Evolution of Hepatitis B and C serum markers: a still challenging issue

The HBsAg and anti-hepatitis C virus (HCV) are respectively the hallmarks of hepatitis B virus (HBV) and HCV infections because they are the best and most reliable diagnostic markers. However, because most studies do not rely on longitudinal observations but mostly on crosssectional studies, little is known on time changes in these markers and their incidence. HBV chronic infection is characterized by the persistence of HBsAg in the plasma over a time interval of 6 months. Although HBsAg is detectable for several decades, the viral load decreases over the years, which coincides with the disappearance of HBeAg, followed by a transient increase in serum aminotransferases levels and seroconversion to anti-HBe. The evolution of the serological markers has been characterized by four phases depending on the activity of virus replication and specific immune response: immune tolerance, immune clearance, low or nonreplicative phase and reactivation phase (1, 2). Chronic infection is a consequence of the inability of the immune system to control HBV infection and its propensity depends on age at which infection occurs and the route of transmission. In neonates infected perinatally, the progression to chronic infection is as high as 90%; however, the frequency in adults is o 10% and drops to 20–30% in children (3). Moreover, antibody to hepatitis B core antigen (anti-HBc) is found in individuals who have experienced natural infection with HBV, and its presence in the absence of HBsAg is usually interpretable as evidence of past HBV infection. In a number of studies, attention has been drawn to a subgroup of patients with anti-HBc antibodies as the only serological marker of hepatitis B infection (anti-HBc alone) (4). In areas of low HBV endemicity (e.g. Western Europe, USA), the ‘anti-HBc alone’ profile is found in 10–20% of all individuals with HBV markers (5, 6). Anti-HCV tests detect the presence of antibodies to hepatitis C, indicating exposure to HCV. However, this test cannot distinguish between active or previous and cleared past HCV infection. Anti-HCV antibodies can be detected in 80% of patients within 15 weeks after exposure, in 4 90% within 5 months after exposure and in 4 97% by 6 months after exposure. Overall, HCV antibody tests have a strong positive predictive value for exposure to HCV, but they can miss either patients recently infected who have not yet developed antibodies, or those who do not elicit sufficient antibody levels to become detectable. The occurrence of seroconversion and serum clearance of HBsAg and anti-HCV is important not only for disease control and prognosis but also to appreciate the impact of such infections in the aetiology of cirrhosis and most importantly hepatocellularcarcinoma (HCC) because they are usually the only markers taken into account. Seroconversion and seroclearance of HBsAg and anti-HCV are also very difficult to evaluate because they require longitudinal studies in endemic areas to reach a sufficient power. Until now, these phenomena have only been evaluated in very few hospital-based studies (7–9). If HBsAg detection means ongoing HBV infection, its disappearance may have two quite different meanings, either true clearance of the virus or just its decline to lowgrade persisting occult HBV infection. Through a large number of studies, it has indeed become evident that HBV may persist in the form of serologically silent infections, leading to the concept of seronegative occult infection. Such infection may significantly contribute to the population burden of HBV-related diseases and represents a major hurdle for transfusional medicine and transplantation. In a recent expert guideline, occult HBV infection has been defined as the presence of HBV DNA in the liver, in the absence of HBsAg and with low titre or even absence of HBV DNA in serum (10). Occult HBV infections are spread worldwide, and are not necessarily associated to mutations in the ‘a’ determinant of the HBsAg. Rather, they may represent an ultimate form of natural persistent infection and there is strong evidence supporting that occult HBV infection may lead to the development of cirrhosis and eventually HCC (11, 12). Antibody to hepatitis B core antigen alone may either follow serum clearance of HBsAg or seroreversion by loss of anti-HBs. Although the majority of these ‘anti-HBc alone’ individuals seem to be healthy, some are not and most of them may harbour HBV DNA, which could be detected by polymerase chain reaction. Previous reports have shown that a high proportion of ‘anti-HBc alone’ patients had co-existing infection with human immunodeficiency virus (HIV) (33.1%) (13) and HCV (9.3%) (14). Indeed co-infection of HBV with HIV or HCV could lead to down-regulation of HbsAg production or interference with its detection. Concerning anti-HCV detection, its appearance reflects HCV infection with or without recovery and its disappearance may either suggest complete HCV recovery or even occult HCV infection as suggested by several recent studies (15, 16). The past 8 years witnessed the