At present, only interferon-based therapies are licensed for chronic HDV hepatitis treatment, but these approaches achieve the objective of curing the infection (namely, HDV clearance) in only a very few cases (5). Chronic hepatitis D is thus considered a nearly incurable liver disease. Moreover, since HDV does not produce selleck inhibitor its own enzymatic proteins (21, 30), there is no room for typical antiviral therapeutic approaches based on the use of specific inhibitors of viral enzymes (20). Natural recovery from HDV infection is a rare event, usually occurring only in the event of HBsAg seroclearance (21, 35), thus confirming that studying the mechanisms of HBV and HDV interplay may have great importance not only from the virological point of view but also in identifying new methods for the cure of HDV-related diseases.

Very few data are currently available on intrahepatic HBV and HDV molecular status for coinfected patients (2, 12), and most of the existing evidence derives from experiments with animal models (1, 8, 15, 29). In this study, we applied sensitive molecular assays to evaluate serologic and intrahepatic quantitative profiles of HBV and HDV in chronic infections. In accordance with previous studies (9, 10, 23, 40), our results seem to confirm that HDV exerts a dominant role over HBV, as indicated by its higher levels of replication and by the lower levels of serum and intrahepatic HBV DNA, cccDNA, and HBV transcripts detected in the majority of coinfected patients than those in HBV-monoinfected individuals.

However, in agreement with previously reported data, we found that serum HBsAg levels were comparable between HDV-positive and HDV-negative patients (8) and that amounts of pre-S/S RNAs and HBsAg produced per cccDNA molecule were higher in HDV-positive patients. Considering that HDV depends on HBV only to acquire HBsAg and that HDV nucleoproteins may be considered competitors of replicating HBV genomes (21, 35), our findings support the hypothesis that HDV might be able to induce an opposing effect on HBV replication and on HBV transcription (3, 13). In fact, our results showing a significantly smaller proportion of pgRNA among HBV transcripts imply that the reduction of virion production might be due mainly to a selective suppression of pgRNA transcription, thus suggesting a kind of dissociation between pgRNA and pre-S/S RNA production in cases of HDV coinfection.

This hypothesis is biologically plausible, since the transcription of pgRNA and that of pre-S/S RNAs Batimastat are under the control of two different HBV genomic regulatory regions (14, 26). However, the molecular mechanisms possibly implicated in the discrepancy between pgRNA and pre-S/S RNA steady-state levels are unknown, and one cannot exclude that the discrepancy might be dependent on differences in transcript stabilities.