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

Abstract

BackgroundHBsAg 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 consequence of the overlapping structure of HBV genome, some immune-escape mutations or stop-codons in HBsAg can derive from drug-resistance mutations in RT. This study is aimed at gaining insight in prevalence and characteristics of immune-associated escape mutations, and stop-codons in HBsAg in chronically HBV-infected patients experiencing nucleos(t)ide analogues (NA) in Europe.MethodsThis 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-escape mutations sI195M, sI196S, and sE164D (resulting from drug-resistance mutation rtM204 V, rtM204I, and rtV173L) were retrieved from literature and examined. Mutations were defined as an aminoacid substitution with respect to a genotype A or D reference sequence.ResultsAt least one immune-associated escape mutation was detected 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 analysing 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.ConclusionsImmune-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.Electronic supplementary materialThe online version of this article (10.1186/s12879-018-3161-2) contains supplementary material, which is available to authorized users.

Hepatitis B virus genotyping, detection of reverse transcriptase resistance and immune escape mutations in persons with chronic hepatitis B from Croatia

“…29 In addition, the high frequency of drug resistance mutations in genotype A patients observed by Colagrossi et al (2018) corresponds to our findings as well. 29 Distribution of HBV genotypes A (27.3%) and D (61.3%) observed in that study is, to some extent, similar to our findings as well. 29 Similarly to our results, immune escape mutations were more frequently detected in genotype D-infected individuals.…”

“…29 Distribution of HBV genotypes A (27.3%) and D (61.3%) observed in that study is, to some extent, similar to our findings as well. 29 Similarly to our results, immune escape mutations were more frequently detected in genotype D-infected individuals. 29 Literature data on HBV immune escape mutation frequency in the region are currently not available.…”

“…28 Colagrossi et al (2018) conducted a study that included 935 chronic hepatitis B patients from 15 European countries, including Croatia, to investigate immune escape mutations, but due to overlapping of the reverse transcriptase and the S gene region, there are data on drug resistance mutations as well. 29 Drug resistance mutation rtM204V/I that was detected by Colagrossi et al (2018), has also been detected in our study. 29 In addition, the high frequency of drug resistance mutations in genotype A patients observed by Colagrossi et al (2018) corresponds to our findings as well.…”

“…29 Drug resistance mutation rtM204V/I that was detected by Colagrossi et al (2018), has also been detected in our study. 29 In addition, the high frequency of drug resistance mutations in genotype A patients observed by Colagrossi et al (2018) corresponds to our findings as well. 29 Distribution of HBV genotypes A (27.3%) and D (61.3%) observed in that study is, to some extent, similar to our findings as well.…”

Global prevalence and phylogeny of hepatitis B virus (HBV) drug and vaccine resistance mutations

“…G145A/R is the best described mutation associated with resistance to HBV vaccine/HBIg (11)(12)(13). Several other mutations across the entire antigenic determinant have been reported, which also have associations with vaccine resistance (11,(14)(15)(16).…”