Author/Editor		Colagrossi, Luna; Hermans, Lucas Etienne; Salpini, Romina; Di Carlo, Domenico; Diepstraten Pas, Suzan; Alvarez, Marta; Ben Ari, Ziv; Boland, Greet; Lunar, Maja M.; Poljak, Mario
Title		Immune-escape mutations and stop- codons in HBsAg develop in a large proportion of patients with chronic HBV infection exposed to anti-HBV drugs in Europe
Type		članek
Vol. and No.		Letnik 18, št. 1
Publication year		2018
Volume		str. 1-12
ISSN		1471-2334 - BMC infectious diseases
Language		eng
Abstract		Background: HBsAg immune-escape mutations can favor HBV-transmission also in vaccinated individuals, promote immunosuppression-driven HBV-reactivation, and increase fitness of drug-resistant strains. Stop-codons can enhance HBV oncogenic-properties. Furthermore, as a consequ ence of the overlapping structure of HBV genome, some immune-escape mutations or stop-codons in HBsAg can deriv e from drug-resistance mutations in RT. This study is aimed at gaining insight in prevalence and characteristics of immu ne-associated escape mutation s, and stop-codons in HBsAg in chronically HBV-infected pati ents experiencing nucleos(t) ide analogues (NA) in Europe. Methods: This study analyzed 828 chronically HBV-infected European patients exposed to >- 1 NA, with detectable HBV- DNA and with an available HBsAg-sequence. The immune-associated escape mutations and the NA-induced immune-esc ape mutations sI195M, sI196S, and sE164D (resulting from drug-resistance mutati on rtM204 V, rtM204I, and rtV173L) were re trieved from literature and examined. Mutations were defined as an aminoacid substitution w ith respect to a genotype A or D reference sequence. Results: At least one immune-associated escape mutation was dete cted in 22.1% of patients with rising temporal-trend. By multivariable-analysis, genotype-D correlated with higher selection of >- 1 immune-associated escape mutation (OR[95%CI]:2.20[1.32 % 3.67], P = 0.002). In genotype-D, the presence of >- 1 immune-associated escape mutations was significantly higher in drug-exposed patients with drug-resistant strains than with wild-type virus (29.5% vs 20.3% P = 0.012). Result confirmed by analys ing drug-naïve patients (29.5% vs 21. 2%, P = 0.032). Strong correlation was observed between sP120T and rtM204I/V ( P < 0.001), and their co- presence determined an increased HBV-DNA. At least one NA-induced immune-escape mutation occurred in 28.6% of patients, and their selection correlated with genotype-A (OR[95%CI]:2.03[1.32 - 3.10], P = 0.001). Finally, stop-codons are present in 8.4% of patients also at HBsAg-positions 172 and 182, described to enhance viral oncogenic-properties. Conclusions: Immune-escape mutations and stop-codons develop in a large fraction of NA-exposed patients from Europe. This may represent a potential threat for horizontal and vertical HBV transmission also to vaccinated persons, and fuel drug-resistance emergence.
Keywords		HBV drug resistance treatment effectiveness HBV odpornost na zdravila učinkovitost zdravljenja