Acute hepatitis C: Current status and remaining challenges☆

Article Outline

• Abstract
• 1. Introduction
• 2. Epidemiology
• 3. Risk factors, routes of transmission and diagnosis
• 4. Spontaneous resolution of acute hepatitis C
• 5. Treatment of acute hepatitis C
  • 5.1. Conventional interferon-alfa
  • 5.2. Pegylated interferon alfa
  • 5.3. Treatment of acute hepatitis C among HIV-co-infected patients
  • 5.4. Treatment of acute hepatitis C among hemodialysis patients
• 6. Remaining questions and future directions
• 7. Conclusions
• Acknowledgement
• References
• Copyright

The acute phase of hepatitis C virus (HCV) infection represents a key point in the evolution of hepatitis C. In some patients, the infection resolves spontaneously, whereas in others it develops into chronic disease. However, because acute hepatitis C is often asymptomatic, detection and diagnosis are usually difficult. What is more, there are no established treatment guidelines, leaving physicians to make several challenging decisions, such as whether to treat, when to treat and what treatment regimen to use. Pegylated interferon alfa monotherapy is most commonly used to treat patients with acute hepatitis C; the role of ribavirin has yet to be established. In this review, we discuss the epidemiology of acute hepatitis C, its risk factors and routes of transmission and current treatment practices. We also discuss data from published clinical studies and focus on unresolved issues for which additional studies are needed in order to establish standardized treatment guidelines for the management of acute hepatitis C.

Keywords: Acute hepatitis C, Interferon alfa, Pegylated interferon alfa, Antiviral therapy, Hepatitis C virus (HCV)

Back to Article Outline

1. Introduction 

In the past decade, the introduction of pegylated interferons (PEG-IFNs) and the identification of host and viral factors that can predict sustained virological response (SVR) have improved the treatment of chronic hepatitis C. In contrast, because of the lack of a diagnostic marker for acute hepatitis C virus (HCV) infection and its relatively silent nature, prospective clinical investigations of acute hepatitis C have been difficult to conduct. In this review, we attempt to synthesize existing information on acute hepatitis C to provide a comprehensive overview of this condition, describe the natural history and epidemiology of the disease and discuss the best treatment practices.

Back to Article Outline

2. Epidemiology 

Patients with acute HCV infection are generally asymptomatic, which renders diagnosis difficult and results in under-reporting [1], [2]. Identification of patients with acute hepatitis C is also hindered because many patients are reluctant to divulge habits that may lead to infection. As a result, estimates of the incidence vary widely and are probably lower than the real figure. For example, in Italy, incidence estimates range from 1 to 14 cases per 100,000, according to whether the population evaluated included patients with acute HCV reported to the National Surveillance Agency [3], Italian blood donors, [4] or the general population [5]. In the United States, the incidence of acute hepatitis C has declined in recent years [6], [7], [8], with the Department of Health and Human Services Center for Disease Control and Prevention reporting 671 acute hepatitis C cases in 2005 for an overall national rate of 0.2 per 100,000. However, after accounting for under-reporting of asymptomatic infections, the estimated total was 20,000 new infections [9].

Back to Article Outline

3. Risk factors, routes of transmission and diagnosis 

Currently, intravenous drug use, unprotected sex with multiple partners, and viral exposure during medical procedures, such as surgery, dialysis and dental treatment, are factors associated with the highest degree of risk for HCV infection [9], [10], [11], [12], [13]. Health care employees are at risk for acute hepatitis C through accidental exposure, such as needlestick injury; however, recent reports indicate that the risk for HCV transmission after needlestick injury is lower than that previously believed (mean value 0.75%; in Europe 0.42%; in Eastern Asia 1.5%) [14]. Of note, risk factor patterns vary according to geography. For example, within many Western countries intravenous drug use is the greatest risk factor, with sexual transmission and medical practices representing other less common risk factors [10], [11], [15]. Conversely, in Egypt, occupational exposure seems to be the greatest hazard, with intravenous drug use and sexual transmission less evident [16], [17]. Although guidelines exist for the management of chronic hepatitis C [18], [19], they do not specifically address acute hepatitis C. Table 1 summarizes recommendations for persons who are at risk and should be tested for HCV infection.

Table 1. Relative risk for hepatitis C transmission and recommendations for testing

Table adapted from 2004 AASLD practice guidelines [18], [19].

After exposure to HCV, there is a window of 1–3 weeks before serum HCV RNA can be detected. In patients in whom symptoms are developing, the incubation period between exposure and appearance of symptoms can range from 2 to 12 weeks [1]. The most common symptoms are fatigue and jaundice, with dyspepsia and abdominal pain often reported [20], [21]. Given that most symptoms are non-specific, many patients do not consult a physician and do not receive a diagnosis during the acute phase. The first indication of hepatic injury is an elevated alanine aminotransferase (ALT) level, which can occur 4–12 weeks after viral exposure [22]. Fulminant liver injury is rare and occurs in less than 1% of patients.

Diagnosis of acute HCV infection is confirmed by the detection of HCV RNA with documented anti-HCV antibody seroconversion (Table 2). Seroconversion may occur 4–10 weeks after exposure to HCV [23], [24]. Other criteria that can aid in diagnosing HCV infection include significantly elevated ALT levels (>10× ULN or >20× ULN), known or suspected exposure to HCV and increasing numbers of reactive proteins in a recombinant immunoblot assay confirmation test [23], [25].

Table 2. Proposed criteria for diagnosis of acute hepatitis C infection

Back to Article Outline

4. Spontaneous resolution of acute hepatitis C 

An average of 26% of patients with acute hepatitis C (range 20–67%) experience spontaneous clearance of the virus, an event that occurs primarily during the first 3 months after clinical onset of disease [10], [11], [21], [26], [27], [28]. If viremia persists for more than 6 months, chronic disease should be considered. Several host and viral factors, such as HLA, HCV genotype, co-infection with human immunodeficiency virus (HIV), gender, race and advanced age seem to influence the clinical course of disease [29], but none of these parameters can accurately predict spontaneous resolution [2]. However, it seems that spontaneous resolution occurs more frequently in the presence of symptomatic disease [10], [21], [27], [30]. Interestingly, several reports have now stated that a strong and multispecific cellular immune response is an important host factor for spontaneous viral eradication [31], [32], [33], [34], [35], [36], [37], [38].

Follow-up testing of HCV RNA levels in patients who experience spontaneous resolution is highly recommended because a late relapse may occur after the initial HCV RNA clearance [27]; therefore, HCV RNA should be monitored for a period of at least 6 months with 2–3 consecutive tests, and subsequent testing if ALT elevation is observed. Ultimately, comparison of rates of spontaneous viral clearance across studies of acute hepatitis C natural history will be possible only with the introduction of standardized definitions and methodologies [39].

Back to Article Outline

5. Treatment of acute hepatitis C 

Clinical trials focusing on the treatment of acute hepatitis C are hindered by the difficulties in its diagnosis. Many patients who might otherwise be candidates for treatment manifest high-risk behavior, such as ongoing intravenous drug abuse, and are thus unsuitable for clinical trials. As a result, most studies of acute hepatitis C are open-label, non-comparative investigations with small patient populations that differ widely with respect to design, patient population and treatment regimens; therefore, discerning the most effective intervention remains difficult. The lack of comparative studies has precluded the possibility that any one treatment regimen can become a gold standard.

5.1. Conventional interferon-alfa 

Treatment of acute hepatitis C patients with conventional (non-pegylated) interferon (IFN) alfa has been investigated in several small clinical trials, which typically used 3–6 million units (MU) IFN alfa administered three times weekly for 4–24 weeks. These studies examined biochemical and virological response rates, and the results have been summarized in several meta-analyses (Fig. 1). Overall, 32–52% of patients treated with IFN alfa attained SVR (defined as undetectable HCV RNA 24 weeks after completing therapy) compared with only 4–11% of untreated patients [40], [41], [42]. The most recent meta-analysis by Licata et al. [43] showed that IFN treatment significantly increased SVR rates (risk difference, 49%; 95% CI, 32.9–65%) compared with untreated control patients. Moreover, SVR rates increased with higher weekly doses of IFN. Thus, higher IFN dosages during the first month appear to be the best treatment option. In fact, an induction regimen of IFN alfa-2b (5 MU/day for 4 weeks, followed by 5 MU three times weekly for another 20 weeks) was shown to be highly effective in treating patients with acute hepatitis C [44]. In this study, 43 of 44 (98%) patients attained SVR, with a mean time of 3.2 weeks from initiation of treatment to undetectable HCV RNA. Twenty-four of these patients were followed up for a median of 135 weeks; all had undetectable HCV RNA and no evidence of liver disease [45].

• 
  • View Large Image
  • Download to PowerPoint

• Fig. 1. 

  Sustained virological response rates among patients with acute hepatitis C who received standard or induction doses of conventional interferon alfa-2b (IFN alfa-2b) [40], [41], [42], [43], [44], [46], [47], [48]. Studies of Poynard [42], Cammà [41], and Licata [43] are meta-analyses that included at least one study of interferon-beta. Data from Licata et al. [43] include one study of induction therapy (Jaeckel et al. [44]) and represent the risk difference for attaining undetectable HCV RNA versus no treatment. ALT, alanine aminotransferase; HLB IFN, human lymphoblastoid interferon.

Other studies have evaluated the efficacy of early treatment intervention with high-dose IFN alfa and shorter treatment durations (Fig. 1). In two studies, SVR was reported in 21 of 28 (75%) patients receiving high-dose regimens of IFN alfa (5 MU/day) for 8 weeks [46] and in 20 of 24 (83%) patients treated with 10 MU IFN alfa administered daily until normalization of ALT levels [47]. In a separate study, administration of intramuscular human lymphoblastoid IFN alfa (6 MU/day) for 4 weeks resulted in SVR in 13 of 15 (87%) patients [48]. Two patients with detectable HCV RNA at the end of the treatment subsequently attained SVR when treated with IFN alfa (6 MU three times weekly) for an additional 20 weeks [48]. In addition, Nomura and colleagues also compared the response rate achieved with early initiation of treatment (8 weeks after disease onset) with a delayed treatment strategy and demonstrated that therapy initiated after one year is clearly less effective [48]. Similarly, in the meta-analysis by Licata et al. delaying initiation of therapy until 60 days after onset of disease did not compromise the probability of a favorable response [43]. Overall, published data indicate that acute hepatitis C can be effectively managed with early or delayed treatment (8-weeks) using a 4- to 24-week course of conventional IFN alfa.

5.2. Pegylated interferon alfa 

Treatment of chronic hepatitis C has advanced with the introduction of pegylated interferon (PEG-IFN) alfa, which, in combination with ribavirin, has become the current standard of care. Different strategies have been explored to optimize SVR rates in patients with acute hepatitis C treated with PEG-IFN alfa-2b (Table 3, Fig. 2). When considering treatment initiation, several time points have been evaluated, ranging from immediately after diagnosis to after an observation period of several weeks. In a study conducted by Wiegand et al. [15], 89 patients were treated after a median time from symptoms to therapy of 27 days (range 5–131) using the standard dosage for chronic HCV infection (1.5μg/kg/wk); after 24 weeks of treatment, the overall SVR rate was 71%, but it increased to 89% in the subset of patients receiving 80% of the scheduled dosage within 80% of the planned treatment period. The difference in response rates between adherent and intent-to-treat populations was attributed to the large number of patients lost to follow-up, protocol violations, and treatment failure among the patients receiving PEG-IFN alfa-2b. Three serious adverse events, including one suicide, might have been related to the study drug [15].

Table 3. Treatment of acute hepatitis C with pegylated interferon alfa

Study	Study design	Treatment	Therapy duration (wk)	Time from diagnosis/infection to treatment (median)	EOT	SVR	Predictors of SVR
Wiegand et al. [15]	Open label, uncontrolled (n=89)	PEG-IFN alfa-2b (1.5μg/kg/wk)	24	76 days	82%a	63/89 (71%)a,b	ALT >500 U/L (P=0.039)
De Rosa et al. [50]	Open label, uncontrolled (n=19)	PEG-IFN alfa-2b (1.06-1.66μg/kg/wk)	12	31 days	NR	14/19 (74%)	PEG-IFN dose: ⩾1.33μg/kg/wk (P=0.0379)
Calleri et al. [52]	Open label, uncontrolled (n=46)	PEG-IFN alfa-2b (1.0-1.5μg/kg/wk)	12	15 daysc	41/46 (89%)	33/46 (72%)	PEG-IFN alfa-2b dose⩾1.2μg/kg/wk (P=0.014)
Santantonio et al. [49]	Open label, uncontrolled (n=16)	PEG-IFN alfa-2b (1.5μg/kg/wk)	24	12-week observation period	15/16 (94%)	15/16 (94%)	NR
Broers et al. [67]	Open label, uncontrolled (n=14)	PEG-IFN alfa-2b (1.5μg/kg/wk)	24	1–50 weeks	86%	57%	Active IVDU >80% of the scheduled drug
Kamal et al. [30]	Randomised, comparative (n=40)	PEG-IFN alfadvs PEG-IFN alfad + RBV (800mg/d or >10.6mg/kg/d)	24	12-week observation period	18/20 (90%) vs 19/20 (95%)	17/20 (85%) vs 16/20 (80%)	NR
Kamal et al. [17]	Randomised comparative (n=68e)	PEG-IFN alfa-2b (1.5μg/kg/week)	12	8–12 weeks	30/34 (88.2%)	28/34 (82.4%)	NR
			24	8–12 weeks	32/34 (94.1%)	31/34 (91.2%)	NR

EOT, end-of-treatment response; IVDU, intravenous drug users; NR, not reported; SVR, sustained virological response.

• 
  • View Large Image
  • Download to PowerPoint

• Fig. 2. 

  Sustained virological response (SVR) among patients with acute hepatitis C who received pegylated interferon alfa-2b for 12 or 24 weeks. Data from Kamal et al. [17] were derived from separate treatment arms in the same study.

Immediate treatment of patients after diagnosis may mean some patients who would have cleared the infection spontaneously will be exposed to antiviral therapy unnecessarily and may experience treatment-related adverse events. Therefore, treatment strategies involving delayed therapy have also been investigated. In an early pilot study [49], treatment was delayed for 12 weeks after clinical presentation of the disease; patients with detectable HCV RNA then received PEG-IFN alfa-2b (1.5μg/kg/wk) for 24 weeks [15]. Fifteen of 16 treated patients (94%) attained SVR. Moreover, HCV RNA remained undetectable up to 12 months after therapy discontinuation [49]. Similar results were also reported in a randomized controlled trial in which 129 patients received 12-weeks’ treatment with PEG-IFN alfa-2b (1.5μg/kg/wk) after a clinical observation period of 8, 12, or 20 weeks [16]. The SVR was equivalent in patients treated after a delay of 8 or 12 weeks (95% versus 93%) but was significantly lower in patients treated after a 20-week delay (76%; P⩽0.03 for both comparisons). When results were evaluated according to HCV genotype, genotype 1 patients appeared to obtain greater benefit from earlier treatment initiation [16].

Regarding treatment duration, several recent trials have evaluated the efficacy of a short, 12-week course of PEG-IFN therapy [50], [51], [52]. In these studies, most patients were asymptomatic and many were intravenous drug users. Patients were treated with PEG-IFN alfa-2b (1.0–1.5μg/kg/wk) within a median time of 13.5–31 days after peak ALT levels. SVR was attained in 72–74% of patients, and higher rates of SVR (83–92%) were attained by patients receiving higher PEG-IFN alfa-2b dosages (>1.33 and >1.2μg/kg/wk). This short course of therapy might be particularly useful in difficult-to-treat patients, such as intravenous drug users who typically have more frequent side effects that lead to treatment discontinuation. In the only randomized trial conducted to date, 102 patients with acute hepatitis C who still had detectable HCV RNA after 8–12 weeks of observation were randomly assigned to receive PEG-IFN alfa-2b (1.5μg/kg/wk) for 8, 12 or 24 weeks. Overall SVR rates were 62%, 82% and 91%, respectively. When analyzing the results according to genotype, patients infected with genotype 1 required a longer period of therapy (24 weeks) to maximize their likelihood of attaining SVR [17]. Finally, on the basis of the limited data in the literature, combination therapy with ribavirin does not result in improved treatment outcomes [30].

In most studies performed to date, response rates appear to be independent of HCV genotype, and patients with genotype 1 have demonstrated results similar to those of patients with genotype 2 or 3 [46], [49]. Kamal et al. [16], [17] reported a possible lower response rate in genotype 1 patients, but this observation requires confirmation. In the German Acute HCV II trial, baseline HCV RNA was not associated with treatment outcome, but multivariate regression analysis indicated that SVR was correlated with pretreatment ALT levels (P=0.039) [15]. In contrast, in the trial by Calleri et al. [52], the peak viral load before treatment was predictive of SVR in univariate analysis (P=0.0005); they also found that undetectable HCV RNA at weeks 4 and 12 of treatment was predictive of SVR. These preliminary observations indicate that, as in chronic hepatitis C, viral kinetics may become an important predictor of treatment outcome in acute hepatitis C.

5.3. Treatment of acute hepatitis C among HIV-co-infected patients 

Co-infection with HIV seriously complicates the management of chronic hepatitis C. Co-infected patients experience an accelerated disease course and reduced SVR rates when compared with mono-infected HCV [53], [54], [55]. Evidence also suggests that HIV co-infection can alter the disease course and treatment outcome for patients in the acute stages of HCV infection, but studies are few and patient numbers are small.

Co-infection with HIV renders spontaneous resolution of HCV infection unlikely. In one study of 25 patients with acute hepatitis C and HIV, only one (4%) attained spontaneous resolution. Most of these patients were receiving highly active antiretroviral therapy, and the median CD4⁺ T-cell count in this cohort was 345 cells/μl [56]. HIV co-infection is may also exert an unfavorable impact on treatment outcome; however, this remains controversial, and data from several small studies report SVR rates ranging from 0% to 71% among co-infected patients receiving PEG-IFN alfa alone or PEG-IFN alfa plus ribavirin for 24 weeks. These studies indicate that no clear clinical benefit is derived by the addition of ribavirin to PEG-IFN alfa-2b monotherapy [56], [57], [58], [59]. These SVR rates are generally lower than those observed in patients with acute HCV mono-infection but are higher than those in HIV patients with chronic HCV infection (27–40% [53], [54], [55]). Taken together, early antiviral therapy seems to be appropriate in co-infected patients in the absence of contraindications to treatment.

5.4. Treatment of acute hepatitis C among hemodialysis patients 

HCV infection is common in patients with end-stage renal disease; estimates suggest that 3–22% of patients undergoing maintenance dialysis may have HCV infection [60]. Little is known regarding the treatment of acute hepatitis C in this population, and only a small number of observational studies have been published [61], [62], [63]. In general, these studies demonstrated that IFN alfa or PEG-IFN alfa therapy is effective; each produced SVR rates of 57–86% and was well tolerated [61], [62], [64], [65], but further studies are required.

Back to Article Outline

6. Remaining questions and future directions 

Recent studies have begun to address several important questions with regard to best treatment practices for patients with acute hepatitis C. Unfortunately, available data lack the robust quality required to develop standardized treatment recommendations. Nevertheless, an abundance of useful information can be drawn from currently published data. Questions that remain unanswered and the current status of ongoing studies are as follows:

1.When should therapy be initiated? Data from trials using immediate or delayed treatment strategies (8–12 weeks) have demonstrated high SVR rates ranging from 71% to 94% (Fig. 2). Delaying treatment for 2–3 months after disease onset permits the identification of patients whose infections spontaneously resolve. Whether an immediate treatment approach is more appropriate in patients with asymptomatic disease or in those infected with genotype 1b still requires confirmation. The German Competence Network for Viral Hepatitis (HEP-NET) [66] is conducting a randomised, controlled trial comparing immediate treatment (PEG-IFN alfa-2b 1.5μg/kg/wk for 24 weeks) at the onset of symptoms with a delayed treatment strategy in which patients undergo a 12-week observation period, after which only those patients who have detectable HCV RNA receive therapy. Asymptomatic patients are entered into an immediate treatment strategy. It is anticipated that the results from this study will help define the most appropriate time to initiate treatment of acute hepatitis C within various subpopulations.

3.What is the optimal dosage of PEG-IFN alfa-2b? In the studies of Calleri [52] and De Rosa [51], patients received PEG-IFN alfa-2b doses ranging from 1.06 to 1.66μg/kg/wk. Improved SVR rates were associated with PEG-IFN alfa-2b doses >1.2μg/kg/wk [52] or >1.33μg/kg/wk [51]. These data suggest that the recommended 1.5μg/kg/wk dose of PEG-IFN alfa-2b should be used when treating patients with acute disease.

4.What is the optimal treatment duration? At present, the optimal duration of PEG-IFN monotherapy seems to be 24 weeks; however, a 12-week course is also effective in patients treated with a full dosage of PEG-IFN who attain undetectable HCV RNA at week 4. A large, ongoing, randomised, multicentre trial in Italy is investigating the efficacy of shortened treatment duration (12 versus 24 weeks). In this study, all patients with diagnoses of acute hepatitis C undergo a 12-week observation period followed by repeat testing of HCV RNA levels; those with detectable HCV RNA are then randomized to receive PEG-IFN alfa-2b (1.5μg/kg/wk) for 12 or 24 weeks. This study also includes a third treatment arm consisting of combination therapy with PEG-IFN alfa plus ribavirin (>10.6mg/kg/day) administered over a 12-week period.

Back to Article Outline

7. Conclusions 

In conclusion, treatment of acute hepatitis C with IFN alfa offers the opportunity to maximise the rates of viral eradication with SVR in excess of 90%. However, the identification of ideal candidates for treatment, the optimal time for initiating therapy and the optimal dose and duration of therapy require further investigation. Results of ongoing randomised trials will contribute to answering these questions. Surveillance programs designed to monitor populations at high risk represent the best approach for identifying patients with acute hepatitis C. Such programs, together with a standardized approach to treatment, should increase the recognition of acute hepatitis C and the benefits associated with its effective treatment.

Back to Article Outline

Acknowledgement 

Writing assistance was provided by Tim Ibbotson, PhD and Lynn Brown, PhD. This assistance was funded by Schering-Plough.

Back to Article Outline

References 

1. Orland JR, Wright TL, Cooper S. Acute hepatitis C. Hepatology. 2001;33:321–327
   • View In Article
   • MEDLINE
   • CrossRef
2. Blackard JT, Shata MT, Shire NJ, Sherman KE. Acute hepatitis C virus infection: a chronic problem. Hepatology. 2008;47:321–331
   • View In Article
   • CrossRef
3. Mele A, Tosti ME, Marzolini A, Moiraghi A, Ragni P, Gallo G, et al. Prevention of hepatitis C in Italy: lessons from surveillance of type-specific acute viral hepatitis. SEIEVA collaborating Group. J Viral Hepat. 2000;7:30–35
   • View In Article
   • MEDLINE
   • CrossRef
4. Tosti ME, Solinas S, Prati D, Salvaneschi L, Manca M, Francesconi M, et al. An estimate of the current risk of transmitting blood-borne infections through blood transfusion in Italy. Br J Haematol. 2002;117:215–219
   • View In Article
   • MEDLINE
   • CrossRef
5. Kondili LA, Chionne P, Costantino A, Villano U, Lo Noce C, Pannozzo F, et al. Infection rate and spontaneous seroreversion of anti-hepatitis C virus during the natural course of hepatitis C virus infection in the general population. Gut. 2002;50:693–696
   • View In Article
   • MEDLINE
   • CrossRef
6. Alter MJ, Kruszon-Moran D, Nainan OV, McQuillan GM, Gao F, Moyer LA, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med. 1999;341:556–562
   • View In Article
   • MEDLINE
   • CrossRef
7. Centers for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR Recomm Rep. 1998;47:1–39
   • View In Article
   • MEDLINE
8. Williams I. Epidemiology of hepatitis C in the United States. Am J Med. 1999;107:2S–9S
   • View In Article
   • MEDLINE
9. Centers for Disease Control and Prevention. Surveillance for acute viral hepatitis United States, 2005. 56th ed. Atlanta, GA: Centers for Disease Control and Prevention; 2007. p. 1–24.
   • View In Article
10. Santantonio T, Medda E, Ferrari C, Fabris P, Cariti G, Massari M, et al. Risk factors and outcome among a large patient cohort with community-acquired acute hepatitis C in Italy. Clin Infect Dis. 2006;43:1154–1159
    • View In Article
    • CrossRef
11. Corey KE, Ross AS, Wurcel A, Schulze Zur Wiesch J, Kim AY, Lauer GM, et al. Outcomes and treatment of acute hepatitis C virus infection in a United States population. Clin Gastroenterol Hepatol. 2006;4:1278–1282
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (138 KB)
    • CrossRef
12. Esteban JI, Sauleda S, Quer J. The changing epidemiology of hepatitis C virus infection in Europe. J Hepatol. 2008;48:148–162
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (442 KB)
    • CrossRef
13. Martinez-Bauer E, Forns X, Armelles M, Planas R, Sola R, Vergara M, et al. Hospital admission is a relevant source of hepatitis C virus acquisition in Spain. J Hepatol. 2008;48:20–27
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (137 KB)
    • CrossRef
14. Kubitschke A, Bader C, Tillmann HL, Manns MP, Kuhn S, Wedemeyer H. Injuries from needles contaminated with hepatitis C virus: how high is the risk of seroconversion for medical personnel really?. Der Internist (Berl). 2007;48:1165–1172
    • View In Article
15. Wiegand J, Buggisch P, Boecher W, Zeuzem S, Gelbmann CM, Berg T, et al. Early monotherapy with pegylated interferon alpha-2b for acute hepatitis C infection: the HEP-NET acute-HCV-II study. Hepatology. 2006;43:250–256
    • View In Article
    • MEDLINE
    • CrossRef
16. Kamal SM, Fouly AE, Kamel RR, Hockenjos B, Al Tawil A, Khalifa KE, et al. Peginterferon alfa-2b therapy in acute hepatitis C: impact of onset of therapy on sustained virologic response. Gastroenterology. 2006;130:632–638
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (242 KB)
    • CrossRef
17. Kamal SM, Moustafa KN, Chen J, Fehr J, Abdel Moneim A, Khalifa KE, et al. Duration of peginterferon therapy in acute hepatitis C: a randomized trial. Hepatology. 2006;43:923–931
    • View In Article
    • MEDLINE
    • CrossRef
18. Strader DB, Wright T, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C. Hepatology. 2004;39:1147–1171
    • View In Article
    • MEDLINE
    • CrossRef
19. Dienstag JL, McHutchison JG. American Gastroenterological Association technical review on the management of hepatitis C. Gastroenterology. 2006;130:231–264
    • View In Article
    • Full Text
    • Full-Text PDF (442 KB)
    • CrossRef
20. World Health Organization. Hepatitis C. World Health Organization 2000 October [cited 2006 Apr 12];1-3.
    • View In Article
21. Santantonio T, Sinisi E, Guastadisegni A, Casalino C, Mazzola M, Gentile A, et al. Natural course of acute hepatitis C: a long-term prospective study. Dig Liver Dis. 2003;35:104–113
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (763 KB)
    • CrossRef
22. Heathcote J, Elewaut A, Fedail S, Gangl A, Hamid S, Shah M, et al. WGO practice guideline: management of acute viral hepatitis. World Gastroenterology Organisation Web site 2003 December [cited 2007 Sep 14]. Available from: URL: http://www.worldgastroenterology.org/management-of-acute-viral-hepatitis.html.
    • View In Article
23. Mondelli MU, Cerino A, Cividini A. Acute hepatitis C: diagnosis and management. J Hepatol. 2005;42:S108–S114
    • View In Article
    • Full Text
    • Full-Text PDF (164 KB)
    • CrossRef
24. Pawlotsky JM. Use and interpretation of virological tests for hepatitis C. Hepatology. 2002;36:S65–S73
    • View In Article
    • MEDLINE
    • CrossRef
25. Heller T, Rehermann B. Acute hepatitis C: a multifaceted disease. Semin Liver Dis. 2005;25:7–17
    • View In Article
    • MEDLINE
    • CrossRef
26. Micallef JM, Kaldor JM, Dore GJ. Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies. J Viral Hepat. 2006;13:34–41
    • View In Article
    • MEDLINE
    • CrossRef
27. Gerlach JT, Diepolder HM, Zachoval R, Gruener NH, Jung M-C, Ulsenheimer A, et al. Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance. Gastroenterology. 2003;125:80–88
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (229 KB)
    • CrossRef
28. Hofer H, Watkins-Riedel T, Janata O, Penner E, Holzmann H, Steindl-Munda P, et al. Spontaneous viral clearance in patients with acute hepatitis C can be predicted by repeated measurements of serum viral load. Hepatology. 2003;37:60–64
    • View In Article
    • MEDLINE
    • CrossRef
29. Lehmann M, Meyer MF, Monazahian M, Tillmann HL, Manns MP, Wedemeyer H. High rate of spontaneous clearance of acute hepatitis C virus genotype 3 infection. J Med Virol. 2004;73:387–391
    • View In Article
    • MEDLINE
    • CrossRef
30. Kamal SM, Ismail A, Graham CS, He Q, Rasenack JW, Peters T, et al. Pegylated interferon α therapy in acute hepatitis C: relation to hepatitis C virus-specific T cell response kinetics. Hepatology. 2004;39:1721–1731
    • View In Article
    • MEDLINE
    • CrossRef
31. Diepolder HM, Zachoval R, Hoffmann RM, Wierenga EA, Santantonio T, Jung MC, et al. Possible mechanism involving T-lymphocyte response to non-structural protein 3 in viral clearance in acute hepatitis C virus infection. Lancet. 1995;346:1006–1007
    • View In Article
    • CrossRef
32. Gerlach JT, Diepolder HM, Jung MC, Gruener NH, Schraut WW, Zachoval R, et al. Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T-cell response in acute hepatitis C. Gastroenterology. 1999;117:933–941
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (181 KB)
    • CrossRef
33. Gruner NH, Gerlach TJ, Jung MC, Diepolder HM, Schirren CA, Schraut WW, et al. Association of hepatitis C virus-specific CD8+ T cells with viral clearance in acute hepatitis C. J Infect Dis. 2000;181:1528–1536
    • View In Article
    • MEDLINE
    • CrossRef
34. Lechner F, Gruener NH, Urbani S, Uggeri J, Santantonio T, Kammer AR, et al. CD8+ T lymphocyte responses are induced during acute hepatitis C virus infection but are not sustained. Eur J Immunol. 2000;30:2479–2487
    • View In Article
    • MEDLINE
    • CrossRef
35. Thimme R, Oldach D, Chang KM, Steiger C, Ray SC, Chisari FV. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med. 2001;194:1395–1406
    • View In Article
    • MEDLINE
    • CrossRef
36. Grakoui A, Shoukry NH, Woollard DJ, Han JH, Hanson HL, Ghrayeb J, et al. HCV persistence and immune evasion in the absence of memory T cell help. Science. 2003;302:659–662
    • View In Article
    • CrossRef
37. Kamal SM, Amin A, Madwar M, Graham CS, He Q, Al Tawil A, et al. Cellular immune responses in seronegative sexual contacts of acute hepatitis C patients. J Virol. 2004;78:12252–12258
    • View In Article
    • MEDLINE
    • CrossRef
38. Lucas M, Ulsenheimer A, Pfafferot K, Heeg MH, Gaudieri S, Gruner N, et al. Tracking virus-specific CD4+ T cells during and after acute hepatitis C virus infection. PLoS ONE. 2007;2:e649
    • View In Article
39. Amin J, Law MG, Micallef J, Jauncey M, Van BI, Kaldor JM, et al. Potential biases in estimates of hepatitis C RNA clearance in newly acquired hepatitis C infection among a cohort of injecting drug users. Epidemiol Infect. 2007;135:144–150
    • View In Article
    • MEDLINE
    • CrossRef
40. Myers RP, Regimbeau C, Thevenot T, Leroy V, Mathurin P, Opolon P, et al. Interferon for acute hepatitis C (review). The Cochrane Library. 2002;(3):CD000369
    • View In Article
41. Cammà C, Almasio P, Craxı` A. Interferon as treatment for acute hepatitis C: a meta-analysis. Dig Dis Sci. 1996;41:1248–1255
    • View In Article
    • MEDLINE
    • CrossRef
42. Poynard T, Leroy V, Cohard M, Thevenot T, Mathurin P, Opolon P, et al. Meta-analysis of interferon randomized trials in the treatment of viral hepatitis C: effects of dose and duration. Hepatology. 1996;24:778–789
    • View In Article
    • MEDLINE
    • CrossRef
43. Licata A, Di Bona D, Schepis F, Shahied L, Craxı` A, Cammà C. When and how to treat acute hepatitis C?. J Hepatol. 2003;39:1056–1062
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (151 KB)
    • CrossRef
44. Jaeckel E, Cornberg M, Wedemeyer H, Santantonio T, Mayer J, Zankel M, et al. Treatment of acute hepatitis C with interferon alfa-2b. N Engl J Med. 2001;345:1452–1457
    • View In Article
    • MEDLINE
    • CrossRef
45. Wiegand J, Jackel E, Cornberg M, Hinrichsen H, Dietrich M, Kroeger J, et al. Long-term follow-up after successful interferon therapy of acute hepatitis C. Hepatology. 2004;40:98–107
    • View In Article
    • MEDLINE
    • CrossRef
46. Delwaide J, Bourgeois N, Gerard C, De Maeght S, Mokaddem F, Wain E, et al. Treatment of acute hepatitis C with interferon α-2b: early initiation of treatment is the most effective predictive factor of sustained viral response. Aliment Pharmacol Ther. 2004;20:15–22
    • View In Article
    • MEDLINE
    • CrossRef
47. Vogel W, Graziadei I, Umlauft F, Datz C, Hackl F, Allinger S, et al. High-dose interferon-α_2b treatment prevents chronicity in acute hepatitis C: a pilot study. Dig Dis Sci. 1996;41:81S–85S
    • View In Article
    • MEDLINE
    • CrossRef
48. Nomura H, Sou S, Tanimoto H, Nagahama T, Kimura Y, Hayashi J, et al. Short-term interferon-alfa therapy for acute hepatitis C: a randomized controlled trial. Hepatology. 2004;39:1213–1219
    • View In Article
    • MEDLINE
    • CrossRef
49. Santantonio T, Fasano M, Sinisi E, Guastadisegni A, Casalino C, Mazzola M, et al. Efficacy of a 24-week course of PEG-interferon α-2b monotherapy in patients with acute hepatitis C after failure of spontaneous clearance. J Hepatol. 2005;42:329–333
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (160 KB)
    • CrossRef
50. De Rosa FG, Bargiacchi O, Audagnotto S, Garazzino S, Cariti G, Raiteri R, et al. Dose-dependent and genotype-independent sustained virological response of a 12 week pegylated interferon alpha-2b treatment for acute hepatitis C. J Antimicrob Chemother. 2006;57:360–363
    • View In Article
    • MEDLINE
    • CrossRef
51. De Rosa FG, Bargiacchi O, Audagnotto S, Garazzino S, Cariti G, Calleri G, et al. Twelve-week treatment of acute hepatitis C virus with pegylated interferon-α-2b in injection drug users. Clin Infect Dis. 2007;45:583–588
    • View In Article
    • CrossRef
52. Calleri G, Cariti G, Gaiottino F, De Rosa FG, Bargiacchi O, Audagnotto S, et al. A short course of pegylated interferon-α in acute HCV hepatitis. J Viral Hepat. 2007;14:116–121
    • View In Article
    • MEDLINE
    • CrossRef
53. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, Lissen E, Gonzalez-Garcia J, Lazzarin A, 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
    • View In Article
    • CrossRef
54. Carrat F, Bani-Sadr F, Pol S, Rosenthal E, Lunel-Fabiani F, Benzekri A, et al. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA. 2004;292:2839–2848
    • View In Article
    • CrossRef
55. Chung RT, Andersen J, Volberding P, Robbins GK, Liu T, Sherman KE, et al. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med. 2004;351:451–459
    • View In Article
    • CrossRef
56. Dominguez S, Ghosn J, Valantin M-A, Schruniger A, Simon A, Bonnard P, et al. Efficacy of early treatment of acute hepatitis C infection with pegylated interferon and ribavirin in HIV-infected patients. AIDS. 2006;20:1157–1161
    • View In Article
    • MEDLINE
57. Gilleece YC, Browne RE, Asboe D, Atkins M, Mandalia S, Bower M, et al. Transmission of hepatitis C virus among HIV-positive homosexual men and response to a 24-week course of pegylated interferon and ribavirin. J Acquir Immune Defic Syndr. 2005;40:41–46
    • View In Article
    • MEDLINE
    • CrossRef
58. Serpaggi J, Chaix ML, Batisse D, Dupont C, Vallet-Pichard A, Fontaine H, et al. Sexually transmitted acute infection with a clustered genotype 4 hepatitis C virus in HIV-1-infected men and inefficacy of early antiviral therapy. AIDS. 2006;20:233–240
    • View In Article
    • MEDLINE
59. Vogel M, Nattermann J, Baumgarten A, Klausen G, Bieniek B, Schewe K, et al. Pegylated interferon-α for the treatment of sexually transmitted acute hepatitis C in HIV-infected individuals. Antiviral Therapy. 2006;11:1097–1101
    • View In Article
    • MEDLINE
60. Poordad FF, Fabrizi F, Martin P. Hepatitis C infection associated with renal disease and chronic renal failure. Semin Liver Dis. 2004;24:69–77
    • View In Article
    • CrossRef
61. Rocha CM, Perez RM, Narciso JL, Ferreira AP, Lemos LB, Medina-Pestana JO, et al. Interferon-alpha therapy within the first year after acute hepatitis C infection in hemodialysis patients: efficacy and tolerance. Eur J Gastroenterol Hepatol. 2007;19:119–123
    • View In Article
    • MEDLINE
    • CrossRef
62. Al-Harbi ASB, Malik GH, Subaity Y, Mansy H, Abutaleb N. Treatment of acute hepatitis C virus infection with alpha interferon in patients on hemodialysis. Saudi J Kidney Dis Transpl. 2005;16:293–297
    • View In Article
63. Griveas I, Germanidis G, Visvardis G, Morice Y, Perelson AS, Pawlotsky JM, et al. Acute hepatitis C in patients receiving hemodialysis. Ren Fail. 2007;29:731–736
    • View In Article
    • CrossRef
64. Gursoy M, Gur G, Arslan H, Ozdemir N, Boyacioglu S. Interferon therapy in haemodialysis patients with acute hepatitis C virus infection and factors that predict response to treatment. J Viral Hepat. 2001;8:70–77
    • View In Article
    • MEDLINE
    • CrossRef
65. Engel M, Malta FM, Gomes MM, Mello IM, Pinho JR, Ono-Nita SK, et al. Acute hepatitis C virus infection assessment among chronic hemodialysis patients in the Southwest Parana State, Brazil. BMC Public Health. 2007;7:50
    • View In Article
    • MEDLINE
    • CrossRef
66. Manns MP, Meyer S, Wedemeyer H. The German network of excellence for viral hepatitis (Hep-Net). Hepatology. 2003;38:543–544
    • View In Article
    • MEDLINE
    • CrossRef
67. Broers B, Helbling B, Francois A, Schmid P, Chuard C, Hadengue A, et al. Barriers to interferon-α therapy are higher in intravenous drug users than in other patients with acute hepatitis C. J Hepatol. 2005;42:323–328
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (132 KB)
    • CrossRef