The recent National Institutes of Health (NIH) Consensus Development Conference helped to clarify which patients should be treated. The Consensus Statement began by noting that all patients with chronic hepatitis C were to be considered as potential candidates for antiviral therapy. Treatment was particularly recommended for those patients at increased risk of developing cirrhosis.

It has long been recognized that interferon therapy of chronic hepatitis C is associated with a significant reduction in the degree of necroinflammatory change within the liver. It has only recently become apparent that antiviral therapy might also have an impact on the degree of hepatic fibrosis.

There is considerable variability in the virologic response of patients with chronic hepatitis C to antiviral therapy. Recently, the NIH Con-sensus Development Panel affirmed that a sustained virologic response (SVR) is the optimal outcome of therapy. SVR is defined as undetectable HCV RNA in serum at the end of therapy and for at least 6 months thereafter.

General principles of therapy

Goals

The goals of therapy for chronic hepatitis C include prevention of progressive liver disease, control of extrahepatic manifestations (where present) and decreasing the infectivity of patients with HCV infection. These end points are difficult to measure and may take many years to evaluate, given the prolonged natural history of this condition. Efforts at therapy have therefore focused on elimination of HCV infection which is almost always associated with improvement in the severity of liver disease as assessed by liver biopsy.

The natural history of HCV infection is quite variable but is notable for a strong propensity to become chronic. Thus, as many as 85% of those individuals infected with HCV develop persistent infection marked by the ongoing presence of HCV RNA in serum for more than 6 months after the onset, although the rate of chronicity appears to be lower among younger individuals.

The clinical features of acute and chronic hepatitis C are not specific for this form of hepatitis. Many patients with either acute or chronic hepatitis C are asymptomatic. Acute hepatitis C may sometimes result in jaundice, nausea, vomiting and general malaise.

Individuals who are currently infected with HCV have HCV RNA detectable in their serum. The levels of HCV RNA typically found with human infection are not easily detected using standard hybridization assays and require amplification of either the target (by PCR) or signal. As few as 50 copies of viral RNA per ml of serum can be detected with some modern assays.

The diagnosis of hepatitis C is relatively simple and is based on detection of anti-HCV through enzyme-linked immunoassays (EIA) that are both sensitive http://www.ncbi.nlm.nih.gov/pubmed/25053704 and specific. The EIA now in use represents a third generation of this assay and consists of recombinant viral protein cores, NS3 and NSS regions of the viral genome in a solid phase assay. The presence of anti-HCV appearance of anti-HCV may be delayed a few weeks after HCV RNA following acute infection.

A liver biopsy would show features of acute rather than chronic hepatitis but is not routinely recommended. The diagnosis of acute hepatitis C cannot be made with certainty unless the patient was known to be HCV negative previously and then developed HCV RNA in serum with or without clinical features of acute hepatitis.

HCV is transmitted by parenteral contact with blood or blood products. Recognized routes of infection include transfusion of blood or blood products, injection drug use, needlestick or other forms of contaminated injury among healthcare workers, maternal-infant transmission and sexual spread. In most developed countries post-transfusion HCV has been virtually eliminated by screening of donated blood, but chronic infection remains prevalent as demonstrated in studies of volunteer blood donors.

HCV is thought to be a non-cytopathic virus and liver damage is probably immune mediated. The large majority of infected individuals exposed to HCV become chronically infected although the mechanisms underlying this high rate of chronicity are not known. Neutralizing antibodies to HCV can be detected in serum and T-helper (CD4) lymphocytes responsive to both structural and non-structural HCV proteins can often be detected in patients with chronic HCV infection.

Cytotoxic T lymphocytes (CTLs) are thought to be particularly important in viral pathogenesis as they recognize viral antigens on cell surfaces in conjunction with major histocompatibility complex (MHC) class I proteins and lyse infected target cells.

Progression of liver disease due to HCV is marked by prog-ressive increases in hepatic fibrosis associated with activation of hepatic stellate cells, presumably through cytokine mediators produced as part of the immune response to HCV.