We read with interest the article by Lok et al. that assessed occult hepatitis B virus (HBV) infection in patients who are negative for hepatitis B surface antigen and who have advanced chronic hepatitis, from the Hepatitis Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial, who did or did not develop hepatocellular carcinoma (HCC).1 They conclude by affirming that occult HBV infection has no role in HCC development in U.S. patients with chronic hepatitis C.
After a detailed evaluation, we have several concerns regarding this conclusion. The authors themselves admit that their study has at least four main limitations. First, a limited number of patients with HCC were evaluated, and the diagnosis of cancer was simply presumed in some cases. In the HALT-C trial, the patients were randomly assigned to maintenance pegylated interferon or to no further treatment, and it would be relevant to know how the occult-positive patients were distributed according to treatment received and to definite or presumed HCC diagnosis. The second and third stated limitations concern the long storage duration and the very limited size of biopsy specimens examined: 2-3 mm of tissue obtained by percutaneous needle biopsy cannot provide reliable results. Theoretically, such a small piece of tissue may not actually be liver or could be fibrotic tissue. The fourth stated limitation concerns the lower number of HBV genomic regions tested as compared to previous studies that provided different results. It is also highly surprising that the X genomic region (the viral gene mainly involved in the direct oncogenic role of HBV) was not searched in a study evaluating the association between HBV persistence and HCC development. Moreover, there is generic information about patient origins and, consequently, about the presumable infecting genotypes. Thus, the possibility that sensitivity and specificity of both amplification primers and probes was inadequate in a number of cases cannot be ruled out.
This study confirms previously reported (and not denied) data concerning the association between occult HBV and severe chronic hepatitis C in the United States.2 Considering the very low prevalence of HBV infection in the United States, this observation is interesting,3 and it would be very important to know the prevalence of occult HBV in U.S. patients infected with hepatitis C virus, with minimal liver damage.
Altogether, we feel that there is still ample room for a role of occult HBV infection in the development of HCC in patients with chronic hepatitis, and that its categorical exclusion in the U.S. population is not sufficiently proven in the study by Lok et al.