Gastroenterology
Volume 130, Issue 3 , Pages 632-638, March 2006

Peginterferon Alfa-2b Therapy in Acute Hepatitis C: Impact of Onset of Therapy on Sustained Virologic Response

  • Sanaa M. Kamal

      Affiliations

    • Division of Gastroenterology and Liver Disease Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
    • Department of Gastroenterology and Liver Diseases, Ain Shams University, Cairo, Egypt
    • Department of Gastroenterology and Hepatology, University of Freiburg, Freiburg, Germany
    • Corresponding Author InformationAddress requests for reprints to: Sanaa M. Kamal, MD, Liver Disease Center, Beth Israel Deaconess Medical Center, 4 Blackfan Circle, Boston, Massachusetts 02115.fax:
    • ,
  • Amr E. Fouly

      Affiliations

    • Department of Gastroenterology and Liver Diseases, Ain Shams University, Cairo, Egypt
    • ,
  • Refaat R. Kamel

      Affiliations

    • Department of Gastroenterology and Liver Diseases, Ain Shams University, Cairo, Egypt
    • ,
  • Bridgette Hockenjos

      Affiliations

    • Department of Gastroenterology and Hepatology, University of Freiburg, Freiburg, Germany
    • ,
  • Ahmed Al Tawil

      Affiliations

    • Department of Gastroenterology and Liver Diseases, Ain Shams University, Cairo, Egypt
    • ,
  • Khalifa E. Khalifa

      Affiliations

    • Department of Gastroenterology and Liver Diseases, Ain Shams University, Cairo, Egypt
    • ,
  • Qi He

      Affiliations

    • Division of Gastroenterology and Liver Disease Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
    • ,
  • Margaret J. Koziel

      Affiliations

    • Division of Gastroenterology and Liver Disease Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
    • ,
  • Khairy M. El Naggar

      Affiliations

    • Department of Gastroenterology and Liver Diseases, Ain Shams University, Cairo, Egypt
    • ,
  • Jens Rasenack

      Affiliations

    • Department of Gastroenterology and Hepatology, University of Freiburg, Freiburg, Germany
    • ,
  • Nezam H. Afdhal

      Affiliations

    • Division of Gastroenterology and Liver Disease Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA

Received 23 August 2005; accepted 21 December 2005.

Article Outline

Background & Aims: Pegylated interferon therapy has not been adequately evaluated in acute hepatitis C virus (HCV) infection. This randomized trial assessed the efficacy, safety, and timing of pegylated interferon alfa-2b for treatment of acute hepatitis C. Methods: One hundred seventy-five patients acutely infected with HCV were screened. Patients whose infection did not spontaneously resolve by week 8 were randomized to once weekly peginterferon alfa-2b monotherapy (1.5 μg/kg per week) started at weeks 8, 12, or 20 for a duration of 12 weeks. The primary endpoint was undetectable HCV RNA 24 weeks after the end of treatment (sustained virologic response [SVR]). All patients were followed for 48 weeks after cessation of therapy. Results: One hundred twenty-nine subjects started treatment at week 8 (group A, n = 43), week 12 (group B, n = 43), or week 20 (group C, n = 43). By using an intent-to-treat analysis, the overall SVR rate was 87%. The SVR rates were 95%, 92%, and 76% with treatment onset at 8, 12, and 20 weeks, respectively. Overall, SVR rates were better for patients infected with genotypes 2, 3, and 4 than those infected with genotype 1. Earlier initiation of therapy improved SVR rates for patients infected with genotype 1 with high viral load. Peginterferon alfa-2b was well tolerated. Subjects with SVR maintained undetectable HCV RNA 48 weeks after therapy. Conclusions: Peginterferon alfa-2b monotherapy in acute hepatitis C induces high sustained virologic response rates, prevents chronic evolution, and is well tolerated. Initiation of treatment at week 8 or 12 results in higher sustained virologic rates than initiation at week 20.

Abbreviations used in this paper:  AEs, adverse events , CI, confidence interval , HCV, hepatitis C virus , IFN, interferon , PCR, polymerase chain reaction , PEG-IFN α, pegylated interferon alpha , SVRs, sustained virologic response rates

 

Acute hepatitis C virus (HCV) infection is usually asymptomatic and difficult to diagnose.1, 2 However, it occurs relatively frequently in injection-drug users and in health care workers exposed to needle-stick injury.3, 4 In addition, acute sexually acquired HCV is not uncommon.5, 6 Spontaneous resolution of infection is rare. Of the approximately 50%–70% of patients who develop chronic hepatitis, 20% progress to cirrhosis and hepatocellular carcinoma.1, 2

Several trials have examined the efficacy of different conventional interferon (IFN) α regimens in acute HCV infection and found variable clearance rates relative to the onset of disease.7, 8, 9, 10, 11, 12, 13, 14 The diverse enrollment criteria, the small number of subjects, the heterogeneity of the patients, the lack of controls, the different types and doses of IFN α, and the differences in the definition of response and duration of follow-up render the results of such trials difficult to interpret.1, 2, 13

Pegylated interferon alpha (PEG-IFN α) in combination with ribavirin is currently the standard treatment for chronic HCV infection, with sustained virologic response rates (SVRs) reaching 82% in patients with genotypes 2 or 3. However, the overall SVR in genotype 1 and 4 chronic HCV ranges between 42% and 60%, leaving almost half of patients as virologic nonresponders.14, 15, 16, 17, 18, 19 The optimum efficacy, safety, timing, and duration of PEG-IFN therapy has not been adequately assessed in acute HCV because of the difficulty of conducting large randomized trials given that most cases are asymptomatic.

We have previously shown in a small cohort of patients with acute HCV comparable rates of SVR with a combination of PEG-IFN α-2b and ribavirin (85%) and PEG-IFN α-2b monotherapy (80%), suggesting that the addition of ribavirin had no effect on treatment outcome.20 In this randomized, controlled, multicenter trial, we evaluated the efficacy and safety of PEG-IFN α-2b in a large cohort of patients with acute HCV infection. In addition, given that 30%–50% of subjects with acute HCV may spontaneously resolve infection, we set out to identify the optimal timing of therapy as well.

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Materials and Methods 

Selection of Patients 

This multicenter, prospective, randomized, controlled trial was conducted in 8 Egyptian, American, and German centers. Between September 2002 and March 2005, all subjects with a proven diagnosis of acute HCV were screened for eligibility. The diagnosis of acute HCV infection and eligibility for the study was based on the following criteria in previously healthy individuals with or without symptoms: elevated serum alanine aminotransferase (5–10 times the upper limit of normal), conversion from negative to positive polymerase chain reaction (PCR) for HCV RNA (Amplicor HCV PCR test version 2.0 [HCV PCR], Roche Diagnostics, Branchburg, NJ), a lower limit of detection of 50 IU/mL and HCV transcription-mediated amplification (TMA) with a limit of detection of 6 IU/mL (VERSANT HCV RNA 3.0 Assay; Bayer Healthcare, Berkeley, CA), and seroconversion from negative to positive anti-HCV antibody status (third-generation enzyme-linked immunosorbent assay). Other causes of hepatitis were ruled out by history and appropriate serologic studies. Subjects were excluded from they study if they had decompensated liver disease, coinfection with human immunodeficiency virus or Schistosoma mansoni (excluded by rectal snip and serology), neutropenia (<1500/mm3), thrombocytopenia (<90,000/mm3), a serum creatinine concentration >1.5 times the upper limit of normal, serum alpha fetoprotein >25 ng/mL, an organ transplant, neoplastic disease, severe cardiac or pulmonary disease, unstable thyroid dysfunction, or a psychiatric disorder; were currently pregnant or breast-feeding; or underwent therapy with immunomodulatory agents within the last 6 months.

Patients participating in the study gave written informed consent before enrollment and before any study-related procedures. The study protocol was approved by the institutional review boards of the participating centers and was conducted according to the Declaration of Helsinki and the ICH/CPMP (Good Clinical Practice) guidelines.

Study Design 

The design of this prospective, randomized, controlled clinical trial is outlined in Figure 1. The participating centers conducted patient prescreening by using the same set of inclusion and exclusion criteria. If inclusion criteria were met, the patients were enrolled and followed on a weekly basis for an initial 8-week observation period starting from the time of their first positive HCV-RNA PCR, during which monthly serum alanine aminotransferase and HCV-RNA measurements were made. Patients who did not resolve spontaneously (loss of HCV RNA without treatment) by the end of the 8-week observation period were initially randomized to start treatment at week 8 (group A), week 12 (group B), or week 20 (group C). Restricted randomization performed by using permuted blocks was used to achieve balance between groups in size and characteristics. Stratification with blocking within strata was done for center, mode of transmission, and genotype to make sure that this covariate was balanced between the arms of the trial.

  • View full-size image.
  • Figure 1. 

    Study design flow chart. Patients were randomized after an 8-week observation period. Patients who did not resolve spontaneously by week 8 were randomized to start treatment immediately at week 8 (group A), week 12 (group B), or week 20 (group C). Patients who resolved spontaneously or withdrew prematurely from treatment were encouraged to return for follow-up.

Patients with spontaneous remission during the initial 8-week observation period were excluded from the treatment analysis but were encouraged to remain in the study and to come regularly for follow-up until the end of the study. Patients who declined treatment during the acute phase were enrolled and prospectively followed as a control group for the outcome of acute HCV. Treated cohorts and the untreated controls showed no significant differences in clinical characteristics.

Intervention and Compliance 

Patients were treated with PEG-IFN α-2b monotherapy (1.5 μg/kg; PEG-Intron, Schering Corp, Kenilworth, NJ) once per week for 12 weeks. All patients randomized to a treatment arm after the 8-week observation period were included in the intent-to-treat analysis based on their original assignment to treatment duration groups, regardless of whether patients failed to fully participate in the trial for any reason, including whether they actually received their allocated treatment (such as those who might resolve spontaneously while awaiting treatment initiation), did not comply to therapy, or dropped out of the trial.

All patients allocated to a given study group were closely followed during treatment. All efforts were made to ensure maximum compliance, that patients continued to take the allocated treatments, and that all patients were accounted for in the trial report. We assessed adherence constantly during the study. To ensure compliance, PEG IFN α-2b injections were given in the respective centers by qualified nurses and the empty vials and used returned syringes were monitored.

Assessment of Efficacy and Safety 

Patients were evaluated as outpatients for efficacy and safety before treatment allocation; at allocation; at weeks 2, 4, 8, and 12 during treatment; and at weeks 12, 14, 24, and 48 after the end of treatment. The primary efficacy endpoint was sustained virologic response defined as undetectable serum HCV-RNA levels (Amplicor HCV; Roche Molecular Diagnostics, Pleasanton, CA; lower limit of detection of 50 IU/mL confirmed by HCV TMA with an LLD of 6 IU/mL; Bayer VERSANT HCV RNA 3.0) 24 weeks after treatment. Secondary endpoints included a virologic response at the end of treatment.

Stepwise reductions in drug dose were allowed to manage adverse events (AEs) or laboratory abnormalities that had reached predetermined thresholds of severity. If the AE resolved or improved, a return to initial dosing levels was permitted unless the patient had received the reduced dose for more than 4 weeks. Patients were withdrawn from treatment if they missed 3 or more consecutive doses. Patients who discontinued therapy prematurely because of intolerance were encouraged to remain in the study.

Statistical Analysis 

The primary statistical analysis was the determination of the 95% confidence interval for the sustained virologic response rates between groups A, B, and C. The study was designed to have an 80% power to detect a difference of 20% or more between groups and to detect a difference of 30% or more between treated and untreated subjects with a power of at least 90%. A Fisher exact test and chi-square tests were used to compare different rates. Analysis of the SVR rates in the 3 groups was performed according to an intent-to-treat strategy in which all patients randomly assigned to one of the treatments were analyzed regardless of whether or not they completed or received that treatment. Prognostic variables included age, gender, and viral load. Predictors of treatment response were examined by stepwise logistic-regression analysis or multivariate Cox regression analysis. Results were expressed as mean ± standard deviation. All reported P values are 2 sided. Significance was accepted at P ≤ .05.

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Results 

Between September 2002 and March 2004, 175 consecutive subjects with proven acute hepatitis were screened. According to the inclusion and exclusion criteria, 168 subjects were eligible, but 27 declined therapy during the acute phase. These patients did consent to be enrolled in the study as a control group for the outcome of acute HCV. Therefore, 141 subjects were enrolled as the treatment group and were all followed without randomization or assignment to treatment for an 8-week observation period (Figure 1). The mean time between infection and referral was 11 ± 1.5 days (range, 1–15 days). Enrolled patients included health care workers or individuals who reported HCV exposure with either archived pre-exposure or immediate baseline postexposure-negative HCV serum specimens confirmed by PCR. Sexual transmission was confirmed in 9 patients by genotyping and genetic sequencing of strains from sexual partners. These studies showed a very high degree of homology of the HCV genomes in these patients and the strains identified from sexual partners. Of the 141 patients in the intent-to-treat group, 31 patients (22%) had symptoms and jaundice versus 10 symptomatic patients in the control group (37%). In symptomatic patients, the time from exposure to onset of symptoms ranged from 4 to 8 weeks.

Outcome of Acute Infection 

The flow of subjects through the study is shown in Figure 1. Of the 141 patients in the treatment group, 12 (9 women and 3 men, 8.5%) had spontaneous resolution during the initial 8-week observation period before randomization, and they maintained normal levels of aminotransferases with no detectable serum HCV RNA during further follow-up. At the end of the 8-week observation period, 129 patients (male:female ratio, 63:66; mean age 35.8 ± 13.8 years) remained viremic so they were randomized to the 3 treatment groups. Random blocks of 3 were used to allocate the patients to start treatment at weeks 8 (group A, n = 43), 12 (group B, n = 43), or 20 (group C, n = 43). The pretreatment characteristics of enrolled patients were similar among the three treatment groups and the control group (Table 1).

Table 1. Demographic and Baseline Characteristics of Enrolled Patients
ParameterGroup A onset week 8 (n = 43)Group B onset week 12 (n = 43)Group C onset week 20 (n = 43)Control group (n = 27)
M/F21/2218/2520/2318/19
Age (y):mean ± SD36.9 ± 9.534.7 ± 7.538.6 ± 3.540.6 ± 5.8
Mode of infection n (%)
Occupational exposure19262719
Drug use3754
Surgery5230
Sexual2214
Symptoms N (%)8 (18.6)9 (21)9 (21)6 (22)
Total bilirubin (mg/dL ± SD)3.9 ± 1.74.2 ± 3.44.3 ± 2.95.1 ± 1.2
Mean ALT (U/L ± SD)633.5 ± 148.9642.3 ± 113.5653.5 ± 121.2578.7 ± 132.2
Mean AST (U/L ± SD)505.5 ± 127.3653.4 ± 182.2623.5 ± 143.8584.3 ± 98.5
Genotype 11616169
Genotype 24544
Genotype 36455
Genotype 417181818
Mean RNA (IU/mL ± SD)648,000 ± 420,000631,000 ± 461,000693,000 ± 501,000533,000 ± 420,000

While waiting to start treatment, 9 patients assigned to group B and 10 patients assigned to group C had spontaneous resolution before starting therapy. Seventeen patients resolved the infection spontaneously before week 12, and 2 resolved before week 20 (at week 14). Thus, of the 141 patients who consented to therapy, 31 patients (22%) achieved spontaneous resolution (8 patients during the observation period before randomization and an additional 19 patients between weeks 8 and 14. Of the patients who spontaneously resolved, 9 were assigned to group B and 10 were assigned to group C). The rate of spontaneous resolution in the control group was 29.6% (8/27), of whom 86% had undetectable HCV RNA within 12 weeks. The majority of those who achieved spontaneous resolution (31/39, 79%) in the entire cohort (treatment group and control group) were young (age >30 years), symptomatic, jaundiced, infected with non-1 genotype, and were most commonly women (29/38 patients, 76%). All patients whose infection resolved spontaneously continued to have undetectable serum HCV RNA until the end of follow-up.

Virologic Response According to Time of Treatment Onset 

All patients assigned to group A were treated, whereas 9 and 10 patients in groups B and C, respectively, resolved spontaneously before starting therapy. Therefore, 34 and 33 patients in groups B and C, respectively, were actually treated and received at least 1 dose of therapy. Given the intent-to-treat analysis, data for all randomized patients were analyzed in the groups to which they were initially assigned, regardless of anything that happened after randomization. The overall intent-to-treat virologic response at the end of therapy for the entire treatment group was 93.7% (121/129 treated patients). The overall intent-to-treat SVR rate was 88.3% (114/129). Taken together, our data show that PEG-IFN α therapy significantly increased the rates of sustained aviremia compared with no treatment (odds ratio, 15.32; 95% confidence interval [CI], 8.45–24.12).

The end-of-treatment response rates in patients treated for 8, 12, and 20 weeks were 97.6%, 95.3%, and 88.3%, respectively (groups A and B: P = .2, groups A and C: P = .05, and groups B and C: P = .05). Earlier initiation of therapy was associated with higher SVR rates (Table 2). The intent-to-treat SVR rates were 95.3%, 93.2%, and 76.6% in patients who were assigned to start PEG-IFN α-2b at weeks 8, 12, and 20, respectively (groups A and B: P = .4, groups A and C: P = .02, and groups B and C: P = .03). In group B, because 9 patients had spontaneous resolution, 31 of 33 treated patients (93.9%) had SVR. In group C, 10 patients had spontaneous resolution, and 23 of 33 treated patients (69.6%) achieved SVR. Comparing the SVR rates in patients actually treated across the 3 groups showed a difference in SVR between groups A and B of 1.4% (P = not significant), between groups A and C of 25.7% (95% CI: 18%–27%, P < .001), and between groups B and C of 24.3% (95% CI: 17%–30%, P = .002). Taken together, these results show that earlier treatment initiation was associated with significantly higher SVR rates both in the intent-to-treat analysis as well as in patients actually treated.

Table 2. Effect of Treatment Onset on End of Treatment and Sustained Response Rates in All Patients Using Intent-to-Treat Analysis
Virologic response (undetectable HCV-RNA)Onset week 8 (n = 43)Onset week 12 (n = 43)Onset week 20 (n = 43)
EndoftreatmentN(%)42(97.6)41(95.3)38(88.3)
SustainedresponseN(%)41(95.3)40(93.2)33(76.6)

Virologic Response According to HCV Genotype and Pretreatment Viremia 

The treated study population was composed of 48 subjects infected with genotype 1, 13 infected with genotype 2, 15 subjects infected with genotype 3, and 53 subjects infected with genotype 4. The overall SVR of the treated group was 72%, 100%, 93%, and 84% in patients infected with genotypes 1, 2, 3, and 4, respectively. All patients infected with genotype 2 in the 3 groups achieved SVR. In patients infected with genotype 3, the SVR rates were 100%, 100%, and 80% (4/5) in groups A, B, and C, respectively. In genotype 1, the highest SVR was achieved when therapy was started at week 8 (group A). In patients infected with genotype 4, initiation of therapy at weeks 8 or 12 was associated with significantly higher SVR rates compared with rates achieved when treatment was delayed until 20 weeks (Figure 2).

  • View full-size image.
  • Figure 2. 

    SVR rates according to genotype. The x-axis represents the different genotypes. The percent of patients showing SVR is represented on the y-axis. Black bars represent group A patients who started therapy at week 8. White bars represent group B patients who started treatment at week 12. Gray bars represent group C patients who started treatment at week 20.

Sustained virologic response rates in genotypes 2, 3, and 4 were not affected by baseline viremia. The SVR rates were 75%, 72%, and 42% among genotype 1 patients with baseline HCV-RNA titers >800,000 IU/mL in groups A, B, and C, respectively (P > .2 between groups A and B; P = .01 between groups A and C; and P = .001 between groups B and C, respectively [data not shown]).

Predictors of Sustained Virologic Response 

From multivariate logistic regression analysis of all treated patients, genotype non-1 and low baseline load were independent factors of sustained virologic response.

Adverse Events 

Although AEs were typical of those previously reported for therapy with (pegylated) interferon, the adverse events were less frequent compared with chronic hepatitis C. The reported AEs included fever (12%), flu-like symptoms (10%), headache (10%), pharyngitis (6%), anxiety (6%), neutropenia (7%), thrombocytopenia (5.4%), fatigue (6%), insomnia (4.5%), generalized urticaria (3%), gastroenteritis (2%), renal colic (1%), chronic fungal infection (4.5%), oral lichen planus (2.3%), self-limiting episode of blurred vision (3%), and chorioretinitis (1.5%).

Dose reduction (1–2 doses) was required in 2 patients in group A, 1 in group B, and 1 in group C. The most common AEs leading to dose reduction or discontinuation were hematologic abnormalities (neutropenia and/or thrombocytopenia). Only 1 patient in group A discontinued therapy prematurely because of neutropenia that was not improved by dose modification.

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Discussion 

Acute HCV infection is associated with variable spontaneous clearance rates,1, 2, 3, 13, 21, 22 and IFN therapy is associated with both adverse events and significant costs. Careful selection of patients for treatment is therefore crucial to avoid treating patients unnecessarily. To date, the appropriate timing of IFN-based therapy in acute hepatitis has not been determined because most previous studies of treatment have been of limited size and power, and therapy was initiated at various time points ranging between 1 and 24 months without sufficient follow-up periods to rule out late relapse P.6, 7, 8, 9, 10, 11, 12, 13, 14 We have previously shown in a smaller cohort that treatment of acute HCV infection with PEG-IFN α-2b induces SVR rates reaching 85%.20 In this randomized, prospective, intent-to-treat clinical trial, we attempted to determine the optimal time to initiate therapy in patients for whom chronic evolution was likely. We thus initiated therapy at 3 time points and included a large cohort of symptomatic and asymptomatic acute HCV patients in addition to an untreated control group.

Irrespective of the timing of therapy, 12 weeks of PEG-IFN α-2b therapy for acute HCV induced SVR rates as high as 88.5% and was well tolerated with very few dropouts or dose modifications. The SVR rates were significantly higher than the rates of spontaneous resolution in untreated patients, which is consistent with previous reports showing that interferon therapy compared with no treatment significantly increased SVR rates.12, 13, 20 In the present study, the sustained virologic response rate was higher than that previously reported with conventional IFN therapy in acute HCV.6, 7, 8, 9, 11, 13 Most importantly, the virologic response was maintained 48 weeks after the end of therapy with no late relapse, suggesting that treatment of HCV infection during the acute stage can reduce the rate of progression from acute to chronic HCV, a concept also supported by Wiegand et al.22

Therapy was associated with high SVR rates reaching 95.3% and 93.2% when treatment was started at weeks 8 and 12, respectively. Although the difference in SVR rates did not differ significantly between the 2 time points, one might speculate that some patients who started treatment at week 8 might have resolved spontaneously if untreated, given that 95% of spontaneous remissions in the control group occurred by 12 weeks and that spontaneous resolution occurred between weeks 8 and 14 in 19 patients in groups B and C while awaiting therapy induction. However, delaying therapy until 20 weeks significantly decreased the SVR rates, suggesting an increased benefit when treatment is started at earlier time points. The significantly lower SVR rates detected when treatment was delayed until week 20 might be attributed to expansion of HCV quasispecies toward a more heterogeneous and resistant virus population or to blunting of the immune response, features that appear to correlate with evolution into chronicity.21

In our cohort, the rates of spontaneous resolution of acute HCV in symptomatic icteric patients were significantly higher than asymptomatic patients, supporting previous reports showing high rates of spontaneous viral clearance that might exceed 50% in symptomatic icteric patients.13, 20, 23, 24 A possible explanation is that symptoms may reflect robust antiviral cellular immunity. We and others5, 22, 23, 24 have shown the role of cellular immunity, namely polyclonal CD4+ and CD8+ T-cell responses, which develop 8–12 weeks after infection in the spontaneous resolution of acute HCV infection. Immediate treatment of all cases with acute HCV infection might result in treatment of some patients who would recover spontaneously and might be counterproductive because antiviral therapy seems to be effective in the setting of an active host immune response to the infection. Taken together, our data suggest that delaying treatment until 12 or 14 weeks, particularly in symptomatic patients, would be optimal to give every opportunity to patients to spontaneously clear the virus through HCV-specific T-cell activity without jeopardizing treatment outcomes in those who will fail to spontaneously clear.

In the present study, the overall sustained virologic response rates were higher in patients infected with genotypes 2, 3, and 4 than in those infected with genotype 1, suggesting that acute HCV treatment needs to be individualized according to genotype as in chronic HCV therapy.15, 16, 17 The sustained virologic response rates in genotype 2– and 3–infected patients were above 95%, irrespective of the onset of therapy. In genotype 4, no significant differences were detected between week 8 and 12 onset, but the SVR rates were significantly higher when treatment was delayed to 20 weeks. Our results thus show that initiating treatment at week 12 allows the achievement of high SVR rates in patients infected with genotypes 2, 3, and 4 even with 12 weeks therapy, which would spare patients unnecessary adverse events and costs while increasing the benefit of therapy. However, our findings concerning SVR rates in genotype 1 suggest that a different algorithm may be required. In genotype 1, the highest SVR rates were achieved when treatment was started at week 8, particularly in patients with a baseline HCV RNA concentration of more than 800,000 IU/mL, suggesting that patients infected with genotype 1 might need earlier initiation of therapy. However, these observations need to be further investigated because treatment in the current study was administered for 12 weeks. Therefore, we are currently comparing different durations of peginterferon therapy in the setting of acute HCV infection.

In conclusion, our results show that PEG-IFN α-2b treatment of acute HCV infection results in high SVR rates, reduces chronic evolution, and is well tolerated even in asymptomatic patients with difficult-to-treat genotypes. Starting treatment between weeks 8 and 12 increases the virologic response while allowing those patients who might recover spontaneously to do so.

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 Supported by the National Institutes of Allergy and Infectious Diseases (grant nos. R21 AI054887, R21 AI41563, and R01 AI068966); Fulbright Commission, USA (TEMPUS: grant no. IMG 04-E.G. 1096); Alexander von Humboldt Foundation, Germany; and International Society of Infectious Diseases, USA (grant no. RF-9641).

PII: S0016-5085(06)00061-8

doi:10.1053/j.gastro.2006.01.034

Gastroenterology
Volume 130, Issue 3 , Pages 632-638, March 2006