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Original Contribution |

Pegylated Interferon Alfa-2b vs Standard Interferon Alfa-2b, Plus Ribavirin, for Chronic Hepatitis C in HIV-Infected Patients:  A Randomized Controlled Trial FREE

Fabrice Carrat, MD, PhD; Firouzé Bani-Sadr, MD; Stanislas Pol, MD, PhD; Eric Rosenthal, MD; Françoise Lunel-Fabiani, MD, PhD; Asmae Benzekri, MD; Patrice Morand, MD, PhD; Cécile Goujard, MD; Gilles Pialoux, MD, PhD; Lionel Piroth, MD, PhD; Dominique Salmon-Céron, MD, PhD; Claude Degott, MD; Patrice Cacoub, MD; Christian Perronne, MD, PhD; for the ANRS HCO2 RIBAVIC Study Team
[+] Author Affiliations

Author Affiliations: Groupe Hospitalier Universitaire Est, Université Paris 6, INSERM U444 (Drs Carrat and Bani-Sadr) and Groupe Hospitalier Universitaire Ouest, Université Paris 5, INSERM U370 (Dr Pol), Paris; Hôpital de l’Archet, Faculté de médecine, Nice (Dr Rosenthal); Groupe Hospitalier, Faculté de médecine, Angers (Dr Lunel-Fabiani); Groupe Hospitalier Universitaire Nord, Université Paris 7, (Drs Benzeckri and Degott), Centre Hospitalier Universitaire, Grenoble (Dr Morand), Groupe Hospitalier Universitaire Sud, Université Paris 11 (Dr Goujard), and Groupe Hospitalier Universitaire Est, Université Paris 6, (Drs Pialoux and Cacoub) Paris; Centre Hospitalier Universitaire, Dijon (Dr Piroth); and Groupe Hospitalier Universitaire Ouest, Université Paris 5, (Dr Salmon-Céron), Centre Hospitalier Universitaire Raymond Poincaré, Université de Versailles, Garches (Dr Perronne), France.

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JAMA. 2004;292(23):2839-2848. doi:10.1001/jama.292.23.2839.
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Published online

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 weeks.

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 patients.

Figures in this Article

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.37

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).1012

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.1619 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 alfa-2b.

Patient Selection

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.

Study Design and Treatment Regimens

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 planned.

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 responses.

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.

Statistical Analysis

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).

Characteristics of the Patients

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).

Table Graphic Jump LocationTable 1. Baseline Characteristics of the Patients*
Virologic Responses

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).

Figure 2. End-of-Treatment Virologic Responses (Week 48) and Sustained Virologic Responses (Week 72)
Graphic Jump Location

*This represents all patients who took at least 80% of the planned total dose by hepatitic C virus genotype.

Independent Factors Associated With Sustained Virologic Response

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.

Table Graphic Jump LocationTable 2. Virologic Responses According to Baseline Variables
Histological Responses

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).

Table Graphic Jump LocationTable 3. Histologic Responses in Patients With Paired Pretreatment and Posttreatment Biopsy Samples by Treatment and Sustained Virologic Responses

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 (–13%, P<.001).

Safety

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).

Table Graphic Jump LocationTable 4. Incidence of Treatment Discontinuation, Dose Modifications, and Adverse Events*

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 didanosine.

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%.1618 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.1416,18,29,30 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 hepatic decompensation.38

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 setting.

Corresponding Author: Fabrice Carrat, MD, PhD, Groupe Hospitalier Universitaire Est, Université Paris 6, INSERM U444, Paris.

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, Piroth, Perronne.

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 by Schering-Plough.

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.

Lauer G, Walker B. Hepatitis C virus infection.  N Engl J Med. 2001;345:41-52
PubMed   |  Link to Article
Alter MJ, Kruszon-Moran D, Nainan OV.  et al.  The prevalence of hepatitis C virus infection in the United States, 1988 through 1994.  N Engl J Med. 1999;341:556-562
PubMed   |  Link to Article
Rockstroh JK. Management of hepatitis B and C in HIV Co-infected patients.  J Acquir Immune Defic Syndr. 2003;34:(suppl 1)  S59-S65
PubMed   |  Link to Article
Darby SC, Ewart DW, Giangrande PL.  et al. UK Haemophilia Centre Directors' Organisation.  Mortality from liver cancer and liver disease in haemophilic men and boys in UK given blood products contaminated with hepatitis C.  Lancet. 1997;350:1425-1431
PubMed   |  Link to Article
Soto B, Sanchez-Quijano A, Rodrigo L.  et al.  Human immunodeficiency virus infection modifies the natural history of chronic parenterally-acquired hepatitis C with an unusually rapid progression to cirrhosis.  J Hepatol. 1997;26:1-5
PubMed   |  Link to Article
Rosenthal E, Poiree M, Pradier C.  et al.  Mortality due to hepatitis C-related liver disease in HIV-infected patients in France (Mortavic 2001 study).  AIDS. 2003;17:1803-1809
PubMed   |  Link to Article
Cacoub P, Geffray L, Rosenthal E, Perronne C, Veyssier P, Raguin G. Mortality among human immunodeficiency virus-infected patients with cirrhosis or hepatocellular carcinoma due to hepatitis C virus in French Departments of Internal Medicine/Infectious Diseases, in 1995 and 1997.  Clin Infect Dis. 2001;32:1207-1214
PubMed   |  Link to Article
Glue P, Fang JW, Rouzier-Panis R.  et al.  Hepatitis C Intervention Therapy Group. Pegylated interferon-alpha2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data.  Clin Pharmacol Ther. 2000;68:556-567
PubMed   |  Link to Article
Bailon P, Palleroni A, Schaffer CA.  et al.  Rational design of a potent, long-lasting form of interferon: a 40 kDa branched polyethylene glycol-conjugated interferon alpha-2a for the treatment of hepatitis C.  Bioconjug Chem. 2001;12:195-202
PubMed   |  Link to Article
Fried MW, Shiffman ML, Reddy KR.  et al.  Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.  N Engl J Med. 2002;347:975-982
PubMed   |  Link to Article
Manns MP, McHutchison JG, Gordon SC.  et al.  Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.  Lancet. 2001;358:958-965
PubMed   |  Link to Article
Hadziyannis SJ, Sette H Jr, Morgan TR.  et al.  Peginterferon-alpha-2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose.  Ann Intern Med. 2004;140:346-355
PubMed   |  Link to Article
Salmon-Céron D, Lassalle R, Pruvost A.  et al.  Interferon-ribavirin in association with stavudine has no impact on plasma human immunodeficiency virus (HIV) type 1 level in patients coinfected with HIV and hepatitis C virus: A CORIST-ANRS HC1 trial.  Clin Infect Dis. 2003;36:1295-1304
PubMed   |  Link to Article
Torriani FJ, Rodriguez-Torres M, Rockstroh JK.  et al.  Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients.  N Engl J Med. 2004;351:438-450
PubMed   |  Link to Article
Chung RT, Andersen J, Volberding P.  et al.  Peginterferon alfa-2a plus ribavirin vs interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons.  N Engl J Med. 2004;351:451-459
PubMed   |  Link to Article
Perez-Olmeda M, Nunez M, Romero M.  et al.  Pegylated IFN-alpha 2b plus ribavirin as therapy for chronic hepatitis C in HIV-infected patients.  AIDS. 2003;17:1023-1028
PubMed   |  Link to Article
Ballesteros AL, Franco S, Fuster D.  et al.  Early HCV dynamics on Peg-interferon and ribavirin in HIV/HCV co-infection: indications for the investigation of new treatment approaches.  AIDS. 2004;18:59-66
PubMed   |  Link to Article
Moreno L, Quereda C, Moreno A.  et al.  Pegylated interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C in HIV-infected patients.  AIDS. 2004;18:67-73
PubMed   |  Link to Article
Laguno M, Murillas J, Blanco JL.  et al.  Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for treatment of HIV/HCV co-infected patients.  AIDS. 2004;18:F27-F36
PubMed   |  Link to Article
Bedossa P, Poynard T.The METAVIR Cooperative Study Group.  An algorithm for the grading of activity in chronic hepatitis C.  Hepatology. 1996;24:289-293
PubMed   |  Link to Article
Ishak K, Baptista A, Bianchi L.  et al.  Histological grading and staging of chronic hepatitis.  J Hepatol. 1995;22:696-699
PubMed   |  Link to Article
Fontaine H, Nalpas B, Poulet B.  et al.  Hepatitis activity index is a key factor in determining the natural history of chronic hepatitis C.  Hum Pathol. 2001;32:904-909
PubMed   |  Link to Article
Molina JM, Ferchal F, Rancinan C.  et al.  Once-daily combination therapy with emtricitabine, didanosine, and efavirenz in human immunodeficiency virus-infected patients.  J Infect Dis. 2000;182:599-602
PubMed   |  Link to Article
Zhang J, Yu KF. What's the relative risk? a method of correcting the odds ratio in cohort studies of common outcomes.  JAMA. 1998;280:1690-1691
PubMed   |  Link to Article
Schaefer M, Schmidt F, Folwaczny C.  et al.  Adherence and mental side effects during hepatitis C treatment with interferon alfa and ribavirin in psychiatric risk groups.  Hepatology. 2003;37:443-451
PubMed   |  Link to Article
Brau N, Bini EJ, Shahidi A.  et al.  Prevalence of hepatitis C and coinfection with HIV among United States veterans in the New York City metropolitan area.  Am J Gastroenterol. 2002;97:2071-2078
PubMed
Soriano V, Puoti M, Sulkowski M.  et al.  Care of patients with hepatitis C and HIV co-infection.  AIDS. 2004;18:1-12
PubMed   |  Link to Article
McHutchison JG, Gordon SC, Schiff ER.  et al. Hepatitis Interventional Therapy Group.  Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C.  N Engl J Med. 1998;339:1485-1492
PubMed   |  Link to Article
Zeuzem S, Feinman SV, Rasenack J.  et al.  Peginterferon alfa-2a in patients with chronic hepatitis C.  N Engl J Med. 2000;343:1666-1672
PubMed   |  Link to Article
Myers RP, Benhamou Y, Bochet M, Thibault V, Mehri D, Poynard T. Pegylated interferon alpha 2b and ribavirin in HIV/hepatitis C virus co-infected non-responders and relapsers to IFN-based therapy.  AIDS. 2004;18:75-79
PubMed   |  Link to Article
Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection.  JAMA. 2000;283:74-80
PubMed   |  Link to Article
Vento S, Garofano T, Renzini C, Casali F, Ferraro T, Concia E. Enhancement of hepatitis C virus replication and liver damage in HIV-coinfected patients on antiretroviral combination therapy.  AIDS. 1998;12:116-117
PubMed
John M, Flexman J, French MA. Hepatitis C virus-associated hepatitis following treatment of HIV-infected patients with HIV protease inhibitors: an immune restoration disease?  AIDS. 1998;12:2289-2293
PubMed   |  Link to Article
Becquemont L, Chazouilleres O, Serfaty L.  et al.  Effect of interferon alpha-ribavirin bitherapy on cytochrome P450 1A2 and 2D6 and N-acetyltransferase-2 activities in patients with chronic active hepatitis C.  Clin Pharmacol Ther. 2002;71:488-495
PubMed   |  Link to Article
Lafeuillade A, Hittinger G, Chadapaud S. Increased mitochondrial toxicity with ribavirin in HIV/HCV coinfection.  Lancet. 2001;357:280-281
PubMed   |  Link to Article
Salmon-Ceron D, Chauvelot-Moachon L, Abad S, Silbermann B, Sogni P. Mitochondrial toxic effects and ribavirin.  Lancet. 2001;357:1803-1804
PubMed   |  Link to Article
 Summary of safety-related drug labeling changes approved by FDA center for drug evaluation and research (CDER) September 2002 Web page. Available at: http://www.fda.gov/medwatch/SAFETY/2002/sep02.htm#videx. Accessed October 12, 2004
Mauss S, Valenti W, DePamphilis J.  et al.  Risk factors for hepatic decompensation in patients with HIV/HCV coinfection and liver cirrhosis during interferon-based therapy.  AIDS. 2004;18:F21-F25
PubMed   |  Link to Article

Figures

Figure 2. End-of-Treatment Virologic Responses (Week 48) and Sustained Virologic Responses (Week 72)
Graphic Jump Location

*This represents all patients who took at least 80% of the planned total dose by hepatitic C virus genotype.

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics of the Patients*
Table Graphic Jump LocationTable 2. Virologic Responses According to Baseline Variables
Table Graphic Jump LocationTable 3. Histologic Responses in Patients With Paired Pretreatment and Posttreatment Biopsy Samples by Treatment and Sustained Virologic Responses
Table Graphic Jump LocationTable 4. Incidence of Treatment Discontinuation, Dose Modifications, and Adverse Events*

References

Lauer G, Walker B. Hepatitis C virus infection.  N Engl J Med. 2001;345:41-52
PubMed   |  Link to Article
Alter MJ, Kruszon-Moran D, Nainan OV.  et al.  The prevalence of hepatitis C virus infection in the United States, 1988 through 1994.  N Engl J Med. 1999;341:556-562
PubMed   |  Link to Article
Rockstroh JK. Management of hepatitis B and C in HIV Co-infected patients.  J Acquir Immune Defic Syndr. 2003;34:(suppl 1)  S59-S65
PubMed   |  Link to Article
Darby SC, Ewart DW, Giangrande PL.  et al. UK Haemophilia Centre Directors' Organisation.  Mortality from liver cancer and liver disease in haemophilic men and boys in UK given blood products contaminated with hepatitis C.  Lancet. 1997;350:1425-1431
PubMed   |  Link to Article
Soto B, Sanchez-Quijano A, Rodrigo L.  et al.  Human immunodeficiency virus infection modifies the natural history of chronic parenterally-acquired hepatitis C with an unusually rapid progression to cirrhosis.  J Hepatol. 1997;26:1-5
PubMed   |  Link to Article
Rosenthal E, Poiree M, Pradier C.  et al.  Mortality due to hepatitis C-related liver disease in HIV-infected patients in France (Mortavic 2001 study).  AIDS. 2003;17:1803-1809
PubMed   |  Link to Article
Cacoub P, Geffray L, Rosenthal E, Perronne C, Veyssier P, Raguin G. Mortality among human immunodeficiency virus-infected patients with cirrhosis or hepatocellular carcinoma due to hepatitis C virus in French Departments of Internal Medicine/Infectious Diseases, in 1995 and 1997.  Clin Infect Dis. 2001;32:1207-1214
PubMed   |  Link to Article
Glue P, Fang JW, Rouzier-Panis R.  et al.  Hepatitis C Intervention Therapy Group. Pegylated interferon-alpha2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data.  Clin Pharmacol Ther. 2000;68:556-567
PubMed   |  Link to Article
Bailon P, Palleroni A, Schaffer CA.  et al.  Rational design of a potent, long-lasting form of interferon: a 40 kDa branched polyethylene glycol-conjugated interferon alpha-2a for the treatment of hepatitis C.  Bioconjug Chem. 2001;12:195-202
PubMed   |  Link to Article
Fried MW, Shiffman ML, Reddy KR.  et al.  Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.  N Engl J Med. 2002;347:975-982
PubMed   |  Link to Article
Manns MP, McHutchison JG, Gordon SC.  et al.  Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.  Lancet. 2001;358:958-965
PubMed   |  Link to Article
Hadziyannis SJ, Sette H Jr, Morgan TR.  et al.  Peginterferon-alpha-2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose.  Ann Intern Med. 2004;140:346-355
PubMed   |  Link to Article
Salmon-Céron D, Lassalle R, Pruvost A.  et al.  Interferon-ribavirin in association with stavudine has no impact on plasma human immunodeficiency virus (HIV) type 1 level in patients coinfected with HIV and hepatitis C virus: A CORIST-ANRS HC1 trial.  Clin Infect Dis. 2003;36:1295-1304
PubMed   |  Link to Article
Torriani FJ, Rodriguez-Torres M, Rockstroh JK.  et al.  Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients.  N Engl J Med. 2004;351:438-450
PubMed   |  Link to Article
Chung RT, Andersen J, Volberding P.  et al.  Peginterferon alfa-2a plus ribavirin vs interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons.  N Engl J Med. 2004;351:451-459
PubMed   |  Link to Article
Perez-Olmeda M, Nunez M, Romero M.  et al.  Pegylated IFN-alpha 2b plus ribavirin as therapy for chronic hepatitis C in HIV-infected patients.  AIDS. 2003;17:1023-1028
PubMed   |  Link to Article
Ballesteros AL, Franco S, Fuster D.  et al.  Early HCV dynamics on Peg-interferon and ribavirin in HIV/HCV co-infection: indications for the investigation of new treatment approaches.  AIDS. 2004;18:59-66
PubMed   |  Link to Article
Moreno L, Quereda C, Moreno A.  et al.  Pegylated interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C in HIV-infected patients.  AIDS. 2004;18:67-73
PubMed   |  Link to Article
Laguno M, Murillas J, Blanco JL.  et al.  Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for treatment of HIV/HCV co-infected patients.  AIDS. 2004;18:F27-F36
PubMed   |  Link to Article
Bedossa P, Poynard T.The METAVIR Cooperative Study Group.  An algorithm for the grading of activity in chronic hepatitis C.  Hepatology. 1996;24:289-293
PubMed   |  Link to Article
Ishak K, Baptista A, Bianchi L.  et al.  Histological grading and staging of chronic hepatitis.  J Hepatol. 1995;22:696-699
PubMed   |  Link to Article
Fontaine H, Nalpas B, Poulet B.  et al.  Hepatitis activity index is a key factor in determining the natural history of chronic hepatitis C.  Hum Pathol. 2001;32:904-909
PubMed   |  Link to Article
Molina JM, Ferchal F, Rancinan C.  et al.  Once-daily combination therapy with emtricitabine, didanosine, and efavirenz in human immunodeficiency virus-infected patients.  J Infect Dis. 2000;182:599-602
PubMed   |  Link to Article
Zhang J, Yu KF. What's the relative risk? a method of correcting the odds ratio in cohort studies of common outcomes.  JAMA. 1998;280:1690-1691
PubMed   |  Link to Article
Schaefer M, Schmidt F, Folwaczny C.  et al.  Adherence and mental side effects during hepatitis C treatment with interferon alfa and ribavirin in psychiatric risk groups.  Hepatology. 2003;37:443-451
PubMed   |  Link to Article
Brau N, Bini EJ, Shahidi A.  et al.  Prevalence of hepatitis C and coinfection with HIV among United States veterans in the New York City metropolitan area.  Am J Gastroenterol. 2002;97:2071-2078
PubMed
Soriano V, Puoti M, Sulkowski M.  et al.  Care of patients with hepatitis C and HIV co-infection.  AIDS. 2004;18:1-12
PubMed   |  Link to Article
McHutchison JG, Gordon SC, Schiff ER.  et al. Hepatitis Interventional Therapy Group.  Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C.  N Engl J Med. 1998;339:1485-1492
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