Hepatitis B virus reverse transcriptase sequence variant database for sequence analysis and mutation discovery

Abstract

Drug resistance resulting from reverse transcriptase (RT) mutations is one of the main obstacles to successful hepatitis B virus (HBV) therapy. Indeed, HBV treatment guidelines recommend HBV genotypic resistance testing for patients receiving nucleos(t)ide RT inhibitors (N(t)RTIs) who develop virological failure. N(t)RTI-resistance mutations at 10 RT positions have been well characterized in phenotypic studies, however, data are lacking on the relative frequency of these mutations in N(t)RTI-treated and untreated individuals. There are also few published data on the extent of amino acid variation at most of the 344 positions of HBV RT and the extent to which this variation is influenced by N(t)RTI treatment. We retrieved 23,871 HBV RT sequences from GenBank and reviewed the published reports of these sequences to ascertain the number of individuals from whom the sequences were obtained, the N(t)RTI treatments of these individuals, and the year and region of virus sampling. We then used these data to populate a relational database we named HBVrtDB. As of July 2010, HBVrtDB contained 6811 sequences from 3869 individuals reported in 281 references. Among these 3869 individuals, 73% were N(t)RTI-naïve and 27% received one or more N(t)RTIs. Among the 10 well-characterized N(t)RTI-resistance mutations, L80I/V, V173L, L180M, A181T, T184S, S202G and M204I/V were significantly associated with treatment with lamivudine, an l-nucleoside analog, and A181S/T/V and N236T were significantly associated with treatment with adefovir, an acyclic nucleoside phosphonate. A similar analysis of ten additional less well-characterized resistance mutations demonstrated a significant association with N(t)RTI treatment for four of the mutations: L82M, S85A, A200V, and Q215S. We also created an interactive program, HBVseq, to enable users to identify mutations in submitted sequences and retrieve the prevalence of these mutations in HBVrtDB according to genotype and N(t)RTI treatment. HBVrtDB and HBVseq are available at http://hivdb.stanford.edu/HBV/releaseNotes/.