long-term clearance of hepatitis c virus following interferon α-2b or peginterferon α-2b, alone or...

Long-term clearance of hepatitis C virus following interferona-2b or peginterferon a-2b, alone or in combination withribavirinM. P. Manns,1 P. J. Pockros,2 G. Norkrans,3 C. I. Smith,4 T. R. Morgan,5 D. H€aussinger,6

M. L. Shiffman,7 S. J. Hadziyannis,8 W. N. Schmidt,9 I. M. Jacobson,10 R. B�arcena,11

E. R. Schiff,12 O. S. Shaikh,13 B. Bacon,14 P. Marcellin,15 W. Deng,16 R. Esteban-Mur,17

T. Poynard,18 L. D. Pedicone,16* C. A. Brass,16* J. K. Albrecht16* and S. C. Gordon191Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; 2Division of Gastroenterology and

Hepatology, The Scripps Clinic, La Jolla, CA, USA; 3Department of Infectious Diseases, Sahlgrenska University Hospital, G€oteborg, Sweden;4Minnesota Gastroenterology and Division of Gastroenterology and Hepatology, University of Minnesota, Minneapolis, MN, USA; 5Gastroenterology

Section, VA Long Beach Healthcare System, Long Beach, CA, USA; 6Department of Internal Medicine, Gastroenterology, Hepatology and Infectious

Diseases, Heinrich Heine Universit€at, D€usseldorf, Germany; 7Liver Institute of Virginia, Bon Secours Health System, Richmond and Newport News,

VA, USA; 8Department of Medicine and Hepatology, Henry Dunant Hospital, Athens, Greece; 9Department of Internal Medicine, University of Iowa,

Iowa City, IA, USA; 10Division of Gastroenterology and Hepatology, Center for the Study of Hepatitis C, Weill Cornell Medical College, New York,

NY, USA; 11Gastroenterology Service, Hospital Ramon y Cajal, Madrid, Spain; 12Schiff Liver Institute/Center for Liver Diseases, University of

Miami Miller School of Medicine, Miami, FL, USA; 13Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of

Medicine, Pittsburgh, PA, USA; 14Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, MO, USA;15Department of Hepatology, University of Paris-Diderot, Beaujon Hospital, Clichy, France; 16Merck Sharp & Dohme Corp., a subsidiary of Merck

& Co., Inc., Whitehouse Station, NJ, USA; 17Liver Unit, Department of Medicine, Hospital Universitari Valle Hebron, Barcelona, Spain; 18Service

d’Hepatologie, Universit�e Pierre et Marie Curie Liver Center, Hopital La Piti�e Salpetri�ere, Paris, France; and 19Division of Gastroenterology and

Hepatology, Henry Ford Health Systems, Detroit, MI, USA

Received June 2012; accepted for publication December 2012

SUMMARY. Sustained virologic response (SVR) is the stan-

dard measure for evaluating response to therapy in patients

with chronic hepatitis C (CHC). The aim of this study was to

prospectively assess the durability of SVR in the pivotal stud-

ies of peginterferon (PEG-IFN) a-2b or IFN a-2b. We con-

ducted two phase 3b long-term follow-up studies of patients

previously treated for CHC in eight prospective randomized

studies of IFN a-2b and/or PEG-IFN a-2b. Patients who

achieved SVR [undetectable hepatitis C virus (HCV) RNA

24 weeks after completion of treatment] were eligible for

inclusion in these follow-up studies. In total, 636 patients

with SVR following treatment with IFN a-2b and 366 with

SVR following treatment with PEG-IFN a-2b were enrolled.

Definite relapse (quantifiable serum HCV RNA with no sub-

sequent undetectable HCV RNA) was reported in six patients

treated with IFN a-2b and three patients treated with PEG-

IFN a-2b. Based on these relapses, the point estimate for the

likelihood of maintaining response after 5 years was 99.2%

[95% confidence interval (CI), 98.1–99.7%] for IFN a-2band 99.4% (95% CI, 97.7–99.9%) for PEG-IFN a-2b. Suc-cessful treatment of hepatitis C with PEG-IFN a-2b or IFN a-2b leads to clinical cure of hepatitis C in the vast majority of

cases.

Keywords: clinical, cure, eradication, follow-up, longitudi-

nal.

Abbreviations: ALT, alanine aminotransferase; CHC, chronic hepatitis C; CI, confidence interval; FU, follow-up; HCC, hepatocellular

carcinoma; HCV, hepatitis C virus; IFN, interferon; LLD, lower limit of detection; LLQ, lower limit of quantitation; LTFU, long-term

follow-up; NGI, National Genetics Institute; PEG-IFN, pegylated interferon; RBV, ribavirin; SVR, sustained virologic response; ULN, upper

limit of normal.

Correspondence: Michael P. Manns, MD, Professor and Chairman, Department of Gastroenterology, Hepatology and Endocrinology, Medical

School of Hannover, Carl-Neuberg Str. 1, 30625 Hannover, Germany. E-mail: [email protected]

*Former employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA.

© 2013 Blackwell Publishing Ltd

Journal of Viral Hepatitis, 2013 doi:10.1111/jvh.12074

INTRODUCTION

The validity of using sustained virologic response (SVR) as

a surrogate for viral eradication in the treatment of

chronic hepatitis C (CHC) is based on follow-up studies

showing that most patients who attain SVR remain virus

free during many years of follow-up [1,2]. Recent data also

indicate that SVR is associated with a significant reduction

in the risk for mortality, with a hazard ratio for all-cause

mortality of 0.70 among patients with hepatitis C virus

genotype (G) 1 infection who attain SVR, when followed

up for a median duration of 3.8 years [3]. The present

study aimed to prospectively assess the durability of SVR in

patients with CHC who attained SVR after treatment with

peginterferon (PEG-IFN) a-2b or interferon (IFN) a-2b in

the pivotal prospective studies that defined the use of IFN

a-2b and PEG-IFN a-2b. In particular, this report provides

follow-up information on patients enrolled in the first PEG-

IFN a-2b plus ribavirin clinical trial that set the standard

of care for a decade [4].

METHODS

This analysis is based on two phase 3b, multicenter, long-

term follow-up studies of patients who achieved SVR after

treatment for CHC. The first study followed up patients

who received an IFN-containing regimen in six prospective

randomized studies of IFN a-2b (four of which have been

previously reported in three full publications) [5–7]; the

second study followed up patients who achieved SVR after

treatment with a PEG-IFN a-2b–containing regimen in two

international prospective clinical trials [4,8]. A full account

of the methodology employed in this long-term follow-up

study is provided in the Data S1.

In brief, the primary efficacy endpoint of this long-term

follow-up study was the durability of SVR. Long-term

SVR was defined as undetectable serum HCV RNA at post-

treatment follow-up week 24 of the initial treatment

protocol and no subsequent detectable serum HCV RNA.

Long-term relapse was defined as patients with SVR follow-

ing the initial treatment protocol and subsequent detect-

able HCV RNA during long-term follow-up. For patients

enrolled in the PEG-IFN a-2b studies [4,8], follow-up

assessments were scheduled for 1 year after attainment of

SVR and then yearly for an additional 4 years. For patients

enrolled in the nonpegylated IFN a-2b studies [5–7], fol-

low-up visits were scheduled for 6 months and 1 year after

attainment of SVR, then annually for 4 years.

The definition of long-term relapse was further differenti-

ated into definite relapse and nondefinite relapse. Definite

relapse was defined as quantifiable serum HCV RNA [above

the lower limit of quantitation (LLQ)] with no subsequent

undetectable HCV RNA during follow-up. In addition, fol-

low-up of the early IFN studies [5–7] included a stipulation

for a viral load >4 log copies/mL at late relapse and an

abnormal ALT ratio for categorization as definite relapse.

Nondefinite relapse was defined as: (i) detectable, but not

quantifiable, HCV RNA with no subsequent undetectable

HCV RNA during long-term follow-up, (ii) low-level

relapse, which was verified as undetectable when reana-

lyzed at a second laboratory or (iii) detectable HCV RNA

and then one or more subsequent assays showing unde-

tectable HCV RNA. Time to relapse was defined as the time

from the date of final treatment in the original study to the

date of first detectable HCV RNA during follow-up. The

Kaplan–Meier method was used to plot time to relapse and

estimate [with 95% confidence intervals (CIs)] 5-year con-

tinued sustained response.

Serum HCV RNA was measured annually during long-

term follow-up [TaqMan; Applied Biosystems, Foster City,

CA, USA; lower limit of detection (LLD) for 95% sensitivity

of 125 IU/mL] at the Schering-Plough Research Institute

Laboratory (Kenilworth, NJ, USA). Confirmatory testing

(Quest Nichols Laboratory, San Juan Capistrano, CA, USA)

using TaqMan (LLQ 50 IU/mL) was performed on a subset

of samples tested at the Schering-Plough Research Institute

Laboratory.

RESULTS

Durability of response following SVR with IFN a-2b+/� ribavirin

From the original treatment studies, 640 patients (549

treatment naive and 91 with prior relapse) attained SVR

and were enrolled in long-term follow-up (Data S1) [5–7].

Of the 640 patients enrolled, 636 patients were included

in the late relapse analyses and four subjects

were excluded due to lack of HCV RNA data after con-

firmed SVR. The median duration of follow-up for these

636 patients was 4.94 years.

Six patients had definite virologic relapse, with HCV

RNA >1000 copies/mL at 1 or more time points (Table 1).

In all patients, relapse was confirmed by either a positive

test result at a subsequent visit or a positive retest result

within the same visit window. All six patients had G1

infection, and four had baseline viral loads �3 9 106 cop-

ies/mL before the original treatment study (range, 3 9 106

–6.5 9 106). The original source of infection was paren-

teral (n = 3), transfusion related (n = 2) or sporadic/other

(n = 1). Two patients received 48 weeks of IFN a-2b plus

ribavirin, three were treated for 24 weeks (one with mono-

therapy) and one received 48 weeks of monotherapy. Four

patients relapsed after 6 months of follow-up, one patient

relapsed after 1 year and the final subject relapsed at year

5 after having undetectable HCV RNA confirmed at years

2 and 3. Samples were not available for sequencing to

determine whether these cases represented true relapse or

reinfection. The point estimate for the likelihood of main-

taining response after 5 years in patients who initially


2 M. P. Manns et al.

achieved SVR was 99.2% (95% CI, 98.1–99.7%)

(Fig. 1a). Overall, a total of 24 patients had either definite

or nondefinite relapse; and 13 patients were monitored

for progression of liver disease during follow-up. Addi-

tional details on these groups of patients are provided in

the Data S1.

Table 1 Definite relapse patients: individual characteristics

Prior treatment

Prior

genotype

Year of

relapse Comments*

Definite relapsers: IFN a-2b†

IFN a-2b + RBV (24 weeks):

prior Tx naive

1a 1 Undetectable HCV RNA at month 6 of LTFU; detectable HCV RNA

at year 1 (410 000 copies/mL). ALT was 1.429 ULN at year 1 visit


prior Tx naive

1a Month 6 Detectable HCV RNA at month 6 (2.95 9 106 copies/mL). No data

for years 1–5. ALT was 1.49 ULN at month 6 visit

IFN a-2b + Placebo (24 weeks):

prior Tx naive

1 Month 6 Detectable HCV RNA at month 6 (110 000 copies/mL) and year 1

(9900 copies/mL). Undetectable HCV RNA at year 2

(<100 copies/mL) and detectable HCV RNA at year 3

(10 9 106 copies/mL). ALT data were missing for years 1–2 and

were 1.049 ULN at year 3. This patient also had detectable liver

HCV RNA (600 copies/lg total nucleic acid) post-treatment

IFN a-2b + Placebo (48 weeks):

prior Tx naive

1a Month 6 Detectable HCV RNA at month 6 (1200 copies/mL), year 1

(6200 copies/mL) and year 2 (48 000 copies/mL). ALT was normal

at years 1–2 (0.46 and 0.359 ULN, respectively) and elevated at

year 2 (2.479 ULN)


prior Tx relapse‡1b Month 6 Detectable HCV RNA at month 6 (90 000 copies/mL), year 1

(1.1 9 106 copies/mL) and year 3 (2.4 9 106 copies/mL) of

follow-up. ALT levels also elevated at 6 months, year 1 and year

3 (1.9, 2.85 and 2.189 ULN, respectively)


prior Tx naive

1a 5 HCV RNA was undetectable at years 2 and 3, with no data available

at year 4. At year 5, clinic visit HCV RNA was 4.5 9 106 IU/mL.

There were no subsequent HCV RNA analyses available

Definite relapsers: PEG-IFN a-2bPEG-IFN a-2b0.5 lg/kg/wk (48 weeks)

1b �2 Data for years 1 and 3–5 not available. Detectable HCV RNA

(401 000 IU/mL; Quest) and normal ALT levels at year 2

PEG-IFN a-2b1.5 lg/kg/wk + RBV

800 mg/day (48 weeks)

1a 1 Detectable HCV RNA at years 1 (1744 IU/mL; SPRI) and 2

(143 000 IU/mL; Quest). ALT 1.39 ULN at year 2. Data for years

3–5 not available

PEG-IFN a-2b1.5 lg/kg/wk + RBV

800 mg/day (48 weeks)

1b 5 Undetectable HCV RNA and normal ALT levels at years 1–4.Detectable HCV RNA (2320 IU/mL; Quest) at year 5 and insufficient

serum sample to retest and genotype. ALT 1.39 ULN at year 5.

Considered relapser for this analysis, but retested locally using

COBAS TaqMan; undetectable HCV RNA and considered sustained

responder by treating physician

ALT, alanine aminotransferase; HCV, hepatitis C virus; IFN a-2b, interferon a-2b; LTFU, long-term follow-up; PEG-IFN

a-2b, peginterferon a-2b; RBV, ribavirin; Tx, treatment; ULN, upper limit of normal. *In the original treatment stud-

ies, serum HCV RNA was evaluated using the National Genetics Institute (NGI) quantitative polymerase chain reac-

tion assay [lower limit of quantitation (LLQ) = 100 copies/mL]. During the long-term follow-up study, HCV RNA

analyses (TaqMan; Applied Biosystems, Foster City, CA, USA; lower limit of detection for 95% sensitivity of 125 IU/

mL) were performed centrally at the Schering-Plough Research Institute (SPRI) Laboratory (Kenilworth, NJ, USA).

Confirmatory testing (Quest Nichols Laboratory, San Juan Capistrano, CA, USA) using TaqMan (LLQ 50 IU/mL) was

performed on a subset of samples tested at the Schering-Plough Research Institute Laboratory. †IFN dose was 3 MIU

three times weekly, and ribavirin dose (where applicable) was 1000–1200 mg/day. ‡Prior relapse was defined accord-

ing to biochemical criteria in the study by Davis et al. [5] (normal ALT at end of treatment followed by elevated

ALT at end of follow-up). Because of absence of virologic testing, the possibility that this patient was a prior nonre-

sponder cannot be excluded.


Durabilty of SVR in treatment of hepatitis C 3

Durability of response following SVR with PEG-IFN a-2b +/� ribavirin

In total, 1941 patients were enrolled in two large

international randomized clinical trials [4,8]. Following

completion of the 24-week follow-up period, 366 patients

with SVR were enrolled in the present study (Data S1). Over-

all, 62% of patients were followed up for at least 5 years

after attaining SVR: 16% were followed up for �2 years

and 23% for 3–4 years. Two patients were classified as hav-

ing reinfection during long-term follow-up (Data S1).

Three patients with SVR had definite late relapse

(Table 1). The first patient had G1b infection and received

PEG-IFN a-2b (0.5 lg/kg/wk) monotherapy for 48 weeks

during the original study. This patient relapsed with a viral

load of 401 000 IU/mL at year 2 (viral load at years 1, 3,

4 and 5 was not available). The second patient had G1a

infection and received PEG-IFN a-2b (1.5 lg/kg/wk) plus

ribavirin for 48 weeks. Relapse was documented at years 1

and 2 with viral loads of 1744 IU/mL and 143 000 IU/mL,

respectively. The third patient had G1b infection and

received PEG-IFN a-2b (1.5 lg/kg/wk) plus ribavirin for

Prob

abili

ty o

f con

tinue

d su

stai

ned

resp

onse

0.85

0.86

0.87

0.88

0.89

0.90

0.91

0.92

0.93

0.94

0.95

0.96

0.97

0.98

0.99

1.00

Time since previous treatment stop date0 Year 1 Year 2 Year 3 Year 4 Year 5 >Year 5

0 Year 1 Year 2 Year 3 Year 4 Year 5 >Year 5

5-year estimate of continued sustained

response: 99.2% (95% CI: 98.1%, 99.7%)

Prob

abili

ty o

f con

tinue

d su

stai

ned

resp

onse

0.85

0.86

0.87

0.88

0.89

0.90

0.91

0.92

0.93

0.94

0.95

0.96

0.97

0.98

0.99

1.00

Time since previous treatment stop date

5-year estimate of continued sustained

response: 99.4% (95% CI: 97.7%, 99.9%)

(a)

(b)

Fig. 1 Durability of SVR based upon definite relapsers from (a) a population of 636 patients who achieved SVR after

treatment with an IFN a-2b–containing regimen (n = 6) and (b) a population of 366 patients who achieved SVR after

treatment with a PEG-IFN a-2b–containing regimen (n = 3).



48 weeks. This patient had undetectable HCV RNA and

normal ALT levels at years 1–4 of follow-up, but at year 5

viral load was 2320 IU/mL. Unfortunately, there was

insufficient serum sample to repeat genotype testing. The

patient was considered a relapser for this analysis, but,

when retested using the Roche COBAS TaqMan assay, HCV

RNA was undetectable and the patient was considered to

have a durable SVR by the treating physician. Based on

three patients with definite relapse, the Kaplan–Meier esti-

mate for continued sustained response over 5 years was

99.4% (95% CI, 97.7–99.9%) (Fig. 1b). Overall, a total of

18 patients had either definite or nondefinite relapse. Addi-

tional detail about these patients is provided in the Data S1.

DISCUSSION

The present study indicates that late relapse is extremely

rare among patients attaining SVR, confirming the durabil-

ity of response. The Kaplan–Meier estimate for sustained

response at 5 years was 99% among patients treated with

IFN a-2b or PEG-IFN a-2b, when considering those with

definite relapse. When the definition of relapse was

expanded to include those with protocol-defined relapse,

the likelihood of maintaining response over 5 years

remained high at 95% (Data S1). However, this analysis

includes several patients who had a single test in which

HCV RNA was detectable, followed by subsequent tests in

which HCV RNA was undetectable. Overall, 13 of 18

patients with nondefinite relapse treated with IFN a-2b,and 14 of 15 with nondefinite late relapse treated with

PEG-IFN a-2b, had a subsequent test that failed to detect

serum HCV RNA. Inclusion of these patients as late relaps-

ers captures the inherent practicalities associated with HCV

RNA testing such as assay variability, sample mix-ups and

absence of backup samples for retesting. True late relapse,

as defined by multiple HCV RNA tests showing high viral

load relapse, was notably rare in this analysis, consistent

with several other studies [1,9–11].

Six patients from the IFN a-2b studies were classified as

definite relapsers. Five relapsed within 1 year of SVR, and

all had G1 infection. Furthermore, three of these patients

were treated for only 24 weeks (one received monothera-

py), and one patient received IFN a-2b monotherapy for

48 weeks. Only two patients in this group received

48 weeks of combination therapy. Similarly, all three defi-

nite relapsers from the PEG-IFN a-2b studies had G1 infec-

tion, with one receiving what would now be considered

inadequate therapy (PEG-IFN a-2b 0.5 lg/kg/wk for

48 weeks). Thus, of these nine definite relapsers, five

received treatment regimens now considered suboptimal

for patients with G1 infection. Given our current under-

standing of hepatitis C treatment, these patients would be

considered at high risk of relapse; however, it is unclear

why relapse in these patients appeared to be delayed and

did not occur within the 24-week post-treatment follow-up

window. One possible explanation may relate to the use of

a lower sensitivity assay and the associated risk of false-

positive SVR. Four definite relapsers had detectable HCV

RNA only 6 months after designation of SVR. In each case,

SVR was assigned using the NGI assay with LLD

<100 copies/mL, and, in these patients, residual viremia

that was not detected by the NGI assay might have precipi-

tated the return of detectable HCV RNA. Within the pres-

ent investigation, the inability to differentiate true relapse

from reinfection is also noteworthy when considering the

implications of these data.

In conclusion, SVR defines eradication of the virus and

thus cure in the vast majority of patients with CHC infec-

tion.

ACKNOWLEDGEMENTS

These data were presented in part at the 41st Annual

Meeting of the European Association for Study of the Liver,

April 26–30, 2006, Vienna, Austria, and at the 43rd

Annual Meeting of the European Association for Study of

the Liver, April 23–27, 2008, Milan, Italy.

AUTHORS’ DECLARATION OF PERSONALINTERESTS

Manns: speakers bureau (Roche, Bristol-Myers-Squibb,

GlaxoSmithKline, Gilead, Merck), consultant (Roche, Bristol-

Myers-Squibb, GlaxoSmithKline, Gilead, Merck, Boehringer

Ingelheim, Novartis, Tibotec, Vertex). Pockros: advisory

arrangements, speakers bureau, and grants/contracts – unre-

stricted (Merck). Norkrans: None. Smith: consulting (Vertex),

speakers bureau (Vertex, Bristol-Myers-Squibb), grants/con-

tracts – research (Vertex, Johnson & Johnson). Morgan:

grants/contracts – research (Vertex, Merck, Gilead, Bristol-

Myers-Squibb). Haussinger: None. Shiffman: advisory

arrangements (Achillion, Anadys, Bayer, Boehringer Ingel-

heim, Conatus, Gilead, GlobeImmune, Human Genome Sci-

ences, Novartis, Pfizer, Roche/Genentech, Schering-Plough/

Merck, Vertex, Zymogenetics), consulting (Conatus, Human

Genome Sciences, Pfizer, Roche/Genentech, Romark), grant

support (Abbott, Achillion, Anadys, Bristol-Myers-Squibb,

Boehringer Ingelheim, Conatus, Gilead, Human Genome Sci-

ences, Idenix, Novartis, Roche/Genentech, Schering-Plough/

Merck, Vertex, Zymogenetics), speaker (Bayer, Boehringer

Ingelheim, Gilead, Roche/Genentech, Schering-Plough/

Merck). Hadziyannis: advisory arrangements (Pfizer, Novar-

tis, Gilead), grants/contracts – research (Gilead), travel

grants (Janssen, Roche, Gilead). Schmidt: None. Jacobson:

consultant/advisor (Abbott, Achillion, Boehringer Ingel-

heim, Bristol-Myers-Squibb, Gilead, GlaxoSmithKline, Globe-

Immune, Idenix, Kadmon, Novartis, Pharmasset, Roche/

Genentech, Schering/Merck, Tibotec/Janssen, Vertex),

grant/research support (Achillion, Anadys, Boehringer

Ingelheim, Bristol-Myers-Squibb, Gilead, GlobeImmune,


Durabilty of SVR in treatment of hepatitis C 5

Novartis, Pfizer, Pharmasset, Roche/Genentech, Schering/

Merck, Tibotec/Janssen, Vertex, Zymogenetics), speakers

bureau (Bristol-Myers-Squibb, Gilead, Roche/Genentech,

Schering/Merck). Barcena: None. Schiff: grant/research sup-

port (Abbott, Anadys, Bristol-Myers-Squibb, Gilead, Merck,

Medtronics, Novelos Therapeutics, Orasure Technologies,

Pharmasset, Roche Molecular, Vertex). Shaikh: None.

Bacon: advisory arrangements (Gilead, Three Rivers Phar-

maceuticals, Vertex), consultant (Merck, Romark), research

support (Merck, Roche, Gilead, Bristol-Myers-Squibb, Three

Rivers Pharmaceuticals, Vertex, Wyeth, Romark), speakers

bureau (Merck, Gilead, Three Rivers Pharmaceuticals). Mar-

cellin: grant/research support (Roche, Gilead, Janssen-Tibo-

tec, Merck Sharp & Dohme, Echosens), speakers bureau

(Bristol-Myers-Squibb, Roche, Gilead, Novartis, Pharmasset,

Janssen-Tibotec, Merck Sharp & Dohme), advisory arrange-

ments (Roche, Gilead, Bristol-Myers-Squibb, Vertex, Novar-

tis, Pharmasset, Janssen-Tibotec, Merck Sharp & Dohme,

Abbot). Deng: employment (Merck Sharp & Dohme, a sub-

sidiary of Merck & Co, Inc., Whitehouse Station, NJ, USA).

Esteban-Mur: speakers bureau (Merck Sharp & Dohme, a

subsidiary of Merck & Co, Inc.). Poynard: advisory arrange-

ments/speakers bureau (Merck), stock ownership or equity

(BioPredictive). Pedicone: stock ownership and employment

(Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc.,

Whitehouse Station, NJ, USA). Brass: stock ownership and

previous employment (Merck Sharp & Dohme, a subsidiary

of Merck & Co, Inc., Whitehouse Station, NJ, USA). Albrecht:

previous employment (Merck Sharp & Dohme, a subsidiary

of Merck & Co, Inc., Whitehouse Station, NJ, USA). Gordon:

advisory arrangements, consulting, speakers bureau,

grants/contracts – unrestricted (Merck).

DECLARATION OF FUNDING INTERESTS

These studies were supported by Schering-Plough Corpora-

tion, now Merck & Co., Inc., Whitehouse Station, NJ, USA.

This research received no specific grant from any funding

agency in the public, commercial or not-for-profit sectors.

Writing assistance was provided by Tim Ibbotson, PhD,

and Santo D’ Angelo, PhD, MS. This assistance was funded

by Schering-Plough Corporation, now Merck & Co., Inc.,

Whitehouse Station, NJ, USA.

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SUPPORTING INFORMATION

Additional Supporting Information

may be found in the online version of

this article:

Data S1. Analysis of definite and

nondefinite relapse.



long-term clearance of hepatitis c virus following interferon α-2b or peginterferon α-2b, alone or...

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