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Background The high degree of diversity of the hepatitis B virus (HBV) quasispecies in chronically infected individuals raises the possibility that HBV genetic variants favouring resistance to nucleoside/nucleotide analogues (NAs) might pre-exist to treatment. The aim of this study was to investigate the genetic variability of the entire HBV reverse transcriptase (RT) domain and of the overlapping S gene in a large series of untreated hepatitis B surface antigen carriers and in lamivudine (3TC)-resistant patients.Methods Sequencing analysis of the entire HBV RT domain of isolates from 100 untreated (treatment- naive group) and 59 3TC-resistant (3TC-resistant group) consecutive patients with chronic hepatitis B was performed.Results In the treatment-naive group, primary mutations known to cause resistance to NAs were not detected, but variably combined secondary/compensatory mutations were found in 46 (46%) patients. Moreover, four patients carried mutations that modified the S protein antigenicity. In the 3TC-resistant group, besides the primary 3TC-resistant mutations, various combinations of primary and secondary mutations conferring resistance to other NAs were detected in 41/59 (69.5%) patients. Importantly, the RT mutations induced by 3TC provoked stop codons in the overlapping S gene in two patients and modified the S protein antigenicity in another nine.Conclusions This study shows that HBV mutants associated with resistance to NAs might already be present as the major infecting population in untreated patients, and that variants emerging under 3TC might also carry mutations favouring resistance to other NAs and/or potentially altering the S protein immunoreactivity.

Background Despite the availability of several direct-acting antivirals (DAAs) specifically inhibiting different HCV proteins, treatment of chronic HCV infection is still a challenge also because of the possible selection of resistant viral variants under DAA therapy. Indeed, only the emergence of viruses resistant to the nucleoside inhibitors of the HCV NS5B polymerase (Pol) has not yet been reported, in spite of the fact that in vitrostudies have clearly shown that an S282T amino acid change in the Pol protein may confer resistance to these drugs. On the basis of a previous study showing that viral variants resistant to HCV protease inhibitors are largely present in the liver – but not in the serum – of untreated patients, we investigated the possible natural occurrence of viral populations with the S282T change in the Pol protein, analysing viral isolates from liver and serum of HCV genotype-1b treatment-naive patients.Methods HCV-1b isolates from liver specimens and serum samples of 10 chronic hepatitis C patients were analysed by cloning and sequencing.Results The S282T mutation was not found in any of the viral isolates from either liver or serum samples of all the cases, although an S282G mutation of unknown virological/clinical relevance was detected in 2/19 liver isolates from one patient.Conclusions Our study confirms that the natural selection of the S282T mutation is a rare event, thus explaining the lack of emergence and takeover of these variants under drug pressure.