectively (20, 26, 27). Among patients with genotype 1a but not
genotype 1b infection, lower SVR rates were associated with pretreatment presence of
naturally occurring resistance-associated substitutions (RASs) at positions 28, 30, 31, and 93
of the NS5A region (20, 27). Prolongation of therapy to 16 weeks and addition of ribavirin
led to SVR among 49 treatment-experienced patients, including all 6 patients with baseline
NS5A RASs (27). Ribavirin was associated with greater incidence of anemia (3% to 16% vs.
0%), fatigue, and nausea (25–27). With the exception of patients with genotype 1a infection
with baseline RASs, the SVR rate was similar in those treated with or without ribavirin.
Cirrhosis was not associated with lower SVR rates (14, 16).
Paritaprevir–Ritonavir–Ombitasvir and Dasabuvir: Paritaprevir is an NS3 protease
inhibitor that is coformulated with ritonavir (to provide pharmacologic boosting) and
ombitasvir (an NS5A inhibitor). For patients with genotype 1 infection, dasabuvir (a non-
nucleoside NS5B polymerase inhibitor) was added. We identified 1 study with low risk of
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bias that used the two-DAA regimen without dasabuvir (45) and 9 studies (5 with low risk of
bias and 4 with moderate risk of bias) that used the three-DAA regimen for 12 or 24 weeks
(12, 13, 22, 23, 37, 38, 40, 41). Moderate risk of bias was due to lack of a comparator group
(
n
= 2) and unclear sequence generation and allocation scheme concealment (
n
= 2). The
three-DAA regimen without ribavirin yielded lower SVR rates in persons with genotype 1a
infection (90%) than those with genotype 1b infection (99%); however, with the addition of
ribavirin, the SVR rate among noncirrhotic patients with genotype 1a infection increased to
97% (38). Compared with placebo, ribavirin was associated with more anemia, fatigue,
insomnia, and rash (22, 38). Among cirrhotic patients with genotype 1a infection, the three-
DAA regimen plus ribavirin for 24 weeks led to higher SVR rates than 12 weeks of
treatment (94.2% vs. 88.6%) (41). High rates of SVR were seen among cirrhotic and
noncirrhotic patients with genotype 1b infection treated for 12 weeks with the three-DAA
regimen alone or with ribavirin (97% to 100%) (22, 23, 37, 38, 41, 45).
Simeprevir and Sofosbuvir: Simeprevir is an NS3 protease inhibitor that is used once daily
in combination with sofosbuvir, a nucleoside analogue NS5B polymerase inhibitor. We
identified 3 studies using this regimen (14, 28, 46). Risk of bias was moderate in 2 studies
due to unclear sequence generation (
n
= 1) and lack of a comparator group (
n
= 1). When
used for 12 weeks, the regimen was associated with high rates of SVR (97%) in persons
with HCV genotype 1a or 1b infection without cirrhosis (46). In this population,
pretreatment presence of naturally occurring simeprevir RASs at position 80 of the NS3
region (Q80K) was not associated with lower SVR rates (46). However, lower SVR rates
were observed among patients with cirrhosis (79% to 88%) and, in this population, the
presence of the Q80K RAS was associated with lower SVR rates in patients with genotype
1a infection (74% with Q80K and 92% without) (14).
Regimens That Do Not Include NS3/4A Protease Inhibitors
Daclatasvir and Sofosbuvir: Daclatasvir is an NS5A inhibitor used with sofosbuvir.
Clinical trial data on this combination are limited but suggest high SVR rates with 12- and
24-week treatment (96% to 100%), based on data from 2 studies with moderate risk of bias
(29, 48). Among patients with advanced liver disease, SVR rates were lower (82%) (15).
Ledipasvir–Sofosbuvir: Ledipasvir, an NS5A inhibitor, is coformulated with sofosbuvir as
a once-daily tablet. Eight studies (4 with low risk of bias and 4 with moderate risk of bias)
evaluated different treatment durations (8, 12, and 24 weeks) and the addition of ribavirin
(17, 30–34, 43, 44). Moderate risk of bias was due to lack of a comparator (
n
= 1) and
unclear sequence generation or allocation scheme concealment (
n
= 3). In treatment-naive
patients, SVR rates were greater than 95% with 12 weeks of treatment, and longer treatment
did not yield higher rates (30, 31, 33). Although 8 weeks of therapy was assessed in 1 RCT
and was found to lead to high SVR rates in noncirrhotic persons with pretreatment HCV
RNA levels less than 6 × 10
6
IU/mL (33), the most data on efficacy are for 12 weeks. In
treatment-naive patients, ribavirin was not associated with higher SVR rates regardless of
cirrhosis status, whereas in treatment-experienced patients, either longer therapy (24 weeks)
with ledipasvir–sofosbuvir or the addition of ribavirin to the regimen for 12 weeks was
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