We read with interest the review by Welker and Zeuzem1 on occult hepatitis C virus (HCV) infection. In this review, the authors claim that viral replication has not been proven in occult HCV infection. However, the presence of the antigenomic HCV RNA strand has been demonstrated in liver and in peripheral blood mononuclear cells (PBMCs) of patients with occult HCV who are negative for anti-HCV and serum HCV RNA2 (and references in Carreño et al.2). There is no doubt that detection of the antigenomic strand is an indicator of viral replication as recognized by Welker and Zeuzem in their review.1 Furthermore, ultracentrifugation of serum samples before performance of real-time reverse transcription polymerase chain reaction (RT-PCR) detects very low levels of viremia in patients with occult HCV infection, and the density of the circulating HCV particles was identical to those found in the serum of patients with chronic hepatitis C.2 In addition, family members of patients with occult HCV infection show serological markers of HCV infection even more frequently than those of patients with chronic hepatitis C.3 Other authors have reported that low-level persisting HCV remains infectious.4 Finally, HCV-specific CD4+ T cell proliferative responses to nonstructural 3 and/or 4 proteins have been detected among patients infected with occult HCV,2 which may not have occurred unless there was ongoing HCV replication, either within the liver or in immune-privileged sites. So, taking all these data into account, one may convincingly assume that HCV replication takes place in patients with occult HCV infection who no doubt are potentially infectious.
However, Welker and Zeuzem1 review two studies that unconvincingly failed to detect occult HCV infection in cryptogenic hepatitis,5, 6 because of several concerns with the methodology employed. Thus, one study5 used whole blood to assess occult HCV infection, but it was demonstrated in patients with occult hepatitis C that the sensitivity of HCV RNA detection substantially decreased when using whole blood instead of PBMCs.2 Another study6 included a very small and heterogeneous population, and these authors did not perform detection of HCV RNA either in liver or in serum by PCR after ultracentrifugation. Thus, their results do not exclude the existence of occult HCV infection. On the other hand, an anti-HCV core antibody assay has been developed recently, which adds another diagnostic tool because it has been proposed as a potential new marker of the serologically silent form of occult HCV infection.7
In contrast, other studies have confirmed the existence of occult HCV infection by detection of HCV RNA in liver.8, 9 Furthermore, contrary to what is concluded by Welker and Zeuzem, HCV proteins have been detected in liver10 and in lymph nodes11 of patients who are negative for anti-HCV and serum HCV RNA.
In summary, considering the data available, there is cumulative evidence strongly supporting the idea that HCV replication takes place in patients with occult HCV infection. Therefore, in order to diagnose occult HCV infection among these patients, it is mandatory to perform appropriate molecular and immunoserological tests in serum, PBMCs, and liver biopsies.