The diagnosis of HCV infection is based on screening individuals with known or suspected exposure. Guidelines for HCV diagnosis, management, and treatment have been recently endorsed by the American Association for the Study of Liver Diseases, the Infectious Diseases Society of America, and the American College of Gastroenterology.12 More recently, the Centers for Disease Control and Prevention issued recommendations urging patients at risk for HCV, based on previously discussed behaviors or exposure, or patients born between 1945 and 1965 (“birth cohort” screening), to undergo laboratory testing using qualitative serologic assays that determine the presence of antibody to HCV (anti- HCV).12,13 The anti-HCV tests have high sensitivity and a specificity greater than 99%. Tests are also available for quantification of HCV in serum plasma. These tests provide a value for the levels of HCV RNA in blood or serum in the form of a viral load, and these tests also have high sensitivity and specificity (in the range of 98% to 99%). A detailed review of these tests is available elsewhere.12 Typically, the anti-HCV test should be performed first, with HCV RNA testing performed when the anti-HCV test is positive, when antiviral treatment is being considered, or in patients with a negative anti-HCV test if the clinician suspects that the patient may be immunocompromised or that the patient may have HCV infection despite a negative anti-HCV test result. When the anti-HCV and HCV RNA tests are negative, this is interpreted as absence of HCV infection. If the anti-HCV test is positive and the HCV RNA test is positive, it may be suggestive of acute or chronic HCV, depending on the clinical context. A positive anti-HCV with a negative HCV RNA constitutes resolution of HCV or acute HCV during a period of low-level viremia. A negative anti-HCV test with a positive HCV RNA test indicates early acute infection, chronic infection in an immunocompromised host, or a false positive HCV RNA test.12 False positive anti-HCV tests may occur when testing is done in a population where the prevalence of HCV is extremely low. All tested patients should be counseled on avoidance of HCV transmission.12

When interferon-based treatment is being considered, HCV genotyping should be performed prior to treatment to plan the dose and duration of therapy and to estimate the likelihood of response.12 A liver biopsy can also be considered in patients with chronic HCV infection in order to obtain more information about fibrosis stage to help determine prognosis or inform treatment decisions. Noninvasive tests have also been developed to evaluate fibrosis, but those require further validation studies before they may be recommended in lieu of liver biopsy.12 In addition, interleukin (IL)-28B testing can be performed (eg, to predict response to pegylated interferon and ribavirin in HCV genotype 1) in cases where the results may influence treatment decisions.13 A single-nucleotide polymorphism in chromosome 19 in the region of the IL28B gene strongly predicts response to treatment in genotype 1–infected patients treated with peginterferon and ribavirin. Individuals with a CC genotype at rs12979860 have a 2-fold increase in sustained virological response (SVR) compared with those with CT or TT genotype.14 A comprehensive workup, as outlined in a position paper from the Department of Veterans Affairs, should be conducted prior to treatment (Table 1).14

Disease Progression

Most patients are asymptomatic after initial exposure to HCV. When symptoms occur with initial viremia, they often present several weeks after the incident and are mild, nonspecific, or intermittent. Symptoms may include jaundice, fatigue, anorexia, weakness, abdominal pain, and dark urine.6 As evidenced in published literature, 50% to 85% of infected individuals progress to chronic infection and then subsequent liver disease–related complications.6,15 Chronic hepatitis leads to cirrhosis in 10% to 20% of patients, depending on the rate of fibrosis (the hallmark feature of hepatic cirrhosis).16 In a study conducted at the National Institutes of Health, untreated patients with chronic hepatitis C with 2 liver biopsies at 4 to 212 months apart (mean 44 months) were analyzed for progression of fibrosis. Liver biopsy specimens were graded using histology activity index and Ishak fibrosis score (range 0-6 [0, no fibrosis; 1-2, portal fibrotic expansion; 3-4, bridging fibrosis; 5-6, cirrhosis]). Among 123 patients, 48 (39%) showed progression of fibrosis score, 46 (37%) showed no change, and 29 (24%) showed improvement. Of those with a worsening of fibrosis, 75% had a 1-point increase in Ishak score and 25% had a 2-point increase in Ishak score. The overall rate of progression was 0.12 fibrosis units per year, suggesting progression to cirrhosis in about 50 years, if linear. However, several factors were shown to accelerate the progression of fibrosis. Fibrosis was higher in older patients, patients with extensive periportal necrosis on initial liver biopsy, and those with higher serum alanine and aspartate aminotransferase.16 High levels of alcohol consumption (4 or 5 drinks or more per day) have also been shown to increase the rate of progression of liver fibrosis
Approximately 10% to 20% of individuals who develop chronic hepatitis C will develop chronic liver disease complications, such as cirrhosis and hepatocellular carcinoma (HCC).7 In a small portion of patients, HCC may develop before cirrhosis, but more frequently, HCC develops as a result of cirrhosis.15,17 Cirrhosis often develops within 20 to 30 years, and HCC occurs in 1% to 5% of individuals with advanced fibrosis/cirrhosis.7 HCV is estimated to cause 27% of cirrhosis and 22% to 25% of HCC cases worldwide.5,7 Once cirrhosis develops, outcomes typical of advanced liver disease are expected, including ascites, variceal bleeding, hepatic encephalopathy (requiring transplantation), and death from cirrhosis. The current estimate for HCV-related mortality in the United States is 8000 to 10,000 deaths per year.5 The mortality rate for HCV is expected to peak in 2030, with an estimated mortality rate of 4300 (confidence interval [CI], 3500-5100) women and 8600 (CI, 8300-9000) men, for a total of 12,900 deaths per year.1 The presence of HCV RNA increases the risk of mortality, which is further increased as HCC, cirrhosis, and chronic liver disease develop. Mortality from HCV has surpassed mortality from HIV, although HIV increases the risk of death in coinfected individuals.18,19
In an effort to characterize the progression of HCV-related liver disease, the HALT-C (Hepatitis C Antiviral Long-term Treatment against Cirrhosis) trial was conducted. This 3.5- year randomized trial evaluated the effect of maintenance peginterferon monotherapy versus no therapy on liver disease progression among patients who had not cleared the virus on peginterferon and ribavirin therapy.20 Among 1050 subjects (60% with advanced fibrosis, 40% with cirrhosis), investigators determined the rate of progression to cirrhosis over 4 years and evaluated clinical outcomes for 8 years. As patients progressed through fibrosis to cirrhosis, changes in laboratory values suggested biochemical progression of liver dysfunction. One of the main conclusions in this study was that maintenance therapy with interferon did not impact clinical outcomes. Observable changes in laboratory values included reductions in albumin and platelets, and increases in serum creatinine, bilirubin, prothrombin time/international normalized ratio, and MELD score (a liver transplantation priority score). These factors comprised the CTP score, which was used as an overall assessment of disease severity. Patients with fibrosis or cirrhosis were compared with respect to mortality. The mortality rate was 12.2% with advanced fibrosis and 31.5% with cirrhosis.20 This study determined the incidence of cirrhosis among patients with fibrosis to be 9.9% per year.20
Journal of Hepatology Jan 2013
Improved Inflammatory Activity With Peginterferon Alfa-2b Maintenance Therapy
in Non-cirrhotic Prior Nonresponders: a Randomized Study 
Download the PDF here 
Disease progression is therefore impacted by many factors, but a recent meta-analysis demonstrated that patients who experienced SVR when treated for HCV had improvements in mortality (relative risk [RR], 0.23; 95% CI, 0.01-0.52), HCC (RR, 0.21; 95% CI, 0.16-0.27), or hepatic decompensation (RR, 0.16; 95% CI, 0.04-0.59) compared with patients who experienced treatment failure.21 The next article in this supplement will discuss the treatment of HCV.
Summary HCV is an important public health concern because it is frequently underdiagnosed and undertreated. The prevalence of HCV infection is increasing, and increased awareness of the disease and its consequences is needed among both clinicians and patients. In addition to the development of cirrhosis and consequent liver disease manifestations, the risks of mortality and cancer are increased with HCV. The first step in improving outcomes in HCV is ensuring diagnosis and treatment. Effective treatment, the focus of the next article in this supplement, is associated with reductions in mortality, HCC, and hepatic decompensation
Affiliation Author affiliation: Cedars-Sinai Medical Center, Los Angeles, CA. Funding source: This activity is supported by an educational grant from Merck & Co, Inc and Bristol-Myers Squibb. Author disclosure: Dr Tran has served as a consultant/advisory board member for Vertex Pharmaceuticals. Authorship information: Drafting of the manuscript; critical revision of the manuscript for important intellectual content; administrative, technical, or logistic support; and supervision. Address correspondence to: E-mail:

Volume 18: December 2012 
Number 14 Suppl