Department of Gastroenterology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan
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Abstract |
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Keywords: chronic hepatitis , genotypes , hepatitis B e antigen , hepatitis B virus , interferon , lamivudine
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Introduction |
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Genotypes of HBV |
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Clinical manifestations of persistent HBV infection with distinct genotypes |
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The synthesis of hepatitis B e antigen (HBeAg) is regulated at both translational and transcriptional levels.15 Mutations to create stop codons in the precore region, typified by the G-to-A mutation at nucleotide (nt) 1896 (G1896A), shut down the translation of HBeAg completely. The double mutation in the core promoter, A-to-T at nt 1762 and G-to-A at nt 1764 (A1762T/G1764A), interferes with the proper transcription of HBeAg precursor, thereby downregulating the synthesis of HBeAg. The precore stop codon mutation (G1896A) is detected more frequently in persons infected with genotype B than C; it is inhibited in those with genotype A, because it destabilizes the e encapsidation signal.16 In remarkable contrast, the core promoter double mutation (A1762T/G1764A) is more common in those with genotype C than B. Overall, the ramifications of this are that the seroconversion to the loss of HBeAg takes longer in individuals infected with genotype C than B, and is accompanied by the development of severe liver disease.
Sugauchi et al.17 reported two subtypes of genotype B, one of which possesses a recombination with genotype C over the precore region plus core gene (subtype Ba) while the other does not (subtype Bj). The distribution of subtype Bj is restricted to Japan (hence the j for Japan), in contrast to subtype Ba found in all Asian countries other than Japan (a for Asia, therefore). Since HBeAg and the double mutation in the core promoter (A1762T/G1764A) are significantly more frequent in carriers of subtype Ba than Bj,18 subtypes of genotype B may influence the clinical outcome and the response to antiviral therapies for chronic hepatitis B.
To a lesser extent, clinical differences between genotype A and D infections have been reported from Europe, where these genotypes are frequent. HBV infection is contracted in adulthood in these countries, principally through sexual contacts and illicit drug use, and HBV infection is more likely to persist in persons infected with genotype A rather than D or the other genotypes.19 These findings stand at variance with those of Sanchez-Tapias et al.20 who found sustained biochemical remission and clearance of HBV DNA to be more frequent in infection with genotype A than genotype D (log-rank, 14.2, P=0.002) or genotype F (log-rank, 4.2, P=0.03); the rate of HBsAg clearance was also found to be higher in genotype A compared with D infection (log-rank, 4.06, P=0.03). Likewise in a comparison between 60 and 63 patients in India infected with HBV genotype A or D, respectively, genotype D was significantly associated with severe liver disease (61% compared with 30%, P < 0.05) and tended to be more frequent in those with HCC below 40 years of age (63% compared with 44%, P=0.06).21 Clinical differences amongst HBV genotypes manifest themselves in the distribution of acute and chronic liver disease in those who visit hospitals. In our Toranomon Hospital in metropolitan Tokyo, 57 adult patients with acute hepatitis B and 1077 with chronic hepatitis B were admitted during the same period.22 The distribution of genotypes were: genotype A (acute, 22.8% versus chronic, 1.9%; P < 0.00001); B (14.0% versus 9.4%); C (43.9% versus 87.7%, P=0.004); D (1.8% versus 0.2%); F (1.8% versus 0.2%); and untypeable (15.8% versus 0.6%, P=0.001).
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Influence of HBV genotype on the response to antiviral therapy |
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Zhang et al. compared the response between 10 patients with genotype A infection and 21 patients with genotype D or E infection.28 Since all patients they studied were positive for anti-HBe antibodies, the negative influence of genotype A on seroconversion to anti-HBe was excluded. They found the response to interferon was higher in patients infected with genotype A compared with D or E (70% versus 40%, P=0.001).28 Likewise, Kao et al.29 reported the response to interferon to be higher in patients infected with genotype B rather than C [13/32 (41%) versus 4/26 (15%), P=0.045]. More recently, Wai et al.30 compared the response between patients randomized to interferon or placebo. They found the response was better in patients with genotype B than C infection who were allocated to interferon treatment [12/31 (39%) versus 7/42 (17%), P=0.034]; the response rate did not differ in those who received placebo.
Lamivudine [()-ß-L-2',3'-dideoxy-3'-thiacytidine] is a nucleoside analogue with a potent antiviral activity. Since its approval in 1998, lamivudine has gained wide popularity for the treatment of chronic hepatitis B due to high a efficacy with minimal untoward effects.3135 We believe in continued lamivudine treatment for patients with or without serum HBeAg,3639 and have accumulated experience with 286 patients including seven who have received lamivudine for 7 years or longer.40 HBV genotype also makes a difference in the response to lamivudine in patients with chronic hepatitis B. Among the 16 patients who had received lamivudine for 3 years or longer, the virological response with the loss of HBV DNA detectable by non-amplified method was achieved in two of the three (67%) patients infected with genotype B and in seven of the 13 (54%) patients infected with genotype C.
Kao et al.41 reported on the response to lamivudine in patients treated for 630 months infected with genotype B compared with C [3/13 (23%) versus 2/18 (11%), no significant differences]. They found resistance to lamivudine in two (15%) patients with genotype B and in four (22%) with genotype C. Chien et al.42 reported that the sustained response to lamivudine was much higher in patients infected with genotype B compared with genotype C [38/62 (61%) versus 5/20 (20%), P=0.009]. We monitored 213 patients on continued lamivudine treatment for drug-resistant HBV variants for mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) motif in the viral DNA polymerase/reverse transcriptase.43 The emergence of YMDD mutants was no different amongst patients infected with genotype A, B or C. However, YMDD mutants developed significantly more frequently in patients infected with subtype Ba than Bj during 2 years on lamivudine [3/4 (75%) versus 1/14 (7%), P < 0.05]. Severe acute exacerbation of hepatitis occurred in four of the 185 (2%) patients with genotype C along with the emergence of YMDD mutants, but in none of the 28 patients with the other genotypes. In patients with chronic hepatitis B in Germany, risk of lamivudine resistance was significantly higher in carriers of HBsAg of serotype adw than ayw [7/13 (54%) versus 1/13 (8%), P=0.03];44 serotype adw corresponded to genotype A and ayw to D.45
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Conclusion |
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References |
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