Nejmoa 1306218

The n e w e ng l a n d j o u r na l of m e dic i n e
original article
Daclatasvir plus Sofosbuvir for Previously

Treated or Untreated Chronic HCV Infection
Mark S. Sulkowski, M.D., David F. Gardiner, M.D., Maribel Rodriguez-Torres, M.D.,
K. Rajender Reddy, M.D., Tarek Hassanein, M.D., Ira Jacobson, M.D., Eric Lawitz, M.D.,
Anna S. Lok, M.D., Federico Hinestrosa, M.D., Paul J. Thuluvath, M.D.,
Howard Schwartz, M.D., David R. Nelson, M.D., Gregory T. Everson, M.D.,
Timothy Eley, Ph.D., Megan Wind-Rotolo, Ph.D., Shu-Pang Huang, Ph.D., Min Gao, Ph.D.,
Dennis Hernandez, Ph.D., Fiona McPhee, Ph.D., Diane Sherman, M.S.,
Robert Hindes, M.D., William Symonds, Pharm.D., Claudio Pasquinelli, M.D., Ph.D.,
and Dennis M. Grasela, Pharm.D., Ph.D., for the AI444040 Study Group
A bs t r ac t
Background
All-oral combination therapy is desirable for patients with chronic hepatitis C virus From Johns Hopkins University (M.S.S.)
(HCV) infection. We evaluated daclatasvir (an HCV NS5A replication complex inhibitor) and Mercy Medical Center (P.J.T.) — both
in Baltimore; Bristol-Myers Squibb, Hope
plus sofosbuvir (a nucleotide analogue HCV NS5B polymerase inhibitor) in patients well (D.F.G., T.E., D.S., C.P., D.M.G.), and
infected with HCV genotype 1, 2, or 3. Bristol-Myers Squibb, Princeton (M.W.-R.,
S.-P.H.) — both in New Jersey; Fundacion
Methods de Investigacion, San Juan, Puerto Rico
In this open-label study, we initially randomly assigned 44 previously untreated (M.R.-T.); University of Pennsylvania, Phila-
patients with HCV genotype 1 infection and 44 patients infected with HCV geno- delphia (K.R.R.); Southern California GI and
Liver Center, Coronado (T.H.); Weill Cor-
type 2 or 3 to daclatasvir at a dose of 60 mg orally once daily plus sofosbuvir at a nell Medical College, New York (I.J.); Uni-
dose of 400 mg orally once daily, with or without ribavirin, for 24 weeks. The study versity of Texas Health Science Center,
was expanded to include 123 additional patients with genotype 1 infection who San Antonio (E.L.); University of Michi-
gan, Ann Arbor (A.S.L.); Orlando Immu-
were randomly assigned to daclatasvir plus sofosbuvir, with or without ribavirin, nology Center, Orlando (F.H.), Miami Re
for 12 weeks (82 previously untreated patients) or 24 weeks (41 patients who had search Associates, South Miami (H.S.),
previous virologic failure with telaprevir or boceprevir plus peginterferon alfa– and University of Florida, Gainesville
(D.R.N.) — all in Florida; University of
ribavirin). The primary end point was a sustained virologic response (an HCV RNA Colorado Denver, Aurora (G.T.E.); Bristol-
level of <25 IU per milliliter) at week 12 after the end of therapy. Myers Squibb, Wallingford, CT (M.G., D.H.,
F.M.); Skillman, NJ (R.H.); and Gilead
Results Sciences, Foster City, CA (W.S.). Address
Overall, 211 patients received treatment. Among patients with genotype 1 infection, reprint requests to Dr. Sulkowski at the
Department of Medicine, Johns Hopkins
98% of 126 previously untreated patients and 98% of 41 patients who did not have a
University School of Medicine, 600 N.
sustained virologic response with HCV protease inhibitors had a sustained virologic Wolfe St., 1830 Bldg., Rm. 445, Baltimore,
response at week 12 after the end of therapy. A total of 92% of 26 patients with geno- MD 21287, or at [email protected].
type 2 infection and 89% of 18 patients with genotype 3 infection had a sustained
This article was updated on January 16,
virologic response at week 12. High rates of sustained virologic response at week 12 2014, at NEJM.org.
were observed among patients with HCV subtypes 1a and 1b (98% and 100%, respec-
N Engl J Med 2014;370:211-21.
tively) and those with CC and non-CC IL28B genotypes (93% and 98%, respectively), as DOI: 10.1056/NEJMoa1306218
well as among patients who received ribavirin and those who did not (94% and 98%, Copyright © 2014 Massachusetts Medical Society.
respectively). The most common adverse events were fatigue, headache, and nausea.
Conclusions
Once-daily oral daclatasvir plus sofosbuvir was associated with high rates of sustained
virologic response among patients infected with HCV genotype 1, 2, or 3, including
patients with no response to prior therapy with telaprevir or boceprevir. (Funded by
Bristol-Myers Squibb and Pharmasset (Gilead); A1444040 ClinicalTrials.gov number,
NCT01359644.)
n engl j med 370;3 nejm.org january 16, 2014 211

The New England Journal of Medicine
Downloaded from nejm.org on March 11, 2021. For personal use only. No other uses without permission.
Copyright © 2014 Massachusetts Medical Society. All rights reserved.
C
hronic infection with hepatitis C an HCV RNA level of 100,000 IU per milliliter or
virus (HCV) affects approximately 170 mil- higher. Patients did not have evidence of cirrho-
lion people worldwide and is a major cause sis as documented by means of either liver bi-
of cirrhosis and hepatocellular carcinoma.1,2 HCV- opsy within the previous 24 months or noninva-
related morbidity and mortality are increasing; sive assessment of serum markers of fibrosis (a
since 2007, HCV-related deaths in the United States FibroTest score of ≤0.72, on a scale of 0 to 1, with
have exceeded those from human immunodefi- higher scores indicating more severe fibrosis,
ciency virus (HIV) infection.3,4 HCV is classified and an aspartate aminotransferase:platelet ratio
into six major genotypes.5,6 Genotypes 1, 2, and 3 index of ≤2, with higher scores indicating a greater
are found worldwide, with subtype 1a predomi- likelihood of extensive fibrosis) at screening.24,25
nating in the United States and subtype 1b pre- Patients who had received prior treatment
dominating in Europe, Japan, and China.5,7,8 had confirmed virologic failure during or after
Peginterferon alfa–ribavirin treatment for treatment with telaprevir (at a dose of 750 mg
chronic HCV infection is associated with a sus- three times daily) or boceprevir (at a dose of
tained virologic response (undetectable HCV RNA 800 mg three times daily) plus peginterferon
level after treatment) in approximately 40% of alfa–ribavirin. Virologic failure was defined as
patients with genotype 1 infection and 75% of a nonresponse (detectable HCV RNA levels at
patients infected with genotype 2 or 3.9,10 Add- the end of the treatment period), breakthrough
ing boceprevir or telaprevir has been shown to (>1 log10 increase from the nadir in the HCV
improve the response in patients with genotype 1 RNA level or a quantifiable HCV RNA level in a
infection.11,12 However, the addition of bocep patient with an undetectable level during the
revir or telaprevir is limited to HCV genotype 1 treatment period), or relapse (a quantifiable
and is associated with adverse events, compli- HCV RNA level during follow-up in a patient
cated dose regimens, and viral resistance.11-14 with an undetectable level at the end of the
Currently, patients who have virologic failure treatment period).
(no sustained virologic response) with telaprevir Patients who had discontinued telaprevir or
or boceprevir plus peginterferon alfa–ribavirin boceprevir because of adverse events were ex-
have no other treatment options. cluded. Other exclusion criteria were chronic
Daclatasvir is a first-in-class HCV NS5A repli- liver disease other than HCV infection and coin-
cation complex inhibitor, and sofosbuvir is a fection with HIV or hepatitis B virus. All pa-
nucleotide analogue HCV NS5B polymerase in- tients provided written informed consent.
hibitor.15,16 Both have potent antiviral activity and
broad genotypic coverage and are administered Study Oversight
orally once daily.15,17,18 Each is effective in pa-The study was conducted in accordance with
tients infected with genotype 1, 2, or 3 when this Good Clinical Practice guidelines and was ap-
treatment is combined with peginterferon alfa– proved by the institutional review board or inde-
ribavirin,19-22 and sofosbuvir plus ribavirin is ef-
pendent ethics committee at each site. Bristol-
fective in patients infected with genotype 1, 2, or 3
Myers Squibb (the sponsor) and Pharmasset (now
in the absence of treatment with peginterferon Gilead Sciences), which provided the study drug,
alfa–ribavirin.23 We evaluated daclatasvir plus designed the study; the sponsor conducted the
sofosbuvir, with or without ribavirin, in previ- study in collaboration with the principal investi-
ously untreated patients infected with genotype gators, collected the data, monitored the conduct
1, 2, or 3, and in patients with genotype 1 infec-of the study, and performed the statistical analy-
tion who had not had a response to previous ses. The first draft of the manuscript was pre-
treatment with telaprevir or boceprevir. pared by the academic and industry authors,
with assistance from a medical writer paid by
Me thods the sponsor. The academic authors vouch for
the completeness and accuracy of the data and
Patients data analyses and for the fidelity of the study to
Eligible patients were 18 to 70 years of age and the protocol (available with the full text of this
had chronic HCV genotype 1, 2, or 3 infection with article at NEJM.org).
212 n engl j med 370;3 nejm.org january 16, 2014

Daclatasvir plus Sofosbuvir for Chronic HCV Infection
Study Design Adverse events were recorded throughout the

In this open-label study, untreated patients were study. Clinical laboratory tests, physical exami-
randomly assigned, in a 1:1:1 ratio, to receive so- nations, and electrocardiographic monitoring
fosbuvir for 1 week, then daclatasvir and sofos- were performed at screening, at baseline, and
buvir for 23 weeks (groups A and B); daclatasvir at scheduled visits throughout treatment.
and sofosbuvir for 24 weeks (groups C and D); or
daclatasvir, sofosbuvir, and ribavirin for 24 weeks Virologic Breakthrough, Relapse,
(groups E and F). Patients with genotype 1 infec- and Resistance Monitoring
tion were assigned to group A, C, or E, and patients Virologic breakthrough during the treatment
infected with genotype 2 or 3 were assigned to period was defined as a confirmed increase
group B, D, or F (Fig. S1a in the Supplementary from the nadir in the HCV RNA level of at least
Appendix, available at NEJM.org). 1 log10 IU per milliliter or a confirmed HCV RNA
The purpose of the lead-in period of therapy level of 25 IU per milliliter or higher at or after
with sofosbuvir was to determine whether ini- week 8. In groups A through F, breakthrough also
tial HCV suppression with sofosbuvir would included detectable HCV RNA of less than 25 IU
reduce the emergence of daclatasvir-resistant per milliliter at or after week 8; results from the
variants. In accordance with a protocol amend- first cohort showed that detectable but unquanti-
ment, 123 additional patients with genotype 1 fiable HCV RNA was not associated with the
infection were randomly assigned in a 1:1 ratio clinical outcome, so this definition was later re-
to daclatasvir plus sofosbuvir, with or without moved. For patients with virologic breakthrough,
ribavirin, for 12 weeks (82 untreated patients, peginterferon alfa and ribavirin could be added
assigned to group G or H) or 24 weeks (41 pa- as rescue therapy (unless they were already re-
tients who did not have a response to prior treat- ceiving ribavirin). Virologic relapse was defined
ment with HCV protease inhibitors, assigned to as a confirmed HCV RNA level of 25 IU per milli-
group I or J) (Fig. S1b and S1c in the Supple- liter or higher in patients with an HCV RNA level
mentary Appendix). that was less than 25 IU per milliliter at the end
Daclatasvir and sofosbuvir were administered of treatment.
orally at a dose of 60 mg once daily and 400 mg At baseline, the HCV NS5A and NS5B regions
once daily, respectively. Ribavirin was administered from all samples and the NS3 region from sam-
orally twice daily at a dose of 1000 to 1200 mg per ples in groups I and J were analyzed by means of
day, according to body weight (1000 mg in pa- population sequencing (sensitivity, approximately
tients with a body weight of <75 kg, and 1200 mg 20%). Samples from patients with virologic break-
in patients with a body weight ≥75 kg), in pa- through or relapse were analyzed by means of
tients with genotype 1 infection, and at a dose population sequencing if the HCV RNA level was
of 800 mg per day in patients infected with at least 1000 IU per milliliter. After viral RNA was
genotype 2 or 3. A reduction in the dose of isolated from plasma, the HCV NS3, NS5A, and
ribavirin to 600 mg daily was permitted if the NS5B regions were amplified by means of poly-
hemoglobin level decreased to below 10 g per merase chain reaction and sequenced. Consensus
deciliter. sequences in samples obtained from the patients
were compared with the appropriate reference se-
Efficacy and Safety Monitoring quences (GT1a [H77], GT1b [Con1], GT2 [JFH1],
Serum HCV RNA levels were assayed centrally and GT3 [S52]) by means of the Basic Local
with the use of the COBAS TaqMan HCV test, Alignment Search Tool.
version 2.0 (Roche Molecular Systems), with a
lower limit of quantification of 25 IU per milliliter End Points
and a lower limit of detection of 10 IU per milli- The primary efficacy end point was the propor-
liter. HCV RNA levels were measured at baseline; tion of patients with a sustained virologic re-
on treatment days 1 through 7, 9, 11, 14, and 21; sponse (an HCV RNA level of less than 25 IU per
every 2 weeks from treatment week 4 through milliliter) at week 12 after the end of treatment.
week 24; and at weeks 4, 12, and 24 after the end Secondary efficacy end points included a sus-
of the treatment period. tained virologic response at 4 weeks after treat-

ment and at 24 weeks after treatment. Safety Virologic Response

end points included adverse events, discontinu- During the initial 48 hours, the slope of the mean
ation of a study drug due to adverse events, and viral decline was steeper in groups receiving da-
grade 3 or 4 laboratory abnormalities. clatasvir and sofosbuvir than in those receiving
sofosbuvir alone (P<0.001) (Fig. S2 in the Supple-
Statistical Analysis mentary Appendix). This difference did not per-
With sample sizes of 14, 20, and 40 patients, the sist; all patients had an HCV RNA level of less
probability of observing at least one safety event than 25 IU per milliliter by week 4.
occurring at an incidence rate of 10% was 0.771, All patients infected with genotype 2 or 3 had
0.878, and 0.985, respectively. With these three an undetectable HCV RNA level during the treat-
sample sizes, the two-sided 80% exact confi- ment period. One patient with genotype 3 infec-
dence intervals for a sustained virologic response tion who was treated without ribavirin had a
at week 12 after treatment were, respectively, detectable HCV RNA level of less than 25 IU per
58 to 92% if the observed rate was 79% (11 of milliliter at weeks 8 and 10, which, per protocol,
14 patients with an event), 59 to 87% if the ob- was defined as a virologic breakthrough (Table 2).
served rate was 75% (15 of 20 patients with an However, before the initiation of rescue therapy at
event), and 64 to 84% if the observed rate was week 12, HCV RNA was undetectable; the patient
75% (30 of 40 patients with an event). For effi- had a sustained virologic response at 24 weeks
cacy end points, the analyses included all pa- after rescue therapy (Table S4 in the Supplemen-
tients who received at least one dose of study tary Appendix). Overall, 91% of the patients
medication (modified intention-to-treat popula- infected with genotype 2 or 3 had a sustained
tion). Patients for whom data were missing were virologic response 12 weeks after treatment and
classified as not having had a response at that 93% had a sustained virologic response 24 weeks
visit but could be classified as having a response after treatment (Table 2). Rates of sustained vi-
at future visits if the lack of response was solely rologic response 12 weeks after treatment were
due to the missing HCV RNA measurement. Pa- 92% among patients with genotype 2 infection
tients who required rescue therapy were classi- (24 of 26 patients) and 89% among patients with
fied as not having had a response at the time of genotype 3 infection (16 of 18).
rescue and at all subsequent visits. None of the patients with genotype 1 infec-
tion had a virologic breakthrough, and all had
R e sult s an HCV RNA level of less than 25 IU per milli-
liter at the end of the treatment period (Table 2).
Characteristics of the Patients After the treatment period, no patient had a vi-
A total of 211 patients received treatment at rologic relapse. Overall, 164 of 167 patients with
18 centers in the United States between June 2011 genotype 1 infection (98%) had a sustained viro-
and November 2012. A total of 44 were infected logic response at week 12 after treatment, includ-
with HCV genotype 2 or 3, and 167 had geno- ing 84 of 85 patients who received treatment for
type 1 infection (126 untreated patients and 24 weeks (all 44 patients who had not received
41 patients who did not have a response to prior previous treatment and 40 of 41 patients who
treatment with protease inhibitors) (Fig. S1 in had received a protease inhibitor) and 80 of 82
the Supplementary Appendix). Among patients patients who received treatment for 12 weeks. Of
with genotype 1 infection, the median age the 3 patients who were classified as not having a
ranged from 54 to 59 years, and most had fibro- sustained virologic response 12 weeks after treat-
sis of Metavir stage 2 or higher (on a scale from ment, 2 missed the assessment visit at 12 weeks
F0 to F4, with higher stages indicating a greater but had a sustained virologic response at week 24
degree of fibrosis) (Table 1, and Table S1 in the after treatment, and 1 was lost to follow-up
Supplementary Appendix). Of the 41 patients (Table 2, and Tables S2 and S4 in the Supplemen-
who did not have a response to prior treatment tary Appendix).
with protease inhibitors, 19 (46%) had NS3 poly Rates of sustained virologic response 12 weeks
morphisms conferring resistance to telaprevir after treatment were similar in subgroups defined
or boceprevir (Tables S2 and S3 in the Supple- according to viral subtype (genotype 1a, 98%
mentary Appendix). [129 of 132 patients]; genotype 1b, 100% [35 of

Table 1. Baseline Demographic Characteristics of the Patients and Characteristics of the Disease.*
Genotype 2 or 3, Genotype 1, Genotype 1,

Characteristic Previously Untreated Previously Untreated Previously Treated
Group B: Group F: Group A: Group E: Group H: Group J:

SOF for 7 days, Group D: DCV and SOF SOF for 7 days, Group C: DCV and SOF Group G: DCV and SOF Group I: DCV and SOF
then SOF and DCV and SOF plus RBV then SOF and DCV and SOF plus RBV DCV and SOF plus RBV DCV and SOF plus RBV
DCV for 23 wk for 24 wk for 24 wk DCV for 23 wk for 24 wk for 24 wk for 12 wk for 12 wk for 24 wk for 24 wk
(N = 16) (N = 14) (N = 14) (N = 15) (N = 14) (N = 15) (N = 41) (N = 41) (N = 21) (N = 20)
Median age — yr 51 50 52 56 54 54 55 54 59 57
Male sex — no. (%) 11 (69) 6 (43) 5 (36) 7 (47) 9 (64) 7 (47) 20 (49) 21 (51) 13 (62) 12 (60)
Race — no. (%)†
White 16 (100) 10 (71) 12 (86) 11 (73) 11 (79) 12 (80) 33 (80) 33 (80) 19 (90) 18 (90)
Black 0 2 (14) 0 4 (27) 3 (21) 2 (13) 5 (12) 7 (17) 2 (10) 1 (5)
Other 0 2 (14) 2 (14) 0 0 1 (7) 3 (7) 1 (2) 0 1 (5)
n engl j med 370;3

HCV RNA — log10 IU/ml‡ 6.5±0.7 6.8±0.5 6.6±0.6 6.5±0.5 6.6±0.3 6.7±0.6 6.2±0.5 6.4±0.6 6.3±0.4 6.3±0.4
HCV genotype — no. (%)§
1a 0 0 0 11 (73) 10 (71) 11 (73) 34 (83) 33 (80) 16 (76) 17 (85)
nejm.org
1b 0 0 0 4 (27) 4 (29) 4 (27) 7 (17) 8 (20) 5 (24) 3 (15)
2 9 (56) 8 (57) 9 (64) 0 0 0 0 0 0 0
3 7 (44) 6 (43) 5 (36) 0 0 0 0 0 0 0
IL28B genotype CC — no. (%) 8 (50) 5 (36) 7 (50) 4 (27) 8 (57) 4 (27) 9 (22) 15 (37) 1 (5) 0
january 16, 2014

Metavir score for fibrosis —
no. (%)¶
F0 or F1: none or minimal 6 (38) 6 (43) 6 (43) 4 (27) 6 (43) 6 (40) 15 (37) 13 (32) 2 (10) 3 (15)
F2 or F3: moderate 7 (44) 7 (50) 6 (43) 8 (53) 7 (50) 6 (40) 19 (46) 22 (54) 14 (67) 11 (55)

F4: clinically significant 3 (19) 1 (7) 2 (14) 3 (20) 1 (7) 2 (13) 6 (15) 5 (12) 3 (14) 6 (30)
* Plus–minus values are means ±SD. Previously treated patients were those who had virologic failure during or after treatment with telaprevir or boceprevir. The doses of medication
were as follows: daclatasvir (DCV), 60 mg once daily; sofosbuvir (SOF), 400 mg once daily; and ribavirin (RBV), administered twice daily, at a dose of 1000 to 1200 mg per day accord-
ing to weight in patients with genotype 1 infection and 800 mg per day in patients infected with genotype 2 or 3. Percentages may not total 100 because of rounding. None of the char-
acteristics differed significantly among the randomized groups. HCV denotes hepatitis C virus.
† Race was self-reported.
‡ The HCV RNA assay had a limit of detection 10 IU per milliliter.
§ Genotypes 2 and 3 are indicated for groups B, D, and F, and genotypes 1a and 1b are indicated for groups A, C, E, and G through J.
¶ The Metavir score (on a scale from F0 to F4, with higher scores indicating a greater degree of fibrosis) was derived from a FibroTest score and classified according to information on
the FibroTest manufacturer’s website (www.biopredictive.com). Patients with a score of F4 were required to have no evidence of cirrhosis on the basis of a liver biopsy. Data were not
available for one patient in group E, one patient in group G, one patient in group H, and two patients in group I. For additional clinical findings according to the fibrosis score, see
Table S1 in the Supplementary Appendix.
215
Table 2. Virologic Response during and after Treatment.
Virologic Response Genotype 2 or 3, Previously Untreated
Group B: Group F:
SOF for 7 days, Group D: DCV and SOF Total:
then SOF and DCV DCV and SOF plus RBV Groups B, D,
for 23 wk for 24 wk for 24 wk and F
(N = 16) (N = 14) (N = 14) (N = 44)
number of study participants (percent)
During treatment
Week 2
HCV RNA <25 IU/ml 13 (81) 12 (86) 12 (86) 37 (84)
HCV RNA undetectable 5 (31) 4 (29) 4 (29) 13 (30)
Week 4
HCV RNA <25 IU/ml 16 (100) 14 (100) 14 (100) 44 (100)
End of treatment‡
HCV RNA <25 IU/ml 15 (94)§ 14 (100) 14 (100) 43 (98)
HCV RNA undetectable 15 (94)§ 13 (93) 14 (100) 42 (95)
After treatment
Week 4
HCV RNA <25 IU/ml 14 (88)¶ 14 (100) 12 (86)‖** 40 (91)
HCV RNA undetectable 14 (88)¶ 14 (100) 11 (79)‖** 39 (89)
Week 12
HCV RNA <25 IU/ml 14 (88) 14 (100) 12 (86)** 40 (91)
HCV RNA undetectable 14 (88) 13 (93) 12 (86)** 39 (89)
Week 24
HCV RNA <25 IU/ml 14 (88) 14 (100) 13 (93) 41 (93)
* Data on HCV RNA levels were missing for two patients at week 4; both had an HCV RNA level of less than 25 IU
per milliliter at week 3 and again at week 6.
† Data on the HCV RNA level were missing for one patient.
‡ The end-of-treatment analysis (week 24 for groups A through F and week 12 for groups G and H) included patients
who discontinued treatment early, for whom the last HCV RNA measurement was considered “end of treatment.”
§ One patient had a protocol-defined virologic breakthrough (detectable HCV RNA level of <25 IU/ml).
¶ One patient had a relapse.
‖ One patient was lost to follow-up.
** Data on the HCV RNA level were missing for one patient, who had a sustained virologic response at week 24 after
the end of treatment.
†† Data on the HCV RNA level were missing for one patient, who had a sustained virologic response at week 12 after
‡‡ One patient with an unconfirmed HCV RNA level of 54 IU per milliliter at week 4 after treatment had a sustained
virologic response at week 12 after the end of treatment.
§§ Data on the HCV RNA level were missing for one patient, who had a sustained virologic response at week 24 after
the end of treatment, and one patient was lost to follow-up.
¶¶ Data on the HCV RNA level were missing for one patient, who had a sustained virologic response at week 24 after
‖‖ One patient probably had reinfection.
*** Data on the HCV RNA level were missing for two patients, both of whom had a sustained virologic response at
week 36 after the end of treatment.
††† Data on the HCV RNA level were missing for two patients, both of whom had a sustained virologic response at
week 36 after the end of treatment, and one patient was lost to follow-up.

Genotype 1, Previously Untreated Genotype 1, Previously Treated
Group A: Group E: Group H: Group J:

SOF for 7 days, Group C: DCV and SOF Group G : DCV and SOF Total: Group I: DCV and SOF
then SOF and DCV DCV and SOF plus RBV DCV and SOF plus RBV Groups A, C, DCV and SOF plus RBV
for 23 wk for 24 wk for 24 wk for 12 wk for 12 wk E, G, and H for 24 wk for 24 wk
(N = 15) (N = 14) (N = 15) (N = 41) (N = 41) (N = 126) (N = 21) (N = 20)
10 (67) 11 (79) 10 (67) 36 (88) 34 (83) 101 (80) 19 (90) 16 (80)

7 (47) 2 (14) 3 (20) 12 (29) 13 (32) 37 (29) 3 (14) 3 (15)
15 (100) 14 (100) 15 (100) 39 (95)* 41 (100) 124 (98) 21 (100) 19 (95)†

13 (87) 13 (93) 11 (73) 31 (76)* 32 (78) 100 (79) 17 (81) 14 (70)†
15 (100) 14 (100) 15 (100) 41 (100) 41 (100) 126 (100) 21 (100) 20 (100)

15 (100) 14 (100) 15 (100) 41 (100) 41 (100) 126 (100) 19 (90) 19 (95)
15 (100) 14 (100) 15 (100) 40 (98)†† 39 (95)††‡‡ 123 (98) 21 (100) 20 (100)

15 (100) 14 (100) 15 (100) 40 (98)†† 39 (95)††‡‡ 123 (98) 21 (100) 19 (95)
15 (100) 14 (100) 15 (100) 41 (100) 39 (95)§§ 124 (98) 21 (100) 19 (95)¶¶

15 (100) 14 (100) 15 (100) 41 (100) 39 (95)§§ 124 (98) 21 (100) 19 (95)¶¶
14 (93)‖‖ 14 (100) 15 (100) 39 (95)*** 38 (93)††† 120 (95)

14 (93)‖‖ 14 (100) 15 (100) 39 (95)*** 38 (93)††† 120 (95)
35 patients]), IL28B genotype (CC, 93% [57 of follow-up. The remaining patient, whose his-
61 patients]; non-CC, 98% [147 of 150 patients]), tory included injection-drug use, had a high
race (white, 97% [170 of 175 patients]; black, 96% level of viremia (HCV RNA level, 670,772 IU per
[25 of 26 patients]; and other race, 90% [9 of milliliter), and viral sequences at week 24 after
10 patients]), ribavirin status (ribavirin, 94% treatment that differed from the sequences at
[85 of 90 patients]; no ribavirin, 98% [119 of baseline suggested a new HCV infection. Fur-
121 patients]), and history of treatment failure thermore, no daclatasvir-resistant or sofosbuvir
with protease inhibitors (98% [40 of 41 patients]). resistant variants were detected (Fig. S3 in the
Of 126 patients with previously untreated Supplementary Appendix).
genotype 1 infection, 120 (95%) had a sus-
tained virologic response at week 24 after treat- Virologic Breakthrough, Relapse,
ment (Table 2). Of the 6 patients who were and Resistance
classified as not having a sustained virologic Virologic relapse was confirmed in 1 patient with
response at week 24 after treatment, 4 missed genotype 3 infection who received treatment with-
the assessment visit at week 24 but were clas out ribavirin; adherence to the treatment regimen
sified as having a sustained virologic response was documented on the basis of pill counts, as
at week 36 after treatment, and 1 was lost to well as plasma concentrations of daclatasvir and

major sofosbuvir metabolites that were consis- liter after 12 weeks of therapy. The ribavirin
tent with those in other patients. Resistance dose was reduced in five patients because of
analysis showed a preexisting NS5A-A30K poly- anemia. Additional safety findings are listed in
morphism, associated with daclatasvir resistance, Tables S6, S7, and S8 in the Supplementary
at baseline and at the time of relapse. No other Appendix.
resistance-associated changes were detected at
the time of relapse. Of the available baseline Discussion
samples, pretreatment polymorphisms, including
NS5A-A30K and others known to confer loss of We assessed daclatasvir plus sofosbuvir in un-
susceptibility to daclatasvir in vitro, were observed treated patients and patients in whom previous
in 10 of 123 untreated patients with genotype 1 treatment with telaprevir or boceprevir had failed.
infection (8%), 3 of 40 patients with genotype 1 in- Overall, most patients had a sustained virologic
fection in whom prior treatment with protease response, including 98% of patients with geno-
inhibitors had failed (8%), 14 of 23 patients with type 1 infection, regardless of viral subtype or
genotype 2 infection (61%), and 5 of 18 patients failure of prior treatment with protease inhibi-
with genotype 3 infection (28%) (Table S5 in the tors, and 91% of patients infected with genotype
Supplementary Appendix). Except for the patient 2 or 3. The most common adverse event was fa-
described above, all patients with preexisting dacla- tigue, which was reported in approximately one
tasvir resistance variants had a sustained virologic third of patients. Our study shows that the com-
response. With respect to sofosbuvir, no preexisting bination of an NS5A inhibitor and an NS5B in-
NS5B-S282T polymorphisms were detected. In the hibitor was associated with high cure rates in a
only patient with protocol-defined virologic break- range of HCV-infected patients, including pa-
through, no baseline daclatasvir or sofosbuvir tients who had persistent HCV variants con
resistance-associated polymorphisms were detect- ferring resistance to protease inhibitors after
ed, and the HCV RNA level at the time of virologic unsuccessful treatment with telaprevir or bo-
breakthrough was too low (<25 IU per milliliter) ceprevir.
for resistance testing; the patient had a sustained Daclatasvir plus sofosbuvir was associated with
virologic response after rescue therapy. high rates of sustained virologic response among
patients with characteristics that were previously
Safety associated with a poor response to treatment
The most common adverse events were fatigue, — HCV genotypes 1a and 3, the non-CC IL28B
headache, and nausea (Table 3, and Table S6 in genotype, and black race. Studies evaluating
the Supplementary Appendix). Two patients dis- peginterferon alfa–ribavirin plus a single direct-
continued treatment because of adverse events acting antiviral agent11,12,26,27 or different com-
(fibromyalgia in one patient and a stroke in one binations of direct-acting antiviral agents28-30 have
patient); both had a sustained virologic response shown that patients with genotype 1a infection
(Table S7 in the Supplementary Appendix). Seri- have a worse response than patients with geno-
ous adverse events during the treatment period type 1b infection; indeed, some oral regimens are
(Table 3, and Table S8 in the Supplementary Ap- effective primarily in patients with genotype 1b
pendix) included single events of gastroenteri- infection. In our study, most of the patients had
tis, colitis, stroke, acute renal failure from dehy- genotype 1a infection, and the rates of response
dration that resolved with administration of were high in both these patients and those with
fluids, forearm fracture, anxiety and pleuritic genotype 1b infection. Recent evidence suggests
pain, exacerbation of psoriasis, and hypokale- that HCV genotype 3 may also be less responsive
mia. The most common grade 3 or 4 laboratory to treatment than other genotypes.21,31 In our
abnormalities were low phosphorus and elevat- study, 16 of 18 patients with genotype 3 infection
ed glucose levels. The mean change in the he- had a sustained virologic response at week 12
moglobin level associated with regimens that after treatment. With regard to host factors,
contained ribavirin versus those that did not lower response rates have been observed with
contain ribavirin was −2.2 g per deciliter versus non-CC IL28B genotypes than with the CC geno-
−0.3 g per deciliter after 24 weeks of therapy type in studies of peginterferon alfa–ribavirin
and −2.8 g per deciliter versus −0.9 g per deci with or without telaprevir or boceprevir11,26,32

Table 3. Adverse Events during the Treatment Period.
Adverse Event Previously Untreated Previously Treated

Treatment for 24 Wk Treatment for 12 Wk Treatment for 24 Wk
Groups A Groups E
and B: Groups C and F: Group H: Group J:
Lead-in SOF and D: DCV and SOF Group G: DCV and SOF Group I: DCV and SOF
and DCV DCV and SOF and RBV DCV and SOF and RBV DCV and SOF and RBV
(N = 31) (N = 28) (N = 29) (N = 41) (N = 41) (N = 21) (N = 20)
Any adverse event 25 (81) 26 (93) 26 (90) 38 (93) 38 (93) 16 (76) 20 (100)
Adverse event occurring in ≥25%
of patients in any group*
Fatigue 9 (29) 14 (50) 9 (31) 16 (39) 15 (37) 6 (29) 9 (45)
Headache 5 (16) 8 (29) 11 (38) 14 (34) 9 (22) 7 (33) 7 (35)
Nausea 5 (16) 9 (32) 9 (31) 8 (20) 8 (20) 0 2 (10)
Grade 3 or 4 adverse event 0 2 (7)† 2 (7) 1 (2) 1 (2) 0 1 (5)
Discontinuation of treatment due to 0 1 (4) 1 (3) 0 0 0 0
adverse event‡
Serious adverse event§ 2 (6) 4 (14) 2 (7) 1 (2) 0 0 1 (5)
Grade 3 or 4 laboratory abnormality
occurring in ≥3 patients
across all groups
Phosphorus <2.0 mg/dl 0 1 (4) 1 (3) 0 3 (7) 0 0
Glucose
Fasting value >250 mg/dl 0 1 (4) 1 (3) 1 (2) 0 1 (5) 0
Random value >250 mg/dl 0 0 1 (5)¶ 0 0 1 (5) 1 (5)
* All events listed were mild or moderate in intensity; further details are in Table S6 in the Supplementary Appendix. To convert values for
glucose to millimoles per liter, multiply by 0.05551.
† Two patients had a total of four events.
‡ Further details are in Table S7 in the Supplementary Appendix.
§ Further details are in Table S8 in the Supplementary Appendix. Five events of overdose (extra study medication doses), classified as serious
adverse events, are not included in the table; no clinically significant effects were reported from any of the overdoses.
¶ This percentage was calculated according to the number of available samples (21).
and in studies of some direct-acting antiviral these patients were infected with subtype 1a
combinations.29,30 Most patients in our study had (80%), had a non-CC IL28B genotype (98%), and
non-CC IL28B genotypes, and the rate of response had evidence of at least moderate hepatic fibro-
was high among these patients. sis (score ≥2) at baseline (83%) (Table 1). Despite
Patients with HCV genotype 1 infection who these characteristics, early HCV RNA suppres-
have virologic failure during telaprevir-based or sion was similar in previously treated and un-
boceprevir-based therapy despite acceptable ad- treated patients (Fig. S2 in the Supplementary
herence are frequently infected with HCV geno- Appendix), and all patients in whom prior treat-
type 1a, and they often have a poor response to ment with protease inhibitors had failed had a
interferon, as indicated by a non-CC IL28B geno- sustained virologic response. This represents
type.13,26 In our study, patients in whom prior proof of concept that a sustained virologic re-
treatment with protease inhibitors had failed were sponse can be achieved in patients in whom
characterized according to prior virologic re- previous treatment with telaprevir or boceprevir
sponse: 71% had virologic breakthrough or non had failed, including patients who have persis-
response, indicating poor interferon responsive- tent HCV variants with resistance to protease in-
ness, HCV resistance, or both (Table S2 in the hibitors (Fig. S4 in the Supplementary Appendix).
Supplementary Appendix). Furthermore, most of Virologic breakthrough and relapse were rare

in our population and were not observed in any of fected with genotype 2 or 3.23,29,34 In our study,
the 193 patients infected with HCV genotype 1 response rates were similar among patients treated
or 2, despite preexisting daclatasvir-resistant vari- with ribavirin and those treated without it; how-
ants in 27 patients. Of the 5 patients infected ever, ribavirin recipients had a greater decrease
with HCV genotype 1 or 2 who were classified in the hemoglobin level. Our findings may re-
as not having a sustained virologic response at flect the antiviral potency and high resistance
week 12 after treatment, 3 had missing data at barrier of the daclatasvir–sofosbuvir combina-
week 12 but had a sustained virologic response tion and suggest that ribavirin is not required
at week 24 after treatment (including 1 who re- with every oral direct-acting antiviral regimen.
turned after the database lock) and 2 were lost Ribavirin requires twice-daily dosing, is associ-
to follow-up. Among the 18 patients with HCV ated with hemolytic anemia, and is highly tera-
genotype 3 infection, virologic relapse occurred togenic. Ribavirin-sparing regimens are there-
in 1 of 5 patients with a preexisting daclatasvir- fore desirable and warrant further investigation.
resistant variant, and in a second patient, who In conclusion, once-daily, oral treatment with
did not have preexisting daclatasvir-resistant the NS5A inhibitor daclatasvir plus the NS5B
variants, an HCV RNA level below 25 IU per mil- polymerase inhibitor sofosbuvir was associated
liliter was detected at weeks 8 and 10. Although with high rates of sustained virologic response in
HCV RNA was undetectable at week 12, this re- untreated patients infected with genotype 1, 2,
sponse pattern was predefined in the original or 3 and in patients with genotype 1 infection in
protocol as virologic breakthrough, and rescue whom previous treatment with protease inhibi-
therapy was initiated. Because of low virus levels tors had failed and who had no current treat-
during the treatment period and a sustained vi- ment options. The response rate was high
rologic response at week 12 after treatment, we across subgroups of patients defined according
could not assess the role of viral variants in this to IL28B genotype, HCV genotype 1 subtype,
patient. Sofosbuvir-resistant variants were not receipt of ribavirin, and the presence of HCV
detected in any of the patients. Our observations protease inhibitor–resistant variants.
suggest that the development of resistance is
Presented in part at the 48th annual meeting of the European
uncommon with daclatasvir plus sofosbuvir. Association for the Study of the Liver, Amsterdam, April 24–28,
Many HCV treatment regimens have been as- 2013; the 63rd annual meeting of the American Association for
sessed with and without ribavirin, and the re- the Study of Liver Diseases, Boston, November 9–13, 2012; and
the 47th annual meeting of the European Association for the
sponse rates have been lower in the absence of Study of the Liver, Barcelona, April 18–22, 2012.
ribavirin. This has been observed with peginter- Supported by Bristol-Myers Squibb and Pharmasset (Gilead).
feron alfa–ribavirin plus a protease inhibitor33 Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
and with interferon-free regimens, including so- We thank Jennifer Tobin of Articulate Science for editorial
fosbuvir with or without ribavirin in patients in- assistance with an earlier version of the manuscript.
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The n e w e ng l a n d j o u r na l of m e dic i n e

Daclatasvir plus Sofosbuvir for Previously

n engl j med 370;3 nejm.org january 16, 2014 211

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Study Design Adverse events were recorded throughout the

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ment and at 24 weeks after treatment. Safety Virologic Response

214 n engl j med 370;3 nejm.org january 16, 2014

The New England Journal of Medicine

Genotype 2 or 3, Genotype 1, Genotype 1,

Group B: Group F: Group A: Group E: Group H: Group J:

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Copyright © 2014 Massachusetts Medical Society. All rights reserved.

Table 2. Virologic Response during and after Treatment.

Virologic Response Genotype 2 or 3, Previously Untreated

216 n engl j med 370;3 nejm.org january 16, 2014

The New England Journal of Medicine

Genotype 1, Previously Untreated Genotype 1, Previously Treated

Group A: Group E: Group H: Group J:

10 (67) 11 (79) 10 (67) 36 (88) 34 (83) 101 (80) 19 (90) 16 (80)

15 (100) 14 (100) 15 (100) 39 (95)* 41 (100) 124 (98) 21 (100) 19 (95)†

15 (100) 14 (100) 15 (100) 41 (100) 41 (100) 126 (100) 21 (100) 20 (100)

15 (100) 14 (100) 15 (100) 40 (98)†† 39 (95)††‡‡ 123 (98) 21 (100) 20 (100)

15 (100) 14 (100) 15 (100) 41 (100) 39 (95)§§ 124 (98) 21 (100) 19 (95)¶¶

14 (93)‖‖ 14 (100) 15 (100) 39 (95)*** 38 (93)††† 120 (95)

n engl j med 370;3 nejm.org january 16, 2014 217

218 n engl j med 370;3 nejm.org january 16, 2014

The New England Journal of Medicine

Table 3. Adverse Events during the Treatment Period.

Adverse Event Previously Untreated Previously Treated

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