Hepatitis B Virus Genotype Distribution and Genotype-Specific BCP/preCore Substitutions in Acute and Chronic Infections in Argentina

Abstract

AimIn order to assess Hepatitis B Virus genotype (g) and subgenotype (sg) implications in the course of infection, 234 HBsAg positive patients in different infection stages were characterized (66 acute infections, 63 HBeAg positive chronic infections and 105 anti-HBe positive chronic infections).ResultsOverall, sgA2 (17.9%), gD (20.9%), sgF1b (34.2%) and sgF4 (19.7%) were the most prevalent. Subgenotype F1b was overrepresented in acute and chronic HBeAg infections (56.1%), whereas gD was the most frequent (40.0%) in anti-HBe positive chronic infections. Among chronic infections, HBeAg positivity rates were 50.0, 12.5, 62.8 and 35.3% for sgA2, gD, sgF1b and sgF4, respectively (p <0.05). A bias toward BCP/preCore mutations was observed among genotypes. In anti-HBe positive chronic infections, sgF1b was more prone to have A1762T/G1764A mutation than sgA2, sgF4 and gD (75.0, 40.0, 33.3 and 31.8%, p<0.005), whereas in the pC region, gD and sgF4 were more likely to have G1896A than sgA2 and sgF1b (81.0, 72.7, 0.0 and 31.3%, p <0.001). The unexpected low frequency of the G1896A mutation in the sgF1b (despite carrying 1858T) prompted us to perform a further analysis in order to identify genotype-specific features that could justify the pattern mutations observed. A region encompassing nucleotides 1720 to 1920 showed the higher dissimilarity between sgF1b and sgF4. Genotypes and subgenotypes carrying the 1727G, 1740C and 1773T polymorphisms were prevented to mutate position 1896.DiscussionHBeAg seroconversion is a critical event in the natural history of HBV infection. Differences in the HBeAg positivity rate might be relevant since different studies have observed that delayed HBeAg seroconversion is associated with a more severe clinical course of infection, highlighting the critical role that genotypes/subgenotypes might play in the progression of HBV infection. Polymorphisms in the regions 1720 to 1920 could be involved in the molecular mechanisms underlying seroconversion of each genotype/subgenotype.

Molecular epidemiology of hepatitis B virus in Misiones, Argentina

“…The time-scaled MCCT showed that the three sequences would have a common ancestor dated only four years before the sampling date, suggesting that, unlike the gt-D, the F1b has been recently introduced in Misiones. This is consistent with the current epidemiological data from other regions of Argentina, pointing to this sgt as responsible for most of the acute and new chronic HBV infections (Barbini et al, 2013;Gallego et al, 2014;González López Ledesma et al, 2015;Pezzano et al, 2011).…”

“…It is worth mentioning that almost all gt-D samples presented stop codons that preclude the HBeAg expression and one-third of them exhibit more than one mutation related to HBeAg negative phenotype. Particularly, the substitution G1896A was frequently observed in both: gt-D and sgt-F4 isolates (76.6% and 100% respectively), consistent with previous reports (González López Ledesma et al, 2015). In addition, all the F1b strains analyzed in this study displayed a wild type BCP sequence, possibly related to more recent infections, as discussed above.…”

“…Previous studies have described the circulation of this gt in Argentina, particularly in the metropolitan area of Buenos Aires and the Central region. However the prevalence reported in this areas were lower than that found in Misiones (Barbini et al, 2013;Gallego et al, 2014;González López Ledesma et al, 2015;Piñeiro y Leone et al, 2008). On the contrary, a higher prevalence has been reported in the Southern region of Brazil (Bertolini et al, 2012;Carrilho et al, 2004;Mello et al, 2007;Reis et al, 2011), suggesting that the HBV epidemiology of Misiones resembles that found in this neighboring area more than that described for other regions of Argentina.…”

“…In the present study, a 30.8% of isolates corresponded to gt-F. This proportion is lower than that found in other provinces of Northern Argentina (91.7%) or in the metropolitan area of Buenos Aires (54.3%) (Barbini et al, 2013;Gallego et al, 2014;González López Ledesma et al, 2015;Piñeiro y Leone et al, 2008). This finding highlights the relevance of gt-D introduction to the region associated to European migrations, as described above.…”

“…The role of genotypes (gts) or subgenotypes (sgts) in the outcome of infection is still controversial, although an increasing number of studies suggest a significant role in the progression and severity of liver disease, seroconvertion rate and antiviral treatment outcome (Cao, 2009;González López Ledesma et al, 2015;Lin and Kao, 2011;Livingston et al, 2007a).…”