*This represents all patients who took at least 80% of the planned total
dose by hepatitic C virus genotype.
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Carrat F, Bani-Sadr F, Pol S, et al. Pegylated Interferon Alfa-2b vs Standard Interferon Alfa-2b, Plus Ribavirin, for Chronic Hepatitis C in HIV-Infected PatientsA Randomized Controlled Trial. JAMA. 2004;292(23):2839–2848. doi:10.1001/jama.292.23.2839
Context Treatment of chronic hepatitis C virus (HCV) infection in human immunodeficiency
virus (HIV)–infected patients is a growing concern. Most data on the
virologic efficacy and safety of the combination of peginterferon alfa-2b
and ribavirin in coinfected patients come from uncontrolled studies.
Objective To study the safety and efficacy of peginterferon alfa-2b plus ribavirin
vs standard interferon alfa-2b plus ribavirin in HIV-HCV coinfected patients.
Design and Settings A multicenter, randomized, parallel-group, open-label trial. Patients
were enrolled from February 2000 to February 2002 and followed up for 72 weeks.
Patients Four hundred twelve HIV-HCV coinfected patients with detectable serum
HCV-RNA, abnormal liver histology, a CD4 cell count of at least 200 × 106/L, and stable plasma HIV-RNA.
Intervention Treatment with ribavirin 400 mg twice a day, orally, plus either peginterferon
alfa-2b (1.5 μg/kg subcutaneous injection once a week) or standard interferon
alfa-2b (3 million units of subcutaneous injection 3 times a week) for 48
Main Outcome Measures Sustained virologic response, defined by undetectable serum HCV-RNA
at week 72.
Results More patients had sustained virologic responses in the peginterferon
group than in the standard interferon group (27% vs 20%, P = .047). This difference between the treatments was found
in patients with HCV genotype 1 or 4 infection (17% for peginterferon vs 6%
for standard interferon, P = .006) but
was not found in patients with HCV genotype 2, 3, or 5 (44% for peginterferon
vs 43% for standard interferon, P = .88).
Together, a decline in HCV-RNA of less than 2 log10 from baseline
and detectable serum HCV-RNA at week 12 predicted 99% of treatment failures.
Histologic activity diminished and fibrosis stabilized in virologic responders.
The 2 regimens showed similar tolerability although dose modifications for
clinical and biological events were more frequent with peginterferon. Eleven
cases of pancreatitis or symptomatic hyperlactatemia were observed, all in
patients receiving didanosine-containing antiretroviral regimens.
Conclusion In combination with ribavirin, treatment with peginterferon alfa-2b
is more effective than standard interferon alfa-2b for HCV infection in HIV-infected
About one third of human immunodeficiency virus (HIV)–infected
patients in Europe and the United States are also infected by hepatitis C
virus (HCV) while 5% to 10% of HCV-infected patients are also infected by
HIV.1,2 Human immunodeficiency
virus coinfection accelerates the progression of HCV infection, which is now
a leading cause of morbidity and mortality among HIV-infected individuals.3-7
The treatment of chronic HCV infection was transformed in the 1990s
by the advent of the interferon-ribavirin combination and was further improved
with the use of pegylated interferon (peginterferon), in which a polyethylene
glycol molecule is added to standard interferon, yielding a longer half-life
and more favorable pharmacokinetics.8,9 Two
forms of peginterferon (alfa-2a and alfa-2b) have been approved for use with
or without ribavirin. In combination with ribavirin, both peginterferons provide
sustained virologic responses in 54% to 63% of HIV-seronegative HCV-infected
patients (7% to 12% higher than with standard interferon-ribavirin).10-12
In vitro antagonism between ribavirin and some antiretrovirals (especially
zidovudine and stavudine) delayed the use of ribavirin in HIV-coinfected patients,
but a recent randomized trial of the stavudine-ribavirin combination showed
no negative impact on antiretroviral efficacy.13
Recently, 2 randomized controlled studies showed the efficacy and safety
of peginterferon alfa-2a plus ribavirin in HIV-HCV coinfected patients.14,15 The few available data on the virologic
efficacy and tolerability of peginterferon alfa-2b plus ribavirin in HIV-HCV
coinfected patients come mainly from small uncontrolled or single-center trials.16-19 The
aim of our prospective randomized study of initial treatment of chronic HCV
in HIV-infected patients was to compare the efficacy of a 48-week course of
ribavirin combined with either standard interferon alfa-2b or peginterferon
Adults who had never received interferon and who had the following characteristics
were eligible for the study: second-generation enzyme-linked immunosorbent
assay positivity for anti-HCV antibodies and polymerase chain reaction–based
assay positivity for HCV-RNA in serum; interpretable results of liver biopsy
performed within the previous 18 months, showing at least mild activity or
fibrosis; anti-HIV antibody positivity and a stable plasma HIV-1 RNA level
(variation of less than 1 log10 copies × 106/L during the 3 months before randomization); stable antiretroviral
treatment during the preceding 3 months (or no antiretroviral treatment);
and a CD4 cell count higher than 200 × 106/L. Patients
were not eligible if they had neutropenia (<1.5 × 109/L neutrophils); thrombocytopenia (<100 × 103/μL platelets); anemia (<11.0 g/dL hemoglobin); a serum creatinine
level higher than 1.70 mg/dL (150 μmol/L); circulating hepatitis B surface
antigen positivity; decompensated cirrhosis (defined as biopsy-proved cirrhosis
with serum albumin below the lower limit of normal: a prothrombin level <60%;
a total bilirubin level higher than the upper limit of normal; or a history
of ascites, hepatic encephalopathy or esophageal varices); biliary, tumoral,
or vascular liver disease; psychiatric disorders (history of major depression,
suicide attempts, suicidal ideation, or other severe psychiatric disorders;
psychosis); a history of seizures; cardiovascular disease; poorly controlled
diabetes mellitus; or autoimmune disorders; or if they had actively injected
illicit drugs 3 months before enrollment or reported daily alcohol intake
greater than 40 g (women) or 50 g (men). Women were not eligible if they were
unwilling to use effective contraception.
This randomized, phase 3, open-label, parallel-group study was conducted
in 71 French centers. The study was approved by the ethics committee of Saint-Germain
en Laye hospital and by the sponsor's institutional review board (Agence
Nationale de Recherches sur le SIDA [ANRS]). All the patients gave their written
informed consent. The study was designed by the Groupe d'Etude et de
Recherche en Médecine Interne et Maladies Infectieuses sur le Virus
de l'Hépatite C (GERMIVIC) joint study group, which comprised
experts in internal medicine, infectious diseases, and hepatology. Data analysis
was performed by the sponsor and the authors, both of whom were independent
of the drug manufacturers. The study followed the Helsinki Declaration and
Good Clinical Practices.
Patients were randomly assigned to receive subcutaneous injections of
1.5 μg/kg peginterferon alfa-2b (Peg Intron, Schering-Plough, Kenilworth,
NJ) once a week or subcutaneous injections of 3 million units of interferon
alfa-2b (Intron A, Schering-Plough) 3 times a week for 48 weeks. All patients
also received 400 mg of ribavirin twice a day (Rebetol, Schering-Plough),
orally. Randomization was managed by the central data center (INSERM U444,
Paris, France). Randomization was balanced within centers, with blocking within
strata. The randomization code was developed using a computerized random number
generator to select random permuted block sizes of 2, 4, 6, and 8. The randomization
list was concealed from the medical monitor (located in the data center),
who assigned participants to the treatment groups after reviewing the eligibility
criteria. Allocated treatments were communicated to the investigator during
the week preceding the visit at which the first treatment prescription was
The patients were evaluated after 2 and 4 weeks of treatment, every
4 weeks thereafter during treatment, and 4, 12, and 24 weeks after treatment
was completed. Patients were followed up until week 72 to assess sustained
Biochemical and hematologic tests were performed in local laboratories.
Hepatitis C virus–RNA tests, viral genotyping, and histological evaluation
of biopsy specimens were performed in central laboratories. Liver biopsy was
performed at the end of follow-up.
Assessment and End Points. Hepatitis C virus–RNA
was detected with a polymerase chain reaction assay (Amplicor 2.0 HCV Monitor,
Roche Diagnostics Systems, Basel, Switzerland) with a detection limit of 50
IU (100 copies) × 103/L. Hepatitis C virus–RNA levels
were measured with a branched-chain DNA assay (bDNA3.0, Bayer Diagnostics,
Tarrytown, NY) with a detection limit of 615 IU (3200 copies) × 103/L. Hepatitis C virus genotyping was performed by sequence analysis
of the 5′ untranslated region. The primary end point for efficacy was
a sustained virologic response, defined as undetectable serum HCV-RNA at week
72. The secondary end point was histological improvement. Virologic and histologic
end points were evaluated by individuals blinded to the treatment assignments.
Pretreatment biopsy specimens were examined locally before randomization and
were then coded and evaluated in parallel with those obtained at week 72,
by 2 experienced pathologists (A.B. and C.D.). Hepatic inflammation and fibrosis
were graded with the Metavir scoring system20 (scores
ranging from 0 [none] to 3 for severe necroinflammatory activity, and 0 [none]
to 4 for cirrhosis) and Ishak’s classification21 (scores
ranging from 0 [none] to 12 for severe inflammation, and 0 [none] to 6 for
cirrhosis). Histological improvement in disease activity or fibrosis was defined
as a decrease of 1 point or more between the relevant pretreatment and posttreatment
Metavir and Ishak subscores.22 Histological
aggravation was defined as a score increase of 1 point or more.
Special attention was paid to the possible effect of treatment on HIV
infection (CD4 cell count, HIV viral load). Adverse events were graded 1 (mild)
to 4 (life-threatening), using the ANRS grading system.23 Stepwise
reductions in the peginterferon alfa-2b dose to 1 and 0.5 μg/kg per week,
and reductions in the interferon alfa-2b dose to 1.5 million units 3 times
a week or the ribavirin dose to 600 mg/d, were allowed to manage adverse events
or laboratory abnormalities that had reached predefined thresholds. Patients
who discontinued therapy prematurely because of adverse effects were encouraged
to remain in the study.
The study was designed to have a power of 80% to detect a 15% difference
(chosen for its clinical relevance) between the rates of sustained virologic
response (from 20% vs 35% to 40% vs 55%) at a 5% level of significance (2-tailed
test). Intention-to-treat analysis was used as the primary analysis for all
measures of efficacy. Patients violating major eligibility criteria were excluded
from the analyses. Patients who missed the final examination (week 72) were
included as nonresponders. Histological responses were only analyzed in patients
who underwent both a pretreatment and a posttreatment biopsy. Patients who
received at least 1 dose of study medication were included in the safety analysis.
The Cochran-Mantel-Haenszel test (or Fisher exact test) was used to
compare categorical variables, with stratification by center for comparisons
between treatment groups and stratification by center and treatment group
for other categorical variables. The Wilcoxon rank-sum test was used to compare
quantitative variables between the groups. Logistic regression analyses were
used to explore the influence of treatment and pretreatment characteristics
on the response. Characteristics with P values below
0.20 in univariate analysis were included in multivariate models based on
a backward elimination procedure. Adjusted odds ratios were transformed into
approximated risk ratios (RRs) to correct for overestimation due to common
events.24 The Mac-Nemar χ2 test
or the Wilcoxon signed-rank test was used to compare pretreatment and posttreatment
characteristics. All statistical tests were 2-tailed; P<.05 was considered statistically significant. We used SAS, version
8.2 (SAS Institute Inc, Cary, NC).
Patients were enrolled from February 2000 to February 2002. The trial
ended in October 2003. A total of 442 patients were screened for eligibility,
of whom 416 met the entry criteria and were randomly assigned to a treatment
group (Figure 1). Four patients were
excluded after randomization: 3 patients tested HCV-RNA–negative in
the central laboratory, and one patient had previously received interferon
alfa. Twenty-nine patients withdrew before receiving the study treatment because
they refused or did not come for treatment or because a serious medical event
occurred between randomization and the first treatment visit. During the follow-up
period 4 patients in the peginterferon group and 1 patient in the standard
interferon group withdrew. The pretreatment characteristics of the patients
were similar in the 2 groups (Table 1).
A sustained virologic response (main end point) was obtained in 56 patients
(27%) in the peginterferon group and 41 patients (20%) in the standard interferon
group (P = .047). End-of-treatment virologic
responses (at 48 weeks) were obtained in 72 (35%) and 44 (21%) of patients,
respectively (P = .001). Undetectable serum
HCV-RNA was obtained in 30 patients (15%) in the peginterferon group and 15
patients (7%) in the standard interferon group (P = .04)
at week 4, 67 (33%) and 51 (25%) at week 12 (P = .09),
and 83 (40%) and 57 (28%) at week 24 (P = .004).
A total of the 67 (99%) of the 68 patients in the peginterferon group
and all 91 (100%) of patients in the standard interferon group who had detectable
serum HCV-RNA and a viral load decline of less than 2 log10 IU
× 103/L from baseline at week 12 failed to achieve a sustained
virologic response at week 72 (P = .43,
Fisher exact test).
Twenty-one patients (17%) with HCV genotype 1 or 4 infection who received
peginterferon alfa-2b plus ribavirin had a sustained virologic response compared
with 8 patients (6%) who received interferon-alfa2b plus ribavirin (P = .006, Figure
2). Among patients with HCV genotype 2, 3, or 5 infection, the rates
of sustained virologic response were not different between the 2 treatment
groups (35 [44%] vs 33 [43%], respectively, P = .88).
Among patients who took at least 80% of the planned total dose, sustained
virologic responses were achieved in 44 (40%) of 111 patients in the peginterferon
group and 33 (29%) of 115 patients in the standard interferon group (P = .30).
Table 2 shows the variables that
were included in the multiple logistic regression models on the basis of univariate
analysis. Preliminary analysis showed that the sustained virologic response
rates were influenced by the HCV genotype. A first multiple logistic regression
model confirmed this result and showed that HCV genotypes 2, 3, or 5 were
the main predictors of response (adjusted risk ratio [RR], 3.77; 95% confidence
interval [CI], 2.69-4.93; P<.001). Other predictors
were no protease inhibitor treatment, age 40 years or younger, and baseline
alanine aminotransferase greater than 3 upper limits of normal. Because preliminary
findings also indicated that the treatment effect differed according to the
HCV genotype, further exploratory analyses were stratified according to the
genotype. In patients with HCV genotype 1 or 4 infection, peginterferon treatment
(RR, 2.43; 95% CI, 1.12 to 3.79; P = .03)
and HCV viral load ≤5.7 log10 IU x 103/L (RR, 2.07;
95% CI, 1.04 to 3.74; P = .04) were independently
associated with a sustained virologic response. In patients with HCV genotypes
2, 3, or 5, the absence of protease inhibitor treatment (RR, 1.80; 95% CI,
1.17-2.42; P = .01), age 40 years or younger
(RR, 1.60; 95% CI, 1.08-2.10; P = .02),
and baseline alanine aminotransferase more than 3 times the upper limits of
normal (RR, 1.57; 95% CI, 1.07-2.02; P = .03)
were independently associated with a sustained virologic response. Liver histology,
the per kilogram body weight ribavirin dose, and the CD4 cell count were not
independently associated with a sustained virologic response.
Paired pretreatment and posttreatment histological results were available
for 205 patients (50%, Table 3). The
reasons for missing posttreatment results were refusal of biopsy in 153 cases
(74%), failure to return in 46 cases (22%), and clotting disorders in 8 cases
(4%). The only significant difference in baseline characteristics between
patients with and without posttreatment biopsy was a higher mean (SD) Metavir
fibrosis score in patients with available posttreatment results (2.4 [1.0]
vs 2.2 [1.0]), P = .03).
For disease activity, the Metavir score change was –0.19 in the
peginterferon group and 0.01 in the standard interferon group (P = .02); and the mean changes in the Ishak grade were –0.57
and –0.26 (P = .24), respectively.
The decline in both subscores was significant among sustained virologic responders
while the subscores were stable among nonresponders. Changes in fibrosis did
not differ between the 2 groups, but fibrosis worsened in patients who did
not have a sustained virologic response. Steatosis improved significantly
in patients infected by HCV genotype 3 who had a sustained virologic response
Similar proportions of patients in the 2 groups withdrew from the study
because of clinical adverse events or laboratory abnormalities (Table 4). The doses of the study treatments were modified in 31
(16%) of patients in the peginterferon group and 13 (7%) of patients in the
standard interferon group because of clinical adverse events (P = .004), and in 38 (20%) and 13 (7%) of patients respectively
because of laboratory abnormalities (P = .004).
The incidence of most clinical adverse events was similar between the
2 treatment groups. The following parameters were not significantly different
by week 12 in the peginterferon vs standard interferon groups: hemoglobinemia
(–18 and –14 g/L, respectively, P = .01,
at week 12), platelets (–34.3 vs –21.3 × 103/μL, P = .004), neutrophils (–1.10
vs –0.70 × 109/L, P = .009),
lymphocytes (–0.66 vs –0.54 × 109/L, P = .06), and CD4 cells (–121 vs –110 × 106/L, P = .21). These parameters generally
remained stable after week 12, then returned to near baseline values shortly
after treatment cessation. When viral loads less than 400 copies/mL were attributed
a value of 2.6 log10, mean (SD) HIV viral load (log10 copies/mL)
was 2.96 (0.66) at baseline and 3.12 (0.86) at the end of treatment in the
peginterferon group (P<.001), 3.04 (0.73) and
3.09 (0.78) respectively, in the standard interferon group (P = .12).
Seven deaths occurred among randomized patients: there were 5 deaths
in the peginterferon group (2 from liver failure, 1 from metastatic neuroendocrine
carcinoma, 1 from metastatic vulvar cancer—the patient who tested negative
for HCV infection in the central laboratory—and 1 from accidental nitrate
propyl overdose before the first dose of study treatment), and 2 deaths in
the standard interferon group (1 from liver failure and 1 from liver cancer).
One of the deaths from liver failure was considered possibly related to peginterferon-ribavirin
therapy. This patient had fibrosis (F2) on a biopsy performed 9 months before
the first dose of study treatment, was at Centers of Disease Control and Prevention
stage A, and received didanosine, stavudine, and abacavir. He discontinued
the study treatment after 8 weeks because of severe thrombocytopenia. He was
hospitalized at week 12 with symptoms of decompensated cirrhosis and ascites
infection. Liver biopsy showed significant cirrhosis (F4). Death occurred
at week 32 from sepsis and liver failure. The proportion of patients reporting
serious adverse events was generally similar among the groups. Symptomatic
mitochondrial toxicity (symptomatic hyperlactatemia, lactic acidosis, or acute
pancreatitis) occurred in 11 patients, 9 patients receiving peginterferon
and 2 patients receiving standard interferon. All these patients were receiving
In this population of HIV-infected patients with chronic HCV, peginterferon
alfa-2b plus ribavirin yielded more sustained virologic responses than standard
interferon alfa-2b plus ribavirin. Efficacy and tolerability in the peginterferon
group were in keeping with the results of 3 uncontrolled trials, in which
the sustained virologic response rates to peginterferon alfa-2b plus ribavirin
were 28% to 31%.16-18 However,
the absolute difference between the 2 groups (7%) was smaller than initially
expected (15%); and was also smaller than in recent trials comparing peginterferon
alfa-2a with standard interferon alfa-2a14,15 and
in a small single-center trial comparing peginterferon alfa-2b with standard
interferon alfa-2b.19 A high frequency of severe
HIV- and/or HCV-related disease (62% of serious adverse events were unrelated
to the study treatments, and 40% of our patients had bridging fibrosis or
cirrhosis) and a high baseline prevalence of characteristics associated with
poorer adherence to treatment (injection drug use, 79%; psychiatric disorders,
21%)25 may have contributed to the smaller
than expected difference between the 2 treatment groups in our study. However,
the fact that we did not exclude such patients may make our results relevant
to the general population of patients living with HIV and HCV coinfection
in the United States and Europe.26,27
The benefit of peginterferon alfa-2b relative to standard interferon
alfa-2b was most apparent in patients with genotype 1 or 4 infection. No significant
differences were found between the treatment groups in patients with genotype
2 or 3 infection. Similar findings have been reported for HIV-seronegative
and HIV-seropositive patients in studies comparing either peginterferon alfa-2b11,19 or peginterferon alfa-2a12 plus ribavirin with standard interferon plus ribavirin.
The HCV genotype was the predominant predictor of a sustained virologic
efficacy, consistent with most previous studies of both HIV-seropositive16,18 and HIV-seronegative patients.10,11,28,29 A
young age, a lower HCV-RNA level, or a higher pretreatment alanine amino transferase
level are also reported to be predictive of sustained virologic responses.14-16,18,29,30 The
higher virologic failure rates that we observed among patients treated with
protease inhibitors may be related to drug hepatotoxicity,31 increased
HCV replication,32 restoration of anti–HCV
immune responses33 or cytochrome P450–mediated
drug interactions.34 Liver histology and the
CD4 cell count were not independent predictors of the virologic response in
our study, contrary to some previous reports16,18 but
in line with recently published clinical trials.14,15
The effect of treatment on histologic activity was similar to that observed
in the HIV-seronegative population.11 Interestingly,
the progression of fibrosis was slowed when a virologic response was achieved.
Overall, tolerability was similar in the peginterferon and standard
interferon groups. However, serious adverse events were far more frequent
(35%) than what has been reported among HIV-seronegative patients (10%-15%).
The incidence of opportunistic infections did not appear to be affected by
anti-HCV therapy. Mitochondrial toxicity was particularly frequent in patients
receiving didanosine, as previously reported,16,18,35,36 possibly
owing to increased intracellular concentrations of active triphosphorylated
didanosine metabolites. As a result, a warning was added to the didanosine
product information in September 2002, stating that ribavirin should be used
cautiously in patients also receiving didanosine.37 It
is noteworthy that the patient who died from liver failure that was possibly
related to the treatment had cirrhosis at the time of death and received didanosine;
both these factors were recently reported as independent risk factors for
In combination with ribavirin, peginterferon alfa-2b is more effective
than standard interferon alfa-2b for initial treatment of HCV infection with
genotypes 1 and 4 in HIV-infected patients. Treatment can be discontinued
after 3 months if a satisfactory virologic response is not obtained at this
time. Coadministration of ribavirin with didanosine should be avoided. However,
the poor outcome of HIV-coinfected patients and particularly that of patients
with HCV genotype 1 infections calls for new therapeutic approaches in this
Corresponding Author: Fabrice Carrat, MD,
PhD, Groupe Hospitalier Universitaire Est, Université Paris 6, INSERM
Financial Disclosures: Dr Carrat has received
research grants, served as a consultant for, or has received travel expenses
from Roche, GlaxoSmithKline, Chiron, Schering-Plough, and Aventis; Dr Bani-Sadr
has received travel expenses from Bristol-Myers Squibb and Gilead; Dr Pol
has served as a consultant for Roche, Schering-Plough, and Gilead; Dr Lunel-Fabiani
has received travel expenses from Schering-Plough, Roche, and Ortho-Clinical
Diagnostics; Dr Morand has received research grants from or has served as
a consultant for GlaxoSmithKline and Bristol-Myers Squibb; Dr Pialoux has
received research grants from or served as a consultant for Aventis, Roche,
GlaxoSmithKline, Bristol-Myers Squibb; Dr Piroth has received research grants
from, served as a consultant for, or has received travel expenses from Roche
and Boehringer-Ingelheim; Dr Salmon-Céron has served as a consultant
for and received travel expenses from Roche, Bristol-Myers Squibb, GlaxoSmithKline,
and Gilead; Dr Pialoux has received a grant from Aventis; Dr Degott has served
as a consultant for Roche and Schering-Plough; and Dr Cacoub has served as
a consultant for or has received travel expenses from Sanofi Synthelabo, Servier,
Schering-Plough, and Chiesi.
Author Contributions: Dr Perronne had full
access to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Carrat, Bani-Sadr,
Pol, Rosenthal, Lunel-Fabiani, Morand, Goujard, Salmon-Ceron, Cacoub, Perronne.
Acquisition of data: Carrat, Bani-Sadr, Pol,
Rosenthal, Lunel-Fabiani, Morand, Goujard, Piroth, Degott, Perronne.
Analysis and interpretation of data: Carrat,
Bani-Sadr, Pol, Rosenthal, Lunel-Fabiani, Benzekri, Pialoux, Cacoub, Perronne.
Drafting of the manuscript: Carrat, Benzekri,
Critical revision of the manuscript for important
intellectual content: Bani-Sadr, Pol, Rosenthal, Lunel-Fabiani, Morand,
Goujard, Pialoux, Salmon-Ceron, Degott, Cacoub.
Statistical analysis: Carrat.
Obtained funding: Salmon-Ceron, Cacoub.
Administrative, technical, or material support:
Carrat, Bani-Sadr, Lunel-Fabiani, Benzekri, Degott, Cacoub.
Study supervision: Carrat, Bani-Sadr, Pol,
Rosenthal, Lunel-Fabiani, Goujard, Pialoux, Cacoub, Perronne.
ANRS HC02 RIBAVIC Trial Participants Scientific Committee: F. Bani-Sadr, P. Cacoub, F. Carrat, C. Degott, C. Lemonnier, C. Goujard,
C. Grillot-Courvalin, F. Lunel-Fabiani, D. Merrien, P. Morand, J. M. Pawlotsky,
C. Perronne, L. Piroth, S. Pol, G. Raguin, A. Rimaihlo, E. Rosenthal, D. Salmon-Céron,
N. Squalli, H. Zylberberg.
Clinical Centers: J. M. Molina, F. Bani Sadr,
N. Colin De Verdière, S. Fournier, A. Furco, R. Hor, M. Lafaurie, D.
Ponscarme (Hôpital Saint Louis, Paris); J. F. Delfraissy, C. Goujard,
Y. Quertainmont (Hôpital de Bicêtre, Le Kremlin Bicêtre);
J. A. Krivitsky, M. Bentata, R. Djebbar, H. Khadir, R. Mansouri, F. Rouges,
A. Mosnier, J. P. Pathe (Hôpital Avicenne, Bobigny); J. Cassuto, C.
Ceppi, E. Rosenthal, M. Poiree (Hôpital de l’Archet, Nice); A.
Sobel, M. Bertocchi, F. Bourdillon, N. Brahimi, C. Douvin, A. S. Lascaux,
P. Lesprit, Y. Levy (Hôpital Henti Mondor, Créteil); S. Pol,
C. Bréchot, H. Fontaine, R. Sobesky, A. Vallet Pichard (Hôpital
Necker, Paris); J. M. Ragnaud, M. Dupon, T. Galperine, D. Neau (Hôpital
Pellegrin, Bordeaux); G. Pialoux, A. Baakili, N. Kerbouche, T. H. Nguyen,
L. Nait Ighil, W. Rozenbaum, L. Slama (Hôpital Tenon, Paris); J. Beylot,
P. Morlat, M. Bonarek, S. De Witte, M. C. Pertusa (Hôpital Saint André,
Bordeaux); P. Yeni, E. Bouvet,Y. Bennai, I. Fournier, N. Sohier (Hôpital
Bichat, Paris); J. F. Bergmann, M. Bendenoun, P. Sellier, M. Diemer (Hôpital
Lariboisière, Paris); P. Galanaud, F. Boue, V. Chambrin, G. A. Estocq,
I. Luquet Besson, C. Pignon (Hôpital Antoine Béclère,
Clamart); F. Raffi, C. Allavena, E. Billaud, B. Bonnet, J. L. Esnault, S.
Leautez, V. Reliquet (Hôpital Hôtel Dieu, Nantes); J. D. Grange,
X. Amiot, B. Dieumegard, P. Jouet (Hôpital Tenon, Paris); C. Perronne,
F. Bani Sadr, C. Billy, P. De. Truchis, J. C. Melchior, J. Salomon (Hôpital
Raymond Poincaré, Garches); S. Herson, M. Bonmarchand, E. Capitaine,
N. Amirat, A. Simon (Hôpital de la Pitié Salpetrière,
Paris); C. Trepo, C. Augustin Normand, F. Bailly, L. Cotte, P. Miailhes, I.
Schlienger (Hôpital Hôtel Dieu, Lyon); J. Reynes, V. Baillat,
J. P. Benezech, V. Le Moing, A. Lotthe, C. Merle (Hôpital Gui de Chauliac,
Montpellier); H. Gallais, I. Ravaux (Hôpital de la Conception, Marseille);
E. Pichard, J. M. Chennebault, P. Fialaire, I. Hubert Fouchard, J. Loison,
E. Vivien (Hôpital Hôtel Dieu, Angers); H. Portier, M. Buisson,
P. Chavanet, M. Duong, M. Froidure, M. Grappin, L. Piroth (Hôpital du
Bocage, Dijon); Y. Mouton, F. Ajana, A. Cheret, O. Dos Santos, D. Sissoko
(Centre Hospitalier de Tourcoing); A. P. Blanc, T. Allègre, P. Mours,
J. M. Riou, C. Wartelle (Centre Hospitalier du Pays d’Aix, Aix en Provence);
Y. Welker (Centre Hospitalier de Saint Germain en Laye); B. Jarrousse, P.
Cohen, O. Launay (Hôpital Avicenne, Bobigny); D. Sicard, C. Bernasconi,
A. Calboreanu, D. Salmon Ceron, B. Silbermann (Hôpital Cochin, Paris);
F. Bricaire, C. Katlama, M. V. Bochet, S. Dominguez (Hôpital de la Pitié
Salpetrière, Paris); P. Barel (Centre Hospitalier d’Albi); J.
Doll (Hôpital A Mignot, Le Chesnay); P. M. Girard, O. Picard, D. Berriot,
F. Besse, D. Bollens, B. Lefebvre, P. Tangre (Hôpital Saint Antoine,
Paris); M. Choustermann, P. Cattan, I. Rosa (Centre Intercommunal de Créteil);
D. Vittecoq, L. Escaut, C. Minozzi (Hôpital Paul Brousse, Villejuif);
J. P. Coulaud, S. Matheron, S. Masson, P. Ralaimazava (Hôpital Bichat,
Paris); P. Dellamonica, V. Rahelinirina (Hôpital de l’Archet,
Nice); M. Bourlière, S. Benali (Fondation hôpital Saint Joseph,
Marseille); K. Barange (Hôpital Purpan, Toulouse); C. Penalba (Hôpital
Corvisart, Charleville Mézières); R. Laurent, B. Hoen, G. Achard,
Y. Bourezane, S. Bresson Hadni, F. Coquet, C. Drobacheff, C. Nicol, R. Pichon,
C. Vanlemmens (Hôpital Saint Jacques, Besançon); G. Bordes, N.
Djaghri (Centre Hospitalier Romieu, Digne les Bains); O. Bletry, S. Hillaire,
C. Majerholc, D. Zucman (Hôpital Foch, Suresnes); J. A. Gastaut, T.
Dinh, V. Frixon Marin, I. Poizot Martin (Hôpital Sainte Marguerite,
Marseille); P. Leclercq (Hôpital Michallon, Grenoble); P. Veyssier,
D. Merrien (Centre Hospitalier de Compiègne); X. Roblin, L. Pelissier
(Centre Hospitalier de Gap); D. Valla, P. Marcellin, C. Castelnau (Hôpital
Beaujon, Clichy); D. Sereni, C. Lascoux Combe, C. Pintado, O. Prevoteau (Hôpital
Saint Louis, Paris); J. P. Bru, M. Bensalem, J. Gaillat, C. Michon (Centre
Hospitalier d’Annecy); J. Beytout, C. Jacomet (Hôpital Hôtel
Dieu, Clermont Ferrand); T. May, L. Boyer, C. Burty (Hôpital Brabois,
Vandoeuvre les Nancy); D. Peyramond, A. Boibieux, F. Daoud (Hôpital
de la Croix Rousse, Lyon); O. Rogeaux, B. De Goer, V. Gay, C. Penas (Centre
Hospitalier de Chambéry); C. Michau (Hôpital de Saint Nazaire);
E. Lerebours, O. Goria, S. Hervé (Hôpital Charles Nicolle, Rouen);
F. Tremolieres, V. Perronne (Hôpital F Quesnay, Mantes la Jolie); E.
Oksenhendler, L. Gérard (Hôpital Saint Louis, Paris); M. Duffaut,
L. Alric, M. Mularczyk (Hôpital Purpan, Toulouse); P. Perre, O. Aubry,
S. Leautez (Centre Hospitalier les Oudaries, La Roche sur Yon); C. Bazin,
S. Dagere, M. Six, R. Verdon (Centre Hospitalier la côte de Nacre, Caen);
J. Delmont, J. J. Moreau, S. Mokhtari, L. Serraf (Hôpital Nord, Marseille);
E. Rouveix, V. Jubault (Hôpital Ambroise Paré, Boulogne); M.
Brunel, V. Faucherre, P. Andre, S. David (Hôpital Saint Eloi, Montpellier);
G. Naudin, S. Grimbert (Hôpital des Diaconesses, Paris); D. Champetier
de Ribes, G. Force (Hôpital Notre Dame du Perpétuel Secours,
Levallois Perret); J. L. Schmit, Y. Douadi, F. X. Lescure (Hôpital Nord,
Amiens); M. D. Kazatchkine, N. Bengrait, M. C. Bernard, M. Karmochkine, A.
Landau (Hôpital Européen Georges Pompidou, Paris); J. L. Vilde,
G. Chiriot, S. Roloff (Hôpital Bichat, Paris); J. M. Lang, D. Rey, V.
Krantz (Hôpital Civil, Strasbourg); P. Arsac (Centre Hospitalier d’Orléans);
M. Uzan, A. Bicart See, D Garipuy (Hôpital Joseph Ducuing, Toulouse);
D. Vincent, J. M. Mauboussin (Centre Hospitalier de Nîmes).
Coordinating Trial Center: F. Carrat, J. Deshayes,
H. Driss, I. Goderel, L. Hannachi, R. Hor, P. Jouany, A. Lavenu, C. Lirzin,
G. Pannetier, V. Millul (INSERM U444), L. Allain, F. Agid, M-A. Bach, V. Daurat,
C. Grillot-Courvalin, C. Paul, N. Squalli (ANRS).
Virologic Centers: F. Lunel-Fabiani, C. Payan,
A. Pivert (Centre Hospitalier d’Angers), P. Morand, A. Signori-Schmuck
(Centre Hospitalier de Grenoble).
Liver Histology Center: C. Degott, A. Benzeckri
(Hôpital Beaujon, Clichy).
Data and Safety Monitoring Board: F. Barin,
G. Chêne, L. Geffray, O. Lortholary, C. Rouzioux.
Schering-Plough: C. Lemonnier, A. Rimailho.
Funding/Support: The study was supported by
a grant from the Agence Nationale de Recherches sur le SIDA, a publicly funded
agency involved in clinical research on HIV and HCV. The drugs were provided
Role of the Sponsor: Agence Nationale de Recherches
sur le SIDA staff participated in the design and conduct of the study, and
in data collection and analysis. However the agency had no role in data interpretation
or in the preparation, review, or approval of the manuscript. Schering-Plough
had no role in the study design or conduct, data collection, analysis or interpretation,
or the preparation, review, or approval of the manuscript.
Acknowledgment: We thank David Young for his
critical review of the manuscript, and we thank the patients who participated
in the study.