Περίληψη:
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 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. 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-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. Results: At 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. 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. © 2018 The Author(s).
Συγγραφείς:
Colagrossi, L.
Hermans, L.E.
Salpini, R.
Di Carlo, D.
Pas, S.D.
Alvarez, M.
Ben-Ari, Z.
Boland, G.
Bruzzone, B.
Coppola, N.
Seguin-Devaux, C.
Dyda, T.
Garcia, F.
Kaiser, R.
Köse, S.
Krarup, H.
Lazarevic, I.
Lunar, M.M.
Maylin, S.
Micheli, V.
Mor, O.
Paraschiv, S.
Paraskevis, D.
Poljak, M.
Puchhammer-Stöckl, E.
Simon, F.
Stanojevic, M.
Stene-Johansen, K.
Tihic, N.
Trimoulet, P.
Verheyen, J.
Vince, A.
Lepej, S.Z.
Weis, N.
Yalcinkaya, T.
Boucher, C.A.B.
Wensing, A.M.J.
Perno, C.F.
Svicher, V.
HEPVIR working group of the European Society for translational antiviral research (ESAR)
Λέξεις-κλειδιά:
adefovir dipivoxil; antivirus agent; entecavir; hepatitis B surface antigen; lamivudine; telbivudine; tenofovir; virus DNA; antivirus agent; hepatitis B surface antigen, adult; amino acid sequence; amino acid substitution; antiviral resistance; Article; controlled study; disease severity; drug exposure; Europe; female; gene sequence; genetic correlation; genotype; hepatitis B; human; immune escape mutation; immune response; major clinical study; male; mutation; mutational analysis; nonhuman; prevalence; stop codon; trend study; unindexed sequence; virus detection; virus strain; chronic hepatitis B; clinical trial; genetics; Hepatitis B virus; immunology; middle aged; multicenter study; virology, Adult; Amino Acid Substitution; Antiviral Agents; Codon, Terminator; Europe; Female; Genotype; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Middle Aged; Mutation
