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.
Highlights
HBV surface antigen (HBsAg) immune-escape mutations can favor hepatitis B virus (HBV)-transmission in vaccinated individuals, promote immunosuppression-driven HBV-reactivation, and increase fitness of drug-resistant strains
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)
At least one nucleos(t)ide analogues (NAs)-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)
Summary
HBsAg immune-escape mutations can favor HBV-transmission in vaccinated individuals, promote immunosuppression-driven HBV-reactivation, and increase fitness of drug-resistant strains. HBV is a highly evolving pathogen characterized by a high degree of genetic-variability (a unique property among DNA viruses) that is driven by the lack of proof-reading function of HBV reverse transcriptase (RT) and exacerbated by the high speed of the HBV replication cycle [2] This high degree of HBV genetic-variability allows the virus to react to endogenous (i.e. immune system), and exogenous (i.e. vaccination, hepatitis B immunoglobulin, antiviral drugs) selective pressures by further modulating its genome structure. Around 30 immune-escape mutations in HBsAg (hereafter defined as immune-associated escape mutations), have been identified [3,4,5] to evade neutralizing-antibodies, to allow persistent HBV-infection and to promote viral fitness [2, 6] These mutations can have relevant pathobiological implications at the time of immunosuppression-driven HBV-reactivation, favoring the reuptake of viral replication during the initial weakening of immune responses [6,7,8,9]. Immune-associated escape mutations can decrease/abrogate HBsAg-binding to antibodies used in diagnostic assays for HBsAg-detection and -quantification [6, 10, 11], and determine a false-negativity or an underestimation of HBsAg levels, that can pose an issue for a proper diagnosis and staging of chronic HBV-infection
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