Annals of Internal Medicine REVIEW

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

Background: Rapid improvements in hepatitis C virus (HCV) tion, particularly those with ChildTurcottePugh class C disease,
therapy have led to the approval of multiple oral direct-acting had lower SVR rates (78% to 87%) than other populations. The
antiviral (DAA) regimens by the U.S. Food and Drug Administra- addition of ribavirin was associated with increased SVR rates for
tion (FDA) for treatment of chronic HCV infection. certain DAA regimens and patient groups. Overall rates of seri-
ous adverse events and treatment discontinuation were low
(<10% in the general population); regimens that included ribavi-
Purpose: To summarize published literature on the efcacy and
rin had more mild or moderate adverse events than those
safety of oral DAAs for treatment of persons with chronic HCV
without.
infection.

Limitations: Twenty-three studies had moderate risk of

Data Sources: MEDLINE and EMBASE from inception through
bias (10 were open-label single-group trials, 11 had limited in-
1 November 2016.
formation on concealment of the allocation scheme, and 5 had
selective outcome reporting). All but 1 of the studies were
Study Selection: 42 English-language studies from controlled industry-funded. Heterogeneity of interventions precluded
and single-group registered clinical trials of adults with pooling.
HCV infection that evaluated at least 8 weeks of an FDA-
approved interferon-free HCV regimen that included at least 2
Conclusion: Multiple oral DAA regimens show high rates of
DAAs.
safety, tolerability, and efcacy for treatment of HCV genotype 1
infection, particularly among persons without cirrhosis.
Data Extraction: Two investigators abstracted data on study
design, patient characteristics, and virologic and safety out-
Primary Funding Source: Patient-Centered Outcomes Re-
comes sequentially and assessed quality independently.
search Institute. (PROSPERO: CRD42014009711)

Data Synthesis: Six DAA regimens showed high sustained viro-

logic response (SVR) rates (>95%) in patients with HCV genotype Ann Intern Med. 2017;166:xxx-xxx. doi:10.7326/M16-2575 Annals.org
1 infection without cirrhosis, including those with HIV co- For author afliations, see end of text.
infection. Effective treatments for HCV genotype 3 infection are This article was published at Annals.org on 21 March 2017.
limited (2 DAA regimens). Patients with hepatic decompensa- * Drs. Falade-Nwulia and Suarez-Cuervo contributed equally to this work.

I n the United States, 3.2 to 5 million people are chron-

ically infected with hepatitis C virus (HCV) and are at
risk for cirrhosis, liver cancer, and death if untreated (1,
METHODS
Data Sources and Searches
We developed a protocol for this systematic review
2). Infection with HCV is the primary indication for liver and registered it in PROSPERO (CRD42014009711).
transplantation and causes more deaths than all other We searched MEDLINE and EMBASE for literature pub-
notiable infectious diseases in the United States com- lished in English from inception through 1 November
bined (3, 4). Cure of this infection, dened as the ab- 2016. The search strategy included terms for HCV
sence of detectable HCV RNA in the blood at least 12 infection and the medications of interest (Figure 1). We
weeks after treatment completion (sustained virologic also searched ClinicalTrials.gov and hand-searched the
response [SVR]), is strongly associated with reduced reference lists of included articles and related system-
liver-related morbidity and mortality (5, 6). The devel- atic reviews.
opment of drugs that directly inhibit key steps in viral
replication has led to availability of several oral HCV Study Selection
treatment regimens (7). We systematically reviewed the We included English-language, single-group, ran-
efcacy and safety of oral interferon-free HCV treat- domized, controlled trials (RCTs) of adults with chronic
ment regimens that have been approved by the U.S. HCV infection that evaluated at least 8 weeks of an
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 See also:
events. We reviewed phase 2 and 3 clinical trial data for
Editorial comment . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
patients infected with HCV genotypes 1 to 6 and pa-
tients previously considered difcult to cure with de- Web-Only
compensated cirrhosis, HIV infection, renal failure, or
Supplement
liver transplantation.
2017 American College of Physicians 1

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 REVIEW Oral Direct-Acting Agent Therapy for Hepatitis C Virus Infection

Figure 1. Summary of evidence search and selection. Data Extraction and Quality Assessment
Two reviewers independently screened titles and
abstracts and then the full text of potentially eligible
Search of electronic databases articles to identify studies meeting inclusion criteria. Us-
(n = 1796) ing standardized forms, 1 reviewer extracted informa-
PubMed: 1579
EMBASE: 1458 tion from the selected studies about study characteris-
Hand-search: 89 tics, design, outcomes, and the funding source. A
second reviewer conrmed the accuracy of the extrac-
Duplicates
(n = 242)
tions. Differences were resolved through consensus.
Two reviewers independently assessed risk of bias for
Title review each selected study by using 5 items from the Co-
(n = 1554) chrane risk-of-bias tools for RCTs and a Cochrane tool
for assessment of risk of bias in nonrandomized trials
Excluded (n = 1187)
No original data: 348 and observational studies (8, 9).
Not a clinical trial: 508
Phamacokinetic study: 318 Data Synthesis and Analysis
No comparator of interest
(included peg-interferon or study Detailed evidence tables were generated, and
drug not FDA-approved): 215 studies were summarized by outcomes. The results
were organized by genotype and then by the specic
Abstract review population studied. The heterogeneity of the interven-
(n = 367)
tions precluded quantitative pooling of results.
Excluded (n = 308)
No original data: 47
Comparator included peg-interferon: 29
Role of the Funding Source
No comparator of interest: 51 The Patient-Centered Outcomes Research Institute
Study drug not FDA-approved: 38 (PCORI) funded the study and reviewed the report but
Not a clinical trial: 57
Not a population of interest: 56 did not participate in the formulation of the review's
Phamacokinetic study: 27 questions, data searches, study appraisals, evidence in-
Not in English: 3 terpretation, or the preparation or approval of the man-
Abstract review uscript for publication.
(n = 59)

Excluded (n = 19)
SVR not evaluated: 4
Comparator included peginterferon: 5
RESULTS
Not a clinical trial: 3 Study and Quality Characteristics
Not standard of care: 5
Dose-finding study: 2
Of 1796 citations evaluated, we included 42 stud-
ies published in 40 articles (Figure 1). All but 1 of the
Included articles studies were funded by industry (10). Ten were open-
(n = 40 [42 studies]) label, single-group studies (10 19); 5 had a placebo
group with deferred treatment (20 24); 11 evaluated
FDA = U.S. Food and Drug Administration; SVR = sustained virologic different durations of therapies and the addition of
response.
ribavirin (for example, 8 vs. 12 weeks or 12 vs. 24 weeks
of therapy with or without ribavirin) (2535); 5 evalu-
ated the same duration of therapy with and without
FDA-approved interferon-free HCV regimen that in- ribavirin (36 39); 6 evaluated different durations with
cluded at least 2 DAAs. We included trials that used ribavirin (40 45); and 3 evaluated different durations of
DAA combinationsincluding inhibitors of HCV NS3 therapy without ribavirin (46 48). Only 2 studies had an
protease (grazoprevir, paritaprevir, and simeprevir), active comparator group receiving an HCV treatment
NS5A (daclatasvir, elbasvir, ledipasvir, ombitasvir, and regimen other than that being evaluated in the trial
velpatasvir), and NS5B polymerase (sofosbuvir and das- (49). Three studies had 48 weeks of posttreatment
abuvir), as well as the oral antiviral ribavirinand for follow-up, whereas the remainder had 12 or 24 weeks
which the primary outcome was SVR. We excluded of follow-up.
studies published only as abstracts; dose-nding stud- Of the 42 studies, 19 had low risk of bias and 23
ies; those in which the primary outcome was pharma- had moderate risk. Sources of possible bias included
cokinetics; or those in which the regimens included in- single-group design (n = 10), lack of information on se-
terferon, DAAs that were not FDA-approved, or only 1 quence generation or concealment of the allocation
DAA (for example, sofosbuvir plus ribavirin). Trials were scheme (n = 11), and selective reporting of outcomes
included regardless of participants' cirrhosis, HIV, or (n = 5). Because SVR is a highly objective outcome
liver transplantation status, but trials of limited popula- measure, lack of blinding was not considered an impor-
tions (for example, DAA-experienced patients or those tant threat to validity. Rates of loss to follow-up were
of a single race) were excluded. low (<10% for all studies).
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 Oral Direct-Acting Agent Therapy for Hepatitis C Virus Infection REVIEW

Table. Summary of Clinical Trial Outcomes, by Genotype and Regimen

Regimen, by Genotype Studies Included Summary of Findings Risk of Bias

HCV-1
GZPEBV 4 RCTs (6 articles) SVR with 12 wk 92% in TN and TE patients with and without cirrhosis, HIV Low (n = 3)
(n = 1644) co-infection, and chronic kidney disease. SVR with 12 wk in patients with Moderate (n = 3)
genotype 1a infection varied according to baseline NS5A RAS status
(present, 58%60%; absent, 98%99%).
PTVrOBVDAV RBV 10 RCTs (n = 2702) SVR with 12 wk of 97%100% in TN and TE patients with genotype 1b Low (n = 6)
infection with and without cirrhosis. In noncirrhotic patients with genotype Moderate (n = 4)
1a infection, SVR with 12 wk varied according to RBV use (with, 97%;
without, 90%). In cirrhotic patients, SVR with 12 wk varied according to
treatment duration (12 wk, 87%; 24 wk, 94%). SVR with 12 wk RBV in
patients with HIV infection, 94%; a liver transplant, 97%; and chronic
kidney disease, 85%.
SIM + SOF RBV 2 RCTs (n = 478) SVR with 12 wk varied according to cirrhosis and treatment experience (TN Low (n = 1)
1 single-group study and no cirrhosis, 97%; TN and cirrhosis, 91%; TE and cirrhosis, 79%). SVR Moderate (n = 2)
(n = 103) was lower in patients with cirrhosis and the NS3 RAS Q80K at baseline.
DCV + SOF 2 RCTs (n = 238) SVR with 12 or 24 wk in TN and TE patients, including those with HIV Moderate (n = 3)
1 single-group study co-infection, 95%100%. SVR with 12 wk + RBV in patients with a liver
(n = 168) transplant, 95%; in those with decompensated cirrhosis, 82%.
LDVSOF RBV 7 RCTs (n = 2718) SVR with 12 wk 95% in TN patients with and without cirrhosis. In TE patients Low (n = 4)
1 single-group study with cirrhosis, SVR varied according to RBV use and treatment duration Moderate (n = 4)
(n = 327) (12 wk + no RBV, 86%; 12 wk + RBV, 97%; 24 wk + no RBV, 96%). SVR with
12 wk + RBV in patients with decompensated cirrhosis, 85%87%.
VELSOF RBV 2 RCTs (n = 600) SVR with 12 wk >98% in TN and TE patients with and without cirrhosis. SVR Low (n = 1)
with 12 wk + RBV in patients with decompensated cirrhosis, 94%. Moderate (n = 1)

HCV-2
DCV + SOF 2 RCTs (n = 45) SVR with 12 or 24 wk of 92%100% in TN and TE patients, including those Moderate (n = 3)
1 single-group study with HIV co-infection. SVR with 12 wk + RBV in 5 patients with
(n = 5) decompensated cirrhosis, 80%.
VELSOF RBV 3 RCTs (n = 407) SVR with 12 wk of 99%100% in TN and TE patients with and without Low (n = 2)
cirrhosis. SVR with 12 wk RBV in 8 patients with decompensated Moderate (n = 1)
cirrhosis, 100%.

HCV-3
DCV + SOF RBV 3 RCTs (n = 107) SVR with 12 wk varied according to cirrhosis status (TN/TE + no cirrhosis, Moderate (n = 5)
2 single-group studies 94%97%; TN/TE + cirrhosis, 58%69%). SVR with 12 or 16 wk + RBV in
(n = 169) patients with cirrhosis, 83%89%.
LDVSOF RBV 1 RCT (n = 26) SVR varied according to RBV use (12 wk + RBV, 100%; 12 wk + no RBV, 64%). Low (n = 1)
VELSOF RBV 2 RCTs (n = 591) SVR with 12 wk of 95% in TN and TE patients with and without cirrhosis. SVR Low (n = 1)
in patients with decompensated cirrhosis varied according to RBV use (12 Moderate (n = 1)
wk + RBV, 85%; 12 wk + no RBV, 50%; 24 wk + no RBV, 50%).

HCV-4
GZPEBV RBV 2 RCTs (n = 63) SVR with 12 wk of 96%100% in TN and TE patients with and without Moderate (n = 3)
1 single-group study cirrhosis, including those with HIV co-infection.
(n = 28)
PTVrOBV RBV 1 RCT (n = 135) SVR varied according to RBV use in TN and TE patients without cirrhosis (12 Low (n = 1)
wk + RBV, 100%; 12 wk + no RBV, 91%).
SIM + SOF 1 RCT (n = 63) SVR with 12 wk of 100% in TN and TE patients with and without cirrhosis. Moderate (n = 1)
LDVSOF RBV 2 RCTs (n = 41) SVR with 12 wk of 93%95% in TN and TE patients with and without cirrhosis. Low (n = 2)
3 single-group studies SVR with 12 wk + RBV in 7 patients with decompensated cirrhosis before Moderate (n = 3)
(n = 74) and after liver transplantation, 0%100%.
VELSOF RBV 2 RCTs (n = 146) SVR with 12 wk of 100% in TN and TE patients with and without cirrhosis. SVR Low (n = 1)
with 12 wk RBV in 6 patients with decompensated cirrhosis, 100%. Moderate (n = 1)

HCV-5
LDVSOF 1 single-group study SVR with 12 wk of 95% in TN and TE patients with and without cirrhosis. Moderate (n = 1)
(n = 41)
VELSOF 1 RCT (n = 35) SVR with 12 wk of 97% in TN and TE patients with and without cirrhosis. Moderate (n = 1)

HCV-6
LDVSOF 1 single-group study SVR with 12 wk of 96% in TN and TE patients with and without cirrhosis. Moderate (n = 1)
(n = 25)
VELSOF 2 RCTs (n = 42) SVR with 12 wk of 100% in TN and TE patients with and without cirrhosis. SVR Low (n = 1)
with 24 wk in 1 patient with decompensated cirrhosis, 100%. Moderate (n = 1)
DAV = dasabuvir; DCV = daclatasvir; EBV = elbasvir; GZP = grazoprevir; HCV = hepatitis C virus; LDV = ledipasvir; OBV = ombitasvir; PTVr =
paritaprevirritonavir; Q80K = position 80 of the NS3 region; RAS = resistance-associated substitution; RBV = ribavirin; RCT = randomized, con-
trolled trial; SIM = simeprevir; SOF = sofosbuvir; SVR = sustained virologic response; TE = treatment-experienced; TN = treatment-naive; VEL =
velpatasvir.

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 REVIEW Oral Direct-Acting Agent Therapy for Hepatitis C Virus Infection

Figure 2. HCV genotype 1a and 1b SVR12 rates and 95% CIs, by oral DAA regimen and clinical trial.

Study, Year Regimen Patients, n Treatment Cirrhosis Status Treatment SVR12 Rate
(Reference) Duration, wk History (95% CI), %
HCV-1a
C-EDGE, 2015 (20) GZPEBV 157 12 With/without Naive 92 (8696)
PEARL-IV, 2014 (38) PTVr + OBV + DAV + RBV 100 12 Without Experienced 97 (94100)
PTVr + OBV + DAV + PLAC 205 12 Without Experienced 90 (8794)
SAPPHIRE-l, 2014 (22) PTVr + OBV + DAV + RBV 322 12 Without Naive 95 (9398)
SAPPHIRE-lI, 2014 (23) PTVr + OBV + DAV + RBV 173 12 Without Experienced 96 (9399)
OPTIMIST-l, 2016 (46) SOF + SIM 116 8 Without Both 79 (7287)
SOF + SIM 116 12 Without Both 97 (93100)
OPTIMIST-II, 2016 (14) SOF + SIM 72 12 With Both 83 (7493)
ION-1, 2014 (31) LDVSOF 142 12 With/without Naive 99 (96100)
LDVSOF + RBV 143 12 With/without Naive 100 (97100)
LDVSOF 143 24 With/without Naive 100 (97100)
LDVSOF + RBV 141 24 With/without Naive 100 (97100)
ION-2, 2014 (32) LDVSOF 86 12 With/without Experienced 95 (8899)
LDVSOF + RBV 88 12 With/without Experienced 95 (8999)
LDVSOF 85 24 With/without Experienced 99 (94100)
LDVSOF + RBV 88 24 With/without Experienced 99 (94100)
ION-3, 2014 (33) LDVSOF 171 8 Without Naive 93 (8897)
LDVSOF + RBV 172 8 Without Naive 92 (8796)
LDVSOF 172 12 Without Naive 95 (9098)
ASTRAL-l, 2015 (24) VELSOF 49 12 With Both 100 (93100)
VELSOF 161 12 Without Both 97 (9499)

70 85 100

DAA = direct-acting antiviral; DAV = dasabuvir; DCV = daclatasvir; EBV = elbasvir; GZP = grazoprevir; HCV = hepatitis C virus; LDV = ledipasvir;
OBV = ombitasvir; PLAC = placebo; PTVr = paritaprevirritonavir; RBV = ribavirin; SIM = simeprevir; SOF = sofosbuvir; SVR12 = sustained virologic
response at 12 wk; VEL = velpatasvir.

HCV Genotype 1 Infection fatigue, and nausea (2527). With the exception of pa-
Thirty-two studies enrolled persons with HCV ge- tients with genotype 1a infection with baseline RASs,
notype 1 infection (Table; Figure 2; and Table 1 of the the SVR rate was similar in those treated with or without
Supplement, available at Annals.org). ribavirin. Cirrhosis was not associated with lower SVR
rates (14, 16).
ParitaprevirRitonavirOmbitasvir and Dasabuvir.
Regimens That Include NS3/4A Protease Inhibitors
Paritaprevir is an NS3 protease inhibitor that is cofor-
GrazoprevirElbasvir. Grazoprevir is an NS3 pro-
mulated with ritonavir (to provide pharmacologic
tease inhibitor that is available in a xed-dose combi-
nation with elbasvir, an NS5A inhibitor. This regimen boosting) and ombitasvir (an NS5A inhibitor). For pa-
was studied in 4 multicenter randomized trials pub- tients with genotype 1 infection, dasabuvir (a non-
lished in 6 articles (11, 20, 21, 2527). Risk of bias was nucleoside NS5B polymerase inhibitor) was added. We
moderate in 3 of these studies due to lack of a compar- identied 1 study with low risk of bias that used the
ator group (n = 1) and selective reporting (n = 2). Daily two-DAA regimen without dasabuvir (45) and 9 studies
grazoprevir elbasvir for 12 weeks was associated with (5 with low risk of bias and 4 with moderate risk of bias)
SVR rates of 92% and 99% to 100% in treatment-naive that used the three-DAA regimen for 12 or 24 weeks
and treatment-experienced patients with genotype 1a (12, 13, 22, 23, 37, 38, 40, 41). Moderate risk of bias
and 1b infection, respectively (20, 26, 27). Among pa- was due to lack of a comparator group (n = 2) and un-
tients with genotype 1a but not genotype 1b infection, clear sequence generation and allocation scheme con-
lower SVR rates were associated with pretreatment cealment (n = 2). The three-DAA regimen without riba-
presence of naturally occurring resistance-associated virin yielded lower SVR rates in persons with genotype
substitutions (RASs) at positions 28, 30, 31, and 93 of 1a infection (90%) than those with genotype 1b infec-
the NS5A region (20, 27). Prolongation of therapy to 16 tion (99%); however, with the addition of ribavirin, the
weeks and addition of ribavirin led to SVR among 49 SVR rate among noncirrhotic patients with genotype 1a
treatment-experienced patients, including all 6 patients infection increased to 97% (38). Compared with pla-
with baseline NS5A RASs (27). Ribavirin was associated cebo, ribavirin was associated with more anemia, fa-
with greater incidence of anemia (3% to 16% vs. 0%), tigue, insomnia, and rash (22, 38). Among cirrhotic
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 Oral Direct-Acting Agent Therapy for Hepatitis C Virus Infection REVIEW

Figure 2Continued.

Study, Year Regimen Patients, n Treatment Cirrhosis Status Treatment SVR12 Rate
(Reference) Duration, wk History (95% CI), %
HCV-1b
C-EDGE, 2015 (20) GZPEBV 131 12 With/without Naive 99 (95100)
PEARL-l, 2015 (36) PTVr + OBV + RBV 47 24 With Naive 98 (89100)
PTVr + OBV + RBV 52 24 With Experienced 96 (8799)
PTVr + OBV + RBV 42 24 Without Naive 95 (8499)
PTVr + OBV + RBV 40 24 Without Experienced 90 (7697)
PEARL-ll, 2014 (37) PTVr + OBV + DAV + RBV 88 12 Without Experienced 97 (93100)
PTVr + OBV + DAV + PLAC 91 12 Without Experienced 100 (96100)
PEARL-lll, 2014 (38) PTVr + OBV + DAV + RBV 210 12 Without Naive 99 (99100)
PTVr + OBV + DAV + PLAC 209 12 Without Naive 99 (98100)
SAPPHIRE-l, 2014 (22) PTVr + OBV + DAV + RBV 151 12 Without Naive 98 (96100)
SAPPHIRE-II, 2014 (23) PTVr + OBV + DAV + RBV 123 12 Without Experienced 97 (94100)
OPTIMIST-l, 2016 (46) SIM + SOF 39 8 Without Both 92 (7998)
SIM + SOF 39 12 Without Both 97 (87100)
OPTIMIST-II, 2016 (14) SIMSOF 31 12 With Both 84 (6998)
ION-1, 2014 (31) LDVSOF 66 12 With/without Naive 100 (94100)
LDVSOF + RBV 67 12 With/without Naive 100 (94100)
LDVSOF 68 24 With/without Naive 97 (9097)
LDVSOF + RBV 71 24 With/without Naive 100 (95100)
ION-2, 2014 (32) LDVSOF 23 12 With/without Experienced 87 (6697)
LDVSOF + RBV 23 12 With/without Experienced 100 (85100)
LDVSOF 24 24 With/without Experienced 100 (86100)
LDVSOF + RBV 23 24 With/without Experienced 100 (85100)
ION-3, 2014 (33) LDVSOF 43 8 Without Naive 98 (88100)
LDVSOF + RBV 44 8 Without Naive 95 (8499)
LDVSOF 44 12 Without Naive 98 (88100)
ASTRAL-l, 2015 (24) VELSOF 24 12 With Both 96 (79100)
VELSOF 94 12 Without Both 100 (96100)

50 75 100

patients with genotype 1a infection, the three-DAA reg- RAS was associated with lower SVR rates in patients
imen plus ribavirin for 24 weeks led to higher SVR rates with genotype 1a infection (74% with Q80K and 92%
than 12 weeks of treatment (94.2% vs. 88.6%) (41). High without) (14).
rates of SVR were seen among cirrhotic and noncir-
rhotic patients with genotype 1b infection treated for
12 weeks with the three-DAA regimen alone or with Regimens That Do Not Include NS3/4A Protease
ribavirin (97% to 100%) (22, 23, 37, 38, 41, 45). Inhibitors
Simeprevir and Sofosbuvir. Simeprevir is an NS3 Daclatasvir and Sofosbuvir. Daclatasvir is an NS5A
protease inhibitor that is used once daily in combina- inhibitor used with sofosbuvir. Clinical trial data on this
tion with sofosbuvir, a nucleoside analogue NS5B poly- combination are limited but suggest high SVR rates
merase inhibitor. We identied 3 studies using this reg- with 12- and 24-week treatment (96% to 100%), based
imen (14, 28, 46). Risk of bias was moderate in 2 studies on data from 2 studies with moderate risk of bias (29,
due to unclear sequence generation (n = 1) and lack of 48). Among patients with advanced liver disease, SVR
a comparator group (n = 1). When used for 12 weeks, rates were lower (82%) (15).
the regimen was associated with high rates of SVR LedipasvirSofosbuvir. Ledipasvir, an NS5A inhibi-
(97%) in persons with HCV genotype 1a or 1b infection tor, is coformulated with sofosbuvir as a once-daily tab-
without cirrhosis (46). In this population, pretreatment let. Eight studies (4 with low risk of bias and 4 with
presence of naturally occurring simeprevir RASs at po- moderate risk of bias) evaluated different treatment du-
sition 80 of the NS3 region (Q80K) was not associated rations (8, 12, and 24 weeks) and the addition of riba-
with lower SVR rates (46). However, lower SVR rates virin (17, 30 34, 43, 44). Moderate risk of bias was due
were observed among patients with cirrhosis (79% to to lack of a comparator (n = 1) and unclear sequence
88%) and, in this population, the presence of the Q80K generation or allocation scheme concealment (n = 3).
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 REVIEW Oral Direct-Acting Agent Therapy for Hepatitis C Virus Infection

In treatment-naive patients, SVR rates were greater than moderate risk of bias, 94% to 97% of noncirrhotic
95% with 12 weeks of treatment, and longer treatment treatment-naive and treatment-experienced patients
did not yield higher rates (30, 31, 33). Although 8 achieved SVR with 12 weeks of treatment (16). In the
weeks of therapy was assessed in 1 RCT and was found same study, cirrhosis was associated with a marked re-
to lead to high SVR rates in noncirrhotic persons with duction in SVR (58% to 69%) (16). The addition of riba-
pretreatment HCV RNA levels less than 6 106 IU/mL virin to the regimen for 12 or 16 weeks in patients with
(33), the most data on efcacy are for 12 weeks. In advanced liver disease led to SVR in 86% of cirrhotic
treatment-naive patients, ribavirin was not associated patients (n = 36) in the ALLY-3+ study, which had mod-
with higher SVR rates regardless of cirrhosis status, erate risk of bias due to unclear sequence generation
whereas in treatment-experienced patients, either lon- and allocation scheme (42).
ger therapy (24 weeks) with ledipasvirsofosbuvir or the
addition of ribavirin to the regimen for 12 weeks was
associated with higher SVR rates in patients with cirrho- LedipasvirSofosbuvir
sis (97% vs. 96%) (34). The addition of ribavirin led to In a single-center study with low risk of bias, all
more adverse events, notably anemia, fatigue, and in- 26 treatment-naive patients treated with ledipasvir
somnia (3133). sofosbuvir plus ribavirin for 12 weeks achieved SVR
VelpatasvirSofosbuvir. Velpatasvir, a pangeno- (39). The SVR rate was lower without ribavirin (64%) and
typic NS5A inhibitor, is coformulated with sofosbuvir as in treatment-experienced patients (82%) (39).
a once-daily tablet. This regimen for 12 weeks was as-
sociated with high SVR rates (97% to 99%) in patients
with HCV genotype 1a or 1b infection, including those VelpatasvirSofosbuvir
with cirrhosis and prior treatment experience (24). In In a phase 3 RCT with 552 patients and low risk of
this placebo-controlled, double-blind trial with low risk bias, velpatasvirsofosbuvir for 12 weeks (95%) was su-
of bias, the incidence of adverse events was similar in perior to sofosbuvir plus ribavirin for 24 weeks (80%)
patients receiving velpatasvirsofosbuvir and those re- and was associated with fewer adverse events, particu-
ceiving placebo.
larly less anemia (49). Lower SVR rates were observed
HCV Genotype 2 Infection in patients with pretreatment presence of velpatasvir
Six studies enrolled patients with HCV genotype 2 NS5A RASs, particularly at position 93 (88%), compared
infection (Table and Figure 3); 3 studies (2 with low risk with those without RASs (97%).
of bias and 1 with moderate risk of bias) evaluated the
HCV Genotype 4 Infection
xed-dose combination of velpatasvirsofosbuvir (24,
Twelve studies enrolled persons with HCV geno-
35, 49), and 3 with moderate risk of bias evaluated da-
type 4 infection (Table and Figure 3).
clatasvir plus sofosbuvir (15, 29, 48).

GrazoprevirElbasvir
Daclatasvir and Sofosbuvir
In the C-EDGE study, efcacy of grazoprevir
In the ALLY-2 study, all 13 HIV-infected patients
elbasvir was demonstrated among 18 of 18 treatment-
with genotype 2 infection who were treated for 12
naive patients with genotype 4 infection (SVR of 100%)
weeks achieved SVR (48). In another study, 24 of 26
who received the regimen for 12 weeks; baseline pres-
(92%) treatment-naive, noncirrhotic, HIV-seronegative
ence of NS5A RASs did not affect SVR (20). Among
patients treated for 24 weeks with or without ribavirin
treatment-experienced patients in a randomized trial of
achieved SVR; 2 patients were lost to follow-up (29).
12 or 16 weeks of the regimen with or without ribavirin,
SVR rates were below 95% in all groups except patients
VelpatasvirSofosbuvir who received 16 weeks of the regimen with ribavirin
The ASTRAL-1 and ASTRAL-2 studies reported SVR (27).
in 237 of 238 patients (99%) with genotype 2 infection
who received velpatasvirsofosbuvir for 12 weeks; 1 pa-
ParitaprevirRitonavirOmbitasvir
tient was lost to follow-up (24, 49). Rates of SVR were
In 1 trial with low risk of bias, paritaprevir
not affected by cirrhosis or prior treatment experience.
ritonavir ombitasvir plus ribavirin resulted in high ef-
In an RCT, velpatasvirsofosbuvir was superior to sofos-
cacy (SVR of 100%) in both treatment-naive (n = 42) and
buvir plus ribavirin (SVR of 99% vs. 94%) and was asso-
treatment-experienced (n = 44) patients with genotype
ciated with fewer adverse events (49).
4 infection (36). The absence of ribavirin was associated
HCV Genotype 3 Infection with a lower SVR rate (91%).
Eight studies enrolled patients with HCV genotype
3 infection (Table and Figure 3).
Simeprevir and Sofosbuvir
In an RCT with moderate risk of bias due to unclear
Daclatasvir and Sofosbuvir sequence generation and allocation scheme conceal-
In a phase 2 study, 16 of 18 noncirrhotic patients ment, simeprevir plus sofosbuvir was associated with
treated with or without ribavirin for 24 weeks achieved SVR in all 43 patients (100%) treated for 12 weeks, in-
SVR (29). In the single-group ALLY-3 trial, which had cluding those with cirrhosis (n = 23); however, SVR
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 Oral Direct-Acting Agent Therapy for Hepatitis C Virus Infection REVIEW

Figure 3. HCV genotype 2 to 6 SVR12 rates and 95% CIs, by oral DAA regimen and clinical trial.

Study, Year Regimen Patients, Treatment Cirrhosis Status Treatment SVR12 Rate
(Reference) n Duration, wk History (95% CI), %
HCV-2
ASTRAL-1, 2015 (24) VELSOF 10 12 With Both 100.0 (69.0100.0)
VELSOF 93 12 Without Both 100.0 (96.0100.0)
ASTRAL-2, 2015 (49) VELSOF 134 1 With/without Both 99.0 (96.0100.0)
SOF + RBV 132 12 With/without Both 94.0 (88.097.0)

HCV-3
ASTRAL-3, 2015 (49) SOFVEL 80 12 With Both 91.0 (83.096.0)
SOF + RBV 83 24 With Both 66.0 (55.076.0)
SOFVEL 197 12 Without Both 97.0 (93.099.0)
SOF + RBV 187 24 Without Both 87.0 (81.092.0)
ALLY-3, 2015 (16) DCV + SOF 101 12 With Naive 90.0 (83.095.0)
DCV + SOF 51 12 With Experienced 86.0 (74.094.0)
ALLY-3+, 2016 (42) DCV + SOF + RBV 24 12 With Both 88.0 (68.097.0)
DCV + SOF + RBV 26 16 With Both 92.0 (75.099.0)
Gane et al, 2015 (39) LDVSOF 25 12 With/without Naive 64.0 (43.082.0)
LDVSOF + RBV 26 12 With/without Naive 100.0 (87.0100.0)
LDVSOF 50 12 With/without Experienced 82.0 (69.091.0)

HCV-4
C-EDGE, 2015 (20) GZPEBV 48 12 With/without Naive 100.0 (82.0100.0)
PEARL-I, 2015 (36) PTVr + OBV 44 12 Without Naive 91.0 (78.097.0)
PTVr + OBV + RBV 42 12 Without Naive 100.0 (92.0100.0)
PTVr + OBV + RBV 49 12 Without Experienced 100.0 (93.0100.0)
Kohli et al, 2015 (10) LDVSOF 21 12 With/without Both 95.0 (76.0100.0)
Abergel et al, 2016 (19) LDVSOF 22 12 With/without Naive 95.0 (77.0100.0)
LDVSOF 22 12 With/without Experienced 91.0 (71.099.0)
OSIRIS, 2017 (47) SIMSOF 20 8 Without Both 75.0 (51.091.0)
SIMSOF 20 12 Without Both 100.0 (83.0100.0)
SIMSOF 23 12 With Both 100.0 (85.0100.0)
ASTRAL-1, 2015 (24) VELSOF 27 12 With Both 100.0 (87.0100.0)
VELSOF 28 12 Without Both 100.0 (96.0100.0)

HCV-5
Abergel et al, 2016 (18) LDVSOF 21 12 With/without Naive 95.0 (76.0100.0)
LDVSOF 20 12 With/without Experienced 95.0 (75.0100.0)

ASTRAL-1, 2015 (24) VELSOF 5 12 With Both 100.0 (48.0100.0)

VELSOF 29 12 Without Both 97.0 (82.0100.0)

HCV-6
C-EDGE, 2015 (20) GZPEBV 10 12 With/without Naive 80.0 (44.098.0)

Gane et al, 2015 (39) LDVSOF 25 12 With/without Naive 96.0 (80.0100.0)

ASTRAL-1, 2015 (24) VELSOF 6 12 With Both 100.0 (54.0100.0)

VELSOF 35 12 Without Both 100.0 (90.0100.0)

25 50 75 100

DAA = direct-acting antiviral; DAV = dasabuvir; DCV = daclatasvir; EBV = elbasvir; GZP = grazoprevir; HCV = hepatitis C virus; LDV = ledipasvir;
OBV = ombitasvir; PTVr = paritaprevirritonavir; RBV = ribavirin; SIM = simeprevir; SOF = sofosbuvir; SVR12 = sustained virologic response at 12
wk; VEL = velpatasvir.

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 REVIEW Oral Direct-Acting Agent Therapy for Hepatitis C Virus Infection

rates were lower in 20 patients treated for 8 weeks was more effective than velpatasvirsofosbuvir alone
(75%) (47). for 12 or 24 weeks; however, ribavirin was associated
with more treatment discontinuation due to adverse
events (35). Across all studies, rates of serious adverse
LedipasvirSofosbuvir
events were higher in patients with decompensated cir-
In a single-group trial of 21 patients, 95% who re- rhosis (10% to 52%) than in the general HCV patient
ceived 12 weeks of ledipasvirsofosbuvir achieved SVR; populations (<10%).
the study included few patients with cirrhosis (n = 7) or
prior treatment experience (n = 8) (10). In a similar trial
conducted in France, 41 of 44 patients (93%) who were Patients After Liver Transplantation
treated for 12 weeks achieved SVR (19). No serious ad- Four trials evaluated DAAs in patients who had un-
verse events were reported in these studies (10, 19). dergone liver transplantation. Overall, SVR rates ob-
served in these trials were similar to those reported in
VelpatasvirSofosbuvir patients without a transplant (12, 15, 43, 44). However,
In the ASTRAL-1 RCT, which had low risk of bias, among liver transplant patients with decompensated
velpatasvirsofosbuvir led to SVR in all 116 treatment- liver disease due to recurrent HCV infection, SVR rates
naive and treatment-experienced patients (100%) who were lower (50% to 80%) and adverse event rates were
were treated, including those with cirrhosis (24). higher (16% to 75%) than those observed in liver trans-
plant patients with compensated cirrhosis or those with
HCV Genotype 5 and 6 Infection minimal liver disease (6% to 21%) (12, 43, 44).
Six studies enrolled persons with HCV genotype 5
and/or 6 infection (18, 20, 24, 27, 35, 39) (Figure 3).
Patients With Chronic Kidney Disease
LedipasvirSofosbuvir
In 2 studies of patients with advanced renal dys-
function, including those receiving hemodialysis, high
This combination led to high SVR rates in persons
SVR rates were reported in those with HCV genotype
with genotype 5 (n = 41; SVR of 95%) and genotype 6
1 infection (13, 21). In 1 study with low risk of bias,
(n = 25; SVR of 96%) infection (18, 39). Although the
grazoprevir elbasvir for 12 weeks resulted in SVR in
numbers of patients in these subgroups were small,
94% of patients (n = 111) (21). In a smaller study with
SVR rates were high in treatment-experienced patients
moderate risk of bias due to lack of a comparator
(95%) and those with cirrhosis (89%) (18).
group, a regimen of paritaprevirritonavir ombitasvir
and dasabuvir was effective (SVR of 90%), but ribavirin,
VelpatasvirSofosbuvir which was used for patients with genotype 1a infection,
In 1 RCT with low risk of bias, patients with geno- was poorly tolerated and was discontinued due to ad-
type 5 (n = 35) and genotype 6 (n = 41) infection verse events in 8 of 14 patients (48).
achieved high rates of SVR (97% and 100%, respec-
tively) with 12 weeks of treatment; only 1 patient did
not achieve SVR (death unrelated to treatment) (24). DISCUSSION
Subpopulations Multiple interferon-free, oral DAA regimens are
Patients With HIV Co-infection available for treatment of chronic HCV infection. We
Direct-acting antiviral regimens used for 12 or 24 found high SVR rates for all FDA-approved DAA regi-
weeks showed high SVR rates (91% to 98%) and low mens, with some evidence of variable response inu-
adverse event rates (<10%). These rates were similar to enced by specic patient and virus characteristics.
those observed in persons without HIV (11, 17, 26, 40, Rates of serious adverse events (<10%), loss to
48). Shorter therapy (8 weeks) was evaluated in 1 RCT follow-up (<10%), and treatment discontinuation (<5%)
of daclatasvir plus sofosbuvir and led to lower rates of were low even in patients with comorbid conditions,
SVR (76%) than 12 weeks of therapy (97%) (48). such as HIV infection and cirrhosis.
The evidence was robust for persons with geno-
type 1 infection, which is the most common genotype
Patients With Decompensated Cirrhosis worldwide, infecting approximately 84 million persons
Relatively few patients with decompensated liver (50). We reviewed 6 distinct DAA regimens for geno-
disease (for example, those with jaundice, ascites, en- type 1 infection, with SVR rates greater than 95% for
cephalopathy, or variceal hemorrhage) have been most drug combinations and patient populations. Our
enrolled in DAA trials. Because of impaired metabo- ndings represent an important update of other sys-
lism, NS3 protease inhibitors are not recommended tematic reviews of DAA regimens with and without in-
(simeprevir) or are contraindicated (paritaprevir or gra- terferon for treatment of HCV genotype 1 infection,
zoprevir) in patients with ChildTurcottePugh class B which reported SVR rates in the range of 95% (50, 51)
and C disease. These patients have been treated in tri- and 92% (52). The high treatment response rates in
als of sofosbuvir plus NS5A inhibitors, including dacla- persons with genotype 1 infection are particularly im-
tasvir, ledipasvir, and velpatasvir (15, 35, 43, 44). In 1 portant in light of the historically poor SVR rates ob-
RCT, velpatasvirsofosbuvir with ribavirin for 12 weeks served with interferon in this population.
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 Oral Direct-Acting Agent Therapy for Hepatitis C Virus Infection REVIEW
In contrast, fewer DAA regimens are available and ence. Clinical trials for patients with decompensated
effective for the treatment of HCV genotype 3 infection, cirrhosis and a liver transplant have also largely in-
which is the second most prevalent HCV genotype cluded ribavirin. Although ribavirin was associated with
globally, infecting approximately 54 million persons. an increase in anemia, fatigue, and insomnia, the rates
Our ndings indicate that the most effective DAA regi- of serious adverse events and treatment discontinua-
mens for patients who have genotype 3 infection with- tion were similar in patients treated with and without
out cirrhosis are sofosbuvir plus the NS5A inhibitors it.
velpatasvir or daclatasvir for 12 weeks, whereas higher Limitations of this study include the fact that safety
SVR rates were observed with velpatasvirsofosbuvir in data from clinical trials may not fully represent patient
patients with cirrhosis. This agrees with recent system- experience in clinical practice. Persons with chronic
atic reviews, identied through MEDLINE searches from hepatitis B virus infection were excluded from trials,
2014 to 2016, that identied velpatasvirsofosbuvir as the and the risk for hepatitis B virus reactivation was not
most effective treatment for genotype 3 infection (51, examined. We also included noncontrolled trials; how-
52). Our ndings also suggest that lower SVR rates ever, spontaneous cure of HCV infection is rare. Most of
were achieved in patients with compensated and de- the studies were industry-funded; such studies are
compensated cirrhosis, prior treatment experience, or more likely to be published if results are favorable (58),
NS5A RASs; the addition of ribavirin and longer treat- but we are not aware of large, unpublished studies in
ment duration were associated with higher SVR rates in this eld and the risk of bias with the objective outcome
these patient groups (42, 53). of SVR is low. The heterogeneity of the interventions
Although relatively few studies enrolled patients studied also prevented quantitative pooling of results,
with genotype 2, 4, 5, or 6 infection, high rates of SVR and the relatively short follow-up limits our ability to
(>92%) were observed for all regimens administered comment on late relapse of HCV infection. Several
for at least 12 weeks. Rates of SVR were particularly studies were also population-specic, thus limiting gen-
high (99%) for patients with genotype 2, 4, 5, or 6 in- eralizability of ndings to all patients. Given the multi-
fection treated with velpatasvirsofosbuvir (24). For tude of effective oral DAA regimens with similar rates of
treatment of genotype 4 infection, all but 1 of the DAA SVR and adverse events, RCTs will be needed to deter-
regimens (paritaprevirritonavir ombitasvir) led to high mine the best HCV treatments for different patient
SVR rates (93% to 100%) without ribavirin and were as- populations. One such trial, the PRIORITIZE study
sociated with minimal adverse effects in treatment- (ClinicalTrials.gov: NCT02786537), is under way in per-
naive patients. sons with genotype 1 infection (59).
Oral DAA regimens also showed high SVR rates Finally, our systematic review is limited by the
and minimal adverse events in patient populations that rapidly evolving HCV treatment landscape and the in-
were poorly responsive or could not be treated with ability to include all DAA regimens in ongoing or re-
interferon, including those with HIV co-infection, de- cently completed clinical trials that we identied on
compensated cirrhosis, severe chronic kidney disease, ClinicalTrials.gov (Table 7 of the Supplement). These
and a liver transplant. Patients co-infected with HIV and ongoing clinical trials include 2 novel nucleotide ana-
HCV and those receiving immunosuppressive agents logue NS5B polymerase inhibitors, MK-3682 and AL-
after liver transplantation had SVR rates similar to those 335, which are being evaluated in combination with ap-
of persons without immune dysfunction, suggesting proved NS3 protease inhibitors and novel NS5A
that oral DAAs mitigate the effect of an impaired HCV inhibitors (ruzasvir and odalasvir), as well as 2 novel
immune response (54 56). Direct-acting antiviral op- pangenotypic NS3 protease inhibitors, voxilaprevir and
tions for persons with severe chronic kidney disease glecaprevir, which are being evaluated in combination
remain limited, and although high SVR rates (85% to with approved (sofosbuvirvelpatasvirvoxilaprevir) and
100%) were observed in 2 RCTs for persons with HCV novel (glecaprevirpibrentasvir) DAAs (60).
genotype 1 infection, no trials were identied in per- In conclusion, oral DAA regimens that are highly
sons with genotype 2 or 3 infection, for whom inter- efcacious, well-tolerated, and relatively short in dura-
feron is still recommended (57). Treatment options also tion are now available for all HCV genotypes and for
remain limited in patients with decompensated liver patient populations historically considered difcult to
disease. Current NS3 protease inhibitors are hepatically cure. The ease of dosing, safety prole, and effective-
metabolized and are contraindicated in this popula- ness of these agents provide an opportunity to expand
tion; as such, trials have been restricted to sofosbuvir the number of patients who can be treated for HCV
plus NS5A inhibitors. The evidence indicates that these infection and the pool of treating providers. Rapid de-
regimens provide high rates of SVR (>85%), but serious velopments in oral DAA therapies can be benecial
adverse events are common (10% to 52%). In addition, only if they are linked to efforts to improve rates of
questions remain with regard to the long-term clinical HCV detection, linkage to care, and access to DAA
benet of cure of HCV infection in persons with severe therapy.
liver dysfunction.
Across multiple trials, our ndings indicate that From Johns Hopkins University School of Medicine, Baltimore,
ribavirin continues to have a role in maximizing SVR Maryland; University of Florida, Gainesville, Florida; and Uni-
rates in certain patients, including those with genotype versity of North Carolina at Chapel Hill, Chapel Hill, North
1a or 3 infection, cirrhosis, or prior treatment experi- Carolina.
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 REVIEW Oral Direct-Acting Agent Therapy for Hepatitis C Virus Infection

Disclaimer: This work was partially supported through a re- 4. Mitchell O, Gurakar A. Management of hepatitis C post-liver trans-
search contract from PCORI (HPC-1503-27891). The state- plantation: a comprehensive review. J Clin Transl Hepatol. 2015;3:
ments presented in this article are solely the responsibility 140-8. [PMID: 26357641] doi:10.14218/JCTH.2015.00005
of the authors and do not necessarily represent the views 5. Limketkai BN, Mehta SH, Sutcliffe CG, Higgins YM, Torbenson
of PCORI, its Board of Governors, or its Methodology MS, Brinkley SC, et al. Relationship of liver disease stage and antiviral
therapy with liver-related events and death in adults coinfected with
Committee.
HIV/HCV. JAMA. 2012;308:370-8. [PMID: 22820790] doi:10.1001
/jama.2012.7844
Financial Support: In part by a research contract from PCORI 6. van der Meer AJ, Veldt BJ, Feld JJ, Wedemeyer H, Dufour JF,
(HPC-1503-27891). Dr. Falade-Nwulia was supported by a Lammert F, et al. Association between sustained virological re-
Johns Hopkins Clinician Scholar Award and a National Insti- sponse and all-cause mortality among patients with chronic hepatitis
tutes of Health patient-oriented research career development C and advanced hepatic brosis. JAMA. 2012;308:2584-93. [PMID:
award (K23 DA041294). Dr. Sulkowski was supported by a 23268517] doi:10.1001/jama.2012.144878
7. Liang TJ, Ghany MG. Current and future therapies for hepatitis C
National Institutes of Health midcareer mentor award (K24
virus infection. N Engl J Med. 2013;368:1907-17. [PMID: 23675659]
DA034621).
doi:10.1056/NEJMra1213651
8. Higgins JPT, Green S, eds. Cochrane Handbook for Systematic
Disclosures: Dr. Nelson reports grants from AbbVie, Bristol- Reviews of Interventions. Version 5.1.0. London: The Cochrane Col-
Myers Squibb, Gilead Sciences, Janssen Pharmaceutical, and laboration; 2011.
Merck outside the submitted work. Dr. Fried reports grants 9. Sterne J, Higgins JPT, Reeves B; Development Group for
and personal fees from AbbVie, Bristol-Myers Squibb, Gilead ROBINS-I. A tool for assessing Risk Of Bias in Non-randomized Stud-
ies of Interventions. Version 5. July 2016. Accessed at www.riskofbias
Sciences, and Merck outside the submitted work. Dr. Segal
.info on 3 August 2016.
reports a grant from the Patient-Centered Outcomes Re- 10. Kohli A, Kapoor R, Sims Z, Nelson A, Sidharthan S, Lam B, et al.
search Institute during the conduct of the study. Dr. Sulkowski Ledipasvir and sofosbuvir for hepatitis C genotype 4: a proof-of-
reports a grant from the National Institutes of Health during concept, single-centre, open-label phase 2a cohort study. Lancet In-
the conduct of the study; grants from AbbVie, Gilead Sci- fect Dis. 2015;15:1049-54. [PMID: 26187031] doi:10.1016/S1473
ences, Janssen Pharmaceutical, and Merck outside the sub- -3099(15)00157-7
mitted work; and personal fees from AbbVie, Cocrystal 11. Rockstroh JK, Nelson M, Katlama C, Lalezari J, Mallolas J, Bloch
Pharma, Gilead Sciences, Janssen Pharmaceutical, Merck, and M, et al. Efcacy and safety of grazoprevir (MK-5172) and elbasvir
Trek outside the submitted work. Authors not named here (MK-8742) in patients with hepatitis C virus and HIV co-infection
have disclosed no conicts of interest. Disclosures can also (C-EDGE CO-INFECTION): a non-randomised, open-label trial. Lan-
be viewed at www.acponline.org/authors/icmje/ConictOf cet HIV. 2015;2:e319-27. [PMID: 26423374] doi:10.1016/S2352
InterestForms.do?msNum=M16-2575. -3018(15)00114-9
12. Kwo PY, Mantry PS, Coakley E, Te HS, Vargas HE, Brown R Jr,
et al. An interferon-free antiviral regimen for HCV after liver trans-
Reproducible Research Statement: Study protocol: Registered plantation. N Engl J Med. 2014;371:2375-82. [PMID: 25386767] doi:
in PROSPERO (CRD42014009711). Statistical code: Not appli- 10.1056/NEJMoa1408921
cable. Data set: See the Supplement. Additional data are 13. Pockros PJ, Reddy KR, Mantry PS, Cohen E, Bennett M,
available upon request from Dr. Falade-Nwulia (e-mail, Sulkowski MS, et al. Efcacy of direct-acting antiviral combination for
[email protected]) or Dr. Suarez-Cuervo (e-mail, csuarez3 patients with hepatitis C virus genotype 1 infection and severe renal
@jhmi.edu). impairment or end-stage renal disease. Gastroenterology. 2016;150:
1590-8. [PMID: 26976799] doi:10.1053/j.gastro.2016.02.078
14. Lawitz E, Matusow G, DeJesus E, Yoshida EM, Felizarta F, Ghalib
Requests for Single Reprints: Oluwaseun Falade-Nwulia, R, et al. Simeprevir plus sofosbuvir in patients with chronic hepatitis
MBBS, MPH, Department of Medicine, Johns Hopkins Univer- C virus genotype 1 infection and cirrhosis: a phase 3 study
sity School of Medicine, 725 North Wolfe Street, Suite 215, (OPTIMIST-2). Hepatology. 2016;64:360-9. [PMID: 26704148] doi:10
Baltimore, MD 21205; e-mail, [email protected]. .1002/hep.28422
15. Poordad F, Schiff ER, Vierling JM, Landis C, Fontana RJ, Yang R,
et al. Daclatasvir with sofosbuvir and ribavirin for hepatitis C virus
Current author addresses and author contributions are avail-
infection with advanced cirrhosis or post-liver transplantation recur-
able at Annals.org.
rence. Hepatology. 2016;63:1493-505. [PMID: 26754432] doi:10
.1002/hep.28446
16. Nelson DR, Cooper JN, Lalezari JP, Lawitz E, Pockros PJ, Gitlin N,
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 Current Author Addresses: Dr. Falade-Nwulia: Department of Author Contributions: Conception and design: O. Falade-
Medicine, Johns Hopkins University School of Medicine, 725 Nwulia, C. Suarez-Cuervo, D.R. Nelson, M.W. Fried, J.B. Segal,
North Wolfe Street, Suite 215, Baltimore, MD 21205. M.S. Sulkowski.
Dr. Suarez-Cuervo: Johns Hopkins Evidence-Based Practice Analysis and interpretation of the data: O. Falade-Nwulia, C.
Center, Johns Hopkins University School of Medicine, 624 Suarez-Cuervo, D.R. Nelson, M.W. Fried, J.B. Segal, M.S.
North Broadway, Suite 680, Baltimore, MD 21205. Sulkowski.
Dr. Nelson: Department of Medicine, University of Florida, Drafting of the article: O. Falade-Nwulia, C. Suarez-Cuervo,
2004 Mowry Road, Gainesville, FL 32611. M.S. Sulkowski.
Dr. Fried: Department of Medicine, University of North Caro- Critical revision of the article for important intellectual con-
tent: O. Falade-Nwulia, C. Suarez-Cuervo, D.R. Nelson, M.W.
lina at Chapel Hill, CB 7584, Room 8015 Burnett-Womack,
Fried, J.B. Segal, M.S. Sulkowski.
Chapel Hill, NC 27514.
Final approval of the article: O. Falade-Nwulia, C. Suarez-
Dr. Segal: Department of Medicine, Johns Hopkins University
Cuervo, D.R. Nelson, M.W. Fried, J.B. Segal, M.S. Sulkowski.
School of Medicine, 624 North Broadway, Room 644, Balti-
Provision of study materials or patients: C. Suarez-Cuervo.
more, MD 21205. Statistical expertise: C. Suarez-Cuervo, J.B. Segal.
Dr. Sulkowski: Department of Medicine, Johns Hopkins Uni- Obtaining of funding: M.S. Sulkowski.
versity School of Medicine, 1830 East Monument Street, Bal- Administrative, technical, or logistic support: C. Suarez-
timore, MD 21205. Cuervo, M.S. Sulkowski.
Collection and assembly of data: O. Falade-Nwulia, C. Suarez-
Cuervo, J.B. Segal, M.S. Sulkowski.

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