The profile of mutational clusters associated with lamivudine resistance can be constrained by HBV genotypes.
OBJECTIVE
To investigate the different clusters of mutations associated with lamivudine resistance in HBV genotypes D and A.


METHODS
HBV reverse transcriptase sequences of 89 HBV-infected patients failing lamivudine treatment were analyzed. The association of mutations with HBV genotypes was assessed by Chi-Squared test and multivariate logistic regression analysis. Covariate analysis was based on hierarchical clustering.


RESULTS
In genotype A, the rtM204V (prevalence: 68.2%) was the main sign of lamivudine failure. Multivariate analysis confirmed that genotype A is the only predictor for rtM204V emergence (OR: 14.5 [95% CI: 1.3-158], P=0.02). Covariate analysis showed that rtM204V clusters with rtL180M, rtL229V (corresponding to sF220L in the HBsAg), and, interestingly, with HBsAg mutation sS207N (bootstrap=0.95). Both sF220L and sS207N co-localized in the fourth transmembrane HBsAg domain. In contrast, in genotype D the primary mutations rtM204V and rtM204I occurred with similar prevalence (39.1% versus 45.3%, P=0.47), and showed a distinct pattern of compensatory mutations. rtM204V clusters with mutations localized in the RT-B domain (rtV173L, rtL180M, and rtT184A/S) (bootstrap=0.94), while rtM204I clusters with mutations localized in the RT-A domain (rtS53N, rtT54Y, and rtL80I/V) (bootstrap=0.96) (without associations with HBsAg specific mutations).


CONCLUSIONS
HBV genotype plays an important role in driving RT evolution under lamivudine treatment, and thus can be relevant for therapeutic sequencing, immunological response and disease progression.
Svicher
Valentina
V
Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy.
Gori
Caterina
C
Trignetti
Maria
M
Visca
Michela
M
Micheli
Valeria
V
Bernassola
Martina
M
Salpini
Romina
R
Gubertini
Guido
G
Longo
Roberta
R
Niero
Fosca
F
Ceccherini-Silberstein
Francesca
F
De Sanctis
Giuseppe Maria
GM
Spanò
Alberto
A
Cappiello
Giuseppina
G
Perno
Carlo Federico
CF
D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000627:therapeutic use; D001219:Aspartate Aminotransferases / Q000097:blood; D016000:Cluster Analysis; D017931:DNA Primers; D004279:DNA, Viral / Q000235:genetics / Q000302:isolation & purification; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D005838:Genotype; D015658:HIV Infections / Q000150:complications; D006515:Hepatitis B virus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use*; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012194:RNA-Directed DNA Polymerase / Q000235:genetics
D000998:Antiviral Agents; D017931:DNA Primers; D004279:DNA, Viral; D019259:Lamivudine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D012194:RNA-Directed DNA Polymerase