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Abstract

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Appendix
  8. References

Therapy of acute hepatitis C (AHC) has not yet been standardized and several issues are still unresolved. This open, randomized, multicenter trial aimed to assess the efficacy and safety of a 24-week course of pegylated IFN (Peg-IFN) alpha-2b versus a 12-week course of Peg-IFN alpha-2b alone or with ribavirin (RBV) in AHC patients. One hundred and thirty HCV acutely infected patients who did not spontaneously resolve by week 12 after onset were consecutively enrolled and randomized to receive Peg-IFN alpha-2b monotherapy (1.5 μg/kg/week) for 24 or 12 weeks (arm 1, n = 44 and arm 2, n = 43, respectively) or in combination with RBV (10.6 mg/kg/day) for 12 weeks (arm 3, n = 43). The primary endpoint was undetectable HCV RNA at 6-month posttreatment follow-up (sustained virological response; SVR). All patients were followed for 48 weeks after therapy cessation. HCV RNA levels were determined by real-time polymerase chain reaction (limit of detection: 15 IU/mL) at the central laboratory at baseline, week 4, end of treatment, and 6 and 12 months posttreatment. Using an intent-to-treat analysis, overall SVR rate was 71.5%. In particular, an SVR was achieved in 31 of 44 (70.5%), 31 of 43 (72.1%), and 31 of 43 (72.1%) patients in arms 1, 2, and 3, respectively (P = 0.898). Sixteen patients (12.3%) prematurely discontinued therapy or were lost to follow-up; thus, sustained response rates with per-protocol analysis were 81.6%, 81.6%, and 81.6% for patients in arms 1, 2, and 3 respectively. With multivariate analysis, virologic response at week 4 of treatment was an independent predictor of SVR. Peg-IFN alpha-2b was well tolerated. Conclusion: Peg-IFN alpha-2b induces a high SVR in chronically evolving AHC patients. Response rates were not influenced by combination therapy or treatment duration. (Hepatology 2014;59:2101-2109)

Abbreviations
AE

adverse event

AHC

acute hepatitis C

ALT

alanine aminotransferase

CHC

chronic hepatitis C

CI

confidence interval

CRO

contract research organization

ETR

end-of-treatment response

HCV

hepatitis C virus

Hgb

haemoglobin

HIV

human immunodeficiency virus

Ig

immunoglobulin

IL

interleukin

ITT

intention to treat

IV

intravenous

LTR

long-term virological response

OR

odds ratio

PCR

polymerase chain reaction

Peg-IFN

pegylated interferon

PP

per protocol

RBV

ribavirin

RVR

rapid virological response

SAE

serious AE

SD

standard deviation

SVR

sustained virological response

ULN

upper limit of normal

vRVR

very rapid virological response

Even though acute hepatitis C (AHC) incidence is gradually declining over the years in developed countries,[1] new infections continue to occur. The current major risk factors for hepatitis C virus (HCV) transmission are intravenous (IV) drug use, viral exposure during invasive diagnostic or therapeutic procedures, and sexual contacts.[1, 2] Whereas the clinical course is normally mild, AHC has a high rate of progression to chronic HCV infection, ranging between 50% and 80%.[3]

Treatment of AHC has been shown to be effective in reducing risk of progression to chronic HCV infection with higher rates of hepatitis resolution and HCV clearance, compared to nontreated patients.[4] Moreover, treatment of AHC with interferon (IFN) monotherapy offers the opportunity to maximize rates of sustained virological response (SVR) in more than 80%.[3] On the contrary, once chronic infection has been established, a dual- (pegylated [Peg]-IFN plus ribavirin [RBV]) or triple-therapy (Peg-IFN plus RBV plus protease inhibitor in genotype 1-infected patients) and longer treatment duration are required to achieve comparable SVR rates, determining an increase of side effects and costs. In light of the high risk of developing chronic disease and high response rates, treatment of AHC patients with IFN monotherapy is recommended by national and international guidelines.[5-7]

Currently, there is no standard therapy for AHC because of the difficulty in organizing large clinical trials, which are necessary to produce guidelines for clinical management and treatment. In fact, AHC is usually asymptomatic and therefore rarely recognized, and it is often difficult to diagnose because the available serological markers frequently cannot distinguish AHC from an exacerbation of chronic hepatitis C (CHC). Recently, various strategies have been explored regarding treatment initiation, dose, and duration to optimize SVR rates in AHC patients treated with Peg-IFN alpha-2b.[3, 8] When considering treatment initiation, immediate or delayed treatment strategies (8-12 weeks) have been evaluated. Because response to Peg-IFN treatment administered 8-12 weeks after clinical onset seems similar to that obtained with earlier administration, timing for treatment initiation in AHC patients remains unclear. Moreover, the optimal therapeutic regimen, including duration of treatment and the eventual addition of RBV, have not been defined.

To assess the optimal duration of Peg-IFN monotherapy (24- vs. 12-week treatment) and to verify whether combination therapy would permit a reduced treatment duration, we performed a randomized, multicenter study that compared the efficacy and safety of a 24-week course of Peg-IFN alpha-2b monotherapy versus a 12-week course of Peg-IFN alpha-2b alone or in combination with RBV in AHC patients still viremic after 12 weeks of observation from disease onset.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Appendix
  8. References
Study Design

This phase III, randomized, parallel-group, multicenter, open-label study was conducted in 27 Italian centers between January 2004 and February 2010 (CSP P03552). AHC patients, still viremic after a 12-week observation period from disease onset, were randomized into a 1:1:1 ratio to each of the three treatment arms. Onset of acute hepatitis was defined as the time point at which the increase of serum alanine aminotransferase (ALT) levels was first detected. The randomization list was generated centrally by an independent biostatistician using the Proc Plan of the SAS system (version 9.2; SAS Institute Inc., Cary, NC) and consisted of a computer-generated treatment allocation list in blocks of 9 patients each. Patients in arm 1 received Peg-IFN alpha-2b 1.5 μg/kg/week administered subcutaneously for 24 weeks, patients in arm 2 received Peg-IFN alpha-2b 1.5 μg/kg/week for 12 weeks, and patients in arm 3 received Peg-IFN alpha-2b 1.5 μg/kg/week plus RBV 10.6 mg/kg/day orally administered for 12 weeks (Fig. 1). The study design did not include a control group because the efficacy of Peg-IFN in treatment of AHC has been well recognized. After the treatment period, patients were followed for 12 months.

image

Figure 1. Study design.

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Evaluations were performed at treatment weeks 2, 4, 8, 12, 16, 20, and 24 for patients in arm 1 and at weeks 2, 4, 8, and 12 for patients in arms 2 and 3. In all patients, assessments were performed every month for the first 6 months and every 3 months thereafter up to 12 months posttreatment. The study was conducted according to the Declaration of Helsinki and the International Conference on Harmonization Consolidated Guideline on Good Clinical Practice. The ethics committee of the coordinating center approved the conduction of the trial, and the study protocol was approved by the local independent ethics committee of each center. All patients provided written informed consent.

Patients

Adult patients (18-65 years of age) with diagnosis of AHC still viremic after 12 weeks of observation from disease onset were eligible for inclusion in the study. Diagnosis of AHC was based on documented anti-HCV seroconversion or, alternatively, on the following criteria: abrupt increase of transaminases more than 20 times the upper limit of the normal (ULN) range; absence of other hepatitis viruses (immunoglobulin IgM anti-HAV [hepatitis A virus] negative and IgM anti-HBc [hepatitis B core antibody] negative); or toxic hepatitis in previously healthy individuals. All patients had to be HCV RNA positive.

Exclusion criteria included: liver disease unrelated to HCV infection, hemoglobin (Hgb) <12 g/dL in women and <13 g/dL in men; white blood count <3,000/μL; platelets <100,000/μL, pregnancy, history of severe psychiatric disease, neurologic disease, severe cardiac, gastrointestinal and kidney disease, infection with hepatitis B or human immunodeficiency virus (HIV), positive anti-nuclear antibodies and/or anti-smooth muscle antibody (>1/80), history of having received any systemic antineoplastic or immunomodulatory treatment in the previous 6 months, and history or other evidence of severe illness or any other conditions that would make patients unsuitable for the study (alcohol intake at a daily dose higher than 40 g for males an 30 g for females, thalassemia, and dialysis). Patients with ongoing drug abuse were excluded and those without evidence of ongoing IV drug abuse, but undergoing substitution treatment maintenance, were eligible.

Assessments

Hematological, biochemical, and virological evaluations were carried out locally at each study site. Serum HCV-RNA at baseline, end of treatment, and 6 and 12 months posttreatment were determined by using real-time polymerase chain reaction (PCR) assay (Roche Cobas TaqMan; lower limit of detection: <15 IU/mL; Roche Applied Science, Indianapolis, IN) by the central laboratory at the Clinic of Infectious Diseases, Ospedale Policlinico, University of Bari (Bari, Italy). For 30 patients whose serum samples were not shipped to the central laboratory for various reasons (blackouts, change of local laboratory site, or change of personnel involved in the study), HCV RNA tests were performed by the local laboratories using highly sensitive methods (real-time PCR). Virological responses after 2 and 4 weeks of treatment were evaluated by the local laboratory of each participating site.

Endpoints

The protocol-defined primary endpoint was SVR, defined as serum HCV RNA levels <15 UI/mL at 6 months posttreatment follow-up. Patients who discontinued the study for any reason before the 6-month follow-up visit were considered as nonresponders.

Secondary endpoints included the following: (1) virological responses after 2 weeks of treatment (very rapid virological response; vRVR), after 4 weeks of treatment (rapid virological response; RVR), at the end of treatment (end-of-treatment virological response; ETR), and at 12 months posttreatment follow-up (long-term virological response; LTR); (2) ALT level normalization at the end of treatment and at 6 and 12 months post-treatment follow-up; and (3) safety of Peg-IFN alpha-2b or Peg-IFN alpha-2b plus RBV in AHC.

Statistical Analysis

The sample size was calculated for the primary endpoint SVR at the end of the 6-month posttreatment follow-up period. To detect a difference among the following SVR rates (arm 1 = 95%, arm 2 = 70%, and arm 3= 85%) with a significance level of the chi-square test of 5% (two-sided) and an 80% power, 43 patients were forecasted for treatment in each treatment arm. A total of 129 patients were required to be randomized and treated.

Continuous variables were summarized by descriptive statistics (number of cases, mean, standard deviation [SD], median, minimum, and maximum). Categorical variables were summarized using counts of subjects and percentages. The chi-square test for categorical data and Kruskal-Wallis' test for continuous data were performed to identify possible differences between groups with respect to baseline characteristics.

The primary efficacy variable was SVR. Percentages of SVR patients in the three treatment groups were tested using the chi-square test (two-sided) at the 5% confidence level. Secondary efficacy variables (RVR, ETR, and LTR) were analyzed similarly to the primary efficacy endpoint.

Primary and secondary efficacy parameters were analyzed using the intention-to-treat (ITT) population, including all randomized patients who receive at least one dose of the study medication. Patients with missing data were considered as nonresponders. An efficacy analysis was also performed based on patients adhering to therapy with an available primary endpoint assessment (per-protocol [PP] analysis).

As an exploratory analysis, a multivariate logistic model was performed to assess the effect on SVR of the following covariates: age (>40 vs. ≤40 years); gender (male vs. female); HCV genotype (genotype 1 vs. other genotype); treatment arm (arm 1 vs. arm 2 vs. arm 3); and RVR at week 2 and 4 (responder vs. not responder). All covariates were included in the model as categorical variables. The stepwise procedure was used with a significance level of P = 0.05 to retain variables in the model, and the odds ratio (OR) estimates and their 95% confidence limits were calculated.

Safety parameters were evaluated using the safety population including all dosed patients.

Statistical analysis was carried out using the SAS system (version 9.2; SAS Institute) for Windows.

Results

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Appendix
  8. References

Patient Disposition

Between January 2004 and February 2010, a total of 438 AHC patients were recruited in 27 centers; 178 patients had symptomatic AHC at time of diagnosis. A total of 392 patients completed the 12-week period of observation, whereas 46 were lost to follow-up. A spontaneous resolution was observed in 96 of 392 (24.5%) patients, and 296 remained HCV RNA positive (75.5%). Because of the following reasons, 148 of 296 patients were excluded: age >65 years (20 patients); active IV drug abuse (56 patients); refusal to participate (13 patients); dialysis (24 patients); hepatitis B surface antigen positive (2 patients); HIV positive (3 patients); and presence of severe concomitant diseases (30 patients).

One hundred and forty-eight outpatients with confirmed AHC who were HCV RNA positive after 12 weeks of observation were enrolled in the study and entered the screening period. Eighteen patients were considered a screening failure (14 did not meet the inclusion criteria and 4 withdrew consent); therefore, they were excluded from the study. A total of 130 patients entered the treatment phase and were randomly assigned to 24-week treatment with Peg-IFN alpha-2b (44 patients, arm 1) or to 12-week-treatment with Peg-IFN alpha-2b (43 patients, arm 2) or to 12-week treatment with Peg-IFN alpha-2b plus RBV (43 patients, arm 3). Treatment was completed by 120 patients, and a 12-month follow-up was available for 114 (Fig. 2).

image

Figure 2. Patient disposition: Patients in arm 1 received Peg-IFN alpha-2b 1.5 μg/kg/week for 24 weeks; arm 2 received Peg-IFN alpha-2b 1.5 μg/kg/week for 12 weeks; and arm 3 received Peg-IFN alpha-2b 1.5 μg/kg/week plus RBV 10.6 mg/kg/day for 12 weeks.

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Baseline Characteristics

Treatment groups were comparable regarding clinical and virological characteristics at baseline (Table 1). Risk factors for HCV transmission were reported in 102 of 130 patients (78.5%), including IV drug abuse (38%; 16, 12, and 11 patients for arms 1, 2, and 3, respectively), nosocomial (31%; 8, 12, and 12 patients), sexual (11%; 5, 4, and 2), accidental exposure (11%; 3, 3, and 5), and others (9%; 3, 2, and 4).

Table 1. Baseline Characteristics of 130 Patients With AHC Stratified According to Treatment Arm
ParameterArm 1 (24 Weeks of Peg-IFN) n = 44Arm 2 (12 Weeks of Peg-IFN) n = 43Arm 3 (12 Weeks Peg-IFN+RBV) n = 43P Valuea
  1. a

    Chi-squared test for categorical data and Kruskal-Wallis' test for continuous data.

  2. b

    Genotype 1 versus not-1.

Male sex, n (%)29 (65.9)27 (62.8)37 (86.0)0.034
Age, years, median ± SD31 (13.86)34 (13.95)37 (12.48)0.667
HCV genotype, n (%)    
1a11 (25.0)7 (16.3)6 (14)0.638b
1b8 (18.2)8 (18.6)12 (27.9)
1c001 (2.3)
2a/2c9 (20.5)15 (34.9)11 (25.6)
310 (22.7)12 (27.9)10 (23.3)
43 (6.8)01 (2.3)
Not available3 (6.8)1 (2.3)2 (4.6)
ALT (<40 IU/mL) median, range94 (23-1,007)182 (27-1,001)182 (18-1,078)0.591
HCV RNA IU/mL, median, range172,500 (23-7,250,000)39,350 (18-37,000,000)233,769 (50-9,478,100)0.555
Jaundice, n (%)5 (11.4)4 (9.3)4 (9.3)0.934
No symptoms, n (%)26 (59)24 (56)25 (58)0.950
Anti-HCV seroconversion, n (%)26 (59.1)26 (60.5)32 (74.4)0.257
Risk factors, no. (%)    
- IV drug abuse16 (36.4)12 (28.0)11 (25.6)0.555
- Sexual exposure5 (11.4)4 (9.3)2 (4.7)
- Medical procedures8 (18.2)13 (30.2)15 (34.9
- Accidental exposure3 (6.8)3 (7.0)5 (11.6)
- Other3 (6.8)1 (2.3)0
- Unknown9 (20.4)10 (23.2)10 (23.2)

A documented anti-HCV seroconversion was present in 84 of 130 (64.6%; 26, 26, and 32 patients for arms 1, 2, and 3, respectively). A total of 11 of 130 AHC patients were HCV RNA positive in absence of a positive anti-HCV. ALT levels were >20× ULN in 84 of 130 (64.6%; 27, 29, and 28 patients for arms 1, 2, and 3, respectively). After 12 weeks from disease onset, 11 patients were still viremic despite ALT normalization (6 patients in arm 1, 3 in arm 2, and 2 in arm 3). These patients were eligible to be enrolled in the study because inclusion criteria were HCV RNA positive with normal or elevated ALT levels (as stated in the protocol). We are confident that these patients were acutely infected because diagnosis of AHC was based on a documented seroconversion (negative anti-HCV within the previous 6 months) in 6 patients (4 patients in arm 1 and 2 in arm 3) and on ALT >20× ULN plus exclusion of other causes of acute hepatitis in 5 patients (2 patients in arm 1 and 3 in arm 2).

Jaundice was present in 14 of 130 patients (10.8%), fatigue was reported in 40 of 130 (30.8%), malaise in 28 (21.5%), and dyspepsia in 29 (22.3%); seventy-five patients (57.7%) were asymptomatic.

Virological Response

ITT analysis

A total of 130 randomized patients received at least one dose of the study drug and were included in the ITT analysis. An RVR was achieved by 31 of 44 patients (70.5%), 37 of 43 (86%), and 34 of 43 (79.1%), respectively. At the end of treatment, 34 of 44 patients (77.3%), 40 of 43 (93%), and 38 of 43 (88.4%) showed ETR, respectively (Table 2). Relapse was observed in 14 of 112 patients with ETR, with a higher rate in arms 2 (17.5%) and 3 (13.2%), compared to arm 1 (5.9%; P = 0.318). Overall, 93 of 130 patients (71.5%) obtained an SVR. The response according to arm was 70.5% for arm 1 (31 of 44), 72.1% for arm 2 (31 of 43), and 72.1% for arm 3 (31 of 43).

Table 2. Virological Response Rates According to Treatment Arm (ITT and PP Analysis)
Virological ResponseArm 1 (Peg-IFN × 24 wks) Patients = 44Arm 2 (Peg-IFN 12 × wks) Patients = 43Arm 3 (Peg-IFN+RBV × 12 wks) Patients = 43P Valuea
  1. a

    Chi-squared test.

ITT n (%)    
- vRVR25/44 (56.8)28/43 (65.1)28/43 (65.1)0.653
- RVR31/44 (70.5)37/43 (86.0)34/43 (79.1)0.208
- ETR34/44 (77.3)40/43 (93.0)38/43 (88.4)0.091
- SVR31/44 (70.5)31/43 (72.1)31/43 (72.1)0.981
PP n (%)    
- vRVR25/44 (56.8)28/43 (65.1)28/43 (65.1)0.653
- RVR31/44 (70.5)37/43 (86.0)34/43 (79.1)0.208
- ETR34/39 (87.2)40/40 (100)38/41 (92.7)0.072
- SVR31/38 (81.6)31/38 (81.6)31/38 (81.6)1.000

A 12-month posttreatment follow-up was available for 79 of 93 SVR patients, whereas 14 patients were lost to follow-up. All 79 patients showed LTR, except for 1 patient in arm 1 who experienced a new HCV infection with a different HCV genotype (genotype 3 initially and then genotype 1). LTR was 96.3% for arm 1 (26 of 27), 100% for arm 2 (27 of 27), and 100% for arm 3 (25 of 25). When considering virological response in completer patients, 34 of 39 (87.2%) in arm 1, 40 of 40 (100%) in arm 2, and 38 of 41 (92.7%) in arm 3 showed ETR, respectively. Overall, 93 of 114 patients (81.5%) obtained an SVR. Response by arm was 81.6% for arm 1 (31 of 38), 81.6% for arm 2 (31 of /38), and 81.6% for arm 3 (31 of 38) patients (Fig. 3).

image

Figure 3. Virological response rates (HCV RNA <15 IU/mL) after 24 weeks of posttreatment follow-up in patients treated for 24 (arm 1) or 12 (arm 2) weeks with Peg-IFN alpha-2b and for 12 weeks (arm 3) with Peg-IFN alpha-2b plus ribavirin (ITT analysis [gray column] and PP analysis [black column]).

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Biochemical Response

The ITT analysis of the biochemical response did not demonstrate differences among treatment arms. In patients treated with a 24-week course of Peg-IFN alpha-2b, ALT normalization was achieved by 63.6% at the end of the treatment period and 70.5% after the 6-month follow-up. In patients treated with a 12-week course of Peg-IFN alpha-2b alone or in combination with RBV, ALT normalization was achieved by 72.1% and 74.4% of patients at the end of treatment and 62.8% and 65.1% of patients at 6-month follow-up, respectively. All patients with SVR and ETR maintained normal ALT levels.

Predictors of SVR

Treatment, age, gender, HCV genotype, vRVR, and RVR were evaluated as predictive factors with univariate logistic regression analysis. SVR occurred more frequently in patients with RVR (OR, 7.380; 95% confidence interval [CI]: 2.957-18.418; P < 0.001). There was no association between SVR and age, gender, HCV genotype, and treatment arm. In multivariate logistic regression analysis, the only factor associated with SVR was RVR (OR, 5.616; 95% CI: 1.816-17.369; P = 0.0027). In particular, the correlation between SVR and RVR or vRVR is shown in Table 3. Recently, several studies have reported that genetic variations upstream of the interleukin (IL)28B gene at the polymorphic site, rs12978960, are associated with SVR in CHC patients.[9] In this study, only 23 AHC patients had available rs12978960 IL28B genotyping, 7 of whom demonstrated CC genotype and 16 non-CC genotype (data not shown).

Table 3. Correlation Between SVR and RVR or vRVR
 Treatment ArmSVRP Valuea
YesNo
  1. a

    Fisher's exact test.

RVR127/314/130.0001
229/319/120.123
328/318/120.081
vRVR121/314/130.027
223/315/120.050
324/314/120.010

Adherence and Safety

Treatment was well tolerated and was discontinued by only 10 of 130 patients (4 serious adverse events [SAEs], 1 adverse event [AE], 4 protocol violations, and 1 lost). During posttreatment follow-up, 6 patients withdrew within the first 6 months (5 lost and 1 SAE), whereas 14 were lost before completing the 12-month follow-up.

Overall, the safety profile resulting from study data is consistent with the known safety profile for Peg-IFN alpha-2b and RBV. At least 1 AE was reported by 122 patients (93.8%), considered by the investigators to be related to study drug(s) in the majority of cases (90.7%). The most frequent clinical adverse reactions affected hematologic parameters or consisted of pyrexia, arthralgia, headache, depression, and nausea. Granulocytopenia and leukocytopenia more frequently occurred in 24-week treatment with Peg-IFN alpha-2b therapy (5.8% for both events) than in 12-week Peg-IFN alpha-2b therapy (3.2% and 4.7%, respectively) or in 12-week treatment with Peg-IFN alpha-2b plus RBV (4.4% and 4.8%, respectively). Hgb decrease, although uncommon, was reported mainly by patients treated with Peg-IFN alpha-2b for 24 weeks or with Peg-IFN alpha-2b associated with RBV.

Most of the AEs were mild to moderate in intensity and infrequently required a reduction in treatment dose. Overall, 15 patients reduced Peg-IFN dose (6 patients in arm 1, 1 in arm 2, and 8 in arm 3), whereas 3 of 43 in arm 3 reduced RBV dose.

Of the 5 SAEs, 4 were related to therapeutic drugs (80%) and occurred in the treatment period, determining interruption of study treatment(s): psychotic disorders (1 patient in the 24-week Peg-IFN alpha-2b treatment arm); hypoacusis (1 patient in the 12-week Peg-IFN alpha-2b treatment arm); ALT and aspartate aminotransferase increase (1 patient in the 12-week Peg-IFN alpha-2b treatment arm), and optic ischemic neuropathy (1 patient in 12-week Peg-IFN alpha-2b plus RBV treatment arm). The remaining patient with SAEs was diagnosed with lung cancer during follow-up; this event, although not considered to be related to study treatment, caused patient discontinuation from the trial and death.

Discussion

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Appendix
  8. References

Therapy of AHC has not yet been standardized, and relevant clinical questions have remained unanswered by clinical trials. In this randomized, prospective, multicenter, Italian trial, we attempted to determine the optimal treatment duration of Peg-IFN monotherapy and the eventual benefit of combination therapy for AHC patients. After a 12-week from clinical onset observation period, viremic patients, for whom chronic evolution was likely, were randomly assigned to a 6-month course of Peg-IFN alpha-2b or a 3-month course of Peg-IFN alpha-2b or 3-months of Peg-IFN alpha-2b plus RBV. The 12-week waiting period before treatment was chosen because in a large cohort of acutely infected patients, we found, in agreement with Gerlach et al., that a spontaneous resolution occurred within 12 weeks from disease onset in a consistent subset of patients (30%-50%) who, more often, had symptomatic hepatitis, whereas after this time point, a spontaneous resolution in patients with persistent viremia was rare.[2, 10, 11] Consequently, this time delay allows for spontaneous resolution in those patients who can clear the virus without expensive, potentially harmful treatment, thus reserving therapy for patients with chronic evolution who truly required therapy. Moreover, in a pilot study, we demonstrated that delaying treatment by 12 weeks does not compromise efficacy (SVR = 94%).[12] The results obtained with a delayed therapy are comparable to those obtained in studies using immediate treatment. In a multicenter German study, early treatment initiated after diagnosis of AHC determined a SVR rate of 71%, which increased to 89% in the subset of adherent patients.[13]

The present study provides valuable insight into the optimal treatment duration. Published studies on the optimal duration of Peg-IFN monotherapy have indicated 24 weeks as the optimum length of time; however, a 12-week course might be effective in patients treated with a full dosage of Peg-IFN a2b and attaining undetectable HCV RNA at week 4 or in patients with genotype non-1.[14] Our study results do not evidence any statistically significant difference in terms of SVR between 24-week course of Peg-IFN alpha-2b monotherapy and the 12-week course of Peg-IFN alpha-2b alone or in combination with RBV (70.5% vs. 72.1% vs. 72.1%, respectively). In fact, although the relapse rate was higher in both 12-week treatment arms, when compared to arm 1, the SVR was similar. The lack of correlation between treatment duration and SVR was also confirmed by multivariate analysis. Therefore, we can state that a short treatment is as effective as the longer one and represents an useful option not only for difficult-to-treat patients, such as IV drug users who typically have more frequent side effects, which lead to treatment discontinuation.[14, 15]

Another interesting question is the choice of parameters, which can be used to predict treatment outcome. Different baseline parameters, such as gender, age, baseline viral load, and HCV genotype, have been analyzed by several investigators and do not appear to correlate with therapeutic outcome.[12-14, 16] In our study, genotype 1 does not influence treatment outcome and the multivariate analysis suggests that only HCV RNA kinetics affect SVR. Interestingly, RVR correlates with SVR in treatment arm 1, whereas in the shorter treatment arms (arms 2 and 3), SVR correlates only with vRVR, suggesting that in patients with a rapid HCV RNA clearance, a 3-month course of treatment can be effective. In addition, in a limited number of patients, the influence of IL28B genotype on SVR was also evaluated, and, as in all tested patients an SVR was achieved, IL28B polymorphism did not affect response to treatment.

A second issue addressed in this trial is the role of combination therapy with RBV on treatment outcome. On the basis of the limited data in the literature, combination therapy with RBV does not result in improved treatment outcomes in AHC patients. The comparable efficacy of a 12-week regimen of Peg-IFN alpha-2b administered alone or in combination with RBV (arm 2 vs. arm 3) confirms that addition of RBV is not required for patients with AHC.

Results of our study further confirm the efficacy of Peg-IFN alpha-2b monotherapy in the majority of patients with chronic evolving AHC, providing high SVR rates up to 71.5% at ITT analysis and 81.5% when considering the PP patient population. Interestingly, in all SVR patients, the 12-month follow-up after ceasing therapy demonstrated a lack of late relapse, suggesting a virologic cure. In fact, the only SVR patient experiencing a late relapse was found to be infected with a different HCV genotype and therefore was considered to have been superinfected with a new viral strain.

Our study was limited by the fact the HCV RNA assessment by the central laboratory at the end of the 6-month follow-up was lacking for 30 patients. According to the study protocol, these patients were considered as nonresponders by the CRO (contract research organization) responsible for the study. As a consequence, the SVR rates included in the clinical report prepared by CRO were obviously underestimated, thus resulting in rates much lower than those reported in published studies of AHC treatment and even inferior to response rates observed in chronic HCV patients. To overcome this limit, we retrieved HCV RNA tests from the local laboratory evaluated with real-time PCR of those patients whose serum sample was not forwarded to the central laboratory for assessment. Apart from SVR rates (higher), the remaining results are identical to the original study, but the revised results better respect published data. Moreover, our results are in line with those recently obtained in a randomized, controlled trial by the German Network for Viral Hepatitis. In this study, immediate treatment (Peg-IFN alpha-2b 1.5 μg/kg/week for 24 weeks) versus a delayed treatment strategy was evaluated in symptomatic AHC patients. In the delayed treatment arm, patients still viremic after a 12-week observation period received Peg-IFN alpha-2b plus RBV therapy; results indicated that at ITT analysis, SVR was 76% in symptomatic patients who received immediate treatment,[17] whereas in patients treated after 12 weeks with combination therapy, lower response rates were obtained. However, in adherent patients, delayed combination therapy reflected the same efficacy of the immediate treatment strategy.[17]

Last, the safety profile resulting from our study data is consistent with the known safety profile for Peg-IFN alpha-2b and RBV. No unexpected safety data emerged from the study and only 6 of the 16 drop-out patients discontinued treatment because of AEs.

In conclusion, in this study, we demonstrated that Peg-IFN alpha-2b induces a high SVR in chronically evolving AHC patients, and that response rates were not influenced by combination therapy with RBV. In addition, a 6-month treatment course was as effective as a 3-month treatment course.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Appendix
  8. References

The authors are grateful to Ms. Paulene Butts for her assistance in the preparation of the manuscript. This study is registered under ClinicalTrials.gov registration number NCT00686517.

Appendix

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Appendix
  8. References

Members of the Italian Acute hepatitis C Study Group include: Giuseppe Pastore, Angela Guastadisegni, and Anna Volpe (Infectious Diseases, University of Bari); Francesca Stano (Infectious Diseases, Ospedale Santa Caterina Novella, Galatina); Donato Tommasi and Annamaria Maci (Infectious Diseases, Azienda Ospedaliera Vito Fazzi, Lecce); Francesco Resta and Pietro Loperfido (Infectious Diseases, Ospedale San Giovanni Moscati, Taranto); Roberto Esposito and Vanni Borghi (Infectious Diseases, University of Modena); Tommaso Fontana, Ruggiero Francavilla, and Michele Mazzola (Infectious Diseases, Presidio Ospedaliero Bisceglie); Antonella Pipoli (Infectious Diseases, University of Foggia); Marinella Stanzione (Infectious Diseases, Ospedale Gesù e Maria, II University of Napoli); Pietro Amoroso and Gennaro Lettieri (Infectious Diseases, Azienda Ospedaliera Cotugno, Napoli); Vincenzo Messina (Infectious Diseases, Ospedale San Sebastiano, Caserta); Giorgio Antonucci and Silvia Rosati (Infectious Diseases, IRCCS Spallanzani, Roma); Andrea Giacometti (Infectious Diseases, University of Ancona); Chiara Costa (Infectious Diseases, Azienda Ospedaliera Mater Dei, Catanzaro); Carlo Biagio De Stefano (Infectious Diseases, Azienda Ospedale S. Carlo, Potenza); Giuseppe Cariti (Infectious Diseases, Ospedale Amedeo di Savoia, Torino); Giulia Tositti (Infectious Diseases, Ospedale San Bortolo, Vicenza); M. Piera Riccardi (Infectious Diseases, Ospedale Misericordia, Grosseto); Gabriella Verucchi (Infectious Diseases, Azienda Ospedaliera Policlinico Sant'Orsola-Malpighi, Bologna); Daniela Francisci (Infectious Diseases, University of Perugia); Enzo Petrelli and Laura Stoppini (Infectious Diseases, Azienda Ospedaliera San Salvatore, Pesaro); Giovanni Raimondo, Giovanni Squadrito, and Gaia Caccamo (Unità di Epatologia, Dipartimento di Medicina Interna, University of Messina); Picciotto Antonino and Basso Monica (DIMI University of Genova); Adriano Lazzarin and Giulia Morsica (Infectious Diseases, Ospedale San Raffaele, Milano); and Peter Mian and Raffaele Pristerà (Infectious Diseases, Ospedale Generale Regionale di Bolzano).

References

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Appendix
  8. References