Acute HCV Infection: Diagnosis, Natural History and Treatment

It is estimated that nearly 30,000 cases of acute infection with hepatitis C virus (HCV) occur annually. The onset of acute HCV may go unnoticed by infected individuals or may be accompanied by symptoms, which may be mild or severe. Fulminant hepatic failure attributable to acute HCV infection is rarely observed.

A summary of the diagnosis, natural history and treatment of acute HCV infection appears in the July 1, 2005 issue of Clinical Infectious Diseases. Following are excerpts from that summary by Raymond Chung, MD, of the Gastrointestinal Unit and Liver Transplant Program, Massachusetts General Hospital, Boston, MA.

Diagnosis of Acute HCV Infection

Although there are no formal criteria for the diagnosis of acute HCV infection, the following criteria are often used in defining clinical cohorts for treatment studies of acute HCV infection:

·         Acute increase in levels of alanine aminotransferase (ALT) to >10 times the upper limit of normal, with or without increases in total bilirubin level;

·         Positivity for HCV RNA; and

·         Exposure to HCV during the preceding 212 weeks.

Results of testing for anti-HCV may be positive or negative, depending on the phase of acute illness. Most commonly, patients will be seronegative, and subsequent seroconversion will signal the diagnosis. Occasionally, the patient may seroconvert at the time of presentation because of the overlap period between symptomatic presentation and time to seroconversion.

In these cases, because of the inability to reliably distinguish seroreactivity to acute and chronic infection, the diagnosis of acute HCV infection may rely on documentation of prior seronegativity and/or the absence of detectable HCV RNA.

Unfortunately, no reliable serological assay to detect an IgM subclass anti-HCV response has been developed to accurately distinguish acute from chronic infection.

Natural History of HCV and Spontaneous Clearance

Acute hepatitis will typically develop 1014 weeks after infection, at which point sharp increases in serum ALT levels and the appearance of HCV-specific T cells can be detected. On the basis of studies of experimentally infected chimpanzees, the following picture of early events in acute HCV infection emerges.

The appearance of robust and multispecific CD4⁺ and CD8⁺ T cell responses in the blood of persons with acute HCV infection seems to be associated with recovery. In contrast, a lack or waning of such a response appears to predict the onset of chronic infection.

Virologically, the control of acute HCV infection is associated with a narrowing of HCV quasi-species diversity, reflecting a "corralling" of virus diversity with a successful immune response, whereas chronicity is associated with quasi-species expansion.

The rate of spontaneous clearance after acute HCV infection is not known but is conservatively estimated to be 20%25%. Additional host factors associated with spontaneous clearance include young age (<40 years), female sex, and symptomatic (icteric) illness. These findings support the idea that persons with strong basal immune responsiveness (and likelihood of producing jaundice and clinical illness) have a better likelihood of controlling infection with HCV.

In addition, infants who contract HCV infection appear to have a high rate of spontaneous clearance (75%100%). Conversely, it should, therefore, not be surprising that persons who are immunosuppressed, including HIV-infected persons or recipients of organ transplants, experience higher rates of chronicity after acute HCV infection.

Among persons coinfected with HCV and HIV, the importance of CD4⁺ cell immunity has been reinforced by the observation that the vigor of HCV-specific CD8⁺ cytotoxic T cell responses is directly related to CD4⁺ cell count.

These findings, therefore, suggest that initiation of active antiretroviral therapy may play an important role in improving rates of either spontaneous or treatment-induced clearance of HCV infection.

A large clinical trial is currently addressing this question. Interestingly, sporadic reports of spontaneous clearance of HCV infection after initiation of HAART suggest that these persons might otherwise have cleared HCV infection in the absence of HIV infection.

Treatment of Acute Infection: How and When?

Two biological findings support early intervention for persons with acute HCV infection. First, the adaptive immune response is maximal at the outset of infection and wanes in persons who evolve to persistent infection. Second, HCV encodes several proteins implicated in disarming the innate immune response.

Additional clinical considerations favoring early therapy include the prevention of significant histological injury, as well as the likelihood that treatment will be more successful among persons with limited histological damage.

On the other hand, however, empirical early intervention may lead to unnecessary treatment of those persons who are otherwise destined to spontaneously clear the virus. In addition, the functional effects of pharmacological therapy on active T cell responses are unknown.

Against this backdrop, there have been few data to guide treatment decisions among persons with acute HCV infection. Two recent trials have provided the most information, to date, with regard to success rates achieved with IFN-based regimens.

A multicenter German study of acute HCV infection analyzed 44 patients. Importantly, 68% of patients were symptomatic (many of whom were jaundiced), with a mix of risk factors, including injection drug use for 20% of patients, needlestick injury for 32% of patients, and sexual transmission for 23% of patients.

Of the patients, 57% were women, 61% were infected with genotype 1 HCV, and 27% were infected with genotype 2 or 3 HCV. All patients received standard IFN-a2b, at a dose of 5 million units daily for 4 weeks, followed by 5 million units thrice weekly for 20 weeks, at a mean of 12 weeks after onset of infection.

Remarkably, the rate of sustained virological response was 98% in this cohort. Therapy was well tolerated by all but 1 patient.

These findings demonstrated the clear superiority of treatment in the early phase over any regimen given during chronic HCV infection. However, it was not clear how many of these subjects may have spontaneously cleared their infection.

A second German study helped clarify the determinants of spontaneous clearance by enrolling 60 patients with acute HCV infection, 51 of whom had symptomatic disease. Of the patients, 58% were women, 25% were IDUs, and 60% were infected with genotype 1 HCV. Five patients were treated immediately. The remaining patients were observed for at least 12 weeks before treatment was initiated.

Of interest, all 9 asymptomatic patients went on to develop chronic HCV infection. Of the remaining 46 patients, 24 (52%) experienced spontaneous clearance. IFN-based treatment (IFN or IFN plus ribavirin) was begun 12 weeks after symptoms developed and was associated with a rate of sustained virological response of 80%.

In all, 91% of the group experienced spontaneous or treatment-induced clearance.

In general, jaundice and female sex predicted a self-limited course, and viremia was cleared by 12 weeks in nearly all cases of spontaneous clearance.

These data provide a possible rationale for a "watchful waiting" approach in treating symptomatic patients, especially those with jaundice, before the decision to treat with IFN or pegylated IFN with or without ribavirin is made, because there seems to be no apparent decrease in rates of sustained virological response.

Summary

The optimum timing of antiviral therapy for acute HCV infection is not yet established, but it appears that a watch-and-wait strategy among symptomatic persons may be reasonable.

For asymptomatic persons, immediate therapy with IFN-based treatment appears to be warranted. The higher frequency of spontaneous clearance and shortened duration and severity of disease in persons with prior immunity to HCV additionally provides a rationale for vaccination and immunotherapeutic strategies.

Further work is needed to develop more-accurate assays that distinguish acute from chronic infection, so as to delineate host factors, including genetic and immunologic predispositions, and viral factors that accurately predict spontaneous clearance.

The creation of a multicenter diagnostic and therapeutic acute HCV network, with standardized data collection and treatment trials, will be exceedingly important in helping to define the optimal duration and regimen of therapy.

06/20/05

Reference
R T Chung and others. Acute Hepatitis C Virus Infection. Clinical Infectious Diseases 41(1): Supp 14-17. July 1, 2005.

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