Entecavir is the drug of choice as first line treatment for naïve HBV patients. Thanks to the high genetic barrier to resistance, treatment failure remains rare, but occurs within 3 years of initiation, suggesting that viral genetic characteristics may provide a fast lane to resistance. One of the main concerns is the long time to viral suppression observed in some (even naïve) patients. The reasons for this phenomenon were investigated in a group of chronic hepatitis B naive patients.
Out of 23 naïve patients starting treatment, the 5 with the best and those with the worst viral load decay curves were selected for the study. Quasispecies analysis was performed for the RT/HBsAg ORF by Ultra-Deep PyroSequencing. For each patient, the analysis was performed at baseline (T0) and when viremia reached between1000 and 200 IU/ml (T1).
The few resistance mutations present at T0 were not selected by treatment: no other resistance mutations nor suggestive mutational patterns were selected at T1. Selective pressure analysis indicated that both at T0 and T1 the HBsAg ORF was subjected to a significantly higher pressure in rapid responders, especially in a region rich in CTL epitopes.
The results did not provide evidence that a slower response to entecavir is due to the emergence of less sensitive variants. Rather, the lower selective pressure and variability in humoral and CTL epitopes in slow responders suggests that their immune response might be at odds in rapidly clearing infected cells from the liver.