Hepatitis C

Hepatitis C
A Guide to Current Management

HEPATITIS C COLLECTION
Until recently, treatment of hepatitis C required weekly injections of pegylated interferon alfa
along with oral ribavirin for up to a year and was effective in only about half of patients with
the new england genotype 1 of the virus. Since 2013, however, the development of several oral, direct-acting
journal of medicine
agents (DAAs) has completely revolutionized treatment. Six highly effective, fast-acting,
nejm journal watch all-oral, interferon-free regimens, consisting of various combinations of 9 drugs, are now
Cardiology
FDA-approved, and several others are in development. The excitement is tempered a great
Dermatology
deal, however, by the very high cost of these new and forthcoming DAAs. This collection
Emergency Medicine
Gastroenterology of NEJM Group content summarizes recent changes and challenges in the treatment of
General Medicine hepatitis C.
Hospital Medicine
NEJM Group delivers information and services in biomedical research, clinical practice, health
Infectious Diseases
Neurology
care delivery, and ongoing medical education. This collection brings together content from the
Oncology and Hematology New England Journal of Medicine, NEJM Journal Watch, and Physician’s First Watch. NEJM Journal
Pediatrics and Adolescent Medicine Watch surveys, summarizes, and provides expert commentary on articles from more than 250
Physician’s First Watch medical journals. Its physician editors select the most relevant research studies and clinical
Psychiatry practice guidelines, summarize the findings and recommendations, and place them in context.
Women’s Health
Physician’s First Watch is our news arm.
nejm careercenter
In addition, we have included several relevant posts from “HIV and ID Observations,” a blog by
nejm knowledge+ Paul Sax, MD, whose keen-eyed and often irreverent perspective brings issues critical to clinical
practice into sharp focus.
We hope you find this collection illuminating, useful, and enjoyable.
— Atif Zaman, MD, MPH

Associate Professor,
Department of Gastroenterology and Hepatology,
Oregon Health & Science University, Portland
Associate Editor, NEJM Journal Watch Gastroenterology
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October 2015
Clinical Collections — Hepatitis C
Table of Contents
INTRODUCTION
WHAT IS THE CURRENT LANDSCAPE OF HEPATITIS C THERAPY, AND HOW DID

IT COME ABOUT?
7 Figure 1A: Life Cycle of the Hepatitis C Virus (HCV)
Adapted from “Current and Future Therapies for Hepatitis C Virus Infection”
New England Journal of Medicine May 16, 2013
8 Figure 1B: Cleavage and Replication of HCV with Targets of Therapy

Adapted from “Current and Future Therapies for Hepatitis C Virus Infection”
9 Therapy of Hepatitis C — Back to the Future

WHAT IS THE CURRENT STANDARD OF CARE?

15 New All-Oral Hepatitis C Regimens Are on the Horizon
NEJM Journal Watch General Medicine Apr 24, 2014
17 Ledipasvir and Sofosbuvir for Untreated HCV Genotype 1 Infection

27 ABT-450/r–Ombitasvir and Dasabuvir with or without Ribavirin for HCV

37 Sofosbuvir-Based Therapy for HCV Infection: The Results Are In

NEJM Journal Watch Gastroenterology Apr 23, 2013
38 Sofosbuvir Works for Patients Who Cannot Take Peginterferon

NEJM Journal Watch Gastroenterology May 24, 2013
39 Combined Simeprevir and Sofosbuvir Is Promising for HCV Genotype 1 Infection

NEJM Journal Watch Gastroenterology Aug 11, 2014
40 Progress Toward All-Oral, Interferon-Free Therapy for HCV Genotype 1 Infection

NEJM Journal Watch Gastroenterology Jan 15, 2014
41 Simeprevir, Sofosbuvir, and the Limitations of the COSMOS

NEJM Journal Watch HIV and ID Observations Blog Jul 31, 2014
43 Approval of Sofosbuvir/Ledipasvir Was Expected, but Still Is a Huge Advance

NEJM Journal Watch HIV and ID Observations Blog Oct 12, 2014
continued
3
Downloaded from collections.nejm.org. For personal use only. No other uses without permission.
Copyright © Massachusetts Medical Society. All rights reserved.
WHAT OTHER ALL-ORAL REGIMENS FOR PATIENTS WITH GENOTYPE 1 ARE

IN THE PIPELINE?
46 Another Fixed-Dose Single-Pill Regimen for Treatment of HCV Infection
NEJM Journal Watch Gastroenterology May 11, 2015
47 The Next Single-Pill HCV Regimen?

NEJM Journal Watch Gastroenterology Apr 24, 2015
WHAT IS THE FUTURE OF HEPATITIS C SCREENING AND TREATMENT?

49 Curing Chronic Hepatitis C — The Arc of a Medical Triumph
New England Journal of Medicine Apr 10, 2014
52 Hepatitis C Drug’s Price Draws Legislative Attention, Stock Analysts Sanguine

Physician’s First Watch Mar 24, 2014
53 Therapy for Hepatitis C — The Costs of Success

New England Journal of Medicine Apr 17, 2014
55 Consider Clinical Effectiveness in Cost Assessments of HCV Regimens

NEJM Journal Watch Gastroenterology Oct 16, 2014
56 Duration of Interferon-Free Regimens for HCV Infection: How Short Can We Go?
NEJM Journal Watch Gastroenterology Jan 28, 2015
57 It’s OK to Limit Who Prescribes HCV Therapy, but Insurers Shouldn’t Be Deciding
NEJM Journal Watch HIV and ID Observations Blog Sep 7, 2014
58 HCV Treatment for HIV-Coinfected Patients — Getting Better All the Time
NEJM Journal Watch Infectious Diseases Aug 10, 2015
59 State Medicaid Programs Seek Discounts on Pricey Hepatitis C Drugs

Physician’s First Watch Feb 2, 2015
60 HCV Treatment Coverage Restrictions Among Medicaid Programs

NEJM Journal Watch Gastroenterology Jul 1, 2015
61 Hepatitis C: In Support of Age-Based Screening

NEJM Journal Watch General Medicine Apr 30, 2015
62 O
pposition to HCV Screening Raises a Few Interesting Points — But Has Some Really
Wacky “Facts”
NEJM Journal Watch HIV and ID Observations Blog Jan 18, 2015
THE BOTTOM LINE
4
Back to Table of Contents
INTRODUCTION
Hepatitis C has an indolent course; patients can be asymptomatic until the disease has progressed to cirrhosis or
even cancer. In many patients, the hepatitis C virus can be eradicated by drug therapy, especially if it is discovered
before cirrhosis has developed. Therefore, the Centers for Disease Control has recommended screening all
individuals born between 1945 and 1965 for hepatitis C. When a screening test for hepatitis C antibody is
positive, it should be confirmed with hepatitis C viral testing (HCV RNA quantitative). Once HCV is confirmed,
hepatitis A and B vaccinations should be considered and counseling about harm reduction, such as minimizing
or eliminating alcohol consumption, should be given. What to do once these basic steps are complete, however,
is by no means clear.
Natural History of Hepatitis C Virus (HCV) Infection
50
40
Cirrhosis (%)
30
20
10
0
0 5 10 15 20 25 30
Years after HCV Exposure
Cumulative rates of cirrhosis are shown according to the number of years since HCV
exposure. The curve is derived from Thein et al. (Hepatology 2008; 48:418) Factors asso-
ciated with an increased rate of fibrosis development include a longer duration of infec-
tion, an older age at the time of exposure (more rapid progression in patients who acquire
HCV after 40 years of age), male sex, coinfection with other viruses such as hepatitis B
virus (HBV) or the human immunodeficiency virus (HIV), and daily alcohol consumption
(especially >50 g per day).
From Rosen HR. Chronic Hepatitis C Infection. N Engl J Med 2011 Jun 23; 364:2429.
5
WHAT IS THE CURRENT LANDSCAPE OF HEPATITIS C THERAPY, AND

HOW DID IT COME ABOUT?
Two articles from the New England Journal of Medicine — a review article published at the beginning of the recent
direct-acting-agent (DAA) era and an editorial published a year later — provide a solid framework for understanding
the current state of hepatitis C therapy. Both articles are authored by T. Jake Liang, MD, and Marc G. Ghany, MD.
On the following pages, you will find two figures that, taken together, update a very useful infographic from
the review article. Shown are the mechanisms of viral infection and the specific targets of new and forthcoming
therapeutic agents. Further information is provided in the text of the review article, which is not included in this
collection but is available online.
The editorial is presented here in its entirety.
6
Source: The New England Journal of Medicine
7
8
The n e w e ng l a n d j o u r na l of m e dic i n e
edi t or i a l
Therapy of Hepatitis C — Back to the Future

T. Jake Liang, M.D., and Marc G. Ghany, M.D., M.H.Sc.
A book on hepatitis C would read like a marriage NS5A inhibitor) among patients with HCV geno-
of an Orson Welles mystery and a Shakespearean type 1 infection, as compared with the rates
play — awash in enigma, tragedy, despair, resil- with the previously approved interferon-based
ience, redemption, and triumph. It is only fitting single-DAA combination therapy.13
that treatment of hepatitis C virus (HCV) infec- Other studies reported in the Journal show
tion stands at center stage of such a book. After similarly high response rates with a different
the initial introduction of interferon alfa as the combination of DAAs among patients with HCV
mainstay of therapy, the field stalled for more genotype 1 infection.2,3,8,9 This regimen includes
than 10 years. Although the introduction of riba- three DAAs — ABT-450 (an NS3/4A inhibitor)
virin combination therapy and pegylated inter- coadministered with ritonavir (ABT-450/r), ombit-
ferons had increased response rates, the real asvir (an NS5A inhibitor), and dasabuvir (a non-
breakthrough came with the development of nucleoside NS5B inhibitor) — with or without
direct-acting antiviral agents (DAAs).1 The first ribavirin. These studies evaluated the efficacy
generation of DAAs in combination with pegin- and safety of this regimen in patients who either
terferon and ribavirin showed improved response were previously untreated or were previously
rates, but they were accompanied by worsening treated with peginterferon and ribavirin but with-
side effects that have precluded a great majority out a sustained virologic response. In addition,
of patients from benefiting from therapy. safety and efficacy in patients with compensated
In a previous article in the Journal, we reviewed cirrhosis were examined specifically in one study.3
the current and future therapies for HCV infec- Like the studies of sofosbuvir and ledipasvir,
tion and commented on the rapidly shifting ther- these studies could use historical controls (treat-
apeutic landscape.1 We speculated that highly ment responses in previous phase 3 studies with
effective interferon-free regimens would be avail- the regimen of peginterferon, ribavirin, and a
able and should revolutionize the treatment of protease inhibitor) for comparison because of
HCV infection in the near future. Now, just 1 year the anticipated wide difference in therapeutic
after that review, we would have to say that the margins between the old and new treatments.
future is here. In both studies involving patients without cir-
The results of several phase 3 studies of inter- rhosis who were previously untreated or previous-
feron-free combination regimens of DAAs report- ly treated, the sustained-virologic-response rates
ed in the Journal now2-4 and recently5-9 (Table 1) were all about 96%,8,9 findings that suggest that
unequivocally show the superiority of two such patients with a previous nonresponse to pegin-
regimens over the standard-of-care treatment terferon and ribavirin are not particularly diffi-
(a combination of peginterferon, ribavirin, and cult to treat with this regimen. Patients with cir-
a protease inhibitor) for HCV genotype 1 infec- rhosis did not have quite as robust a response to
tion. A previous editorial in the Journal high- this regimen, though the response rate was still
lighted the significantly improved response rates more than 90%.3 The study involving patients with
(rates of sustained virologic response of 93% to cirrhosis also evaluated a treatment duration of
99%) with a coformulated regimen of sofosbuvir either 12 weeks or 24 weeks and showed a mod-
(a nucleotide NS5B inhibitor) and ledipasvir (an estly higher response rate in the 24-week group
n engl j med
9 nejm.org 1
overall (96%, vs. 92% in the 12-week group), and ground, IL28B genotype, and baseline HCV RNA
secondary subgroup analyses suggest a greater re- level, have been shown to influence treatment
sponse to the 24-week regimen, as compared with response to interferon-based therapy.14 As in the
the 12-week regimen in patients with genotype 1a studies of sofosbuvir and ledipasvir,5-7 these fac-
infection who had had a prior null response to tors do not play a prominent role in determining
peginterferon and ribavirin (93% vs. 80%).3 treatment response in these newer studies.2,3
Several factors, such as racial or ethnic back- Probably because these factors are specifically
Table 1. Phase 3 Trials of Interferon-free Regimens for the Treatment of HCV Infection.*
Status with Regard to No. of Sustained Virologic Response

Trial Name and Study Group† Study Design Previous Treatment Patients at Post-Treatment Wk 12
Overall Genotype 1a Genotype 1b
percent
HCV genotype 1
ION-15 Randomized, open-label Untreated
study; historical control
LDV–SOF, 12 wk 214 99 98 100
LDV–SOF + RBV, 12 wk 217 97 97 99
LDV–SOF, 24 wk 217 98 98 97
LDV–SOF + RBV, 24 wk 217 99 99 100
ION-26 Randomized, open-label Treated
LDV–SOF, 12 wk 109 94 95 87
LDV–SOF + RBV, 12 wk 111 96 95 100
LDV–SOF, 24 wk 109 99 99 100
LDV–SOF + RBV, 24 wk 111 99 99 100
ION-37 Randomized, open-label Untreated
LDV–SOF, 8 wk 215 94 93 98
LDV–SOF + RBV, 8 wk 216 93 92 95
LDV–SOF, 12 wk 216 95 95 98
SAPPHIRE-I8 Randomized, placebo-con- Untreated
trolled study; historical
control
AOD regimen + RBV, 12 wk 473 96 95 98
Placebo 158
SAPPHIRE-II9 Randomized, placebo-con- Treated
trolled study; historical
control
Placebo 97
PEARL-III2 Open-label study; historical Untreated
control
AOD regimen + RBV, 12 wk 210 100
AOD regimen, 12 wk 209 99
PEARL-IV2 Open-label study; historical Untreated
control
AOD regimen + RBV, 12 wk 100 97
AOD regimen, 12 wk 205 90
2 n engl j med
10 nejm.org
editorial
Table 1. (Continued.)
Status with Regard to No. of Sustained Virologic Response

Trial Name and Study Group† Study Design Previous Treatment Patients at Post-Treatment Wk 12
Overall Genotype 1a Genotype 1b
percent
TURQUOISE-II3‡ Open-label study; historical Untreated and treated
control
HALLMARK DUAL10 Randomized, controlled Untreated and treated
study (previously untreated
patients); open-label
study (other patients)
DCV + ASV, 24 wk 205§ 90
Placebo, 12 wk 102§
DCV + ASV, 24 wk 205¶ 82
DCV + ASV, 24 wk 235‖ 82
Overall Genotype 2 Genotype 3
HCV genotypes 2 and 3
FISSION11 Randomized, active-control Untreated
study
SOF–RBV, 12 wk 256 67 97 56
PEG–RBV, 24 wk 243 67
POSITRON12 Randomized, placebo- Untreated
controlled study
SOF–RBV, 12 wk 207 78 93 61
Placebo 71 0
FUSION12 Randomized, active-control Treated
study
SOF-RBV, 12 wk 103 50 86 30
SOF–RBV, 16 wk 98 73 94 62
VALENCE4 Randomized, placebo- Untreated and treated
controlled study
initially; switched
to open-label study
SOF–RBV, 12 wk 84 85 93 27
SOF–RBV, 24 wk 250 85
* HCV denotes hepatitis C virus.

† Coformulated ledipasvir (LDV)–sofosbuvir (SOF) was administered as a once-daily dose of 90 mg of LDV and 400 mg of SOF, with or without
1000 to 1200 mg of ribavirin (RBV) daily. Coformulated ABT-450 with ritonavir (ABT-450/r)–ombitasvir and dasabuvir (AOD regimen) was admin-
istered as a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir as well as 250 mg of dasabuvir twice daily, with
or without 1000 to 1200 mg of RBV daily. Daclatasvir (DCV, an NS5A inhibitor) and asunaprevir (ASV, an NS3/4A inhibitor) were administered as
60 mg of DCV once daily and 100 mg of ASV twice daily. SOF–RBV was administered as 400 mg of SOF once daily and 1000 to 1200 mg of RBV
daily. Peginterferon (PEG)–RBV was administered as 180 μg of subcutaneous PEG once weekly and 800 mg of oral RBV daily.
‡ All patients in this study had compensated cirrhosis.
§ These patients were previously untreated.
¶ These patients had a prior null or partial response to PEG–RBV.
‖ These patients were considered “intolerant to or ineligible for” PEG–RBV.
linked to the actions of interferon in the treat- DAA-containing regimens. The only factor that
ment of HCV infection, they do not appear to was modestly associated with treatment response
affect the response rates of the more potent in the trials of combination regimens of DAAs
n engl j med nejm.org

11 3
was body-mass index in one study.8 HCV geno- the longer duration regimen resulted in a re-
type 1a infection has been shown previously to sponse rate of more than 90%. However, among
respond less well to DAA-based therapy than previously treated patients with cirrhosis, the
genotype 1b infection,15,16 but in these recent response rate was significantly lower (62%). A
studies, HCV subgenotype did not seem to mat- close examination of the data suggests that re-
ter, other than in patients with cirrhosis. In one lapse appeared to be the major reason for the
study, patients with genotype 1a infection seemed nonresponse; among previously treated patients,
to benefit from the addition of ribavirin, whereas extending therapy reduced the relapse rate from
no significant difference was observed in pa- 66% with the 12-week duration to 20% with the
tients with genotype 1b infection.2 24-week duration.
The concept of response-guided therapy was Drug resistance against these DAAs is com-
introduced previously to tailor treatment dura- mon in preclinical studies and with single-drug
tion on the basis of virologic response during regimens in early clinical trials. Mathematical
treatment.16,17 In the era of potent DAA combina- modeling has been applied to predict how many
tion therapies, the decline in serum viral levels of these drugs are needed to minimize the
was rapid and dramatic: by week 4 of treatment, drug-resistance problem.18 Practically, the num-
99% of patients had nonquantifiable HCV RNA ber of drugs needed in a treatment regimen de-
in the blood. Therefore, response-guided ther- pends on their anti-HCV potency and the genetic
apy is no longer necessary with these interferon- barrier to the development of resistant muta-
free DAA-based regimens. All patients could tions. In the case of sofosbuvir and ledipasvir, a
probably be treated with a single duration of two-drug combination is sufficient; in the other
therapy, which will certainly simplify and facili- regimen, a three-drug combination appears to be
tate monitoring during treatment. necessary to achieve high response rates with-
An interferon-free regimen has also been de- out selecting for resistant mutants. For the small
veloped for the treatment of HCV genotype 2 or number of patients who did not have a sus-
3 infection. In two trials reported in the Journal tained virologic response, sequence analysis of
last year,11,12 12 weeks of treatment with sofos- the prevailing viral strains at the time of relapse
buvir and ribavirin resulted in response rates of showed the presence of previously described
more than 90% among previously untreated pa- mutations that are resistant to each of these
tients with genotype 2 infection but only about drugs, with the exception of sofosbuvir. Sofos-
60% among previously untreated patients with buvir seems to have a high genetic barrier to
genotype 3 infection. The authors of one of the resistance, which probably explains its notable
studies also examined the response rate with the efficacy in DAA combination regimens.
same regimen among patients who did not have The side effects associated with interferon-
a response to prior treatment with peginterferon based therapy have prevented many patients
and ribavirin and found lower sustained-viro- from undergoing treatment and are a major
logic-response rates (86% among patients with reason for treatment failure. Perhaps the more
genotype 2 infection and 30% among patients important achievement of these interferon-free
with genotype 3 infection) than observed among regimens is the lower rate and severity of side
previously untreated patients.12 In the same effects associated with treatment. The duration
study, extending the treatment duration to 16 of treatment is shorter, and although constitu-
weeks resulted in a doubling of the sustained- tional symptoms of fatigue, headache, pruritus,
virologic-response rate over the 12-week regimen and nonspecific gastrointestinal symptoms are
(from 30% to 62%) among patients with geno- common, most patients do not rate them as se-
type 3 infection.12 vere. With ribavirin-containing regimens, anemia
As reported in the Journal,4 a follow-up study is a common but manageable problem. Elevated
extended the treatment duration of patients bilirubin levels are often observed and can be
with genotype 3 infection to 24 weeks and in- attributed to inhibition of the bilirubin trans-
cluded both previously untreated patients and porter by one of the drugs in addition to ribavirin-
previously treated patients (with a nonresponse associated hemolysis. Serious adverse events,
to peginterferon and ribavirin). Among previous- although uncommon (affecting <5% of study
ly untreated patients with or without cirrhosis, participants), were reported. Some of the events
4 n engl j med
12 nejm.org
Source: The New England Journal of Medicine editorial
could be related to the treatment regimens. One 2. Ferenci P, Bernstein D, Lalezari J, et al. ABT-450/r–ombitasvir
and dasabuvir with or without ribavirin for HCV. N Engl J Med.
death was reported in the trial involving pa- DOI: 10.1056/NEJMoa1402338.
tients with compensated cirrhosis who received 3. Poordad F, Hezode C, Trinh R, et al. ABT-450/r–ombitasvir
the regimen containing ABT-450/r, ombitasvir, and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl
J Med. DOI: 10.1056/NEJMoa1402869.
dasabuvir, and ribavirin, although it is unclear 4. Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir and
whether this event was related to the treatment. ribavirin in HCV genotypes 2 and 3. N Engl J Med. DOI: 10.1056/
Further monitoring will be necessary. NEJMoa1316145.
5. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir
At this juncture, we are certainly not ready to for untreated HCV genotype 1 infection. N Engl J Med. DOI:
close the book on the treatment of HCV infec- 10.1056/NEJMoa1402454.
tion. The regimens have been tested predomi- 6. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofos-
buvir for previously treated HCV genotype 1 infection. N Engl J
nantly in middle-aged, white men without cir- Med 2014;370:1483-93.
rhosis. More-difficult-to-treat patients, such as 7. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and
those with cirrhosis, human immunodeficiency sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis.
N Engl J Med. DOI: 10.1056/NEJMoa1402355.
virus and HCV coinfection, or renal failure, re- 8. Feld JJ, Kowdley KV, Coakley E, et al. Treatment of HCV with
main a challenge. It is also not clear whether ABT-450/r–ombitasvir and dasabuvir with ribavirin. N Engl J Med
these regimens will be effective in those infect- 2014;370:1594-603.
9. Zeuzem S, Jacobson IM, Baykal T, et al. Retreatment of
ed with HCV genotypes 4, 5, and 6, which are HCV with ABT-450/r–ombitasvir and dasabuvir with ribavirin.
common in many parts of the world. Finally, the N Engl J Med 2014;370:1604-14.
cost of treatment, which was highlighted in a 10. Manns M, Pol S, Jacobson I, et al. All-oral dual therapy with
daclatasvir and asunaprevir in patients with HCV genotype 1b
recent editorial in the Journal,13 will continue to infection: phase 3 study results. J Hepatol 2014;60:S524-S525.
be a deterrent for population-wide applications abstract.
of these highly effective regimens. This dilemma 11. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously
untreated chronic hepatitis C infection. N Engl J Med 2013;368:
is not only a topic of ongoing debate in the 1878-87.
more developed countries, such as the United 12. Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for
States and western European countries, but it is hepatitis C genotype 2 or 3 in patients without treatment op-
tions. N Engl J Med 2013;368:1867-77.
also a truly global public health problem of 13. Hoofnagle JH, Sherker AH. Therapy for hepatitis C — the
enormous impact — the majority of people with costs of success. N Engl J Med 2014;370:1552-3.
HCV infection live in lower-income, resource- 14. Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB.
An update on treatment of genotype 1 chronic hepatitis C virus
constrained regions of the world. As pointed infection: 2011 practice guideline by the American Association
out in our previous review article and a recent for the Study of Liver Diseases. Hepatology 2011;54:1433-44.
Perspective article in the Journal,19 the challenge 15. Poordad F, Bronowicki JP, Gordon SC, et al. Factors that
predict response of patients with hepatitis C virus infection to
will indeed continue to be how we can leverage boceprevir. Gastroenterology 2012;143:608-18.
modern medical advances, such as the treatment 16. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telapre-
of HCV infection, to benefit those who are most vir for previously untreated chronic hepatitis C virus infection.
N Engl J Med 2011;364:2405-16.
in need. 17. Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for un-
Disclosure forms provided by the authors are available with treated chronic HCV genotype 1 infection. N Engl J Med 2011;
the full text of this article at NEJM.org. 364:1195-206.
18. Rong L, Dahari H, Ribeiro RM, Perelson AS. Rapid emer-
From the National Institute of Diabetes and Digestive and Kidney gence of protease inhibitor resistance in hepatitis C virus. Sci
Diseases, National Institutes of Health, Bethesda, MD. Transl Med 2010;2:30ra2.
19. Jayasekera CR, Barry M, Roberts LR, Nguyen MH. Treating
This article was published on May 4, 2014, and updated on May 8, hepatitis C in lower-income countries. N Engl J Med. DOI:
2014, at NEJM.org. 10.1056/NEJMp1400160.
1. Liang TJ, Ghany MG. Current and future therapies for hepa- DOI: 10.1056/NEJMe1403619
titis C virus infection. N Engl J Med 2013;368:1907-17. Copyright © 2014 Massachusetts Medical Society.
n engl j med
13 nejm.org 5
WHAT IS THE CURRENT STANDARD OF CARE?*

The FDA has approved six oral, interferon-free drug regimens for HCV. Although the benefits of all-oral
DAA therapy in the “real world” of myriad clinical risk factors remain to be seen, many patients infected with
genotype-1 HCV will achieve a sustained viral response after just 12 weeks of treatment (see table below). We
provide here two of the seminal research papers from the New England Journal of Medicine and NEJM Journal
Watch summaries of other key studies, both from the Journal and from other publications. Two blog posts
by Dr. Paul Sax provide additional clinical perspective.
*As of October 1, 2015.
FDA-Approved, All-Oral Regimens for Hepatitis C
Genotype 1 Genotype 4
Regimen Genotype 2 Genotype 3
1a 1a 1b 1b
no cirrhosis cirrhosis* no cirrhosis cirrhosis* no cirrhosis cirrhosis*
Sofosbuvir + “Can be “Can be “Can be “Can be Recommended Recommended N/R N/R

ribavirin considered” considered” considered” considered”
only in patients only in only in patients only in patients
intolerant patients intolerant intolerant
to INF intolerant to INF to INF
to INF
Simeprevir + Recommended N/R Recommended N/R N/R N/R N/R N/R

sofosbuvir
Ombitasvir/ Recommended Recommended Recommended Recommended N/R N/R N/R N/R

paritaprevir/ only in only in only in
ritonavir + combination combination combination
dasabuvir with ribavirin with ribavirin with ribavirin
Lediplasvir + Recommended Recommended Recommended Recommended N/R N/R N/R N/R

sofosbuvir
Daclatasvir + N/R N/R N/R N/R N/R Recommended† N/R N/R

sofosbuvir
Ombitasvir/ N/R N/R N/R N/R N/R N/R Recommended N/R

paritaprevir/
ritonavir +
ribavirin
FDA approval data current as of 9/1/2015; INF indicates pegylated interferon, N/R not recommended.
*Cirrhosis = Child-Pugh score B or C.
†Efficacy is reduced in patients with cirrhosis.
14
Source: NEJM Journal Watch
New All-Oral Hepatitis C Regimens Are on the Horizon

Cure rates with two new combinations approach 100% in some patient populations.
Afdhal N et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014 Apr 12; [e-pub].
(http://dx.doi.org/10.1056/NEJMoa1402454)
Kowdley KV et al. Ledipasvir and sofosbuvir for 8 to 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014
Apr 11; [e-pub]. (http://dx.doi.org/10.1056/NEJMoa1402355)
Afdhal N et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014 Apr 17;
370:1483. (http://dx.doi.org/10.1056/NEJMoa1316366)
Feld JJ et al. Treatment of HCV with ABT-450/r–ombitasvir and dasabuvir with ribavirin. N Engl J Med 2014 Apr 24;
Zeuzem S et al. Retreatment of HCV with ABT-450/r–ombitasvir and dasabuvir with ribavirin. N Engl J Med 2014
Apr 24; 370:1604. (http://dx.doi.org/10.1056/NEJMoa1401561)
Poordad F et al. ABT-450/r–ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med 2014
Apr 12; [e-pub]. (http://dx.doi.org/10.1056/NEJMoa1402869)
Hoofnagle JH and Sherker AH. Therapy for hepatitis C — The costs of success. N Engl J Med 2014 Apr 17; 370:1522.
(http://dx.doi.org/10.1056/NEJMe1401508)
ARTICLE SUMMARY
The New England Journal of Medicine has published results of six industry-sponsored randomized trials covering
two new all-oral treatment regimens for chronic hepatitis C virus (HCV) genotype 1 infections.
In three studies, about 2000 patients received various durations of the oral drug combination sofosbuvir (Sovaldi)
plus ledipasvir, given once daily. Sustained viral response rates were consistently in the 94% to 99% range with
8-week or 12-week treatment courses, both among previously untreated patients and among nonresponders to
previous interferon-based regimens. Most of these patients did not have cirrhosis; however, among those with
cirrhosis who had not responded to previous therapy, responses approached 100% when treatment was extended
to 24 weeks.
In three additional studies, about 1400 patients received 12-week or 24-week courses of the oral drug combination
of ABT-450/r, ombitasvir, dasabuvir, and ribavirin; dasabuvir was given twice daily, and the others were given once
daily. Sustained viral response rates ranged from 92% to 96%, depending on duration of treatment, presence or
absence of cirrhosis, and whether patients were treatment-naive or nonresponders to previous treatment (see table
next page).
Although both drug combinations were tolerated well, drug side effects were somewhat more common with the
regimen that included ribavirin.
15
Key Outcomes of Six Hepatitis C Drug Trials
Sustained Virologic
Drug Duration of Response Rate
Trial1 Combination Patient Popularion Treatment (point estimate)
Afdhal N et al. L/S2 Previously untreated 12 weeks 99%
Kowdley KV et al. L/S Previously untreated 8 weeks 94%
Afdhal N et al. L/S Nonresponders to previous 12 weeks 94%

treatment 24 weeks 99%
Feld JJ et al. A/O/D/R3 Previously untreated 12 weeks 96%
Zeuzem S et al. A/O/D/R Nonresponders to previous 12 weeks 96%

treatment
Poordad F et al. A/O/D/R Cirrhotic (previously treated 12 weeks 92%

and untreated) 24 weeks 96%
1
Op. cit.
2
L/S = Ledipasvir and sofosbuvir
3
A/O/D/R = ABT-450/r, ombitasvir, dasabuvir, and ribavirin
COMMENT
These studies demonstrate that nearly all patients with chronic hepatitis C can be cured with all-oral regimens; the
endpoints reported here (sustained virologic response, defined as absence of detectable HCV RNA in serum at
12 weeks posttreatment) generally is considered to indicate cure. Sofosbuvir already is FDA approved; its manu- All of these
facturer is currently seeking FDA approval for the sofosbuvir/ledipasvir fixed-dose combination used in the first drugs have now
set of trials summarized above. None of the drugs (except for ribavirin) used in the second set of trials have been received FDA
FDA approved yet. approval.
Note that these studies involved patients with HCV genotype 1, the most common genotype in the U.S.; an all-
oral regimen (sofosbuvir plus ribavirin) already is FDA approved for treating patients with HCV genotypes 2 and
3, which are generally more responsive to treatment.
An editorialist believes that these regimens will be manageable by primary care physicians. However, the elephant
in the room is cost. Various critics have chastised Gilead, the company that makes sofosbuvir, for pricing the drug
at US$1000 per pill. The company has countered that, in the long run, these new drugs will become cost-effective
by curing most patients and preventing the expensive-to-treat complications of chronic HCV.
— Allan S. Brett, MD
University of South Carolina School of Medicine, Columbia
NEJM Journal Watch General Medicine, published April 24, 2014
16
original article
Ledipasvir and Sofosbuvir for Untreated

HCV Genotype 1 Infection
Nezam Afdhal, M.D., Stefan Zeuzem, M.D., Paul Kwo, M.D., Mario Chojkier, M.D.,
Norman Gitlin, M.D., Massimo Puoti, M.D., Manuel Romero-Gomez, M.D., Ph.D.,
Jean-Pierre Zarski, M.D., Ph.D., Kosh Agarwal, M.D., Peter Buggisch, M.D.,
Graham R. Foster, Ph.D., Norbert Bräu, M.D., M.B.A., Maria Buti, M.D., Ph.D.,
Ira M. Jacobson, M.D., G. Mani Subramanian, M.D., Ph.D., Xiao Ding, Ph.D.,
Hongmei Mo, M.D., Jenny C. Yang, Pharm.D., Phillip S. Pang, M.D., Ph.D.,
William T. Symonds, Pharm.D., John G. McHutchison, M.D.,
Andrew J. Muir, M.D., M.H.S., Alessandra Mangia, M.D.,
and Patrick Marcellin, M.D., Ph.D., for the ION-1 Investigators*
A BS T R AC T
BACKGROUND
In phase 2 studies, treatment with the all-oral combination of the nucleotide poly- The authors’ affiliations are listed in the
merase inhibitor sofosbuvir and the NS5A inhibitor ledipasvir resulted in high rates Appendix. Address reprint requests to Dr.
Afdhal at Beth Israel Deaconess Medical
of sustained virologic response among previously untreated patients with hepatitis C Center, 110 Francis St., Suite 4, Boston, MA
virus (HCV) genotype 1 infection. 02215, or at nafdhal@bidmc.harvard.edu;
or to Dr. Marcellin at Service d’Hépatolo-
gie, Hôpital Beaujon, 100 Blvd. du Gé-
METHODS néral Leclerc, Clichy 92110, France, or at
We conducted a phase 3, open-label study involving previously untreated patients patrick.marcellin@bjn.ap-hop-paris.fr.
with chronic HCV genotype 1 infection. Patients were randomly assigned in a
Drs. Afdhal and Marcellin contributed
1:1:1:1 ratio to receive ledipasvir and sofosbuvir in a fixed-dose combination tablet equally to this article.
once daily for 12 weeks, ledipasvir–sofosbuvir plus ribavirin for 12 weeks, ledipas-
vir–sofosbuvir for 24 weeks, or ledipasvir–sofosbuvir plus ribavirin for 24 weeks. *A complete list of the investigators par-
ticipating in the ION-1 study is provided
The primary end point was a sustained virologic response at 12 weeks after the end in the Supplementary Appendix, avail-
of therapy. able at NEJM.org.
This article was published on April 12,

RESULTS 2014, at NEJM.org.
Of the 865 patients who underwent randomization and were treated, 16% had cir-
N Engl J Med 2014;370:1889-98.
rhosis, 12% were black, and 67% had HCV genotype 1a infection. The rates of DOI: 10.1056/NEJMoa1402454
sustained virologic response were 99% (95% confidence interval [CI], 96 to 100) in Copyright © 2014 Massachusetts Medical Society.
the group that received 12 weeks of ledipasvir–sofosbuvir; 97% (95% CI, 94 to 99)
Related Material:
in the group that received 12 weeks of ledipasvir–sofosbuvir plus ribavirin; 98%
Supplementary Appendix
(95% CI, 95 to 99) in the group that received 24 weeks of ledipasvir–sofosbuvir; and
99% (95% CI, 97 to 100) in the group that received 24 weeks of ledipasvir–sofosbuvir
plus ribavirin. No patient in either 12-week group discontinued ledipasvir–sofosbuvir
owing to an adverse event. The most common adverse events were fatigue, head-
ache, insomnia, and nausea.
CONCLUSIONS
Once-daily ledipasvir–sofosbuvir with or without ribavirin for 12 or 24 weeks was
highly effective in previously untreated patients with HCV genotype 1 infection.
(Funded by Gilead Sciences; ION-1 ClinicalTrials.gov number NCT01701401.)
n engl j med 370;20 nejm.org 17

may 15, 2014 1889
A
lthough the treatment of pa- genotype 1 infection, including those with com-
tients infected with the hepatitis C virus pensated cirrhosis.
(HCV) has evolved greatly in recent years,
newly approved regimens for the treatment of pa- ME THODS
tients with HCV genotype 1 infection still include
weekly injections of recombinant human inter- PATIENTS
feron alfa and ribavirin administered according We enrolled patients at 99 sites in the United
to body weight.1-3 The only interferon-free option States and Europe from October 17, 2012, to May
currently approved by the Food and Drug Admin- 17, 2013. Eligible patients were 18 years of age or
istration for the treatment of HCV genotype 1 older, had chronic HCV genotype 1 infection,
infection is 24 weeks of sofosbuvir and ribavirin and had not received treatment for HCV infection
for patients who are ineligible to receive interferon; previously. There were no upper limits for age or
the reported response rate is 68%.4 body-mass index. The protocol (available with
Interferon treatment is associated with a num- the full text of this article at NEJM.org) specified
ber of side effects, including influenza-like symp- that patients with cirrhosis could account for ap-
toms, depression, and cytopenia.5,6 The side effects proximately 20% of the study population. The
of ribavirin include hemolytic anemia, fatigue, presence of cirrhosis was defined as a liver-biopsy
pruritus, and rash.7 The elimination of interferon specimen showing evidence of cirrhosis (Metavir
and ribavirin from treatment regimens is expect- stage F4 [on a scale of F0 to F4, with higher stages
ed to reduce the incidence and severity of adverse indicating a greater degree of fibrosis] or Ishak
events, to simplify the treatment of patients with score of 5 or 6 [on a scale of 0 to 6, with higher
HCV infection, and to provide a treatment op- scores indicating a greater degree of fibrosis]), a
tion for patients who are ineligible for treatment FibroScan score of more than 12.5 kPa (on a scale
with interferon or ribavirin. Treatment guide- of 1.5 to 75.0 kPa, with higher scores indicating
lines recently issued by the American Associa- a greater degree of fibrosis), or a FibroTest score
tion for the Study of Liver Diseases and the In- of more than 0.75 (on a scale of 0 to 1, with high-
fectious Diseases Society of America recommend er scores indicating more severe fibrosis) and an
interferon-free combinations of newly approved aspartate aminotransferase:platelet ratio index of
direct-acting antiviral agents, but the supporting more than 2 (with higher scores indicating a
data are from small, phase 2 studies.8 greater likelihood of extensive fibrosis). The full
Ledipasvir (Gilead Sciences) is a new HCV NS5A set of eligibility criteria, including details of the
inhibitor with potent antiviral activity against assessment of cirrhosis, are provided in the study
HCV genotypes 1a and 1b.9 Sofosbuvir is a nucle- protocol.
otide polymerase inhibitor approved for the treat-
ment of HCV genotypes 1 through 4 in combina- STUDY DESIGN
tion with ribavirin, with or without peginterferon.1 In this multicenter, randomized, open-label trial,
In phase 2 trials, the combination of ledipasvir all the patients received a fixed-dose combination
and sofosbuvir with or without ribavirin resulted tablet containing 90 mg of ledipasvir and 400 mg
in high rates of sustained virologic response of sofosbuvir, administered orally once daily. Rib-
among previously untreated patients with HCV avirin was administered orally twice daily, with
genotype 1 infection, including those with com- the dose determined according to body weight
pensated cirrhosis.10,11 In the ION-2 phase 3 (1000 mg daily in patients with a body weight
trial, previously treated patients, including those <75 kg, and 1200 mg daily in patients with a
with cirrhosis, had rates of sustained virologic body weight ≥75 kg).
response of 94 to 99% after 12 or 24 weeks of Patients were randomly assigned in a 1:1:1:1
treatment with ledipasvir–sofosbuvir, with or ratio to one of four treatment groups: ledipasvir–
without ribavirin.12 We conducted the ION-1 sofosbuvir for 12 weeks, ledipasvir–sofosbuvir
phase 3 trial to assess the efficacy and safety of plus ribavirin for 12 weeks, ledipasvir–sofosbu-
12 or 24 weeks of a fixed-dose combination of vir for 24 weeks, or ledipasvir–sofosbuvir plus
ledipasvir and sofosbuvir, with or without riba- ribavirin for 24 weeks. Enrollment occurred in
virin (Ribasphere, Kadmon Pharmaceuticals), in two phases. First, 200 patients underwent random-
previously untreated patients with chronic HCV ization and were treated. After patients in the
1890 n engl j med 370;20 nejm.org

18 may 15, 2014
Ledipasvir–Sofosbuvir for Untreated HCV Genotype 1
12-week groups reached post-treatment week 4, 2.0 assay (Siemens Healthcare Diagnostics). IL28B
the data and safety monitoring committee re- genotype was determined by means of polymerase-
viewed safety data collected during treatment for chain-reaction amplification and sequencing of
all four groups and response data at post-treat- the rs12979860 single-nucleotide polymorphism.
ment week 4 in the 12-week groups. A planned Assessments during treatment included stan-
interim analysis indicated that the rate of sus- dard laboratory testing, measurement of the se-
tained virologic response at 4 weeks after the rum HCV RNA level, assessment of vital signs,
end of treatment was more than 60%, and there- electrocardiography, and symptom-directed phys-
fore the prespecified criteria for futility were not ical examinations. All adverse events were re-
met (see the Supplementary Appendix, available corded and graded according to a standardized
at NEJM.org), and an additional 665 patients were scale (see the study protocol).
randomly assigned to the four treatment groups. Population sequencing or deep sequencing of
Randomization was stratified according to HCV the NS5A and NS5B regions of the HCV RNA
genotype 1 subtype (1a or 1b) and the presence was performed for all the patients at baseline.
or absence of cirrhosis. For all the patients who had virologic failure,
deep sequencing of the NS5A and NS5B regions
STUDY OVERSIGHT was conducted at baseline and at the time of fail-
This study was approved by the institutional re- ure. The sequences obtained at the time of viro-
view board or independent ethics committee at logic failure were compared with sequences
each participating site and was conducted in com- from baseline samples and references in order to
pliance with the principles of the Declaration of detect resistance-associated variants that emerged
Helsinki, Good Clinical Practice guidelines, and during treatment. We report resistance-associated
local regulatory requirements. The study was de- variants that were present in more than 1% of
signed and conducted according to the protocol the sequence reads.
by the sponsor (Gilead Sciences) in collaboration
with the principal investigators. The sponsor col- END POINTS
lected the data, monitored the study conduct, The primary efficacy end point was a sustained
and performed the statistical analyses. An inde- virologic response at 12 weeks after the end of
pendent data and safety monitoring committee treatment. It was assessed in all the patients who
reviewed the progress of the study. underwent randomization and received treatment.
The investigators, participating institutions,
and sponsor agreed to maintain confidentiality STATISTICAL ANALYSIS
of the data. All the authors had access to the In the primary efficacy analysis, the rate of sus-
data and assume responsibility for the integrity tained virologic response in each of the treat-
and completeness of the reported data. All the ment groups was compared with an adjusted his-
authors affirm that the study was conducted torical rate of 60%, with the use of a two-sided
with fidelity to the protocol. The first draft of exact one-sample binomial test. This 60% rate
the manuscript was prepared by a professional was based on calculated rates of sustained viro-
writer who is an employee of the sponsor and by logic response of 65% in phase 3 trials of telapre-
the first author, with input from all coauthors. vir13 and boceprevir,14 allowing for a rate that
was 5 percentage points lower, in exchange for
STUDY ASSESSMENTS an expected improved safety profile and shorter
Screening assessments included measurement of duration of treatment. The weighted average rates
the serum HCV RNA level and IL28B genotyping, of response in the telaprevir and boceprevir trials
in addition to standard laboratory and clinical were estimated to be approximately 70% among
tests. The serum HCV RNA level was measured patients without cirrhosis and 44% among those
with the use of the COBAS TaqMan HCV Test, with cirrhosis (see the Supplementary Appendix
version 2.0, for use with the High Pure System for details on the calculation of the control rate).
(Roche Molecular Systems), which has a lower We determined that a sample of 200 patients in
limit of quantification of 25 IU per milliliter. each treatment group would provide the study
HCV genotype and subtype were determined with with more than 91% power to detect an improve-
the use of the Versant HCV Genotype INNO-LiPA ment of at least 13 percentage points in the rate
n engl j med 370;20 nejm.org

19 may 15, 2014 1891
Source: The New England Journal of Medicine T h e n e w e ng l a n d j o u r na l of m e dic i n e
of sustained virologic response from the adjust- tained virologic response (97%; 95% CI, 94 to 99);
ed historical null rate of 60%, with the use of a among 217 who received 24 weeks of ledipasvir–
two-sided, exact one-sample binomial test at a sofosbuvir, 212 had a sustained virologic response
significance level of 0.0125, based on a Bonfer- (98%; 95% CI, 95 to 99); and among 217 who
roni correction. The two-sided 95% exact confi- received 24 weeks of ledipasvir–sofosbuvir plus
dence interval calculated by the Clopper–Pear- ribavirin, 215 had a sustained virologic response
son method is provided for the rate of sustained (99%; 95% CI, 97 to 100) (Table 2).
virologic response at 12 weeks after the end of Of the 865 patients who underwent random-
treatment in each of the four treatment groups. ization and were treated, only 3 had virologic
failure. A total of 1 patient who received 24 weeks
R E SULT S of ledipasvir–sofosbuvir had virologic break-
through during treatment. This patient, a
BASELINE CHARACTERISTICS 63-year-old black man with HCV genotype 1b
Of the 1015 patients who were initially screened, infection, had plasma concentrations of ledipas-
870 underwent randomization, and 865 began vir and GS-331007 (the main circulating metabo-
treatment (Table S1 and Fig. S1 in the Supple- lite of sofosbuvir) that were below the level of
mentary Appendix). A total of 5 patients under- quantification at both weeks 8 and 10, which
went randomization but were not treated owing strongly suggests nonadherence to the study regi-
to withdrawal of consent (4 patients) or errone- men. A total of 2 patients had virologic relapse
ous randomization (1 patient). The demographic after finishing treatment: a 56-year-old white
and baseline clinical characteristics of the pa- man with cirrhosis and HCV genotype 1a infec-
tients were generally balanced among the four tion who received 12 weeks of ledipasvir–sofos-
treatment groups, except that the two treatment buvir had a relapse by post-treatment week 4,
groups that received ribavirin had higher propor- and a 65-year-old black man with cirrhosis and
tions of patients with the CC allele of IL28B than HCV genotype 1b infection who received 24 weeks
did the groups that received ledipasvir–sofosbu- of ledipasvir–sofosbuvir had a relapse between
vir alone (Table 1). post-treatment weeks 4 and 12.
Overall, 67% of the patients had HCV geno- Given the very high levels of sustained viro-
type 1a infection, 12% were black, 70% had the logic response observed overall, high response
non-CC IL28B genotype, 16% had cirrhosis, 3% rates were observed in all patient subgroups,
had a platelet count of less than 90,000 per cubic including patients with characteristics histori-
millimeter, and 4% had an albumin level of less cally associated with a poor response to treat-
than 3.5 g per deciliter. A total of seven patients ment, who had response rates similar to those
had both a platelet count of less than 90,000 per among patients without these characteristics
cubic millimeter and an albumin level of less (Fig. 1). According to the intention-to-treat anal-
than 3.5 g per deciliter. A total of 19% of the ysis, the rates of sustained virologic response in
patients had a history of depression, 14% had the four treatment groups ranged from 94 to
insomnia, 12% had anxiety, and 9% had a his- 100% among patients with cirrhosis, 97 to 99%
tory of diabetes mellitus or were taking medica- among those with HCV genotype 1a infection,
tion for diabetes. Approximately 41% of the pa- 97 to 99% among those with a non-CC IL28B
tients were enrolled in Europe. allele, and 91 to 100% among black patients
(Fig. S2 in the Supplementary Appendix). Of the
EFFICACY seven patients with both an albumin level of less
The rates of sustained virologic response in all than 3.5 g per deciliter and a platelet count of
four treatment groups were superior to the his- less than 90,000 per cubic millimeter at baseline,
torical rate of 60% (P<0.001 for all comparisons). six had a sustained virologic response; the other
The rates of sustained virologic response 12 weeks patient withdrew consent after having received
after the end of treatment were as follows: among only a single dose of ledipasvir–sofosbuvir.
214 patients who received 12 weeks of ledipas-
vir–sofosbuvir, 211 had a sustained virologic re- VIROLOGIC RESISTANCE TESTING
sponse (99%; 95% confidence interval [CI], 96 to At baseline, variants associated with resistance
100); among 217 who received 12 weeks of ledi- to NS5A inhibitors were detected in 92 of 861
pasvir–sofosbuvir plus ribavirin, 211 had a sus- patients (11%) and were confirmed by means of

20 may 15, 2014
Table 1. Demographic and Clinical Characteristics of the Patients at Baseline.*
Characteristic 12-Wk Regimen 24-Wk Regimen
LDV–SOF LDV–SOF + RBV LDV–SOF LDV–SOF + RBV

(N = 214) (N = 217) (N = 217) (N = 217)
Age — yr
Mean 52 52 53 53
Range 18–75 18–78 22–80 24–77
Body-mass index†
Mean 27 27 27 26
Range 18–41 18–42 18–48 18–48
Male sex — no. (%) 127 (59) 128 (59) 139 (64) 119 (55)
Race — no. (%)‡
White 187 (87) 188 (87) 177 (82) 183 (84)
Black 24 (11) 26 (12) 32 (15) 26 (12)
Asian 1 (<1) 0 5 (2) 5 (2)
Other 2 (1) 3 (1) 3 (1) 3 (1)
Ethnic group — no. (%)§
Hispanic 26 (12) 20 (9) 29 (13) 26 (12)
Non-Hispanic 187 (87) 197 (91) 188 (87) 190 (88)
Region — no. (%)
United States 125 (58) 118 (54) 132 (61) 137 (63)
Europe 89 (42) 99 (46) 85 (39) 80 (37)
HCV genotype — no. (%)
1a 144 (67) 148 (68) 146 (67) 143 (66)
1b 66 (31) 68 (31) 68 (31) 71 (33)
Other ¶ 4 (2) 1 (<1) 3 (1) 3 (1)
HCV RNA — log10 IU/ml 6.4±0.69 6.4±0.64 6.3±0.68 6.3±0.65
HCV RNA ≥800,000 IU/ml — no. (%) 169 (79) 173 (80) 168 (77) 173 (80)
IL28B genotype — no. (%)
CC 55 (26) 76 (35) 52 (24) 73 (34)
CT 113 (53) 107 (49) 119 (55) 112 (52)
TT 46 (21) 34 (16) 46 (21) 32 (15)
Cirrhosis — no. (%) 34 (16) 33 (15) 33 (15) 36 (17)
Albumin <3.5 g/dl — no. (%) 6 (3) 6 (3) 11 (5) 12 (6)
Platelet count <90,000 per mm3 — no. (%) 5 (2) 6 (3) 8 (4) 4 (2)
Alanine aminotransferase >1.5× ULN — no. (%) 120 (56) 119 (55) 109 (50) 112 (52)
Interferon eligibility status — no. (%)
Eligible 200 (93) 197 (91) 198 (91) 203 (94)
Ineligible 14 (7) 20 (9) 19 (9) 14 (6)
* Plus–minus values are means ±SD. No significant between-group differences in demographic or clinical variables were
observed. HCV denotes hepatitis C virus, LDV ledipasvir, RBV ribavirin, SOF sofosbuvir, and ULN upper limit of the
normal range.
† The body-mass index is the weight in kilograms divided by the square of the height in meters.
‡ Race was self-reported.
§ Ethnic group was self-reported. Two patients did not report ethnic group (one patient in the group that received 12 weeks
of ledipasvir–sofosbuvir, and one in the group that received 24 weeks of ledipasvir–sofosbuvir and ribavirin).
¶ Patients with an HCV genotype that was not classified as HCV genotype 1a or 1b included four patients with an uncon-
firmed HCV genotype (one patient in each treatment group), two with HCV genotype 4 (one in the 12-week group that
received ledipasvir–sofosbuvir and one in the 24-week group that received ledipasvir–sofosbuvir plus ribavirin), and five
with missing data (two in the 12-week group that received ledipasvir–sofosbuvir, two in the 24-week group that received
ledipasvir–sofosbuvir, and one in the 24-week group that received ledipasvir–sofosbuvir plus ribavirin).

21 may 15, 2014 1893
Table 2. Response during and after Treatment.
Response 12-Wk Regimen 24-Wk Regimen

(N = 214) (N = 217) (N = 217) (N = 217)
HCV RNA <25 IU/ml
During treatment — no./total no. (%)*
At week 2 174/213 (82) 181/217 (83) 179/216 (83) 180/217 (83)
At week 4 213/213 (100) 215/217 (99) 216/216 (100) 217/217 (100)
At week 12 213/213 (100) 214/214 (100) 213/214 (>99) 216/216 (100)
After end of treatment — no. (%)
At week 4 211 (99) 213 (98) 215 (99) 215 (99)
At week 12 211 (99) 211 (97) 212 (98) 215 (99)
Virologic failure during treatment — no. 0 0 1 0
Relapse — no. 1 0 1 0
Lost to follow-up — no. 2 4 2 2
Withdrew consent — no. 0 2 1 0
* Data shown are for patients for whom HCV RNA results were available.
deep sequencing in 140 of 861 patients (16%), Of the 33 patients who had a serious adverse
135 of whom (96%) had a sustained virologic event during treatment, 25 were in the 24-week
response. Of the 3 patients who had virologic groups (18 patients who received ledipasvir–sofos-
failure, the 2 with relapses had NS5A-resistant buvir and 7 who received ledipasvir–sofosbuvir
variants at baseline, whereas the patient with plus ribavirin) and 8 were in the 12-week groups
virologic breakthrough did not. All three sam- (1 who received ledipasvir–sofosbuvir and 7 who
ples obtained at the time of virologic failure had received ledipasvir–sofosbuvir plus ribavirin).
NS5A-resistant variants; the patient with HCV Six serious adverse events occurred in more than
genotype 1a infection had the L31M variant, 1 patient: cellulitis, chest pain, gastroenteritis,
and both patients with HCV genotype 1b infec- hand fracture, noncardiac chest pain, and pneu-
tion had the Y93H variant. Neither of the two monia each occurred in 2 patients (Table S5 in
samples from patients with relapse showed the Supplementary Appendix).
evidence of mutations conferring resistance to The majority of patients in all the treatment
sofosbuvir (Table S4 in the Supplementary Ap- groups (79 to 92%) had at least one adverse
pendix). event. Of the patients who had adverse events,
93% had only events that were mild to moderate
SAFETY in severity (Table 3). The most common adverse
Of the 865 patients who underwent randomiza- events were fatigue, headache, insomnia, and
tion and were treated, 10 discontinued ledipas- nausea. Patients in the groups that received ledi-
vir–sofosbuvir prematurely owing to adverse pasvir–sofosbuvir plus ribavirin for 12 or 24
events: 4 patients (2%) in the group that received weeks had higher rates of events known to be
ledipasvir–sofosbuvir for 24 weeks, and 6 (3%) in associated with ribavirin therapy — fatigue, in-
the group that received ledipasvir–sofosbuvir somnia, asthenia, rash, cough, pruritus, and
plus ribavirin for 24 weeks (Table 3). All 10 of anemia — than did those in the corresponding
these patients had a sustained virologic response; groups that received ledipasvir–sofosbuvir with-
the shortest duration of therapy among these pa- out ribavirin (Table 3).
tients was 8 weeks. No patient who received ledi- Patients who received 12 or 24 weeks of ledi-
pasvir–sofosbuvir for 12 weeks discontinued pasvir–sofosbuvir alone had mean changes (from
treatment early (Table S6 in the Supplementary baseline to the end of treatment) in the hemo-
Appendix). globin level of −0.4 g per deciliter and −0.2 g per
1894 n engl j med 370;20 22

nejm.org may 15, 2014
Subgroup LDV–SOF, 12 Wk LDV–SOF+RBV, 12 Wk LDV–SOF, 24 Wk LDV–SOF+RBV, 24 Wk

Overall
Age
<65 yr
≥65 yr
Sex
Male
Female
Race
Black
Nonblack
Interferon eligibility status
Eligible
Ineligible
HCV genotype
1a
1b
Cirrhosis
No
Yes
HCV RNA
<800,000 IU/ml
≥800,000 IU/ml
Body-mass index
<30
≥30
Alanine aminotransferase
≤1.5× ULN
>1.5× ULN
IL28B genotype
CC
Non-CC
70 75 80 85 90 95 100 70 75 80 85 90 95 100 70 75 80 85 90 95 100 70 75 80 85 90 95 100
Rate of Sustained Virologic Response at Post-Treatment Wk 12 (%)
Figure 1. Rates of Sustained Virologic Response According to Subgroup.

The position of the square indicates the rate of virologic response at 12 weeks after the end of treatment in each subgroup; the horizontal
lines indicate 95% confidence intervals. The vertical lines represent the overall rate of sustained virologic response in each treatment group.
Subgroup results do not include patients who withdrew consent or were lost to follow-up. Figure S2 in the Supplementary Appendix
shows a forest plot that is based on the full intention-to-treat population. HCV denotes hepatitis C virus, LDV ledipasvir, RBV ribavirin,
SOF sofosbuvir, and ULN upper limit of the normal range.
deciliter, respectively; in the patients who re- DISCUSSION

ceived 12 or 24 weeks of ledipasvir–sofosbuvir
plus ribavirin, the mean changes were −2.2 g per In this multicenter, randomized, phase 3 study,
deciliter and −1.9 g per deciliter, respectively. the rates of sustained virologic response in all
Severe hyperbilirubinemia (bilirubin level of >2.5 four treatment groups were 97% or higher, re-
times the upper limit of the normal range) devel- gardless of whether the regimen was given for 12
oped in nine patients (4%) in the 12-week group or 24 weeks and whether it included ribavirin.
that received ribavirin and in seven (3%) in the The rates of treatment discontinuation were high-
24-week group that received ribavirin, as com- er in the groups treated for 24 weeks than in the
pared with hyperbilirubinemia in one patient groups treated for 12 weeks, and the rates of side
(<1%), who had Gilbert’s syndrome, in the group effects were higher in the groups that received
that received 24 weeks of ledipasvir–sofosbuvir ribavirin than in the corresponding groups that
alone. did not. This trial showed that a 12-week regi-
n engl j med 370;20 nejm.org23may 15, 2014 1895

Source: The New England Journal of Medicine The n e w e ng l a n d j o u r na l of m e dic i n e
Table 3. Treatment Discontinuations, Adverse Events, and Hematologic Abnormalities.*
Variable 12-Wk Regimen 24-Wk Regimen

(N = 214) (N = 217) (N = 217) (N = 217)
Duration of treatment — wk 12.1±0.8 12.0±0.7 23.6±2.6 23.7±1.9
Discontinuation of ledipasvir–sofosbuvir owing to 0 0 4 (2) 6 (3)
adverse event — no. of patients (%)
Serious adverse event — no. of patients (%) 1 (<1) 7 (3) 18 (8) 7 (3)
Any adverse event — no. of patients (%) 169 (79) 185 (85) 178 (82) 200 (92)
Common adverse events — no. of patients (%)†
Fatigue 44 (21) 79 (36) 53 (24) 82 (38)
Headache 53 (25) 49 (23) 54 (25) 65 (30)
Insomnia 17 (8) 45 (21) 26 (12) 47 (22)
Nausea 24 (11) 37 (17) 29 (13) 32 (15)
Asthenia 14 (7) 23 (11) 20 (9) 26 (12)
Diarrhea 24 (11) 18 (8) 24 (11) 14 (6)
Rash 16 (7) 21 (10) 16 (7) 27 (12)
Irritability 11 (5) 17 (8) 17 (8) 24 (11)
Cough 6 (3) 21 (10) 16 (7) 25 (12)
Pruritus 11 (5) 22 (10) 8 (4) 20 (9)
Anemia 0 25 (12) 0 22 (10)
Hematologic abnormality — no. of patients (%)
Decreased hemoglobin level
<10 g/dl 0 20 (9) 0 16 (7)
<8.5 g/dl 0 1 (<1) 0 0
Lymphocyte count <350 per mm3 0 1 (<1) 0 0
Neutrophil count 500 to <750 per mm3 1 (<1) 0 3 (1) 0
Platelet count 25,000 to <50,000 per mm3 1 (<1) 0 1 (<1) 0
* Plus–minus values are means ±SD.

† Common adverse events were those that occurred in at least 10% of the patients in any group.
men of ledipasvir–sofosbuvir, without ribavirin, was explored in the ION-3 study (also now re-
constitutes an effective treatment for patients ported in the Journal).16 ION-3 showed that the
who have HCV genotype 1 infection, with the addition of ribavirin in an 8-week regimen or the
lowest rate of adverse events of the four regimens extension of treatment to 12 weeks did not result
evaluated. in better response rates than 8 weeks of ledipas-
The response to interferon-based regimens vir–sofosbuvir alone.
for HCV infection varies considerably according The rates of response to interferon-based
to certain characteristics of patients (e.g., base- therapy, including protease-inhibitor–containing
line viral load, race, HCV genotype, IL28B geno- regimens, have been low in patients with cirrho-
type, and extent of fibrosis) and the presence or sis.13-15,17-19 For the protease-inhibitor–containing
absence of an early response during treatment.15 regimens, 48 weeks of treatment is recommended
In this trial, the rates of response were gener- for all such patients; response-guided shorten-
ally uniform, regardless of the characteristics of ing of the duration of therapy has been associ-
the patients at baseline. Given the high rates of ated with an unacceptable rate of relapse.13 The
response with 12 weeks of therapy, the possibil- low rates of response among patients with cir-
ity of further reducing the duration of therapy rhosis reflect both an increased risk of inter-
1896 n engl j med 370;20 24

feron-related side effects20 and an unidentified common adverse events included fatigue, head-
effect of cirrhosis on responsiveness to treatment. ache, insomnia, and nausea. The type, frequen-
The presence of a low platelet count and an al- cy, and severity of the adverse events observed in
bumin level of less than 3.5 g per deciliter have the groups that received ledipasvir–sofosbuvir
been identified as risk factors for adverse events, without ribavirin were generally similar to those
including infection, hepatic decompensation, and seen in the placebo group in a previous trial of
death. In this study, the presence of cirrhosis sofosbuvir and ribavirin in patients with HCV
had no marked effect on rates of response or the infection.21 However, the groups receiving ledi-
safety profile, even among patients with throm- pasvir–sofosbuvir plus ribavirin in our study had
bocytopenia and a low albumin level. This study, a higher incidence of adverse events and labora-
however, was not designed or powered to for- tory abnormalities that are known to be associ-
mally compare the rates of response among pa- ated with ribavirin therapy — fatigue, insomnia,
tients with cirrhosis and those without cirrhosis. cough, pruritus, and anemia.6 Thus, our find-
Virologic failure was extremely rare in this ings suggest that the addition of ribavirin to a
study population, occurring in only 0.3% of pa- ledipasvir–sofosbuvir regimen increases toxicity
tients (3 of 865). In these patients, we did not without providing additional efficacy.
discern clinical or virologic predictors of viro- In conclusion, our study showed that 12 weeks
logic failure except suspected nonadherence to of the single-tablet regimen of ledipasvir–sofos-
therapy, which was documented by means of se- buvir was a highly effective treatment for a broad
rum assays for drug levels, in one patient with range of patients with HCV genotype 1 infection
virologic breakthrough during treatment. The two who had not been treated previously. No addi-
patients with relapse had no evidence of muta- tional benefit appeared to be associated with the
tions conferring resistance to sofosbuvir, although addition of ribavirin or with extension of the
both patients had mutations associated with re- duration of treatment to 24 weeks.
sistance to NS5A inhibitors both at baseline and
at the time of relapse. A sofosbuvir-based regimen Supported by Gilead Sciences.
Disclosure forms provided by the authors are available with
with a protease inhibitor would be a potential op- the full text of this article at NEJM.org.
tion for retreatment in these patients. We thank the patients and their families, as well as the study-
There was no control group in this study, and site personnel; Lisa Phelan and Anne McDonald (Gilead Sciences)
for contributions to study conduct; and David McNeel (Gilead
we were not able to assess which adverse events Sciences) for editorial assistance with an earlier version of the
resulted from ledipasvir–sofosbuvir. The most manuscript.
appendix
The authors’ affiliations are as follows: Beth Israel Deaconess Medical Center, Boston (N.A.); Johann Wolfgang Goethe University Medi-
cal Center, Frankfurt am Main (S.Z.), and Institut für interdisziplinäre Medizin Studien an der Asklepios Klinik St. Georg, Hamburg (P.B.)
— both in Germany; Indiana University School of Medicine, Indianapolis (P.K.); University of California at San Diego Medical Center, San
Diego (M.C.), and Gilead Sciences, Foster City (G.M.S., X.D., H.M., J.C.Y., P.S.P., W.T.S., J.G.M.) — both in California; Atlanta Gastro-
enterology Associates, Atlanta (N.G.); Azienda Ospedaliera Ospedale Niguarda Ca’ Granda, Milan (M.P.), and Casa Sollievo della
Sofferenza Hospital, San Giovanni Rotondo (A.M.) — both in Italy; Hospital Universitario Nuestra Señora de Valme, Seville (M.R.-G.),
and Hospital Universitario Vall d’Hebron and Ciberhed del Instituto Carlos III, Barcelona (M.B.) — both in Spain; Centre Hospitalier
Universitaire Grenoble, Grenoble (J.-P.Z.), and Hôpital Beaujon, Clichy (P.M.) — both in France; Institute of Liver Studies, Kings Col-
lege Hospital (K.A.), and Queen Mary University of London (G.R.F.) — both in London; James J. Peters Veterans Affairs Medical
Center, Bronx, NY (N.B.); Weill Cornell Medical College, New York (I.M.J.); and Duke University Medical Center, Durham, NC (A.J.M.).
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1898 n engl j med 370;20 26

original article
ABT-450/r–Ombitasvir and Dasabuvir

with or without Ribavirin for HCV
Peter Ferenci, M.D., David Bernstein, M.D., Jacob Lalezari, M.D.,
Daniel Cohen, M.D., Yan Luo, M.D., Ph.D., Curtis Cooper, M.D., Edward Tam, M.D.,
Rui T. Marinho, M.D., Ph.D., Naoky Tsai, M.D., Anders Nyberg, M.D.,
Terry D. Box, M.D., Ziad Younes, M.D., Pedram Enayati, M.D., Sinikka Green, M.D.,
Yaacov Baruch, M.D., Bal Raj Bhandari, M.D., Florin Alexandru Caruntu, M.D., Ph.D.,
Thomas Sepe, M.D., Vladimir Chulanov, M.D., Ph.D., Ewa Janczewska, M.D., Ph.D.,
Giuliano Rizzardini, M.D., Judit Gervain, M.D., Ph.D., Ramon Planas, M.D.,
Christophe Moreno, M.D., Ph.D., Tarek Hassanein, M.D., Wangang Xie, Ph.D.,
Martin King, Ph.D., Thomas Podsadecki, M.D., and K. Rajender Reddy, M.D.
A BS T R AC T
Background
The interferon-free regimen of ABT-450 with ritonavir (ABT-450/r), ombitasvir, and das- The authors’ affiliations are listed in the
abuvir with or without ribavirin has shown efficacy in inducing a sustained virologic Appendix. Address reprint requests to
Dr. Ferenci at the Medical University of
response in a phase 2 study involving patients with hepatitis C virus (HCV) genotype Vienna, Univ. Klinik für Innere Medizin III,
1 infection. We conducted two phase 3 trials to examine the efficacy and safety of this Klinische Abteilung für Gastroenterologie
regimen in previously untreated patients with HCV genotype 1 infection and no cirrhosis. und Hepatologie, Währinger Gürtel 18-20,
1090 Vienna, Austria, or at peter.ferenci@
Methods meduniwien.ac.at.
We randomly assigned 419 patients with HCV genotype 1b infection (PEARL-III Drs. Ferenci and Bernstein contributed
study) and 305 patients with genotype 1a infection (PEARL-IV study) to 12 weeks equally to this article.
of ABT-450/r–ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of
This article was published on May 4, 2014,
ritonavir, and 25 mg of ombitasvir), dasabuvir (250 mg twice daily), and ribavirin at NEJM.org.
administered according to body weight or to matching placebo for ribavirin. The
primary efficacy end point was a sustained virologic response (an HCV RNA level N Engl J Med 2014;370:1983-92.
DOI: 10.1056/NEJMoa1402338
of <25 IU per milliliter) 12 weeks after the end of treatment. Copyright © 2014 Massachusetts Medical Society.
Results
Related Material:
The study regimen resulted in high rates of sustained virologic response among pa-
Supplementary Appendix
tients with HCV genotype 1b infection (99.5% with ribavirin and 99.0% without riba-
virin) and among those with genotype 1a infection (97.0% and 90.2%, respectively).
Of patients with genotype 1b infection, 1 had virologic failure, and 2 did not have
data available at post-treatment week 12. Among patients with genotype 1a infection,
the rate of virologic failure was higher in the ribavirin-free group than in the ribavirin
group (7.8% vs. 2.0%). In both studies, decreases in the hemoglobin level were sig-
nificantly more common in patients receiving ribavirin. Two patients (0.3%) discon-
tinued the study drugs owing to adverse events. The most common adverse events
were fatigue, headache, and nausea.
Conclusions
Twelve weeks of treatment with ABT-450/r–ombitasvir and dasabuvir without riba-
virin was associated with high rates of sustained virologic response among previ-
ously untreated patients with HCV genotype 1 infection. Rates of virologic failure
were higher without ribavirin than with ribavirin among patients with genotype 1a
infection but not among those with genotype 1b infection. (Funded by AbbVie;
PEARL-III and PEARL-IV ClinicalTrials.gov numbers, NCT01767116 and NCT01833533.)

may 22, 2014 1983
H
epatitis C virus (HCV) infection is a ing.22 Ombitasvir (ABT-267) is an inhibitor of the
worldwide health issue, with 3 million HCV NS5A replication complex, and dasabuvir
to 4 million new infections yearly and (ABT-333) is a nonnucleoside NS5B polymerase
infection rates as high as 5% in some countries.1 inhibitor. All three agents have potent activity
Chronic infection leads to liver disease, cirrhosis, against HCV genotype 1 in vitro.23 In a random-
or liver cancer in a large proportion of infected ized, controlled, phase 2b study, a regimen of
persons, and hepatitis C accounts for 25% of all ABT-450/r, ombitasvir, and dasabuvir with riba-
liver cancers, representing the leading indication virin, administered for 12 weeks, was efficacious
for liver transplantation.1-3 Genotype 1 is the in previously untreated patients with HCV geno-
most common HCV genotype worldwide and in- type 1 infection.18 In addition, all 25 patients with
cludes 11 subgenotypes, of which 1a and 1b are genotype 1b infection who were treated without
responsible for the vast majority of infections.4 ribavirin had undetectable HCV RNA levels 24
Genotype 1b infection is the most prevalent form weeks after the end of therapy.
worldwide, particularly in Europe and East Asia, On the basis of these data, two separate
whereas genotype 1a infection is more prevalent phase 3 trials were designed to evaluate the role
in North America.4 of ribavirin in the treatment of patients with geno-
Several all-oral, Approved treatments for HCV genotype 1 in- type 1a or 1b infection. We assessed the efficacy
interferon-free fection include peginterferon and ribavirin com- and safety of a 12-week treatment regimen of
treatments bined with a direct-acting antiviral agent.5-9 Peg- coformulated ABT-450/r–ombitasvir and dasabuvir
have now been interferon is associated with substantial adverse with or without ribavirin in previously untreated
approved. events, including influenza-like symptoms, de- patients without cirrhosis who had HCV geno-
pression, fatigue, and cytopenias that make it type 1a infection (PEARL-IV study) or genotype 1b
difficult for patients to adhere to treatment.10 infection (PEARL-III study). The double-blind,
Cure rates for genotype 1a and 1b infection may placebo-controlled design of these studies permit-
differ depending on the treatment regimen; rates ted a thorough assessment of the contribution of
are generally lower among patients with genotype ribavirin to the adverse-event profile of the com-
1a infection when the treatment regimen includes bination regimen.
an NS3 protease inhibitor or an NS5A replication
complex inhibitor 6,8,11,12 and among patients Me thods
with genotype 1b infection when the regimen
includes the nucleotide analogue sofosbuvir.9 Patients
Data suggest that genotype 1a infection is more Patients 18 to 70 years of age were eligible for
difficult to cure than genotype 1b infection ow- enrollment if they had chronic HCV genotype 1
ing to the development of resistance.7,13-17 Thus, infection with an HCV RNA level of more than
careful assessment of the efficacy of individual 10,000 IU per milliliter and had never received
regimens in patients with different subgeno- any antiviral treatment for HCV. Patients with
types of HCV infection is warranted. genotype 1a infection were screened at 53 sites in
Ribavirin is an important component of peg- Canada, the United States, and the United King-
interferon-based therapy with first-generation dom (PEARL-IV study). Patients with genotype
protease inhibitors, but phase 2 clinical trials of 1b infection were screened at 50 sites in Austria,
interferon-free regimens based on direct-acting Belgium, Hungary, Israel, Italy, Poland, Portugal,
antiviral agents suggest that ribavirin may not Romania, the Russian Federation, Spain, and the
always be required.16,18-20 Although ribavirin ap- United States (PEARL-III study). For both studies,
pears to have less toxicity in the absence of peg- eligible patients had no evidence of cirrhosis as
interferon,9,21 ribavirin is teratogenic and is documented by means of a liver biopsy within the
associated with hemolytic anemia. Therefore, previous 24 months, transient elastography (Fibro-
identifying patients who could be successfully Scan), or noninvasive assessment of serum mark-
treated without ribavirin is of great importance. ers (FibroTest). Patients were excluded if they had
ABT-450, an inhibitor of the HCV nonstruc- coinfection with human immunodeficiency virus
tural 3/4A (NS3/4A) protease, is administered with or hepatitis B virus or if they had infection with
ritonavir (ABT-450/r) to increase ABT-450 plasma any HCV genotype other than 1a (PEARL-IV
levels and half-life, permitting once-daily dos- study) or 1b (PEARL-III study). Detailed eligibility
1984 n engl j med 370;21 28

Antivir al regimen with or without Ribavirin for HCV
criteria and information on fibrosis scoring are

provided in the Supplementary Appendix, avail- HCV Genotype 1a
able with the full text of this article at NEJM.org.
ABT-450/r–
N= 100 ombitasvir+ Post-treatment period
Study Designs dasabuvir+ribavirin
Patients in both studies were stratified according
ABT-450/r–
to IL28B genotype (CC vs. non-CC) and randomly N= 205 ombitasvir+ Post-treatment period
assigned in a 1:2 ratio (genotype 1a study) or a dasabuvir+placebo
1:1 ratio (genotype 1b study) to receive either

Day 0 Wk 12 Wk 24 Wk 60
ribavirin twice daily according to body weight (assessment for sustained
(1000 mg daily if the body weight was <75 kg and virologic response)
1200 mg daily if the body weight was ≥75 kg) or
matching placebo for 12 weeks. All the patients HCV Genotype 1b
received open-label ABT-450/r–ombitasvir (at a
ABT-450/r–
once-daily dose of 150 mg of ABT-450, 100 mg of N= 210 ombitasvir+ Post-treatment period
ritonavir, and 25 mg of ombitasvir) and dasabu- dasabuvir+ribavirin
vir (250 mg twice daily) for 12 weeks (Fig. 1).
ABT-450/r–
Visits were scheduled at weeks 0, 1, 2, 4, 6, 8, 10, N= 209 ombitasvir+ Post-treatment period
and 12 of the treatment period, and patients were dasabuvir+placebo
followed for 48 weeks after the treatment period.
Day 0 Wk 12 Wk 24 Wk 60
The investigators, patients, and study sponsor (assessment for sustained
(AbbVie) were unaware of the treatment assign- virologic response)
ments and hemoglobin or hematocrit values. If a
predefined toxicity criterion for hemoglobin val- Figure 1. Study Designs.
ues was met, all hematologic laboratory data Patients with hepatitis C virus (HCV) genotype 1a infection (PEARL-IV
study) or genotype 1b infection (PEARL-III study) and no cirrhosis were
were disclosed to the site investigator to allow for randomly assigned to receive ribavirin (1000 or 1200 mg daily according to
appropriate patient care. Additional details on body weight) or matching placebo for 12 weeks. All patients received ABT-
study designs are provided in the Supplementary 450 with ritonavir (ABT-450/r)–ombitasvir (at a once-daily dose of 150 mg
Appendix. of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir) and dasabuvir
The studies were conducted in accordance with (250 mg twice daily) for 12 weeks.
the International Conference on Harmonisation
guidelines, applicable regulations, and guidelines
governing clinical-study conduct and ethical prin- sistance testing, and logistic-regression analyses
ciples that have their origin in the Declaration of of response predictors are available in the Sup-
Helsinki. All the patients provided written in- plementary Appendix. Adverse-event assessment
formed consent. The studies were designed by and clinical laboratory testing were performed at
the study sponsor. The investigators and sponsor each study visit during treatment and in the fol-
jointly conducted the study and gathered the low-up period. Adverse events were reported from
data. The sponsor conducted the data analyses. the time of study-treatment initiation until 30 days
All the authors signed a confidentiality agreement after the last dose. Data on serious adverse events
with the sponsor. The first draft of the manu- were collected throughout the study.
script was written by a sponsor-employed medi-
cal writer, with input from all the authors. All the Efficacy End Points
authors made the decision to submit the manu- The primary efficacy end point for both studies
script for publication and vouch for the com- was a sustained virologic response (a plasma
pleteness and accuracy of the data and analyses HCV RNA level of <25 IU per milliliter) 12 weeks
after the end of treatment. The primary objective
and for the fidelity of the studies to the protocol,
available at NEJM.org. of both studies was to assess the noninferiority
of the rate of sustained virologic response at
Efficacy and Safety Assessments post-treatment week 12 in each study group, as
Details of the collection of plasma samples, HCV compared with the historical rate with telaprevir
RNA measurement, virologic-failure criteria, re- plus peginterferon–ribavirin among previously

may 22, 2014 1985
Source: The New England Journal of Medicine The n e w e ng l a n d j o u r na l of m e dic i n e
untreated patients with the corresponding HCV group with virologic failure during treatment or
subgenotype. The historical rate was 72% among relapse after treatment.
patients with genotype 1a infection (95% confi-
dence interval [CI], 68 to 75) and 80% among Statistical Analysis
those with genotype 1b infection (95% CI, 75 to 84) Efficacy analyses were performed in the modi-
(see the Supplementary Appendix for details). Sec- fied intention-to-treat population, defined as all
ondary efficacy objectives in each study were to randomly assigned patients who received at least
assess the noninferiority of the sustained-viro- one dose of a study drug. For the analysis of
logic-response rate in the group that did not re- whether the rate of sustained virologic response
ceive ribavirin as compared with the group that with the interferon-free regimen was noninferior
received ribavirin, the superiority of the rate at to the historical rate with telaprevir plus pegin-
post-treatment week 12 in each group as com- terferon–ribavirin, a noninferiority margin of 10.5
pared with the historical rate with telaprevir plus percentage points was used. To establish that the
peginterferon–ribavirin in the corresponding pa- rate with the interferon-free regimen was nonin-
tient population, the percentage of patients in ferior to the historical rate, the lower boundary
each group with a hemoglobin level below the of the 95% confidence interval (based on the nor-
lower limit of the normal range at the end of mal approximation to the binomial distribution)
treatment, and the percentage of patients in each had to exceed 73% for the genotype 1b study and
Table 1. Baseline Demographic and Clinical Characteristics.*
Characteristic HCV Genotype 1a HCV Genotype 1b

Antiviral Regimen Antiviral Regimen Antiviral Regimen Antiviral Regimen
with Ribavirin without Ribavirin with Ribavirin without Ribavirin
(N = 100) (N = 205) (N = 210) (N = 209)
Male sex — no. (%) 70 (70.0) 129 (62.9) 106 (50.5) 86 (41.1)
Race — no./total no. (%)†
White 86/100 (86.0) 171/205 (83.4) 198/210 (94.3) 196/208 (94.2)
Black 10/100 (10.0) 26/205 (12.7) 10/210 (4.8) 10/208 (4.8)
Other 4/100 (4.0) 8/205 (3.9) 2/210 (1.0) 2/208 (1.0)
Hispanic or Latino ethnic group — no. (%)† 10 (10.0) 18 (8.8) 2 (1.0) 5 (2.4)
Age — yr 51.6±11.0 51.4±10.6 48.4±11.9 49.2±12.0
Geographic region — no. (%)
North America 92 (92.0) 186 (90.7) 48 (22.9) 47 (22.5)
Europe 8 (8.0) 19 (9.3) 162 (77.1) 162 (77.5)
Body-mass index‡ 26.9±4.0 26.7±4.3 25.8±3.8 26.1±4.2
Metavir fibrosis score — no./total no. (%)§
F0 or F1 63/100 (63.0) 132/205 (64.4) 150/210 (71.4) 141/208 (67.8)
F2 21/100 (21.0) 35/205 (17.1) 38/210 (18.1) 47/208 (22.6)
F3¶ 16/100 (16.0) 38/205 (18.5) 22/210 (10.5) 20/208 (9.6)
IL28B CC genotype — no. (%) 31 (31.0) 63 (30.7) 44 (21.0) 44 (21.1)
HCV RNA — log10 IU/ml 6.64±0.50 6.53±0.68 6.29±0.77 6.33±0.67
HCV RNA ≥800,000 IU/ml — no. (%) 92 (92.0) 172 (83.9) 159 (75.7) 148 (70.8)
* Plus–minus values are means ±SD. There were no significant differences in baseline characteristics between treatment groups in either study.
HCV denotes hepatitis C virus.
† Race and ethnic group were self-reported.
‡ The body-mass index is the weight in kilograms divided by the square of the height in meters.
§ The Metavir fibrosis score (on a scale from F0 to F4, with F4 consistent with cirrhosis) was based on liver biopsy or derived from FibroTest
or FibroScan results. Biopsy confirmation of the absence of cirrhosis was required for patients with a FibroTest result of F4.
¶ Four patients in the genotype 1a study were enrolled with a FibroTest result of F4. In three of these patients, a biopsy result subsequently
ruled out the presence of cirrhosis. No confirmatory liver biopsy or FibroScan data were available for the fourth patient.
1986 n engl j med 370;21 nejm.org may 22, 2014

30
65% for the genotype 1a study. Superiority could logic response at post-treatment week 12, for a
be established if the lower boundary of the con- rate of 97.0% (95% CI, 93.7 to 100); 185 of 205
fidence interval for the interferon-free regimen patients who received the regimen without riba-
was greater than the upper boundary of the con- virin had a sustained virologic response, for a
fidence interval for the historical rate: 84% for rate of 90.2% (95% CI, 86.2 to 94.3) (Fig. 2).
the genotype 1b study and 75% for the genotype Hence, the sustained-virologic-response rates for
1a study. The assessment of the noninferiority of the regimens with and without ribavirin were
the regimen without ribavirin as compared with both noninferior and superior to the historical
the regimen with ribavirin was based on a non- rate with telaprevir plus peginterferon–ribavirin
inferiority margin of 10.5 percentage points.24 in previously untreated adults with HCV genotype
Details of the efficacy analyses, including the 1a infection and no cirrhosis. The regimen with-
fixed-sequence testing plan for the primary and out ribavirin did not meet the noninferiority crite-
secondary end points, are provided in the Supple- rion as compared with the regimen with ribavirin,
mentary Appendix. because the lower boundary of the confidence
Safety analyses compared the rate of adverse interval for the difference (−6.8 percentage
events and laboratory abnormalities between treat- points [95% CI, −12.0 to −1.5]) crossed the non-
ment groups in each study with the use of Fish- inferiority margin of 10.5 percentage points. In
er’s exact test. Sample-size determination is de- addition, the upper boundary of the confidence
scribed in the Supplementary Appendix. SAS interval did not cross zero, indicating a significant
software for the UNIX operating system (SAS In- difference between groups.
stitute) was used for all analyses. All statistical A total of 18 patients with genotype 1a infec-
tests and all confidence intervals were two-sided, tion had virologic failure, 16 of whom received
with a significance level of 0.05. the regimen without ribavirin. Of the 3 patients
with genotype 1a infection who received the
R e sult s regimen with ribavirin and did not have a sus-
Baseline Demographic and Clinical

Characteristics HCV Genotype 1a HCV Genotype 1b
In the genotype 1a study, 305 of 436 screened 97.0 99.5 99.0
100 90.2 100
patients underwent randomization and received 90 90
Sustained Virologic Response
at least one dose of a study drug (Fig. S1 in the 80 80

Supplementary Appendix). A total of 629 patients 70 70
(% of patients)
were screened for the genotype 1b study, of whom 60 60

419 underwent randomization and received at least 50 50
one dose of a study drug. Baseline demographic 40 40
and clinical characteristics were well balanced 30 30
between the two groups in each study (Table 1). 20 20
The majority of patients in the genotype 1a study 10 97/100 185/205 10 209/210 207/209
were enrolled in North America, whereas the ma- 0 0
rin
rin
n
ba en
ib en
ba en
ib en
jority of patients in the genotype 1b study were

iri
iri
Ri im
t R gim
Ri im
t R gim
vi
vi
av
av
th eg
th eg
enrolled in Europe. Among patients enrolled in

ou e
ou e
wi l R
th l R
wi l R
th l R
ira
wi ira
ira
wi ira
the United States, blacks accounted for 14.2% of

tiv
tiv
tiv
tiv
An
An
An
An
patients in the genotype 1a study (35 of 247 pa-

tients) and 21.1% of patients in the genotype 1b Figure 2. Sustained Virologic Response at 12 Weeks after the End
study (20 of 95 patients). of Treatment.
The dashed horizontal lines indicate noninferiority thresholds, based on
Efficacy Outcomes the historical rate of sustained virologic response with telaprevir plus peg-
interferon–ribavirin, for the genotype 1a study (65%) and genotype 1b study
Genotype 1a Study
(73%). The solid horizontal lines indicate superiority thresholds, based on
After 12 weeks of treatment with ABT-450/r– the historical rate with telaprevir plus peginterferon–ribavirin, for the geno-
ombitasvir and dasabuvir in the genotype 1a type 1a study (75%) and genotype 1b study (84%). The I bars indicate 95%
study, 97 of 100 patients who received the antivi- confidence intervals.
ral regimen with ribavirin had a sustained viro-
n engl j med 370;21 nejm.org31may 22, 2014 1987

tained virologic response, 2 had virologic failure patients with virologic failure were D168V in NS3,
(1 had a rebound in HCV RNA levels during M28T and Q30R in NS5A, and S556G in NS5B.
treatment and 1 had a relapse after treatment),
and 1 did not complete follow-up testing at post- Genotype 1b Study
treatment week 12. Of the 16 patients with geno- In this study, 209 of the 210 patients who re-
type 1a infection who received the regimen ceived the antiviral regimen with ribavirin had a
without ribavirin and had virologic failure, 6 had sustained virologic response at post-treatment
a virologic rebound during treatment and 10 had week 12, for a rate of 99.5% (95% CI, 98.6 to
a relapse after treatment. All the patients with a 100.0); 207 of the 209 patients who received the
relapse received at least 11 weeks of treatment. regimen without ribavirin had a sustained viro-
Adherence to the dosing regimen for each study logic response, for a rate of 99.0% (95% CI, 97.7
drug was greater than 95% for 16 of the 17 pa- to 100.0). Thus, the sustained-virologic-response
tients with virologic failure for whom data were rates among patients who received ribavirin and
available; 1 patient who received the antiviral those who did not were both noninferior and su-
regimen without ribavirin and had a virologic perior to the historical rate with telaprevir plus
rebound took 88.5% of the planned ABT-450/r– peginterferon–ribavirin among previously un-
ombitasvir doses and 90.8% of the planned treated adults with HCV genotype 1b infection
dasabuvir doses. On the basis of logistic-regres- and no cirrhosis. In addition, the sustained-viro-
sion analyses of baseline demographic and clin- logic-response rate among patients who did not
ical characteristics, only IL28B CC genotype, receive ribavirin was noninferior to the rate
which has historically been associated with in- among those who received ribavirin (difference,
creased rates of response to treatment for HCV −0.5 percentage points [95% CI, −2.1 to 1.1]).
infection, was associated with an increased rate Only one patient with genotype 1b infection
of sustained virologic response among patients had virologic failure during treatment; this pa-
with genotype 1a infection (P = 0.03). tient, who received the antiviral regimen with
At the time of virologic failure, each of the 18 ribavirin, had a virologic rebound during treat-
patients with genotype 1a infection and a viro- ment. The two patients who received the regi-
logic failure had at least one resistance-associated men without ribavirin and did not have a sus-
variant known to be selected by one of the three tained virologic response completed treatment
direct-acting antiviral agents included in the regi- but did not complete follow-up testing at post-
men. The most frequently detected variants in treatment week 12 (Table 2). Owing to the high
Table 2. Sustained Virologic Response and Reasons for Nonresponse.
Variable HCV Genotype 1a HCV Genotype 1b

(N = 100) (N = 205) (N = 210) (N = 209)
Sustained virologic response at post- 97 (97.0) 185 (90.2) 209 (99.5) 207 (99.0)
treatment wk 12 — no. (%)
Reasons for nonresponse
Virologic failure during treatment — 1 (1.0) 6 (2.9) 1 (0.5) 0
no. (%)
Relapse — no./total no. (%)* 1/98 (1.0) 10/194 (5.2) 0/208 0/207
Early discontinuation of study treatment 0 3 (1.5) 0 0
— no. (%)
Missing data at post-treatment wk 12 1 (1.0) 1 (0.5) 0 2 (1.0)
— no. (%)
* Virologic relapse was defined as a confirmed HCV RNA level of 25 IU per milliliter or more between the final visit during the double-blind
treatment period and 12 weeks after the last dose of study drug among patients who completed treatment (duration of study-drug exposure,
≥77 days), had an HCV RNA level of less than 25 IU per milliliter at the final visit during the double-blind treatment period, and had data on
HCV RNA levels available after the completion of treatment.
1988 n engl j med

32370;21 nejm.org may 22, 2014
rates of sustained virologic response, there were curred at a higher frequency among patients who
no significant predictors of virologic failure. received ribavirin than among those who did not in
one or both studies. The majority of adverse events
Adverse Events in all treatment groups were mild; overall, two pa-
In both studies, adverse events were more frequent- tients (both in the genotype 1a study) discontinued
ly reported in the groups receiving antiviral regi- the study drugs owing to adverse events.
mens that contained ribavirin than in the groups Serious adverse events occurred in eight pa-
that received the ribavirin-free regimen (P = 0.03 in tients in the genotype 1b study (four who re-
the genotype 1a study and P = 0.003 in the genotype ceived ribavirin and four who did not) and in
1b study) (Table 3). The most common adverse four patients in the genotype 1a study (three
events reported in the two studies, headache and who received ribavirin and one who did not). All
fatigue, did not differ significantly in either study patients with a serious adverse event had a sus-
between the group that received ribavirin and the tained virologic response. Details of all serious
group that did not receive it. Among other common adverse events are provided in Table S5 in the
adverse events, pruritus, nausea, and insomnia oc- Supplementary Appendix.
Table 3. Adverse Events and Laboratory Abnormalities.*
Event HCV Genotype 1a HCV Genotype 1b

(N = 100) (N = 205) P Value (N = 210) (N = 209) P Value
Any adverse event — no. (%) 92 (92.0) 169 (82.4) 0.03 168 (80.0) 140 (67.0) 0.003
Any severe adverse event — no. (%)† 2 (2.0) 4 (2.0) 2 (1.0) 1 (0.5)
Any serious adverse event — no. (%)‡ 3 (3.0) 1 (0.5) 4 (1.9) 4 (1.9)
Common adverse events — no. (%)§
Headache 25 (25.0) 58 (28.3) 51 (24.3) 49 (23.4)
Fatigue 46 (46.0) 72 (35.1) 45 (21.4) 48 (23.0)
Pruritus 10 (10.0) 12 (5.9) 25 (11.9) 11 (5.3) 0.02
Nausea 21 (21.0) 28 (13.7) 23 (11.0) 9 (4.3) 0.02
Insomnia 17 (17.0) 16 (7.8) 0.02 19 (9.0) 7 (3.3) 0.02
Diarrhea 14 (14.0) 33 (16.1) 9 (4.3) 13 (6.2)
Laboratory abnormalities
Hemoglobin <LLN 42/100 (42.0) 8/203 (3.9) <0.001 106/207 (51.2) 7/205 (3.4) <0.001
— no./total no. (%)¶
Hemoglobin ≤10 g/dl 4 (4.0) 0 0.01 19 (9.0) 0 <0.001
— no. (%)
Total bilirubin >3× ULN — no. (%) 3 (3.0) 1 (0.5) 12 (5.7) 1 (0.5) 0.003
Alanine aminotransferase 1 (1.0) 1 (0.5) 2 (1.0) 0
>5× ULN — no. (%)
Aspartate aminotransferase 0 0 0 0
>5× ULN — no.
Alkaline phosphatase >2.5× 0 0 0 0
ULN — no.
* LLN denotes the lower limit of the normal range, and ULN the upper limit of the normal range.
† A severe adverse event was defined as one that caused considerable interference with the usual activities of the patient and that may have
been incapacitating or life-threatening.
‡ A serious adverse event was defined as one that resulted in hospitalization, persistent or clinically significant disability, or death or that was
life-threatening or required medical intervention or hospitalization to prevent a serious outcome.
§ All other adverse events occurred in less than 10% of patients in any treatment group.
¶ Patients with a hemoglobin level below the LLN at baseline were not included in the analysis.

may 22, 2014 1989
Decreased Hemoglobin Levels with HCV genotype 1 infection and no cirrhosis

Among the patients in the genotype 1a study had a sustained virologic response after 12 weeks
who had a hemoglobin level within the normal of treatment with ABT-450/r–ombitasvir and das-
range at baseline, 42.0% of patients who received abuvir with or without ribavirin. Response rates
the antiviral regimen with ribavirin and 3.9% of in all treatment groups were superior to the his-
patients who received the ribavirin-free regimen torical response rate with a peginterferon-con-
had a hemoglobin level below the lower limit of the taining telaprevir-based regimen.5 These findings
normal range at the end of treatment (P<0.001). suggest that in previously untreated patients with
Similarly, in the genotype 1b study, 51.2% of pa- HCV infection and no cirrhosis, this 12-week
tients who received ribavirin had a low hemoglo- regimen of three direct-acting antiviral agents is
bin level at the end of treatment, as compared efficacious both with and without ribavirin.
with 3.4% of patients who did not receive ribavi- We also assessed the contribution of ribavirin
rin (P<0.001). A hemoglobin level of less than 10 g to the treatment response and safety profile of
per deciliter at any time during treatment occurred the regimen. The effect of ribavirin on the treat-
in 4.0% of patients with genotype 1a infection ment response in patients with HCV genotype 1a
who received ribavirin and in 9.0% of patients infection differed from that in patients with
with genotype 1b infection who received ribavi- genotype 1b infection. The inclusion of ribavirin
rin but did not occur in any patients who received did not significantly affect the sustained-viro-
the ribavirin-free regimen (Table 3). The ribavirin logic-response rate among patients with geno-
dose was reduced in accordance with the proto- type 1b infection, because the rate was 99.0% in
col because of a decreased hemoglobin level in the group that did not receive ribavirin and
6 patients with genotype 1a infection who re- 99.5% in the group that received it. Thus, in this
ceived ribavirin (6.0%) and in 16 patients with patient population, the 12-week regimen of ABT-
genotype 1b infection who received ribavirin (7.6%); 450/r–ombitasvir and dasabuvir resulted in simi-
all these patients had a sustained virologic re- larly high rates of sustained virologic response
sponse. Additional data on hemoglobin levels are with and without ribavirin, results that are con-
provided in the Supplementary Appendix. sistent with those of a phase 2b study18 and
phase 3 studies25,26 of this regimen. In contrast,
Other Laboratory Abnormalities although more than 90% of patients in each
In both studies, the proportions of patients with treatment group in the genotype 1a study had a
elevations in the serum level of bilirubin were sustained virologic response, the response rate
higher in the groups that received the ribavirin- in the group that that received the ribavirin-free
containing regimen than in the groups that re- regimen did not meet the criterion for noninfe-
ceived the ribavirin-free regimen (Tables S6 and riority to the rate in the group that received the
S7 in the Supplementary Appendix). Elevated lev- ribavirin-containing regimen owing to a higher
els of indirect (unconjugated) bilirubin primarily rate of virologic failure with the ribavirin-free
accounted for the abnormalities in both studies. regimen. A total of 18 patients with genotype 1a
Mean bilirubin levels peaked 1 week after the start infection had virologic failure, and only 2 of
of study-drug treatment and stabilized or nor- these patients received ribavirin. Hence, the use
malized thereafter; maximal observed bilirubin of ribavirin in this population appears to confer
levels were 6.5 mg per deciliter (110 μmol per li- an additional benefit.
ter) in the genotype 1a study and 9.4 mg per deci- Regardless of whether the antiviral regimen
liter (160 μmol per liter) in the genotype 1b included ribavirin, the rate of discontinuation of
study. Elevations in the bilirubin level were not the study drugs owing to adverse events was low
associated with elevations in aminotransferase (<1%). As compared with the groups that did not
levels. Additional details on laboratory abnormali- receive ribavirin, the groups that did receive it
ties are provided in the Supplementary Appendix. had more adverse events, particularly pruritus,
nausea, and insomnia — events that are known
Discussion to be associated with ribavirin. In addition, labo-
ratory abnormalities that have historically been
In two phase 3 studies (PEARL-III and PEARL-IV), associated with ribavirin — decreases in the he-
90.2 to 99.5% of previously untreated patients moglobin level and increases in the total biliru-

34 may 22, 2014
bin level — were more common in the groups completely conceal the ribavirin and placebo as-
that received ribavirin. The pattern of bilirubin signments from patients and investigators be-
elevations across treatment regimens confirmed cause of the characteristic adverse events and
that the hyperbilirubinemic effect of ABT-450, an laboratory abnormalities associated with ribavi-
inhibitor of the bilirubin transporter OATP1B1, is rin. In addition, the studies did not include
enhanced by ribavirin-associated hemolysis. How- previously treated patients or patients with cir-
ever, these abnormalities did not appear to affect rhosis, although this regimen with ribavirin was
the likelihood of treatment success and did not associated with a high rate of sustained viro-
result in treatment discontinuation. Overall, the logic response in these patient populations in
adverse events observed in these two phase 3 tri- recent studies.25,26
als were consistent with those observed in past Although the two studies showed that prema-
trials with these regimens. ture discontinuation and serious adverse events
Studies of direct-acting antiviral therapy have were uncommon with the 12-week course of all-
shown that these regimens can result in high oral therapy that included ribavirin, as well as
rates of sustained virologic response. The role of with the ribavirin-free regimen, some patients
and need for ribavirin in maximizing sustained- may benefit from a ribavirin-free treatment op-
virologic-response rates in different patient pop- tion, including patients with contraindications
ulations remain incompletely characterized by to ribavirin therapy, such as hemoglobinopathies
clinical studies. Exploratory studies have shown and severe cardiac or pulmonary disease, and
sustained-virologic-response rates of 95% or those with severe renal impairment. Given the
higher when sofosbuvir is combined with other known teratogenicity of ribavirin, a ribavirin-free
direct-acting antiviral agents (ledipasvir, daclat- regimen would also be preferable for some wom-
asvir, or simeprevir) with or without ribavirin, en of childbearing potential.
although these findings remain to be confirmed In conclusion, previously untreated patients
by larger trials.19,20,27,28 Although these results with HCV genotype 1a or 1b infection and no
suggest that sufficiently efficacious ribavirin-free cirrhosis who received ABT-450/r–ombitasvir
treatments may obviate the need for ribavirin in and dasabuvir with or without ribavirin had high
some patients, larger studies will be needed to sustained-virologic-response rates that were su-
determine which patient populations may require perior to the historical response rate with pegin-
ribavirin for the greatest chance of virologic cure. terferon–ribavirin plus telaprevir. Although riba-
The PEARL-III and PEARL-IV studies were virin did not improve the response in patients
double-blind, randomized trials with large sam- with genotype 1b infection, our findings suggest
ples and a broad geographic scope of enrollment. that ribavirin confers an additional benefit for
The patient populations were representative of patients with genotype 1a infection.
typical North American or European populations Sponsored by AbbVie.
with genotype 1a or 1b infection, the two most Disclosure forms provided by the authors are available with
prevalent subgenotypes in North America, Asia, the full text of this article at NEJM.org.
We thank the trial participants, investigators, and coordina-
and Europe. Rates of premature discontinuation tors who made these studies possible; and Douglas E. Dylla,
and loss to follow-up were low in both trials. A Ph.D., of AbbVie for medical writing support.
limitation of the studies was the inability to
Appendix
The authors’ affiliations are as follows: the Medical University of Vienna, Internal Medicine III, Vienna (P.F.); Hofstra North Shore–LIJ
School of Medicine, Manhasset, NY (D.B.); Quest Clinical Research, San Francisco (J.L.), Kaiser Permanente, San Diego (A.N.), Califor-
nia Liver Institute, Los Angeles (P.E.), eStudySite, La Mesa (S.G.), and Southern California Liver Centers and Southern California Re-
search Center, Coronado (T.H.) — all in California; AbbVie, North Chicago, IL (D.C., Y.L., W.X., M.K., T.P.); University of Ottawa,
Ottawa (C.C.), and Liver and Intestinal Research Centre, Vancouver, BC (E.T.) — both in Canada; Centro Hospitalar Lisboa Norte,
Medical School of Lisbon, Lisbon, Portugal (R.T.M.); the Queen’s Medical Center–Liver Center, Honolulu (N.T.); Clinical Research
Centers of America, Murray, UT (T.D.B.); Gastro One, Germantown, TN (Z.Y.); Rambam Health Care Campus, Haifa, Israel (Y.B.);
Delta Research Partners, Bastrop, LA (B.R.B.); Matei Bals National Institute for Infectious Diseases, Bucharest, Romania (F.A.C.); Uni-
versity Gastroenterology, Providence, RI (T.S.); Central Research Institute of Epidemiology, Moscow (V.C.); ID Clinic, Mysłowice, Po-
land (E.J.); Ospedale Luigi Sacco, Milan (G.R.); Szent György Hospital, Székesfehérvár, Hungary (J.G.); Hospital Universitari Germans
Trias i Pujol, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Badalona, Spain (R.P.); Cliniques
Universitaires de Bruxelles Hôpital Erasme, Université Libre de Bruxelles, Brussels (C.M.); and University of Pennsylvania, Philadelphia
(K.R.R.).

35 may 22, 2014 1991
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Sofosbuvir for previously untreated Sofosbuvir and ledipasvir fixed-dose com- HCV genotype 1 treatment-naive and pri-
chronic hepatitis C infection. N Engl J bination with and without ribavirin in or null responder patients: the COSMOS
Med 2013;368:1878-87. treatment-naive and previously treated study. In: Program and abstracts of the
10. Chung RT. A watershed moment in patients with genotype 1 hepatitis C virus 64th Annual Meeting of the American As-
the treatment of hepatitis C. N Engl J Med infection (LONESTAR): an open-label, sociation for the Study of Liver Diseases,
2012;366:273-5. randomised, phase 2 trial. Lancet 2014; Washington, DC, November 1–5, 2013.
11. Hézode C, Forestier N, Dusheiko G, et 383:515-23. [Erratum, Lancet 2014;383:870.] 28. Sulkowski MS, Gardiner DF, Rodri-
al. Telaprevir and peginterferon with or 21. Jacobson IM, Kowdley KV, Kwo PY. guez-Torres M, et al. Daclatasvir plus so-
without ribavirin for chronic HCV infec- Anemia management in the era of triple fosbuvir for previously treated or untreat-
tion. N Engl J Med 2009;360:1839-50. combination therapy for chronic HCV. ed chronic HCV infection. N Engl J Med
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Randomized trial of daclatasvir and asu- 6:1-16. Copyright © 2014 Massachusetts Medical Society.
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1992 n engl j med 370;21 36

Sofosbuvir-Based Therapy for HCV Infection: The Results Are In

The evidence shows superior efficacy and tolerability of sofosbuvir-based regimens versus those currently
available, particularly in patients with HCV genotype 1.
Lawitz E et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013 Apr 23; [e-pub].
ARTICLE SUMMARY
On the heels of the phase II trial results, phase III trial results are now available on sofosbuvir-based regimens for
the treatment of chronic hepatitis C virus (HCV) infection in treatment-naive patients. The primary endpoint of
the two industry-funded, phase III trials was sustained virologic response at 12 weeks after end of treatment
(SVR12).
In the single-group, open-label NEUTRINO trial, 327 patients with HCV genotypes 1 (89%), 4 (9%), 5 (<1%), and
6 (2%) received oral sofosbuvir (400 mg daily), peginterferon (180 µg weekly), and ribavirin (1000–1200 mg daily)
for 12 weeks. Among the study group, 17% were black, 71% had IL28B genotype TT or TC, and 17% had cirrhosis.
SVR12 was 89% for genotype 1 (92% for genotype 1a and 82% for genotype 1b), 96% for genotype 4, and 100% for
genotype 5 or 6. SVR12 was significantly lower for patients with cirrhosis versus without cirrhosis (80% vs. 92%)
and for patients with IL28B genotypes TT or TC versus genotype CC (87% vs. 98%). SVR12 did not vary by race
or Hispanic ethnicity.
In the open-label FISSION trial, 499 patients with HCV genotypes 2 and 3 were randomized to oral sofosbuvir
(400 mg daily) and ribavirin (1000–1200 mg daily) for 12 weeks or peginterferon (180 µg weekly) and ribavirin
(800 mg daily) for 24 weeks. Cirrhosis was present in 20% of the sofosbuvir group and in 21% of the control group.
In the sofosbuvir group, SVR12 was 97% for genotype 2 and 56% for genotype 3 in the sofosbuvir group compared
with 78% for genotype 2 and 63% for genotype 3 in the control group. Noninferiority analysis demonstrated simi-
lar efficacy between the two groups. Efficacy among patients with cirrhosis was similar between the sofosbuvir
and control groups (47% vs. 38%).
In both studies, resistance did not develop with sofosbuvir treatment. Treatment discontinuation was only 1% to
2% in patients receiving 12-week sofosbuvir regimens with or without interferon compared with 11% in patients
receiving the 24-week peginterferon/ribavirin regimen.
COMMENT
These final results of phase III trials of sofosbuvir in treatment-naive patients with hepatitis C virus genotypes 1
to 6 demonstrate that patients with genotype 1 have excellent treatment response that is superior overall to pub-
lished response rates for combination therapy and currently available triple therapies. For patients with genotypes
2 and 3, efficacy was similar between an interferon-free sofosbuvir regimen and a standard peginterferon/ribavi-
rin regimen. Furthermore, sofosbuvir is achieving sustained response with a shorter duration of therapy, better
tolerability, and no resistance development. The sofosbuvir regimen has recently been submitted to the FDA and,
This regimen
once approved, will usher in the next generation of treatment for HCV infection. A phase III trial of sofosbuvir in
has now
patients coinfected with HIV and HCV is ongoing. received
— Atif Zaman, MD, MPH FDA approval.
Oregon Health and Science University, Portland
NEJM Journal Watch Gastroenterology, published April 23, 2013
37
Sofosbuvir Works for Patients Who Cannot Take Peginterferon

Two phase III studies confirm the efficacy of a sofosbuvir and ribavirin therapy in patients with HCV
genotype 2 or 3 infection for whom peginterferon is not an option.
Jacobson IM et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 2013
May 16; 368:1867. (http://dx.doi.org/10.1056/NEJMoa1214854)
ARTICLE SUMMARY
In patients infected with hepatitis C virus (HCV) genotype 2 or 3, treatment with peginterferon plus ribavirin
has a sustained virologic response (SVR) of 70% to 85%. However, adverse effects of peginterferon are a barrier to
treatment for many patients. Now, two industry-funded, phase III trials have evaluated the efficacy of sofosbuvir
(400 mg daily) plus ribavirin (1000 mg–1200 mg daily) in these patients.
In a blinded, placebo-controlled trial, investigators randomized 280 patients for whom peginterferon therapy was
not an option (e.g., adverse effects, contraindications for interferons, and patient refusal) to receive sofosbuvir/
ribavirin or matching placebo for 12 weeks. In a blinded, active-control trial, researchers randomized 202 patients
with prior nonresponse to peginterferon therapy to receive 12 or 16 weeks of sofosbuvir/ribavirin. The primary
endpoint in both studies was SVR at 12 weeks after therapy ended.
In patients for whom peginterferon therapy was not an option, SVR was 78% for treatment with sofosbuvir/
ribavirin compared with 0% for placebo (P<0.001). In previously treated patients, SVR was 50% for 12 weeks of
therapy versus 73% for 16 weeks (P<0.001). SVR rates were lower for patients with genotype 3 versus genotype 2
in both treatment-naive patients (61% vs. 93%) and treatment-experienced patients who received therapy for
12 weeks (30% vs. 86%) or 16 weeks (62% vs. 94%).
SVR rates were lower in patients with cirrhosis than without, both in treatment-naive patients (overall, 61% vs.
81%; genotype 3 vs. 2, 21% vs. 94%) and treatment-experienced patients (overall, 66% vs. 76%; genotype 3 vs. 2 in
16-week group, 61% vs. 78%). In both studies, investigators found no evidence of resistance development, and dis-
continuation rates were low (1%–2%).
COMMENT
Oral sofosbuvir plus ribavirin is effective in patients with HCV genotypes 2 or 3 for whom peginterferon-based
therapy is not an option or was previously ineffective. Of note, these sustained virologic response rates for sofos-
buvir plus ribavirin are comparable to or higher than those previously reported for therapy with peginterferon
plus ribavirin in this population.

NEJM Journal Watch Gastroenterology, published May 24, 2013
38
Combined Simeprevir and Sofosbuvir Is Promising for HCV Genotype 1 Infection

Sustained virologic response rates were >90% even in previous nonresponders and without the addition
of ribavirin; phase III trial results are awaited.
Lawitz E et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus geno-
type 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: The COSMOS randomised
study. Lancet 2014 Jul 28; [e-pub]. (http://dx.doi.org/10.1016/S0140-6736(14)61036-9)
ARTICLE SUMMARY
Both simeprevir-based and sofosbuvir-based regimens are approved for the treatment of hepatitis C virus (HCV)
infection. Since simeprevir, an NS3/4A protease inhibitor, and sofosbuvir, a nucleotide-analogue NS5B polymerase
inhibitor, have different mechanisms of action, a combination of these two direct-acting antiviral agents (DAAs)
may be an effective interferon-free regimen for the treatment of HCV genotype 1 infection.
In an industry-funded, randomized, open-label study, patients with HCV genotype 1 infection who were treatment-
naive or previously failed treatment with peginterferon and ribavirin received sofosbuvir (400 mg daily) plus
simeprevir (150 mg daily) with or without ribavirin (1000–1200 mg daily) for 12 or 24 weeks. Twice as many
patients were randomized to the 24-week treatment groups as were randomized to the 12-week treatment groups.
The primary endpoint was sustained virologic response 12 weeks after treatment completion (SVR12).
Of 167 patients who started treatment, 154 achieved SVR12 (92%). SVR12 rates were consistently >90% regardless
of prior treatment experience, cirrhosis status, host IL28B genotype, HCV genotype (1a or 1b), receipt of ribavirin,
or duration of treatment (12 or 24 weeks). No patients experienced virologic failure during treatment. Only 2% of
patients discontinued treatment.
COMMENT
This small study demonstrates promising results of a combination of a simple DAA regimen that is safe and effec-
tive in the treatment of HCV genotype 1 infection without the addition of ribavirin and treatment duration of
only 12 weeks. This non–FDA-approved regimen has been used with some success outside of the research setting. This regimen
However, pending results of the phase III trial will determine whether this regimen is included among the is now FDA
next-generation, interferon-free regimens for the treatment of HCV infection. approved.
NEJM Journal Watch Gastroenterology, published August 11, 2014
39
Progress Toward All-Oral, Interferon-Free Therapy for HCV Genotype 1 Infection

Regimens tested in open-label studies achieved high virologic response with low resistance and few
adverse effects.
Sulkowski MS et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med
2014 Jan 16; 370:211. (http://dx.doi.org/10.1056/NEJMoa1306218)
Kowdley KV et al. Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1. N Engl J Med 2014 Jan 16;
ARTICLE SUMMARY
Several
Interferon is still currently required for treating hepatitis C virus (HCV) genotype 1 infection. Now, investigators
interferon-free
report findings of two new studies evaluating interferon-free regimens for these patients.
regimens are
In an open-label study, Sulkowski and colleagues evaluated daclatasvir (an NS5A inhibitor; 60 mg daily) plus now FDA
sofosbuvir (an NS5B inhibitor; 400 mg daily) with or without ribavirin for 24 weeks in patients with genotype 1 approved.
infection (44 treatment-naive and 41 treatment-experienced with telaprevir-based or boceprevir-based regimens).
Another 82 treatment-naive patients received therapy for 12 weeks. Sustained virologic response (SVR) at 12 weeks
posttreatment was 98% and did not vary by ribavirin use, HCV subtype, or IL28B genotype.
In a phase IIB study, Kowdley and colleagues randomized 571 patients with genotype 1 HCV infection without
cirrhosis to receive ABT-450/r (the protease inhibitor ABT-450 plus 100 mg of ritonavir) in daily doses of 100 mg,
150 mg, or 200 mg with ABT-267 (an NS5A inhibitor; 25 mg daily) or ABT-333 (nonnucleoside polymerase inhibi-
tor; 400 mg twice daily) or both for 8, 12, or 24 weeks. In addition, all but one of the subgroups received ribavirin
(1000–1200 mg daily). Among patients receiving ABT-450/r plus ABT-267 or ABT-333 or both plus ribavirin, SVR
rates at 24 weeks posttreatment ranged from 83% to 100% in treatment-naive and treatment-experienced patients.
Rates were highest among patients receiving all three anti-virals plus ribavirin and those receiving 12 weeks of
therapy (vs. 8 weeks). SVR varied significantly by HCV subtype, host IL28B haplotype, race, and baseline HCV
RNA level.
In both studies, resistance was uncommon, and side effects were mild (e.g., fatigue, headache, nausea).
COMMENT
These two all-oral, direct-antiviral regimens for hepatitis C virus genotype 1 infection achieved high sustained
virologic response rates with a short duration of therapy and low resistance and adverse effects. In addition, none
of the traditional predictors of negative response had a significant effect on treatment response. Soon, all-oral
regimens for every HCV-infected patient will be a reality.

NEJM Journal Watch Gastroenterology, published January 15, 2014
40
Simeprevir, Sofosbuvir, and the Limitations of the COSMOS

NEJM Journal Watch Blog: HIV and ID Observations, published July 31, 2014
BLOG POST
These are exciting times for hepatitis C treatment, as the approval
of simeprevir and sofosbuvir in late 2013 have made curing this
disease a whole lot easier.
Since that sentence barely conveys the transformative nature of

this medical advance, allow me this tortured analogy: Before
simeprevir and sofosbuvir, curing hepatitis C was like making a
transatlantic journey by ship, and you had to stay in steerage —
always a long and painful trip, but you’d get there if you could
stand it. Now the cure is like a business-class flight — much
shorter, safer, and more comfortable, but you just have to have
the resources to pay for it.
But our treatments are not perfect. I was reminded of this fact when someone treated with simeprevir and
sofosbuvir — or “SIM-SOF” as it’s commonly abbreviated — just relapsed a month after finishing 12 glorious,
side-effect–free weeks of treatment.
In hindsight you could perhaps have predicted that this patient — or this type of patient — would be a treatment
failure on these new drugs. There was prior treatment failure on interferon/ribavirin; he has genotype 1a (and
hence probably Q80K, didn’t test for it); he’s overweight; he has several other medical problems, including
diabetes.
And, probably of greatest importance, he has cirrhosis, diagnosed by liver biopsy several years ago.
The treatment failure sent me scurrying over to the reason we use this combination anyway — the excellent HCV
treatment guidelines and the remarkable COSMOS study (just published in the Lancet) of simeprevir and sofosbu-
vir, with and without ribavirin, in patients with HCV genotype 1.
Here’s what’s recommended in the guidelines for patients who have failed prior treatment:
Daily sofosbuvir (400 mg) plus simeprevir (150 mg), with or without weight-based RBV (1000 mg [75 kg])
for 12 weeks is recommended for retreatment of HCV genotype 1 infection, regardless of subtype or IFN
eligibility.
And here are the relevant data cited:
Among those null responders with a Metavir fibrosis stage of 3 or 4 (n=47) who received 12 weeks of
sofosbuvir and simeprevir, SVR4 was observed in 14 (93%) of 15 patients in the ribavirin-containing arm
and 100% (all 7 participants) in the RBV-free arm.
A few things stand out from reviewing the study and the guidelines, aside from the high response rate:
• The sample size in the COSMOS study was small.

• The number with actual cirrhosis was even smaller, as they combined stages Metavir 3 and 4.
• The number with actual cirrhosis who did not receive ribavirin and received only 12 weeks of treatment was
smaller still.
• And did I mention — the sample size in this study was small?
41
The reason I’m harping on the sample size is a lesson taught early in every Stats 101 course — namely, that a small
sample size means that the outcome will not be very precise, with lots of potential wobble around the results.
The most recent data presentation of the COSMOS study allows us to drill down a bit more on the data. There
were 7 patients — just 7 — with cirrhosis who received only simeprevir and sofosbuvir for 12 weeks. 6 out of
7 were cured (SVR 12), for a response rate of 86%.
And the lower bound of the 95% confidence interval for this proportion? 60%, at least according to this web gizmo
that does the math for us, if I’ve chosen the right “equation”. So the occurrence of relapses should not be a huge
surprise, despite the > 90% response rate for the study overall.
Some take-home lessons:

• Unlike the real thing, the COSMOS study is very small. (There’s a larger study of this combination ongoing.)
• This small sample size means we can’t predict response rates with much accuracy, especially in the hardest to
treat patients who were not heavily represented in the study.
• SIM-SOF (note it’s rarely “SOF-SIM”) is still a great advance in HCV treatment, but treatment failures will
happen.
So what to do next? The good news is that resistance to sofosbuvir is rare even in treatment failures, and that
the HCV treatment cosmos is about to get bigger — the next class of drugs (NS5A inhibitors) is on the way
Both of these
soon, and the data on sofosbuvir plus ledipasvir or daclatasvir look very promising.
regimens are
A reason for optimism even for those for whom SIM-SOF didn’t do the trick. now FDA approved.
— Paul E. Sax, MD
Clinical Director of the HIV Program and Division of Infectious Diseases at Brigham and Women’s Hospital,
and Professor of Medicine at Harvard Medical School, Boston
42
Approval of Sofosbuvir/Ledipasvir Was Expected, but Still Is a Huge Advance

NEJM Journal Watch Blog: HIV and ID Observations, published October 12, 2014
BLOG POST
As expected, the FDA just approved the first single-pill treatment for hepatitis C genotype 1, a tablet containing
400 mg of sofosbuvir (SOF) and 90 mg of ledipasvir (LDV). For those not following this story closely, sofosbuvir is
the pan-genotypic NRTI polymerase inhibitor approved last December to much rejoicing — and controversy
about the price. Ledipasvir is the first HCV NS5A inhibitor, and is only available as part of this combination.
The brand name is “Harvoni”, which sounds a bit like an exotic offering on a menu that you need to ask your wait-
er to explain — “Ancho chile-rubbed Niman Ranch pork chop roasted in soy, ginger, and sesame, served with
pan-sauted garlic kale, and garnished with corn and pinapple-harvoni salsa.”
But even though the approval was no surprise, and the brand name will (like all of them) take some getting used
to, there’s no denying this is a huge step forward for HCV therapy. Let me list some of the reasons:
• One pill a day. Can it get simpler than that? Full prescribing information here.
• No interferon, no ribavirin. In clinical trials, all the latter added to the SOF/LDV combination was side effects.
Ribavirin offered no additional efficacy even in cirrhotics.
• For most patients, 12 weeks of therapy will have a 95%+ chance of cure.
• For treatment-naive patients without cirrhosis who have a pretreatment HCV RNA level < 6 million copies/mL,
just 8 weeks should do the trick.
• For treatment-experienced patients who do have cirrhosis, 24 weeks is recommended, as “only” around 4 out 5
were cured with 12 weeks.
• The rate of treatment discontinuation due to adverse effects in 3 different studies was 1%, 0%, and <1%, respec-
tively. Think about that for a moment.
So yahoo. This is instantly a treatment of choice — and for now, the treatment of choice — for genotype 1 patients,
and no doubt the HCV treatment guidelines will say as much when they’re revised. I’m not on the guidelines panel,
just stating the obvious: The amount of supporting clinical trials data for SOF/LDV combination is vastly greater
than the simeprevir-sofosbuvir treatment, which is already listed in the guidelines.
As with any new medical treatment, there are a few issues and questions to address with SOF/LDV — so let’s start
with the elephant in the exam room, the cost.
The list price of this combination therapy for 12 weeks will be around $95,000, which means the ledipasvir com-
ponent is priced around the same as 12 weeks of interferon/ribavirin — and substantially less than the current
price of simeprevir. I’ve gone over before the various issues on the cost of HCV treatment — it totally depends on
your perspective. It’s either incredible value for what you’re getting (a virtual guarantee of HCV cure, with no side
effects!), or horribly too much ($95,000! That’s over $1100/pill!).
Regardless, SOF/LDV is already one-third cheaper and more effective than HCV treatment was last week with
SIM/SOF, and will cost even less if the patient qualifies for 8 weeks of treatment. We’ll see how this all shakes
This regimen
out when the next interferon-free drug regimen gets approved. I’m referring, of course, to the parataprevir/
is now
ritonavir/ombitasvir plus dasabuvir regimen, which is now so close to approval that all the drugs have real
FDA approved.
names. The guidelines committee will need to consider this one too when it’s approved.
43
A few more items of note:
• There are remarkably few serious drug-drug interactions. Don’t use rifampin or the tricky anticonvulsants
(phenytoin, carbamazepine, phenobarbital). And rosuvastatin levels go way up, avoid that statin. Further details
in the package insert, linked above.
• For patients with HIV co-infection, ledipasvir will increase tenofovir levels by around 30%, the same magnitude
as ritonavir-boosted protease inhibitors and TDF/FTC/EVG/COBI. If your patient is on the former, the pre-
scribing info advises to monitor closely; if on the latter, to switch. I’d recommend switching both, if possible,
to a raltegravir, dolutegravir, or rilpivirine-based regimen until there are more safety data. A phase III study
of SOF/LDV in HIV-coinfected subjects is fully enrolled.
• No dosage change is required for those with mild-moderate renal impairment; for severe renal impairment
or ESRD, no dose recommendation can be made.
Finally, did the FDA consider cost when they recommended 24 weeks of treatment for treatment-experienced
patients with cirrhosis? Probably not, since an 80% cure would leave just 20% who would need a longer course.
In support of the 24 week up front course of SOF/LDV, however, is that we don’t really have a proven approach
to treatment failures yet (24 weeks of the same treatment with RBV? 24 weeks of SIM-SOF? Other?) Additionally,
this is the group of patients who need HCV treatment most urgently.
— Paul E. Sax, MD
44
WHAT OTHER ALL-ORAL REGIMENS FOR PATIENTS WITH GENOTYPE 1

ARE IN THE PIPELINE?
Several DAAs in various combinations are currently under investigation. Following are NEJM Journal Watch
summaries of published findings on two promising regimens in development. The two studies were originally
published in the Journal of the American Medical Association and Annals of Internal Medicine, respectively.
45
Another Fixed-Dose Single-Pill Regimen for Treatment of HCV Infection

Patients with genotype 1 infection, including those who had cirrhosis or were treatment-experienced,
showed high response rates with daclatasvir/asunaprevir/beclabuvir.
Poordad F et al. Fixed-dose combination therapy with daclatasvir, asunaprevir, and beclabuvir for noncirrhotic patients
with HCV genotype 1 infection. JAMA 2015 May 5; 313:1728. (http://dx.doi.org/10.1001/jama.2015.3860)
Muir AJ et al. Daclatasvir in combination with asunaprevir and beclabuvir for hepatitis C virus genotype 1 infection with
compensated cirrhosis. JAMA 2015 May 5; 313:1736. (http://dx.doi.org/10.1001/jama.2015.3868)
ARTICLE SUMMARY
As treatment for hepatitis C virus (HCV) infection continues to evolve, it is becoming clear that fixed-dose
single-pill regimens will become the norm.
In two manufacturer-funded, open-label, uncontrolled trials involving adults with genotype 1 HCV infection,
researchers have evaluated the efficacy and safety of one such regimen: daclatasvir (a pangenotypic NS5A inhibi-
tor) combined with asunaprevir (an NS3 protease inhibitor) and beclabuvir (a nonnucleoside NS5B inhibitor).
In both trials, participants received the study medication twice daily for 12 weeks; the primary end point was
sustained virologic response 12 weeks after treatment cessation (SVR12).
In UNITY-1, Poordad and colleagues enrolled 415 patients without cirrhosis. The SVR12 rate — 91% overall —
was 92% for the 312 treatment-naive patients and 89% for the 103 with treatment experience.
In UNITY-2, Muir and colleagues enrolled patients with compensated cirrhosis (112 treatment-naive and 90
treatment-experienced). Participants were stratified by genotype 1 subtype (a or b) and within each group were
randomized in a 1:1 ratio to receive ribavirin 1000–1200 mg daily or placebo, in addition to the three-drug study
regimen. In the treatment-naive cohort, the SVR12 rate was 93% without ribavirin and 98% with ribavirin; in the
treatment-experienced cohort, it was 87% without and 93% with ribavirin. Patients with genotype 1b infection
had higher SVR12 rates than those with 1a infection (90% to 100% vs. 86% to 97%).
Serious adverse events leading to discontinuations — mostly grade 3–4 alanine aminotransferase elevations —
were uncommon (<2%) in both studies.
COMMENT
These two trials show promise for another fixed-dose single-pill regimen for the treatment of genotype 1 HCV
infection. Response rates were ≥87% in all groups, including patients who had cirrhosis or were treatment-
experienced. Ribavirin will generally not be required, except for treatment-experienced individuals. Although Daclatasvir has
this regimen is not yet FDA approved, we should expect approval of many of these next-generation regimens been approved
during the second half of 2016. by the FDA, but
asunaprevir and
— Atif Zaman, MD, MPH beclabuvir have
Oregon Health and Science University, Portland not.
NEJM Journal Watch Gastroenterology, published May 11, 2015
46
The Next Single-Pill HCV Regimen?

A 12-week regimen of a once-daily pill combining grazoprevir and elbasvir was highly effective in curing
HCV genotypes 1, 4, and 6 infections.
Zeuzem S et al. Grazoprevir-elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients
with chronic HCV genotype 1, 4, or 6 infection: A randomized trial. Ann Intern Med 2015 Apr 24; [e-pub].
(http://dx.doi.org/10.7326/M15-0785)
ARTICLE SUMMARY
Work continues in the effort to develop a core set of hepatitis C virus (HCV) infection treatment regimens that
require no more than 12 weeks of therapy, are effective in all genotypes, and are not only interferon-free, but also
ribavirin-free.
In the current industry-funded, phase III trial, investigators assessed the efficacy of a fixed-dose combination
of grazoprevir (an NS3/4A protease inhibitor; 100 mg) and elbasvir (an NS5A inhibitor; 50 mg) in treatment-
naive patients with HCV genotype 1, 4, or 6 infection. They randomized 421 participants, stratified by genotype
and fibrosis level, in a 3:1 ratio to receive immediate or delayed treatment with grazoprevir-elbasvir once daily
for 12 weeks. The delayed treatment group received placebo for 12 weeks and, at study week 16, received the open-
label, active drug. Among the study cohort, 22% had cirrhosis, 37% were nonwhite, and 91% had genotype 1
infection. The primary endpoint was sustained virologic response 12 weeks after stopping therapy (SVR12),
which was compared with a historical SVR12 rate of 73%.
Among patients receiving immediate treatment, SVR12 rates were 95% overall, 92% for genotype 1a, 99% for
genotype 1b, 100% for genotype 4 (n=18), 80% for genotype 6 (n=10), 97% for patients with cirrhosis, and 94%
for patients without cirrhosis. The rate of serious adverse events was similar among the treatment and placebo
groups — approximately 3%.
COMMENT
A 12-week course of this single-pill, combination regimen had high cure rates for HCV genotypes 1, 4, and 6
infections, regardless of whether patients had cirrhosis. This was accomplished without interferon or ribavirin.
As this study included only treatment-naive patients and cohort sizes were small for genotypes 4 and 6 infection,
additional studies will be needed in these subpopulations. Nonetheless, we will soon have another single-pill
regimen, in addition to the current FDA-approved sofosbuvir-ledipasvir regimen, in our armamentarium.

NEJM Journal Watch Gastroenterology, published Apr 24, 2015
47
WHAT IS THE FUTURE OF HEPATITIS C TREATMENT?

Cost resistance (by payers, uninsured patients, and pharmacies) is a formidable barrier to a blissful future
in which nearly all patients found to have latent hepatitis C upon screening can be cured by the prescription
of a 3-month regimen of pills. Patients in low-income countries are especially unlikely to benefit from these
treatments until the cost issue is addressed.
We present here a potpourri of NEJM Group content related to the global and practical issues that affected the
development of the new DAAs and continue to affect their use in clinical settings.
48
Perspective april 10, 2014
Curing Chronic Hepatitis C — The Arc of a Medical Triumph

Raymond T. Chung, M.D., and Thomas F. Baumert, M.D.
C hronic hepatitis C is a major

cause of liver cirrhosis and
hepatocellular carcinoma world
ing genuine prospects for the first
comprehensive cure of a chronic
viral infection in humans. This
sive HCV was isolated with the
use of a new expressioncloning
approach that generated a library
wide. Some 130 million to 170 success can be traced to impor of complementary DNA from in
million people, or about 3% of tant scientific, clinical, and reg fectious plasma.1
the world’s population, are chron ulatory developments. The subsequent molecular char
ically infected with the hepatitis C The history of HCV’s discovery acterization of the viral genome
virus (HCV). In the United States, and antiviraldrug development enabled several important discov
chronic hepatitis C, the most com offers a striking example of the eries. First, it revealed HCV to be
mon cause of liverrelated death effect of advances in biomedical a positivestranded RNA virus
and reason for liver transplanta research on disease outcome (see that replicates its genome direct
tion, recently eclipsed human table). The discovery of HCV 25 ly into RNA without traversing a
immunodeficiency virus (HIV) in years ago showed the importance DNA intermediate, so that unlike
fection as a cause of death. The of new scientific approaches: HIV or hepatitis B virus, it lacks
development of directacting anti whereas past virus discovery had a latent, nuclear form that defies
viral agents (DAAs) has revolu relied on direct visualization of ready immunologic clearance. In
tionized HCV treatment by offer viral particles, the previously elu stead, it requires continuous rep
Key Milestones and Their Effects on the Development of Curative Antiviral Treatment for Chronic Hepatitis C.*
Key Milestone Effects

Scientific
Expression cloning of HCV Discovery of viral genome, genomic organization, and viral genotypes; diagnos-
tic assays; safety of blood products
Model systems for viral replication in cell Screening and discovery of direct-acting antiviral agents targeting the HCV
culture (replicons) and ultrastructural NS3/4A protease, NS5B polymerase, and nonstructural protein NS5A
characterization of nonstructural proteins
HCV infectious-tissue culture model Entry and assembly inhibitors; host-targeting agents as adjunctive therapies
Clinical
Interferon-based treatment Discovery that HCV infection is curable; starting point for initial add-on combi-
nations with direct-acting antiviral agents
Successful HIV drug development Combination of potent agents from two or more classes with nonoverlapping resis-
tance profiles produced effective viral suppression without resistance selection
Regulatory
FDA policy Enabled rapid clinical development of direct-acting antiviral agents by permitting
phase 2 studies of all oral regimens without standard-of-care comparators
* FDA denotes Food and Drug Administration, HCV hepatitis C virus, and HIV human immunodeficiency virus.
49
1576 Copyright © Massachusetts Medical Society. All rights reserved.
n engl j med 370;17 nejm.org april 24, 2014
PE RThe
Source: New
S PE England
C T IV E Journal of Medicine
Curing Chronic Hepatitis C
lication for its existence — an In many ways, antiviral devel was clinically effective. It amount
observation that would be lever opment in HCV was guided by the ed to a holding strategy, however,
aged for the design of strategies HIV therapeutic experience and, since its effectiveness was limit
to permanently clear the virus. In accordingly, quickly moved to ed by the sideeffect profile of
addition, molecular characteriza more practicable paradigms. HCV injected interferon regimens and
tion resulted in an appreciation encodes a highly errorprone RNA firstgeneration protease inhibi
of viral genotypes, which led to polymerase that generates extra tors, which induce cytopenias, de
critical epidemiologic discoveries ordinary heterogeneity of the viral pression, autoimmunity, and rash;
and the development of appropri species within infected persons. these toxic effects were particu
ate genotypespecific therapeutic Thus, it came as little surprise larly prominent in patients with
regimens. that initial monotherapy trials of cirrhosis.
Finally, it fostered the creation
of several cellculture systems to It may be possible to imagine the global
explicate the viral life cycle, virus–
host interactions, and pathogene eradication of HCV infection, but three
sis.2 Because of initial difficulty
in cultivating the virus, an impor major challenges remain: infection
tant milestone was the construc is often diagnosed at a late stage,
tion of subgenomic selectable
replicons harboring the viral non the high cost of direct-acting antivirals
structural proteins (NS3–5) re
sponsible for genome replication. may lead to selective use,
The use of replicons permitted ef and reinfection remains possible.
ficient screening, testing, or both
of several classes of DAAs that
blocked these proteins, whose the first HCV protease inhibitors Against this backdrop, the de
structures were themselves suc were thwarted by rapid selection velopment of HCV nucleoside in
cessfully crystallized and eluci of preexisting resistant variants. hibitors, nonnucleoside inhibitors,
dated. These include inhibitors Fortunately, the longrunning and NS5A inhibitors presented the
of NS3/4A protease, NS5A, and standard of care, the broadly act opportunity to apply to HCV the
both nucleoside and nonnucleo ing antiviral cytokine interferon HIV combinationtherapy princi
side NS5B polymerase inhibitors.3 alfa, which inhibits HCV replica ple, whereby a combination of
The subsequent discovery of a tion not by binding viral proteins potent agents from two or more
viral isolate that efficiently in but by inducing hundreds of host classes with nonoverlapping resis
fected a human hepatoma cell genes to produce an antiviral in tance profiles could provide rapid
line enabled the expansion of the tracellular state, combined with and potent suppression of viral
arsenal of therapeutic classes to ribavirin, an agent with both anti replication and prevent emergence
include inhibitors of viral entry, viral and immunomodulatory of resistant variants. In theory,
translation, and assembly, as well properties, showed activity against this regimen, applied for sufficient
as inhibitors that block host pro both proteaseinhibitor–resistant duration, could achieve the goal
teins or microRNAs that are es and wildtype virus. Thus, a key of high cure rates and freedom
sential for maintenance of the first step in the therapeutic revo from dependence on interferon.
viral life cycle. Because replicons lution was the addition of a pro But additional steps were re
and tissueculture models largely tease inhibitor to the backbone of quired to get from these inter
recapitulate in vivo viralreplica peginterferon and ribavirin. This ferontethered regimens to trials
tion behavior, researchers were strategy succeeded in boosting of investigational DAAs in com
able to develop DAA candidates rates of sustained virologic re bination. Traditional study designs
rapidly by circumventing lengthy sponse, or viral cure, from about had, until recently, used a stan
and costly efficacy studies in the 45% to approximately 75% among dardofcare comparator for new
chimpanzee, the only viable ani patients with HCV genotype 1 in agents, which in the case of HCV
mal model of HCV. fection and proved that a DAA meant using an interferonbased
n engl j med 370;17 50

nejm.org april 24, 2014 1577
Curing Chronic Hepatitis C
therapy in the control group — an Still, some drugdevelopment time, effective HCV screening pro
unappealing prospect for many hurdles lie ahead. Although they grams, including full implemen
patients. Buoyed by the success of have achieved spectacular re tation of birthcohort screening
combination HIV therapies and the sponse rates in latestage clinical in the United States, the estab
knowledge that resistance vari trials, DAAs must fulfill their lishment of access to affordable
ants in HCV were not predicted to promise in the real world. Given treatment in low and middle
persist as they do in HIV, the historical trends in realworld pop income countries, and strategies
Food and Drug Administration ulations, a minor but substantial for reducing the risk of transmis
agreed to permit phase 2 trials to fraction of some patient groups sion (e.g., safe injection practic
use new combinations of HCV will probably need alternative ap es) will probably be needed to
DAAs without requiring a stan proaches; these include patients control HCV infection on a global
dardofcare comparator. This de with coexisting conditions such scale. The introduction of DAAs
cision proved catalytic. Because of as renal failure, hepatic decom represents a major breakthrough,
the short durations of, and rapid pensation, or a liver transplant, but it is only a first step toward
enrollment in, these studies, the as well as those with previous eliminating HCV globally.
pace of ensuing clinical drug de failure of a DAA combination. For Disclosure forms provided by the authors
velopment has been breathtaking. such patients, new treatments are available with the full text of this article
These trials have shown that may be required, including host at NEJM.org.
the combination approach is not targeting agents or inhibitors of
From the Liver Center, Gastrointestinal Divi-
only viable in concept, but also viral entry or assembly.5 sion, and the Department of Medicine,
capable of producing sustained It may now be possible to Massachusetts General Hospital, and Har-
virologic response rates exceeding imagine the global eradication of vard Medical School — both in Boston
(R.T.C., T.F.B.); and INSERM Unité 1110, In-
90%, with the use of interferon HCV infection, but three major stitut de Recherche sur les Maladies Virales
free, alloral combinations. Just as challenges remain. First, in the et Hépatiques, Université de Strasbourg;
impressively, several absence of effective screening and Institut Hospitalo-Universitaire, Pôle
An audio interview Hépato-digestif, Hôpitaux Universitaires
roads appear to be programs, HCV infection is often de Strasbourg — all in Strasbourg, France
with Dr. Chung
is available at NEJM.org capable of leading diagnosed at a late stage (in high (T.F.B.).
to the same destina income countries) or seldom diag
tion; combinations of several dif nosed at all (in low or middle This article was published on April 10, 2014,
at NEJM.org.
ferent classes have all yielded income countries). Second, the
high rates of sustained virologic high cost of DAAs will preclude 1. Choo QL, Kuo G, Weiner AJ, Overby LR,
response in phase 2 studies. their use in most infected patients Bradley DW, Houghton M. Isolation of a
Phase 3 studies of many of these in low or middleincome coun cDNA clone derived from a blood-borne
Approvals of non-A, non-B viral hepatitis genome. Sci-
combinations are completed or tries; in highincome countries, ence 1989;244:359-62.
several
under way, and approvals of the the need for payers to provide 2. Scheel TKH, Rice CM. Understanding the
regimens first of these regimens should be major resources for HCV treat hepatitis C virus life cycle paves the way for
have now highly effective therapies. Nat Med 2013;19:
forthcoming within the year. Late ment may lead to the selective 837-49.
occurred. phase studies also show that DAA use of DAAs for certain patient 3. Schaefer EAK, Chung RT. Anti-hepatitis C
combinations are capable of bridg subgroups. Third, reinfection re virus drugs in development. Gastroenterol-
ogy 2012;142(6):1340.e1-1350.e1.
ing most of the performance gap mains possible even after success 4. Ghany MG, Liang TJ. Current and future
between moreconventional pop ful curative therapy. therapies for hepatitis C virus infection.
ulations of previously untreated Ultimately, a preventive vaccine N Engl J Med 2013;369:679-80.
5. Zeisel MB, Lupberger J, Fofana I, Bau-
patients and populations that have would be desirable for the global mert TF. Host-targeting agents for preven-
historically been difficult to treat, eradication of HCV, but the virus’s tion and treatment of chronic hepatitis C —
including patients with cirrhosis, extraordinary sequence heteroge perspectives and challenges. J Hepatol 2013;
58:375-84.
HIVcoinfected persons, and pa neity and ability to evade host im
tients who have not had a re mune responses pose challenges DOI: 10.1056/NEJMp1400986
sponse to conventional interferon for the development of a broadly Copyright © 2014 Massachusetts Medical Society.
based therapies.4 protective vaccine. In the mean
1578 n engl j med 370;17 51

nejm.org april 24, 2014
Source: NEJM Physician’s First Watch
Hepatitis C Drug’s Price Draws Legislative Attention, Stock Analysts Sanguine

Physician’s First Watch, published March 24, 2014
NEWS SUMMARY
Sovaldi (sofosbuvir), which received FDA approval last December to treat hepatitis C, costs an even $1000 per
pill — or $84,000 for a 12-week course of treatment. That has legislators calling for the manufacturer to explain
the price.
In a March 20 letter to Gilead Science’s CEO, three members of the House Committee on Energy and Commerce
write that, because hepatitis C is prevalent in low-income patients, “the affordability problems are likely to be
particularly acute for state Medicaid programs and those patients served by these programs.”
They request that Gilead explain how it arrived at the price, reminding the company of the value afforded by the
FDA’s priority review.
The New York Times reports that the letter sent Gilead’s stock price down almost 5% on Friday. However, it quoted
a Deutsche Bank analyst: “We just look at this letter as a little bit of noise.”
— Joe Elia
Physician’s First Watch
52
Source: The New England Journal of Medicine T h e n e w e ng l a n d j o u r na l of m e dic i n e
edi t or i a l
Therapy for Hepatitis C — The Costs of Success

Jay H. Hoofnagle, M.D., and Averell H. Sherker, M.D.
Welcomed and exciting results from three large, ment week 12 was 94%. In this group of pa-
controlled trials of different regimens of oral anti- tients, the presence of cirrhosis was associated
viral agents for chronic hepatitis C, genotype 1, with a slightly lower response rate (88%, vs. 95%
have now been published in the Journal.1-3 The without cirrhosis), but with the longer course of
regimens all included the combination of ledi- treatment (24 weeks), these differences disap-
pasvir and sofosbuvir, two new direct-acting anti- peared (100% in both groups).2 Preliminary
viral agents with potent activity against hepati- studies with interferon-free drug combinations
tis C virus (HCV). The two drugs were given as in patients with other HCV genotypes (2 or 3)
a single tablet once daily for 8, 12, or 24 weeks, suggest that high rates of response can be ex-
with or without ribavirin. The results were con- pected with those HCV strains as well.5
sistent and striking: the various regimens yield- The combined results of the three trials in-
ed rates of sustained virologic response of 93% clude 1952 patients, of whom 97% had a sus-
to 99%. The combination of ledipasvir and so- tained virologic response. Among the 3% who
fosbuvir alone (without ribavirin) for 12 weeks did not have a response, almost half were lost to
was associated with response rates of 94% in the follow-up or withdrew consent. Only 2 patients
ION-2 study and 99% in the ION-1 study.1,2 Ex- did not have an undetectable level of HCV RNA
tending therapy to 24 weeks increased the rate that was maintained during treatment (on-treat-
minimally (to 98% and 99%, respectively). In ment virologic failure). Furthermore, the relapse
contrast, adding ribavirin provided no further rate after stopping therapy was only 2%. Relapses
benefit, regardless of duration. In previously un- were more common with shorter courses of
treated patients without cirrhosis, shortening the therapy: 5% of patients who received 8 weeks
duration of therapy (without ribavirin) to 8 weeks of treatment had a relapse, as did 2% of those
did not lessen the rate of response (94%, vs. 95% who received 12 weeks and 0.2% of those who
with 12 weeks of therapy in the ION-1 study).3 received 24 weeks of treatment. Trials focusing
Importantly, the single-tablet regimen was easy on retreatment of these rare patients with re-
to administer and had few side effects; among lapse are ongoing and will provide important
the 539 patients who received ledipasvir and so- guidance.
fosbuvir alone for 12 weeks in these three trials, Ledipasvir and sofosbuvir are not the only
only 2 stopped therapy early because of adverse promising antiviral agents for hepatitis C on the Three more
events. near horizon. Several other all-oral antiviral regi- all-oral
The rates of response to ledipasvir and sofos- mens have performed similarly in phase 2 stud- regimens are
buvir were virtually the same in all subgroups of ies, with sustained response rates in the range now approved.
patients, regardless of patients’ age, sex, race, of 90% or higher.6,7 Thus, there are likely to be
liver-enzyme levels, HCV genotype (1a vs. 1b), several options for oral therapy of hepatitis C
preexisting antiviral resistance variants, or host within the next year.
genetic factors. Even in the difficult-to-treat pa- The availability of effective, oral regimens of
tients who had not had a sustained response to a therapy for hepatitis C will lead to major changes
previous course of the most effective interferon- in the management of this disease and probably
based therapies,4 the response rate at post-treat- affect both its morbidity and its mortality. Since
n engl j med nejm.org 1

53
editorial
the first use of antiviral therapy for chronic hep- that they are infected.12 Public health efforts are
atitis C almost 30 years ago,8 treatment has now under way to identify persons with HCV in-
been based on alpha interferon and was limited fection and to direct them to medical care.13
by the common and sometimes serious side ef- With the present estimates of costs, however,
fects of this cytokine, as well as the need for up treating even half the HCV-infected persons in
to a year of therapy and the limited response the United States would add billions of dollars
rates of 50% or less, even among carefully se- to an already overburdened medical care system.
lected patients. In patients with coexisting con- Costs alone cast a pall over the stunning success
ditions such as human immunodeficiency virus in achieving the long-hoped-for goal of a safe
(HIV) infection, an autoimmune disorder, solid- and effective therapy for hepatitis C.
organ transplant, active substance abuse, or se- Disclosure forms provided by the authors are available with
rious heart, renal, or psychiatric disease, inter- the full text of this article at NEJM.org.
feron was usually contraindicated and, if given, From the Liver Diseases Research Branch, Division of Digestive
had a high rate of adverse events and was often Diseases and Nutrition, National Institute of Diabetes and Di-
not effective. In real-life situations, fewer than gestive and Kidney Diseases, National Institutes of Health,
Bethesda, MD.
half the HCV-infected persons qualify for inter-
feron therapy, many patients decline treatment, This article was published on April 12, 2014, at NEJM.org.
and response rates can be far lower than 50%.9
Furthermore, the management of therapy re- 1. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofos-
buvir for previously treated HCV genotype 1 infection. N Engl J
quires physicians and health care staff with Med. DOI: 10.1056/NEJMoa1316366.
special expertise and experience. It is hardly 2. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir
surprising that, despite the availability of inter- for untreated HCV genotype 1 infection. N Engl J Med. DOI:
10.1056/NEJMoa1402454.
feron-based therapy for more than 20 years, the 3. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and
mortality from hepatitis C in the United States sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis.
has continued to increase and now exceeds that N Engl J Med. DOI: 10.1056/NEJMoa1402355.
4. Liang TJ, Ghany MG. Current and future therapies for hepa-
from HIV infection.10 titis C virus infection. N Engl J Med 2013;368:1907-17.
The limitations and medical barriers to treat- 5. Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide poly-
ment, however, may now largely disappear. The merase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl
J Med 2013;368:34-44.
ease of administration, short duration of treat- 6. Suzuki Y, Ikeda K, Suzuki F, et al. Dual oral therapy with
ment, and minimal side effects of all-oral regi- daclatasvir and asunaprevir for patients with HCV genotype 1b
mens will probably mean that most persons will infection and limited treatment options. J Hepatol 2013;58:655-
62.
qualify for therapy. Collectively, these regimens 7. Kowdley KV, Lawitz E, Poordad F, et al. Phase 2b trial of in-
promise to transform hepatitis C from a condi- terferon-free therapy for hepatitis C virus genotype 1. N Engl J
tion requiring complex, unsatisfactory therapies Med 2014;370:222-32.
8. Hoofnagle JH, Mullen KD, Jones DB, et al. Treatment of
and specialist care to one that can be effectively chronic non-A, non-B hepatitis with recombinant human alpha
treated and easily managed by a general physi- interferon: a preliminary report. N Engl J Med 1986;315:1575-8.
cian with few contraindications and side effects. 9. Kramer JR, Kanwal F, Richardson P, Mei M, El-Serag HB.
Gaps in the achievement of effectiveness of HCV treatment in
Unfortunately, not all barriers to treatment national VA practice. J Hepatol 2012;56:320-5.
will be lifted. The major limitation remaining 10. Ly KN, Xing J, Klevens RM, Jiles RB, Ward JW, Holmberg SD.
will be economic. The current cost of a 12-week The increasing burden of mortality from viral hepatitis in the
United States between 1999 and 2007. Ann Intern Med 2012;
regimen of sofosbuvir alone is $84,000, or 156:271-8. [Erratum, Ann Intern Med 2012;156:840.]
$1,000 per tablet.11 The addition of ledipasvir 11. Sofosbuvir (Sovaldi) for chronic hepatitis C. Med Lett Drugs
will add to the costs, and these estimates do not Ther 2014;56:51-6.
12. Holmberg SD, Spradling PR, Moorman AC, Denniston MM.
include expenses for diagnostic assays, monitor- Hepatitis C in the United States. N Engl J Med 2013;368:1859-61.
ing, and physician visits. 13. Recommendations for the identification of chronic hepati-
The predicted costs of the new oral antiviral tis C virus infection among persons born during 1945–1965.
MMWR Recomm Rep 2012;61(RR4):1-32.
agents are as breathtaking as their effectiveness.
Chronic hepatitis C is estimated to affect 3.2 mil- DOI: 10.1056/NEJMe1401508
lion Americans, half of whom may not be aware Copyright © 2014 Massachusetts Medical Society.
2 n engl j med
54 nejm.org
Consider Clinical Effectiveness in Cost Assessments of HCV Regimens

Use of previous-generation, telaprevir-based therapy cost $84,000 per patient but $189,000 per sustained
virologic response.
Bichoupan K et al. Costs of telaprevir-based triple therapy for hepatitis C: $189,000 per sustained virological response.
Hepatology 2014 Oct; 60:1187. (http://dx.doi.org/10.1002/hep.27340)
ARTICLE SUMMARY
In the debate over the high costs of new interferon-free and ribavirin-free regimens for hepatitis C virus (HCV)
infection, the real cost of previous-generation, protease inhibitor– and interferon-based regimens in clinical prac-
tice should be taken into account.
In a single-center study, investigators identified patients who had undergone telaprevir-based therapy for genotype
1 HCV infection and calculated their use of resources and costs, including pretreatment costs (lab and imaging
tests, office visits), on-treatment costs (labs, office visits, cost of therapy, adverse-effect management), and post-
treatment costs (labs, office visits, adverse-effect management). Direct costs were calculated using RED BOOK,
the Healthcare Cost and Utilization Project database, and Medicare reimbursement databases. Costs were ex-
pressed in 2012 U.S. dollars. Cost per sustained virologic response (SVR) was calculated by dividing the median
cost by the SVR rate.
Of 147 patients, 35% had stage 3 or 4 fibrosis, 19% were black, 11% were HIV-positive, and 73% had previously
failed dual therapy. After telaprevir-based therapy, 44% achieved SVR, and 47% prematurely discontinued therapy
(of these, 87% did not achieve SVR). The total cost of care was $11.56 million, including $10.3 million for HCV
medications, $0.88 million for adverse-effect management, $0.23 million for office visits, and $0.15 million for
labs and imaging. The median cost of care was $83,721 per patient, and the median cost per SVR was $189,338.
COMMENT
In comparison with the new-generation, interferon-free HCV regimens, the first-generation, protease inhibitor–
based regimens seem to be less expensive, but in this study, their cost more than doubled when their low SVR rate
was considered. Clinical effectiveness, and not just drug prices, must be taken into account in ongoing discussions
of the costs of HCV therapies.

NEJM Journal Watch Gastroenterology, published October 16, 2014
55
Duration of Interferon-Free Regimens for HCV Infection:

How Short Can We Go?
Six weeks seems feasible based on preliminary data, and shorter courses may be possible.
Kohli A et al. Virological response after 6 week triple-drug regimens for hepatitis C: A proof-of-concept phase 2A cohort
study. Lancet 2015 Jan 12; [e-pub ahead of print]. (http://dx.doi.org/10.1016/S0140-6736(14)61228-9)
ARTICLE SUMMARY
With the advent of potent, interferon-free, direct-acting antiviral agents for hepatitis C virus (HCV) infection,
treatment duration is typically 12 weeks and, in certain cases, 8 weeks. Shorter duration of treatment likely im-
proves compliance and can reduce cost. In the current proof-of-concept, phase IIa, open-label study, researchers
evaluated the efficacy of a shorter course of only 6 weeks.
Sixty treatment-naive patients with HCV genotype 1 infection were sequentially enrolled into one of three groups
receiving the following regimens: 12 weeks of a once-daily combination tablet of sofosbuvir (400 mg) plus ledipasvir
(90 mg) (SOF-LDV), 6 weeks of SOF-LDV plus GS-9669 (500 mg daily; a nonnucleoside NS5B thumb site 3 inhibi-
tor of HCV polymerase), or 6 weeks of SOF-LDV plus GS-9451 (80 mg daily; an inhibitor of the HCV NS3/4A
protease). The primary endpoint was sustained virologic response, defined as an undetectable HCV RNA level
at 12 weeks after treatment ended (SVR12).
The majority of participants were black (88%), had genotype 1a infection (70%), and had a baseline HCV RNA
level >800,000 IU/mL (70%). Among the 12-week SOF-LDV group, SVR12 was 100%, and among the two 6-week
groups (SOF-LDV plus GS-9669 and SOF-LDV plus GS-9451), SVR12 was 95% (19 of 20 patients in each group).
One patient was lost to follow-up after treatment with SOF-LDV and GS-9451. No patients discontinued
treatment.
COMMENT
These results demonstrate that it may be possible to shorten HCV treatment from the typical duration of 12 weeks
down to 6 weeks. The SVR12 rates were similar whether a nonnucleoside or a protease inhibitor was added to
SOF-LDV. This suggests that adding a third potent agent with a different mechanism of action from that of
SOF-LDV may help us achieve shorter and shorter treatment durations while maintaining nearly universal cure
rates. Further studies are warranted.
56
It’s OK to Limit Who Prescribes HCV Therapy, but Insurers Shouldn’t Be Deciding
NEJM Journal Watch Blog: HIV and ID Observations, published September 7, 2014
BLOG POST
Some insurers would like to limit the prescribing of HCV treatment to gastroenterologists, hepatologists, or
infectious diseases specialists. Not surprisingly, this doesn’t sit well with either the HIV Medicine Association
(HIVMA) or the American Academy of HIV Medicine (AAHIVM), both of which have long acknowledged that
some of the most seasoned HIV providers are generalists:
“There is no medical rationale for excluding some HIV providers from prescribing HCV medications,”
said Donna Sweet, MD, AAHIVS, chair of the AAHIVM Board of Directors, an internist and HIV specialist.
“HIV providers who have been treating HCV/HIV co-infected patients for years are uniquely qualified to
manage potential drug toxicities and side effects stemming from combining treatment for HIV and HCV.”
I completely agree. Who is more qualified to prescribe HCV treatment, a provider with extensive experience man-
aging HIV/HCV coinfection, or a gastroenterologist who has spent 90+% of his/her career practicing what some
have called “lumen-oriented medicine”? And there are many ID specialists who do only inpatient ID consults —
they would have as much chance correctly identifying ledipasvir, dasabuvir, and daclatasvir as winning the
lottery.
The problem, of course, is that whether they say it or not, a motivation of the insurers is to delay treatment. I’m not
so cynical to think it’s their only motivation, but it’s inevitably one of them. In the inherent conflict of interest that
exists between medical insurance companies and expenditures for expensive short-term therapies, anything that
delays treatment increases the likelihood that 1) other options will become available that drive down costs, or 2)
the patient’s insurance will change, and it won’t be their problem anymore.
And as everyone learns in Econ 101, dollars spent in the future are worth less than those expended now — it’s
called “discounting,” remember?
But is the concept of limiting who prescribes HCV therapy inherently wrong? Of course not — the benefit to the
patient is so great, and the financial stakes are so high, it is eminently reasonable that only those qualified to do so
should treat HCV.
It just shouldn’t be that the companies paying for the treatment, on their own, get to decide who the qualified
providers are — they’re hardly disinterested enough to make this judgment wisely.
— Paul E. Sax, MD
57
HCV Treatment for HIV-Coinfected Patients — Getting Better All the Time
Two open-label studies confirm that a once-daily combination of sofosbuvir plus either ledipasvir or
daclatasvir cures hepatitis C virus infection in most such patients.
Naggie S et al. Ledipasvir and sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med 2015 Jul 21; [e-pub].
Wyles DL et al. Daclatasvir plus sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med 2015 Jul 21; [e-
pub]. (http://dx.doi.org/10.1056/nejmoa1503153)
ARTICLE SUMMARY
Due to shared transmission routes, hepatitis C virus (HCV) affects many people living with HIV infection. De-
spite better HIV treatment options, HCV continues to be a major cause of morbidity and mortality in such indi-
viduals. The newer HCV treatment regimens have been proven efficacious and well tolerated in HIV-uninfected
patients, but more data are needed regarding coinfected individuals, given the significant drug interactions be-
tween antiretrovirals and anti-HCV medications.
Now, in two manufacturer-supported, open-label trials, researchers have examined the efficacy of once-daily
combination regimens involving the nucleotide analog inhibitor sofosbuvir plus one of two FDA-approved NS5A
inhibitors — ledipasvir (S/L; n=335; 55% treatment-experienced and 20% with compensated cirrhosis) or daclat-
asvir (S/D; n=203; 25% treatment-experienced and 14% with cirrhosis).
Cure rates (i.e., rates of sustained virologic response at posttreatment week 12) were 96.1% overall for the 12-week
S/L regimen, 97.0% for treatment-naive patients with 12 weeks of S/D, 76.0% for treatment-naive patients with 8
weeks of S/D, and 98.1% for treatment-experienced patients with 12 weeks of S/D. Side effects were generally
mild, and not a single patient stopped therapy because of adverse events.
COMMENT
Although some of the subgroups were too small to allow firm conclusions, S/L and S/D resulted in extraordinarily
high HCV cure rates in HIV-coinfected patients in a variety of circumstances (HCV of various genotypes; partic-
ipants with cirrhosis or early infection, pretreated or naive). Daclatasvir, despite its seeming efficacy, suffers a ma-
jor competitive disadvantage, given that the S/D combination costs significantly more than S/L coformulated sin-
gle-tablet regimen. And although S/D has previously demonstrated good efficacy in patients with genotype 3
monoinfection, this study did not include enough such patients to allow evaluation of efficacy. Another hope —
that the addition of daclatasvir would allow shortening therapy duration in treatment-naive patients and thereby
decrease treatment cost — was tempered by the much-poorer response rate in the 8-week arm.
It is encouraging to see that we have a growing arsenal of interferon- and ribavirin-free once-daily options to
treat HIV/HCV-coinfected patients. Dosage adjustment for concomitant antiretroviral medications, as occurred
in the S/D trial, now allows successful treatment of more of these individuals. The unmet need is a more afford-
able option that would allow us not only to treat coinfected patients with advanced disease, but also to address
HCV at the population level without bankrupting the healthcare system.
— Helmut Albrecht, MD
University of South Carolina School of Medicine, Columbia
NEJM Journal Watch Infectious Diseases, published August 10, 2015
58
State Medicaid Programs Seek Discounts on Pricey Hepatitis C Drugs

Physician’s First Watch, published February 2, 2015
NEWS SUMMARY
Several state Medicaid programs are offering to make certain hepatitis C treatments the preferred therapies for
their beneficiaries in return for large rebates from the drugs’ makers, the Wall Street Journal reports. The high
cost of the newer HCV treatments, including Harvoni and Viekira Pak, have come under much scrutiny in recent
months.
This week, Missouri cut a deal with Viekira Pak’s manufacturer to make the treatment the state’s preferred option
(instead of Sovaldi) “in exchange for undisclosed rebates” — a move that may save the state $4.2 million in the
next fiscal year. Up to 25 states could end up making similar arrangements with the company.
The WSJ notes that large private insurers have been striking similar deals with drug makers. One such instance:
UnitedHealth Group has agreed to make Harvoni the preferred treatment for its beneficiaries in exchange for,
again, “undisclosed” discounts.
— Amy Orciari Herman

Physician’s First Watch
59
HCV Treatment Coverage Restrictions Among Medicaid Programs

Reimbursement eligibility criteria vary widely across states.
Barua S et al. Restrictions for Medicaid reimbursement of sofosbuvir for the treatment of hepatitis C virus infection in the
United States. Ann Intern Med 2015 Jun 30. (http://dx.doi.org/10.7326/M15-0406)
Canary LA et al. Limited access to new hepatitis C virus treatment under state Medicaid programs. Ann Intern Med
2015 Jun 30. (http://dx.doi.org/10.7326/M15-0320)
McCance-Katz EF and Valdiserri RO. Hepatitis C virus treatment and injection drug users: It is time to separate fact
from fiction. Ann Intern Med 2015 Jun 30. (http://dx.doi.org/10.7326/M15-0007)
ARTICLE SUMMARY
The new hepatitis C virus (HCV) treatment regimens are safe and highly effective but costly. Because of their
high price, many insurers, including Medicaid, have implemented coverage restrictions and prior-authorization
requirements.
To systematically evaluate state Medicaid policies for HCV treatment with sofosbuvir in the U.S., investigators
searched state Medicaid websites for reimbursement criteria data from the 50 states and the District of Columbia.
Data were limited to Medicaid fee-for-service beneficiaries only.
Reimbursement criteria were publicly available in 42 states, including D.C. (82%). Nine states provided no infor-
mation regarding their criteria, and Nevada did not have reimbursement criteria. Among the 42 programs with
restrictions, results were as follows:
• Eighty-one percent restrict coverage based on fibrosis stage (stage 4 only, 10%; stage 3–4 only, 64%; stages <3
covered, 7%).
• Sixty-nine percent restrict coverage based on prescriber type; half limit prescribing to specialists, and the other
half require consultation with a specialist.
• Eighty-eight percent include drug and alcohol use in eligibility criteria; 19% require evaluation of substance/
alcohol abuse, and 50% require a period of abstinence (6 months, most frequently) prior to starting HCV treat-
ment regardless of abuse history.
Editorialists argue against abstinence restrictions, citing evidence of similarly successful HCV treatment out-
comes in substance-use and non–substance-use populations alike. Moreover, they argue that from a public health
standpoint, treating HCV infection in people receiving substance use treatment would decrease the HCV risk pool
and reduce the risk for HCV infection in the general population.
COMMENT
These findings show wide variability among state Medicaid programs in eligibility criteria for HCV treatment re-
imbursement. These policies seem to be inconsistent with national recommendations from professional societies
(Infectious Diseases Society of America and the American Association for the Study of Liver Diseases) and, more-
over, may violate federal Medicaid laws. The restrictions are not surprising given the financial burden these costly
regimens have placed on the Medicaid system. However, as the authors note, policies that are intended to priori-
tize treatment for patients with the most immediate need should be based on clinical criteria and medical evi-
dence and then applied consistently across all Medicaid programs.

60
Hepatitis C: In Support of Age-Based Screening

Testing based on standard risks will miss most infections.
Smith BD et al. Hepatitis C virus antibody positivity and predictors among previously undiagnosed adult primary
care outpatients: Cross-sectional analysis of a multisite retrospective cohort. Clin Infect Dis 2015 Apr 15; 60:1145.
(http://dx.doi.org/10.1093/cid/civ002)
ARTICLE SUMMARY
Guidelines recently have begun to recommend hepatitis C virus (HCV) testing for all adults born between 1945
and 1965, without regard to specific risks for HCV infection. CDC investigators sought support for this policy
with a review of HCV prevalence among more than 200,000 adults who presented for primary care between 2005
and 2010 at four large health systems across the country.
Of 17,464 patients who were tested for HCV, 1115 (6.4%) were positive. Independent variables that correlated with
positive tests included certain demographic features (e.g., black race, Hispanic ethnicity, never married, male sex),
standard medical risks (i.e., intravenous drug use and elevated serum alanine aminotransferase), and member-
ship in the 1945–1965 birth cohort. A series of statistical assumptions allowed investigators to conclude that about
80% of HCV-positive patients would not have been identified on the basis of standard HCV risks alone.
COMMENT
This study joins others in supporting mass age-based screening for HCV. Diagnosing this infection has become
more important in the last year, now that effective, albeit expensive, therapy is available.
— Abigail Zuger, MD
Columbia University College of Physicians and Surgeons, New York
NEJM Journal Watch General Medicine, published April 30, 2015
61
Opposition to HCV Screening Raises a Few Interesting Points — But Has

Some Really Wacky “Facts”
NEJM Journal Watch Blog: HIV and ID Observations, published January 18, 2015
BLOG POST
Over in the British Medical Journal, there’s a provocative editorial
entitled, “Is widespread screening for hepatitis C justified?”
Based on the title alone, you can guess the authors’ answer to that
question — a resounding “No!”
By taking this position, of course, they are opposing some very da-
ta-driven and well-respected arbiters of policy and clinical practice.
These include not only the Centers for Disease Control — which started
recommending universal screening in 2012 to people born between
1945–1965 (the years of peak incidence) — as well as the World Health
Organization, and, for good measure, those staggeringly data-driven
folks from the U.S. Preventive Services Task Force (USPSTF).
Remember, these USPSTF guys are a scrupulous bunch, opposing many

forms of screening for insufficient evidence. Just the very fact that they
endorse HCV screening is almost reason enough to accept it as worth-
while. Indeed, they reversed their earlier opposition to HCV screening
with their latest review — and did so even before interferon-free therapies became standard of care!
(Why is it so hard to say and write that combination of letters? — “USPSTF” reminds me of the confirmation
codes that the airlines use for flights.)
The key points of the BMJ opinion piece go like this, roughly in order:
1. The natural history of hepatitis C suggests it is generally benign.

2. Achieving a “sustained virologic response,” or SVR, is only a surrogate marker for the important clinical end-
point of liver disease. Proof: Some people who achieve SVR still go on to have decompensated disease and
hepatocellular carcinoma.
3. SVR does not mean HCV is cured anyway.
4. Screening will be dangerous because the treatment could be more harmful than the disease; we also need long-
term safety data on the newer drugs.
5. Before we adopt widespread HCV screening, a large randomized trial should be done comparing broad to risk-
based screening, with clinical outcomes as the primary endpoint.
There’s always room for some dialogue in any policy statement, and the editorial does raise some important
points.
But let’s take these above positions one at a time:
1. Most people with HCV will never develop clinically significant liver disease. Yes, this is true, but HCV is still
the leading single cause of end-stage liver disease leading to liver transplantation in the USA; HCV can further-
more cause numerous non-hepatic complications; and a chronic infection with high rates of ongoing replication
is probably bad for general health, which almost certainly accounts for the higher rates of fatigue, nausea, pain,
and decreased quality of life in those with HCV versus those without.
62
2. SVR is only a surrogate marker. If you’re a real skeptic, you’d argue that the better clinical outcomes observed
in patients who achieve SVR versus those that don’t might be confounded by their better health at baseline. On
the other hand, many believe that the benefits of SVR have been convincingly shown through clinical cohorts,
adjustment of baseline characteristics, and improvement in liver histology among those who achieve SVR. And
what about those patients with SVR who still get liver-related illness? Most had advanced liver disease before
they were treated — one could argue that if they’d been diagnosed decades earlier and cured, their liver disease
never would have happened.
3. “Sustained virologic response is not a cure,“ writes the paper confidently. This is certainly a minority view, and
seems to be based on the existence of case reports of late relapses, with a frequency of no greater than 3% (and
probably lower). Isn’t the very existence of these papers good evidence that most of the time SVR is a cure? Why
would any of them be published unless they were exceedingly rare events?
4. Treatment is harmful — in most patients, more harmful than the disease. For currently relevant treatments,
they cite this paper, where “3% of participants taking sofosbuvir experienced serious adverse events compared
with 1% in the peginterferon plus ribavirin arm.” But these data are for any serious adverse event, not just those
that are drug-related. Bad things can happen to patients who are in clinical trials, especially trials that include
patients with chronic diseases — it doesn’t mean the drugs caused them. In trials of newer HCV drugs, espe-
cially those that don’t include interferon or ribavirin, serious adverse events that are conclusively drug-related
are extraordinarily rare. And one last thing: No review of HCV therapy today should list side effects of telaprevir
or boceprevir as a reason for avoiding treatment (both are cited). These drugs are no longer recommended —
and the former isn’t even available. Even interferon is rarely indicated today.
5. We need to do a large randomized strategy trial of broad versus targeted HCV screening with clinical out-
comes. It’s true we do not definitively know that broad screening will prevent liver disease or death beyond a
risk-based approach. But unfortunately, patients can be infected with HCV (and unaware of that fact) for de-
cades before showing up with advanced liver disease. Seems that a cheap, reliable blood test is highly justified
when we now have such safe and effective treatments.
I agree with the authors that longer-term follow-up data of treated patients are needed, especially using our cur-
rently available drugs.
The good news is that with thousands taking advantage of HCV therapy — including many patients who could
never be treated in the interferon era — and with over 90% of these patients cured (there, I said it), we shouldn’t
have to wait long.
— Paul E. Sax, MD
63
THE BOTTOM LINE

At this time (October 2015), a vaccine for HCV is not on the horizon; however, the recent advances in treat-
ment reviewed in this Collection represent a long stride toward the eradication of hepatitis C. While the
issue of affordability is worked out, a critical first step from a population standpoint is to aggressively screen
and identify persons infected with the hepatitis C virus, vaccinate for hepatitis A and B if indicated, manage
substance-abuse issues, and promote harm reduction. The next step — deciding who should receive treat-
ment — is equally critical but depends on evidence that is still emerging. At this juncture, a reasonable
general approach is to recommend treatment for patients at the highest risk for progressive liver disease,
which typically includes those with advanced (stage 3–4) liver fibrosis. For those at lower risk, treatment
may be offered if the patient is motivated and well-informed about the risks and benefits — and can afford
an all-oral regimen.
Time to roll up our sleeves and get to work!
64
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A Guide to Current Management

— Atif Zaman, MD, MPH

WHAT IS THE CURRENT LANDSCAPE OF HEPATITIS C THERAPY, AND HOW DID

8 Figure 1B: Cleavage and Replication of HCV with Targets of Therapy

9 Therapy of Hepatitis C — Back to the Future

WHAT IS THE CURRENT STANDARD OF CARE?

17 Ledipasvir and Sofosbuvir for Untreated HCV Genotype 1 Infection

27 ABT-450/r–Ombitasvir and Dasabuvir with or without Ribavirin for HCV

37 Sofosbuvir-Based Therapy for HCV Infection: The Results Are In

38 Sofosbuvir Works for Patients Who Cannot Take Peginterferon

39 Combined Simeprevir and Sofosbuvir Is Promising for HCV Genotype 1 Infection

40 Progress Toward All-Oral, Interferon-Free Therapy for HCV Genotype 1 Infection

41 Simeprevir, Sofosbuvir, and the Limitations of the COSMOS

43 Approval of Sofosbuvir/Ledipasvir Was Expected, but Still Is a Huge Advance

WHAT OTHER ALL-ORAL REGIMENS FOR PATIENTS WITH GENOTYPE 1 ARE

47 The Next Single-Pill HCV Regimen?

WHAT IS THE FUTURE OF HEPATITIS C SCREENING AND TREATMENT?

52 Hepatitis C Drug’s Price Draws Legislative Attention, Stock Analysts Sanguine

53 Therapy for Hepatitis C — The Costs of Success

55 Consider Clinical Effectiveness in Cost Assessments of HCV Regimens

59 State Medicaid Programs Seek Discounts on Pricey Hepatitis C Drugs

60 HCV Treatment Coverage Restrictions Among Medicaid Programs

61 Hepatitis C: In Support of Age-Based Screening

THE BOTTOM LINE

Natural History of Hepatitis C Virus (HCV) Infection

WHAT IS THE CURRENT LANDSCAPE OF HEPATITIS C THERAPY, AND

The editorial is presented here in its entirety.

Therapy of Hepatitis C — Back to the Future

Status with Regard to No. of Sustained Virologic Response

AOD regimen, 12 wk 205 90

Status with Regard to No. of Sustained Virologic Response

* HCV denotes hepatitis C virus.

n engl j med nejm.org

WHAT IS THE CURRENT STANDARD OF CARE?*

*As of October 1, 2015.

FDA-Approved, All-Oral Regimens for Hepatitis C

Sofosbuvir + “Can be “Can be “Can be “Can be Recommended Recommended N/R N/R

Simeprevir + Recommended N/R Recommended N/R N/R N/R N/R N/R

Ombitasvir/ Recommended Recommended Recommended Recommended N/R N/R N/R N/R

Lediplasvir + Recommended Recommended Recommended Recommended N/R N/R N/R N/R

Daclatasvir + N/R N/R N/R N/R N/R Recommended† N/R N/R

Ombitasvir/ N/R N/R N/R N/R N/R N/R Recommended N/R

New All-Oral Hepatitis C Regimens Are on the Horizon

Key Outcomes of Six Hepatitis C Drug Trials

Afdhal N et al. L/S2 Previously untreated 12 weeks 99%

Kowdley KV et al. L/S Previously untreated 8 weeks 94%

Afdhal N et al. L/S Nonresponders to previous 12 weeks 94%

Feld JJ et al. A/O/D/R3 Previously untreated 12 weeks 96%

Zeuzem S et al. A/O/D/R Nonresponders to previous 12 weeks 96%

Poordad F et al. A/O/D/R Cirrhotic (previously treated 12 weeks 92%

Ledipasvir and Sofosbuvir for Untreated

This article was published on April 12,

n engl j med 370;20 nejm.org 17

1890 n engl j med 370;20 nejm.org

n engl j med 370;20 nejm.org

1892 n engl j med 370;20 nejm.org

Table 1. Demographic and Clinical Characteristics of the Patients at Baseline.*

Characteristic 12-Wk Regimen 24-Wk Regimen

LDV–SOF LDV–SOF + RBV LDV–SOF LDV–SOF + RBV

n engl j med 370;20 nejm.org

Table 2. Response during and after Treatment.

Response 12-Wk Regimen 24-Wk Regimen

based therapies.4 protective vaccine. In the mean