Treatment of acute hepatitis C virus (HCV) infection has made substantial progress during the last decade. However, standardized approaches are difficult to perform, because certain clinical, diagnostic and social reasons lead to under-reporting and limited epidemiological data .
Clinically, many patients are asymptomatic or develop only nonspecific symptoms. Jaundice, a leading symptom for hepatic injury, occurs in only 20-30% of cases [2,3].
Serological screening with anti-HCV antibodies is hampered by the limitation that it can take up to 12 weeks after exposure until anti-HCV immunoglobulin M antibodies emerge. Thus, in up to 30% of patients, analysis of HCV RNA by the polymerase chain reaction (PCR) is the only way to diagnose acute HCV infection [4,5].
Moreover, identification of individuals with acute hepatitis C is hindered by their reluctance to divulge habits that lead to transmission of the disease. Since the introduction of screening of blood products for HCV RNA by PCR, transfusion-associated transmission is practically non-existent anymore. In contrast, intravenous drug abuse has become the leading risk factor today [5-9]. The incidence per 100 person years in blood donors is only 0.0028 compared to 15.4 – 33.1 in American  or 12.9 in British  intravenous drug users. The prevalence in drug users is at least 50% in many parts of the world . Other possible routes of HCV infection are medical procedures, unprotected sexual intercourse with multiple partners, or needle-stick injuries among healthcare professionals [9,13-17]. Fortunately, needle-stick injuries are associated with a much lower risk than previously reported (mean 0.75%; in Europe 0.42%, in Eastern Asia 1.5%) . However, recent reports highlight potential sources of infection after hospital admission [13,19-22]. Analysis of pooled data from the German HEP-NET acute hepatitis C studies revealed an age-related risk profile, with drug abuse as the leading source of infection in young patients, whereas medical procedures predominated in the >50 years age group. The risk of sexual transmission was equally distributed between different age groups (Figure 1) .
Figure 1. The mode of infection by HCV changes with age in patients with acute hepatitis
C. Whereas drug abuse is the principal source of infection in young patients, medical
procedures become relevant in patients >50 years. This latter age group also has the highest rate of unknown sources of infection. Exposure through sexual contact is equally distributed between the different age groups.
(Data from )
Overall, incidence estimates of acute HCV infection vary widely, depending on evaluation methods and the institution to which the data were reported. In Italy, the incidence of acute HCV infection ranges from 1 to 14 per 100,000, according to the national surveillance agency , the Italian blood donor program , or evaluation in the general population . In the United States, 671 confirmed cases with acute HCV infection were reported in 2005 (0.2 per 100,000 inhabitants); however, after accounting for under-reporting of asymptomatic infections, the estimated incidence was 20,000 new cases . In high epidemic countries like Egypt, up to 7% of adult patients presenting with acute hepatitis have acute HCV infection .
Diagnosis of acute HCV infection is based on the detection of HCV RNA by PCR with documented anti-HCV antibody seroconversion. In cases where anti-HCV seroconversion cannot be proven, additional criteria can support the suspected diagnosis: alanine aminotransferase (ALT) levels >7-20 times the upper limit of normal, known or suspected exposure to the virus, or increasing numbers of reactive proteins in a recombinant immunoblot confirmation assay [5,27]. Moreover, a low viral load at baseline (HCV-RNA <100,000 IU/ml) or viral load fluctuations >1 log during a monitoring period of 10-12 weeks may be considered as possible diagnostic criteria if recent risky behavior has occurred .
PRINCIPLES OF ANTIVIRAL THERAPY IN ACUTE HEPATITIS C
In contrast to chronic hepatitis C, a standard therapy has not yet been identified for the acute phase of the disease. Several important aspects are currently under investigation. Nevertheless, the following principles have been identified so far:
- Both conventional and pegylated interferons can be used in acute hepatitis C [22,29-37]
- Combination therapy with ribavirin is not necessary [22,29-37]
- Treatment duration and sustained virological response (SVR) rates are independent of HCV genotypes [22,29-37]
The current discussion of treatment individualization according to HCV genotype, baseline viral load, and viral kinetics after treatment initiation in chronic hepatitis C also influences the debate in acute hepatitis C. For example, high rates of rapid virological response (HCV-RNA negative after 4 weeks of therapy) can be achieved much more frequently in acute compared to chronic HCV genotype 1 infection (88% vs 16-23%) and are one factor explaining the high efficacy of treatment in the early phase of the disease .
Thus, in addition to the description of landmark studies with conventional and pegylated interferons, the following paragraphs will discuss aspects of the optimal time point for treatment initiation, the optimal treatment duration and the optimal interferon dosage.
TREATMENT OF ACUTE HEPATITIS C WITH CONVENTIONAL INTERFERON ALFA
The first strategies to treat acute hepatitis C were based on conventional non-pegylated interferons. A recent meta-analysis identified therapeutic principles after investigation of 16 heterogeneous clinical studies which treated 320 patients subcutaneously, intramuscularly, or intravenously for a period of 4-24 weeks with different dosages of interferon alfa or beta . Overall, interferon treatment significantly increased SVR rates compared with untreated controls (risk difference 49%; 95% CI: 32.9-65%). SVR rates increased with higher weekly interferon dosages. High-dose therapy during the first months of therapy appeared to be the best treatment option.
An Austrian pilot study treated 24 patients with daily 10 MU interferon alfa-2b subcutaneously (s.c.) until normalization of ALT values and obtained SVR in 75% of the patients (Table 1) .
|TABLE 1. Summary of clinical trials with immediate interferon therapy of acute hepatitis C
The German HEP-NET Acute Hepatitis C I Trial became the landmark study for conventional interferons, treating 44 individuals with a standardized treatment duration of 24 weeks . After induction dosing for 4 weeks with daily 5 MU interferon alfa-2b s.c., patients continued with 5 MU three times weekly s.c. for another 20 weeks. HCV-RNA was eliminated 3.2 weeks after treatment initiation, and 43 of 44 cases (98%) obtained SVR (Table 1). Importantly, viral clearance perpetuated over a long-term follow-up of up to 224 weeks .
More recent trials reported SVR rates of 75% (n=21/28) after daily injection of 5 MU interferon alfa-2b s.c. for 8 weeks  and of 87% (n=13/15) after daily 6 MU human lymphoblastoid interferon alfa intramuscularly (i.m.) for 4 weeks  (Table 1).
Overall, all studies indicate that early treatment strategies for 4-24 weeks with initial daily interferon injection can effectively prevent chronicity of acute hepatitis C infection.
TREATMENT OF ACUTE HEPATITIS C WITH PEGYLATED INTERFERON ALFA
After pegylated interferons had become the standard of care in chronic hepatitis C they were also studied in the acute phase of the disease (Table 1). Due to their long half-lives, treatment protocols were designed with once-weekly injections, which replaced the high-dose induction regimens performed previously with conventional interferons. Importantly, head-to-head studies between monotherapies with pegylated and conventional interferons have not yet been conducted.
The concept of immediate therapy  was transferred to pegylated interferon in the German HEP-NET Acute Hepatitis C II Study . Patients were treated with peginterferon alfa-2b 1.5 µg/kg once weekly s.c. for 24 weeks. In the total study population, 71% of patients achieved SVR. The SVR rate in individuals adherent to therapy was 89%. The difference in the response rates between the intent-to-treat and per-protocol analyses was due to protocol violations, treatment failures and a substantial number of patients lost to follow-up.
Two Italian study groups investigated peginterferon alfa-2b in the setting of immediate therapy of acute hepatitis C for a shorter treatment period of 12 weeks. An SVR was observed in 14 of 19 cases (74%) and in 33 of 46 individuals (72%), respectively [34,35].
In addition to the modified dosing regimens, another important therapeutic aspect of acute hepatitis C was considered after the invention of pegylated interferons: the idea of a delayed, instead of an immediate, therapy to investigate the optimal time point for treatment initiation (Table 2).
||TABLE 2. Summary of clinical trials with delayed therapy of acute hepatitis C
In the trials using conventional interferons, therapy was initiated as early as possible. However, immediate treatment resulted in over-treatment of those patients who would have cleared the infection spontaneously. Prompt therapy exposes these individuals to unnecessary treatment-related adverse events and increases medical costs. Spontaneous clearance of acute hepatitis C occurs in 20-67% of cases, primarily within the first 3 months after the clinical onset of the disease [3,8,15,22,23,37,41-43]. If viremia persists for more than 6 months, chronic infection must be considered. Unfortunately, there are no host or viral factors that can reliably predict spontaneous resolution in individual cases [3,15,42]. In general, patients with symptomatic disease (i.e., jaundice or flulike symptoms) seem to experience spontaneous viral clearance more often than asymptomatic individuals [3,42]. Self-limited disease could be observed in up to 52% (n=24/46) of symptomatic patients in contrast to none among the asymptomatic cases .
The study by Gerlach et al  became the rationale for subsequent studies investigating delayed therapy of acute hepatitis C with pegylated interferons. Only the patients who did not resolve the infection spontaneously were treated with different interferon-based regimens (conventional and pegylated interferons, with or without ribavirin, different treatment durations) and attained SVR in 81% of cases. The overall response rate, including self-limited infections and treatment-induced viral clearance, was 91%. This result was in the same range as the therapeutic approaches with immediate treatment [30,33]. Recent observational data of 109 French patients treated with different mono- or combination regimens showed lower SVR rates than in Germany, but no difference between early or delayed interferon therapy [76% (n=32/42) vs 72% (n=26/36)] .
An Italian trial evaluated delayed therapy within a standardized study protocol, treating patients with 1.5 µg/kg peginterferon alfa-2b once weekly s.c. for 24 weeks after an initial observation period of 12 weeks. At the end, 94% (n=15/16) of patients cleared the infection . In Egypt, SVR was observed in 15 of 17 cases (88%) after only 12 weeks of therapy with peginterferon alfa-2a . Thus, delayed treatment strategies achieve similar results as the immediate treatment concepts. The high SVR rates with both conventional and pegylated interferon monotherapies do not justify combination with ribavirin so far.
WHEN IS THE OPTIMAL TIME POINT FOR TREATMENT INITIATION?
Several studies indicate that the time between presentation and start of therapy influences SVR rates [31,32,44]. In the Japanese interferon trial, SVR dropped from 87% to 40% when therapy was initiated after an observation period of one year . The Australian ATAHC study describes decreasing efficacy of combination therapy with peginterferon alfa-2a plus ribavirin at a time point beyond 52 weeks compared to the period 27-52 weeks (Figure 2) .
||Figure 2. Sustained virological response (SVR) rates in relationship to the duration of infection in intravenous drug users. In cases of short duration of infection, SVR is impaired by presumably recent active drug use. If therapy is postponed >52 weeks, the efficacy of peginterferon alfa-2a plus ribavirin is comparable to that in persons with chronic hepatitis C.
(Data from )
A mathematical model including data from the German Acute HCV II Trial with early treatment [30,33] and the Italian experience with delayed therapy  indicated that treatment should be initiated immediately if HCV-RNA is detected within the first two months after transmission (i.e., during regular observation of health-care workers with needle-stick injuries). In individuals in whom infection is diagnosed later than two months after acquisition, treatment may be postponed until 4-5 months because of a higher rate of spontaneous HCV clearance after two months and a low HCV treatment efficacy between month 3 and months 4-5 .
At present, the German Competence Network for Viral Hepatitis (HEP-NET)  is conducting a randomized, controlled trial comparing immediate treatment versus delayed therapy after an observation period of 12 weeks to further clarify the discussion between both therapeutic concepts  (Table 3). Symptomatic patients are randomized to either immediate monotherapy with peginterferon alfa-2b 1.5 µg/kg for 24 weeks (arm A) or 24 weeks of combination therapy with weight-based ribavirin >10.6 mg/kg after an observation period of 12 weeks (arm B). In addition, asymptomatic patients are treated immediately with peginterferon alfa-2b monotherapy (arm C). In cases of arm A with immediate therapy, SVR rates were 78% in the intention-to-treat analysis, whereas the efficacy was only 54% after delayed treatment (p = .034). Eight of 37 patients achieved spontaneous viral clearance in the observation period (22%). After correction for adherence to therapy, SVR increased to 88% in arms A and C and confirmed the findings of the HEP-NET Acute HCV II trial . Patients with complete therapy and correct follow-up in the delayed-treatment arm (arm B) achieved 100% sustained viral clearance (n=12) (Figure 3). The reason for the significant difference between the immediate and delayed therapy in the intention-to-treat analysis was the high lost-to-follow-up rates.
||TABLE 3. Summary of clinical trials comparing immediate and delayed therapy of acute hepatitis C
||Figure 3. Sustained virological response (SVR) rates during immediate and delayed therapy in the German HEP-NET Acute HCV III trial. The SVR data in arm B (delayed treatment) summarize the spontaneous and treatment-induced viral clearance rates.
(Data from )
Thus, when an observation period is considered the following aspects should be ensured: 1) adherence must be emphasized in both the observation and the treatment periods; and 2) repeated quantitative testing of HCV RNA levels in patients who experience spontaneous resolution is highly recommended because a late relapse may occur after temporary HCV RNA clearance. A single negative HCV-RNA test result should not be considered confirmation of self-limited acute hepatitis C . Frequent HCV-RNA determination during the first months of clinical symptoms may predict spontaneous resolution of the infection ; however, such may not be feasible in everyday clinical practice. Thus, although evidence-based data on optimal follow-up measurements during an observation period are still unknown, repeated tests at least every 4 weeks within the first 3 to 4 months seem to be recommended.
WHAT IS THE OPTIMAL TREATMENT DURATION?
The highest SVR rates have been described with the 24-week treatment schedule of Jaeckel et al , including daily induction dosing with 5 MU interferon alfa-2b s.c. during the first 4 weeks of therapy. Daily dosage of conventional interferon alfa within shorter treatment schedules of four  and eight  weeks indicates that shorter treatment duration may be possible; however, the studies included only a small number of patients with different ethnicities. Monotherapies with peginterferon alfa-2b in the Italian trials indicate that a 12-week treatment period can attain high virological response rates of 72-74% [34,35]. However, randomized trials investigating 12 versus 24 weeks in the setting of immediate therapy of acute hepatitis C have not been performed.
In delayed therapy, both the German treatment schedule for 24 weeks and the Egyptian trial for 12 weeks showed high efficacy [22,23]. A large Italian ongoing randomized trial is currently comparing a 12- versus 24-week treatment period in a randomized study protocol. In addition, this study also includes a third treatment arm consisting of peginterferon alfa-2b plus ribavirin to verify whether combination therapy can reduce treatment duration to 12 weeks without compromising SVR.
WHAT IS THE OPTIMAL INTERFERON DOSAGE?
The optimal dosage cannot be defined for either conventional or pegylated interferon alfa as yet.
Using conventional interferon alfa in an increasing weekly dosage within the first months of therapy increases the risk difference of an SVR from 5% to 90% . The different regimens with daily 5-6 MU interferon alfa s.c. or i.m.  for 4 or 8 weeks  have not been compared head to head.
During immediate therapy with peginterferon alfa-2b, the Italian results indicate that at least 1.2-1.33 µg/kg once weekly should be administered s.c. [34,35]. Importantly, the sub-analyses of these two studies confirmed the hypothesis, that the success of immediate antiviral treatment is independent of HCV genotype ; rather, it is related to optimal interferon dosage [34,35].
In delayed treatment, attempts to treat patients with dosages other than 1.5 µg/kg peginterferon alfa-2b or 180 µg peginterferon alfa-2a s.c. once weekly have not been performed as yet. Data showing that treatment results may depend on HCV genotypes do not exist so far.
WHOM SHOULD BE TREATED?
Patients with acute hepatitis C infection may be difficult to treat. As mentioned above, most of the cases are previous or current intravenous drug users. Although such persons can be effectively treated [22,31,35,44,48], other investigators observed a high number of psychiatric side effects that led to treatment discontinuation . In addition, SVR is compromised by poor adherence, with high lost-to-follow-up rates in patients with low socioeconomic status, short duration of infection, and presumably recent active drug use . Even after exclusion of cases with ongoing drug abuse, adherence to therapy is crucial to successful treatment. In the German HEP-NET Acute HCV II Study, SVR rates between individuals of the intent-to-treat and the per-protocol analyses differed by 18%. This difference was also mainly due to individuals lost to follow-up .
Moreover, interferon treatment can induce life-threatening risks which would not be present if the spontaneous course of acute HCV infection were allowed to proceed. In the HEP-NET Acute II Study, three serious adverse events occurred, including one suicide related to peginterferon alfa-2b . In the ATAHC study, three deaths were observed . Thus, indication for antiviral therapy must be discussed on an individual basis using an interdisciplinary approach, especially if drug use or psychological disorders are present. Response rates comparable to those for non-injecting drug users can be achieved in intravenous drug users in experienced centers with established multidisciplinary infrastructures and with directly observed therapy [50,51]. However, such an approach may be limited to specialists and not practicable in the routine standard of care.
Although the gold-standard therapy of acute hepatitis C has not yet been defined, the infection can be successfully treated with interferon-based monotherapies. Both conventional and pegylated interferon alfa can be effectively used. Combination therapy is not recommended as yet, because of the high SVR rates that are achievable with interferon-based monotherapies. Therapy may be initiated as early as possible or after an observation period of up to 12 weeks. In both settings, treatment duration should be 24 weeks. According to the Italian and Egyptian experiences, a shorter treatment duration of 12 weeks may be suitable in patients with side effects or in difficult-to-treat individuals who become HCV RNA negative within the first 4 weeks of therapy [22,34,35].
However, several limitations have to be considered in the special treatment setting of acute hepatitis C:
(i) Therapy is not yet licensed. Clinical studies are not available in many countries; however, if possible, patients should be enrolled in controlled clinical trials to answer the numerous open questions.
(ii) In all scenarios (immediate versus delayed therapy; treatment of intravenous drug users versus exclusion of ongoing or recent drug users) adherence during the treatment phase and during pre- or post-treatment observation periods is crucial to ensure high virological response rates.
(iii) Importantly, the indication for therapy and the treatment schedule must be thoroughly discussed on an individual patient level. The benefit of an SVR has to be carefully balanced against potential treatment-related serious adverse events.
(iv) Especially in intravenous drug users, clinical attendance should not only be focused on SVR, but also on psychosocial conditions and aspects relevant to addiction medicine.
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