Background: Most persons who acquire hepatitis C virus (HCV) will develop chronic infection. Following acute infection, HCV is very successful in establishing persistent infection by evading the immune system. Although the mechanism for the high rate of viral persistence is not completely understood, several viral and host factors likely play a significant role. The rate of viral production is high, 1010 to 1012 virions per day, and the lack of proofreading by the viral polymerase leads to enormous genetic diversity, which in turn creates a major challenge for the host immune response. This broad genetic diversity contributes to the high likelihood of developing chronic infection. Host factors are also involved in the ability to spontaneously clear the virus.
Role of Immune Response in Clearance versus Chronic Infection: Several studies indicate that clearance of HCV is associated with strong and persistent HCV-specific cytotoxic T-lymphocyte and CD4 lymphocyte responses. In addition, persons who clear HCV generally have limited viral diversity, which also points to enhanced immune-mediated response to acute infection.
Rate of Chronicity: The actual rate of chronicity following initial infection with HCV is not well established in prospective studies. Indeed, there has not been a prospective study of unselected patients to answer this question. The chronicity rate has been estimated from cross sectional population-based studies, such as the National Health and Nutrition Examination Survey (NHANES), and numerous retrospective studies. The best estimate is that 75% to 85% of persons infected with HCV will develop chronic infection.
Host Factors Associated with Viral Clearance: The reason HCV infection persists in most patients but resolves spontaneously in others is not well understood. The following characteristics have been associated with a lower rate of chronicity.
- Younger Age. The chronicity rate of HCV is lower in younger patients. In the NHANES study, the chronicity rate was 30% in subjects below the age of 20 and 76% in those older than 20 years. In one study of 67 children infected with HCV through contaminated blood transfusions, only 55% developed chronic infection.
- Female Gender. In 2 large retrospective analyses involving more than 1600 women who received contaminated Rh immune globulin, the chronicity rate was only 55%, a rate significantly lower than the 75 to 85% typically reported. In contrast, cross sectional studies have not reported gender differences.
- Nonblack Race. The chronicity rate in African Americans in the NHANES study was 86% overall and 98% for African American men. In a prospective cohort study involving 1667 injection-drug users, African Americans were more likely to develop chronic infection than other races (91% versus 64%).
- Symptomatic Acute Infection. In small studies of acute infection and larger follow-up studies of the women infected with hepatitis C virus through contaminated Rh immune globulin, only 45 to 50% of people who developed jaundice become chronically infected. It is believed that severe acute infection reflects a more vigorous immune response that results in higher clearance of HCV and thus a lower rate of chronicity.
- Normal Immune Status. In a prospective study of injection drug users, HIV-infected individuals were more likely to develop chronic infection than those who did not have HIV (Odds ratio 2.19). In another study of acute infection, HCV persisted in 95% of those coinfected with HIV. In these patients, HIV coinfection was associated with a lack of critical CD4 T cell responses.
- IL28B CC Genotype. The single nucleotide polymorphism (SNP) rs12979860 is located upstream from the IL28B gene and this gene encodes for interleukin 28 (which is also referred to as interferon lambda). Variations in the rs12979860 SNP have been associated with probability of clearance of hepatitis C. Individuals with the CC allele of IL28B genotype are more likely to spontaneously clear HCV than those with CT or TT. In one report involving 1,008 individuals, those with CC genotype cleared the virus 53% of the time compared with a clearance rate of 23% for those with the TT genotype (Figure 1).