Lamivudine resistant occult HBV: implications for public health?

Abstract

Few serological assays have played a more crucial role in public health than the hepatitis B surface antigen (HBsAg) test. It became the primary assay for the diagnosis of current and chronic hepatitis B virus (HBV) infection and its suitability for mass screening markedly improved the safety of blood stocks in the transfusion service. Loss of HBsAg and the appearance of its corresponding antibody, anti-HBs, are characteristic of resolution of HBV infection. Along with hepatitis B e antigen seroconversion and the development of antibody to the HBV core protein (anti-HBc), this is indicative of elimination of virus and is supported by clinical, histological and biochemical improvement. However, as described in several case reports, a small proportion of patients show clinical evidence of ongoing HBV infection despite developing such serological profiles (see reviews by Brechot and colleagues [1] and Hu [2]). This apparent paradox has been largely resolved by advances in nucleic acid testing, in particular polymerase chain reaction, which has shown that HBV DNA can be detected after apparent recovery from acute hepatitis and even in some patients with no serological markers of HBV exposure [1–3]. The terminology of occult HBV infection has been applied to patients with detectable HBV DNA and undetectable HBsAg. This definition does have deficiencies in that several HBV DNA detection technologies are available with different levels of sensitivity. Additionally, while samples may have undetectable HBsAg, this may also be a reflection of the specificity and sensitivity of a particular assay. Moreover, the definition of occult HBV infection does not take into consideration the presence or absence of other HBV markers such as anti-HBc and antiHBs which may be useful in further defining this clinical entity [3]. Several mechanisms have been proposed to explain the persistence of HBV DNA and lack of detectable HBsAg which occurs with occult infection. Perhaps a clue lies in the one characteristic which seems to be consistently found in many of the studies on occult infection, namely a low level of viral replication, generally ,10 copies/ml [1]. Is this due to some property of the infecting virus, the host response or a combination of both? Perhaps deficiencies in the host immune response allow a modest level of virus replication, or conversely, a strong and enduring cellular response may require the persistence of limited amounts of virus. In a 30 year follow-up of an outbreak of hepatitis in Southern Sweden, HBV DNA was detected in the liver but not the serum of two patients with serologically verified acute self-limited hepatitis [4]. Furthermore, using the woodchuck hepatitis virus (WHV) as an animal model for HBV, it has been shown that after recovery from acute WHV infection, a lifelong occult infection persisted with low level replication in liver and lymphoid tissue [5]. Investigators have looked for virus mutations in the surface gene which may cause alterations in HBsAg antigenicity and thus, impair its serological detection or its ability to be neutralized by anti-HBs [6]. However, these mutations appear to be uncommon and in the majority of cases of occult infection there are no instances of sequence changes to the important HBsAg epitopes. Besides mutations directly affecting these epitopes, mutations affecting the HBV regulatory elements may also be a possible cause of down regulation of replication. Again, while there are reports of such mutations and even some functional studies to demonstrate reduced replication [7,8], it is likely that these are also rare. Finally, there is mounting evidence of occult HBV infection and a low level of viral replication associated with HCV co-infection. HBV/HCV co-infection is common; the viruses can share the same route of transmission and there are geographical regions where both viruses are endemic. Several groups have reported apparent virus interference between HBV and HCV which may result in a lower level of HBV replication [9,10]. The molecular basis for this inhibition is not known. However, Shih et al. [11] showed a reduced expression of HBV transcripts by HCV core Journal of Hepatology 38 (2003) 526–528