Clinical and Laboratory Features
The diagnosis of acute hepatitis C virus (HCV) infection is infrequently made, primarily because more than 70% of patients do not have symptoms associated with the acute infection[1,2]. Overall, approximately 25% of all patients with acute HCV present with jaundice, and 10 to 20% develop gastrointestinal symptoms (nausea, vomiting, or abdominal pain). As would be expected, among those persons with clinically recognized acute HCV, the reported rates of symptoms are much higher and typically include jaundice, fatigue, flu-like symptoms, and dark urine (Figure 1 and Figure 2)[3,4]. On average, when symptoms do occur, they typically manifest 6-8 weeks after exposure (range 5 to 12 weeks) and last for 2 to 12 weeks[1,2]. In many cases, laboratory abnormalities may provide the initial clue to suggest a diagnosis of acute HCV infection. Rising alanine aminotransferase (ALT) levels are typically observed approximately 40-50 days after infection, although, in one series, the period between post-transfusion HCV infection and ALT elevation had a wide range (6 to 112 days). In large case series involving primarily symptomatic patients, mean peak ALT values have tended to range between 400-1000 IU/L. Overall, ALT levels exceed 1000 U/L in only about 20% of cases of acute hepatitis C. Serum bilirubin levels may also be elevated, but they do not typically exceed 12 mg/dL. During the initial months of infection, ALT levels usually fluctuate, whereas bilirubin levels trend toward normal. Occasionally acute hepatitis C can manifest as a severe illness, but no cases of acute liver failure have been reported in the United States.
The acute phase of hepatitis C is generally defined as the first 6 months of the infection. Our knowledge of the course of acute hepatitis C is incomplete due to the difficulty in identifying patients with acute infection and the limited availability of animal models. In addition, prior research that focused on the course of acute hepatitis C infection and early viral dynamics primarily involved patients with transfusion-related acute hepatitis C, but fewer than 5% of contemporary cases result from the transfusion of blood products. Thus, some older data may not apply to contemporary patients with acute HCV, since the course of illness for patients with transfusion-related acute hepatitis C may significantly differ from patients who acquire infection via other routes, such as injection-drug use. Nevertheless, based on available data, investigators have described the viral dynamics of acute hepatitis as occurring in 3 phases: (1) pre-ramp up phase, also known as the eclipse phase (unknown duration), (2) ramp-up phase (lasting 8-10 days), and (3) plateau phase (lasting 45-68 days) (Figure 3). During the ramp-up phase, exponential growth of HCV occurs, with a doubling of viral load every 10.8 hours. The ramp-up phase transitions to a plateau phase characterized by high-level hepatitis C viremia. Studies involving chimpanzees and humans have shown the plateau phase is typically reached within the first two weeks after inoculation of HCV via transfusion, but in some patients low-level viremia persists for up to 2 months before the virus even enters the ramp-up phase. Serum HCV levels generally peak within 6 to 10 weeks of infection, regardless of eventual progression to chronic or resolved infection. The HCV RNA levels can fluctuate widely in acute hepatitis C. Overall, approximately 70-80% of individuals infected with hepatitis C will progress to persistent infection and about 20-30% will spontaneously resolve the infection (Figure 4).
Immune Response to Acute HCV Infection
The immune response to the acute phase of HCV infection includes both humoral and cellular components. Based on the overall immune response, patients either have persistence of viral infection (Figure 5) or clearance of HCV (Figure 6). In most individuals, anti-HCV antibodies appear 7 to 8 weeks after exposure. Antibodies may appear slightly later after transfusion-related infection than after other modes of HCV transmission. Greater than 80%, 90%, and 97% of patients demonstrate anti-HCV by 15 weeks, 5 months, and 6 months, respectively. Notably, up to 3% of patients with chronic hepatitis C may never seroconvert (Figure 4). The role of antibody production in the control of the HCV remains unclear. Antibodies do not seem to confer protection against re-infection, and some individuals develop abortive infections in which the immune system controls viremia without evidence of seroconversion. In contrast, the cellular immune response appears to play a critical role in controlling acute infection; strong CD4 and CD8 HCV-specific T-cell responses generally correlate with recovery from acute infection. The emergence of the cellular immune response to HCV often corresponds with elevation in serum hepatic aminotransferase levels.
Spontaneous Clearance of HCV
Among those individuals who have spontaneous resolution of the HCV, it typically occurs within 1 year after infection. Although most studies have shown those who clear HCV without specific therapy do so within 12 weeks of the clinical presentation[3,4,10], others have shown a more delayed clearance that occurs after 6-12 months[11,12]. Both the presence of jaundice at the time of initial infection[3,4,13] and a rapid decline in viral load during the first 4 to 8 weeks after infection[4,14] correspond with sustained viral clearance. Other host responses or viral factors, however, have not demonstrated a consistent association with spontaneous clearance of HCV[4,11].
Diagnosis of Acute HCV Infection
Diagnosing acute hepatitis C infection with certainty can be difficult, primarily because of the high proportion of asymptomatic cases, the absence of a reliable and specific IgM-based serologic test, and potential overlapping laboratory findings with acute and chronic hepatitis C infection (elevated ALT levels, positive serum HCV RNA, and anti-HCV antibodies). Acute hepatitis C can be diagnosed with a high level of certainty when the following three criteria are met: (1) the patient reports recent risk factors for acquiring HCV; (2) laboratory studies show positive HCV RNA levels, an elevated ALT level, and a positive HCV antibody test; and (3) laboratory studies obtained within the prior 12 months demonstrate negative HCV viremia, normal serum hepatic aminotransferase levels, and negative HCV antibodies (Figure 7). In the clinical setting, however, most patients do not have a recent retrospective laboratory sample available for comparison. In the absence of historical data, several studies of acute HCV have relied on a stricter biochemical criterion of an ALT level greater than 10 or 20 times normal, along with the caveat that the investigators could not find an alternate explanation for the patient's liver disease[3,4,15]. The presence of HCV RNA without detectable antibody response may also suggest acute hepatitis C, but, as previously noted, some individuals with chronic hepatitis C may never seroconvert. One author also suggested that a diagnosis of acute hepatitis C should be considered when HCV viral load fluctuates widely, as viral load generally remains relatively stable in patients with chronic hepatitis C.
Treatment Recommendations for Acute HCV
The goal of therapy for hepatitis C is to achieve a sustained virologic response (SVR), defined as undetectable HCV RNA at least 6 months after cessation of therapy. Recent studies have revealed that SVR rates after treatment for acute hepatitis C are as high as 60-100%, substantially better than those for observed with therapy for chronic hepatitis C[3,13,15,16,17,18]. These trials have also suggested that patients treated during acute hepatitis C have a significantly higher resolution of hepatitis C than the spontaneous recovery rate in untreated patients with acute hepatitis C. Nevertheless, most acute HCV treatment studies have not been controlled, and they have primarily enrolled patients with symptomatic acute infection, a subset of patients that may have higher spontaneous recovery rates. Although this issue remains controversial, the American Association for the Study of Liver Disease (AASLD) 2004 has generated interim recommendations stating sufficient data exist to support serious consideration for treatment in most instances for patients with acute hepatitis C, after waiting 2-4 months for possible spontaneous clearance and assuming no contraindication for therapy exists. In addition, the AASLD has issued interim recommendations regarding length of therapy and possible therapeutic regimens (Figure 8). Below, we provide a more extensive discussion regarding data related to timing of therapy, specific regimens, and length of therapy.
Timing of Initiating Therapy for Acute HCV
Several studies have helped to better define the optimal timing for initiating therapy in the setting of acute HCV infection. Recent data clearly demonstrated that initiating treatment during the first months after the diagnosis of acute hepatitis C provided substantial benefit when compared with delaying treatment for one year (SVR 100% versus 53%). Since many individuals clear HCV infection spontaneously in the first three months, some experts have argued that beginning treatment too early in the course of the illness might expose those individuals to unnecessary medications and side effects. Several studies have employed a strategy of delaying therapy for 8 to 12 weeks after disease onset and impressive SVR rates were preserved[3,16,19,20]. Unfortunately, whether treatment was initiated 8 to 12 weeks from the time of the exposure or from the time of symptom onset was not uniform among these studies. More recently, preliminary results from one study suggested initiating therapy with peginterferon at 20 weeks (as opposed to 8 weeks) after diagnosis of acute hepatitis C had a significant negative impact on SVR rates (SVR 75% versus 94%). Taken together, these findings suggest a delay of 8-12 weeks is appropriate prior to making a decision to initiate treatment.
Regimens for Treatment of Acute HCV
Early studies involving patients with acute HCV infection used relatively low doses of either alpha or beta interferon, typically only 3 times per week, with lackluster SVR rates of approximately 30-60%. Higher daily doses (5-6 million units) of interferon either during a 1-month induction period or during the entire course of therapy markedly improved the rate of viral clearance to 85-98%[13,15,22]. Moreover, results from a recent meta-analysis led to the recommendation to include daily interferon for at least the first month of therapy for acute hepatitis C (if standard interferon monotherapy is used). Experts have theorized that daily dosing prevents viral rebound and the development of HCV escape mutants early in the course of therapy. The AASLD 2004 recommendations acknowledge peginterferon therapy as a reasonable alternative to standard interferon, especially given the ease of administration. In addition, results from very recent studies using peginterferon therapy for acute hepatitis C have demonstrated SVR rates of 80 to 94%[16,17,18,19,20,23]. If treatment for acute HCV infection is initiated, we favor using peginterferon rather than standard interferon, primarily based on its more patient-friendly dosing schedule and data showing its superior efficacy when compared with standard interferon for treatment of patients with chronic HCV infection. To date, the addition of ribavirin to interferon has not demonstrated a significant improvement in treatment results of acute HCV and insufficient data exist to recommend for or against the use of ribavirin as part of therapy for acute hepatitis C.
Length of Therapy for Acute HCV
The length of treatment for acute hepatitis C has varied from as short as 4 weeks to as long as one year. Multiple studies have established that 24 weeks of appropriate therapy is sufficient to provide excellent response rates for patients with acute hepatitis C infection. Although a recent study showed that overall 12 versus 24 weeks of peginterferon therapy were equivalent, subgroup analysis revealed that 24 weeks of therapy was superior for patients in whom treatment was delayed beyond 20 weeks after diagnosis (SVR 76% versus 67%) and for those with HCV genotype 1 (SVR 89% versus 69%). A Japanese study demonstrated an excellent SVR rate of 87% after only 4 weeks of interferon therapy, but it is questionable whether these results can be generalized to non-Japanese populations. A rapid decline in viral load in the first weeks of therapy appears to predict SVR. Other predictors of SVR have been inconsistent among studies. Data on long-term response to therapy is limited, but long-term follow-up of 31 patients treated for acute HCV infection has revealed sustained undetectable HCV RNA levels in all 31 patients, even when using the highly sensitive transcription-mediated amplification assay[15,24]. If treatment is initiated, we would recommend using 24 weeks of therapy, regardless of genotype.