Abstract
BackgroundLamivudine is an oral nucleoside analogue widely used for the treatment of chronic hepatitis B. The main limitation of lamivudine use is the selection of resistant mutations that increases with time of utilization. Hepatitis B virus (HBV) isolates have been classified into eight genotypes (A to H) with distinct geographical distributions. HBV genotypes may also influence pathogenic properties and therapeutic features. Here, we analyzed the HBV genotype distribution and the nature and frequency of lamivudine resistant mutations among 36 patients submitted to lamivudine treatment for 12 to 84 months.ResultsHalf of the patients were homosexual men. Only 4/36 (11%) patients were HBV DNA negative. As expected for a Brazilian group, genotypes A (24/32 positive individuals, 75%), D (3/32, 9.3%) and F (1/32, 3%) were present. One sample was from genotype C, which is a genotype rarely found in Brazil. Three samples were from genotype G, which had not been previously detected in Brazil. Lamivudine resistance mutations were identified in 20/32 (62%) HBV DNA positive samples. Mean HBV loads of patients with and without lamivudine resistance mutations were not very different (2.7 × 107 and 6.9 × 107 copies/mL, respectively). Fifteen patients showed the L180M/M204V lamivudine resistant double mutation. The triple mutant rt173V/180M/204V, which acts as a vaccine escape mutant, was found in two individuals. The three isolates of genotype G were entirely sequenced. All three showed the double mutation L180M/M204V and displayed a large genetic divergence when compared with other full-length genotype G isolates.ConclusionA high (55%) proportion of patients submitted to long term lamivudine therapy displayed resistant mutations, with elevated viral load. The potential of transmission of such HBV mutants should be monitored. The identification of genotypes C and G, rarely detected in South America, seems to indicate a genotype distribution different to that observed in non treated patients. Disparities in routes of transmission (genotype G seems to be linked to homosexual behavior) and in pathogenic properties (genotype C is very aggressive) among HBV genotypes may explain the presence of rare genotypes in the present work.
Highlights
Lamivudine is an oral nucleoside analogue widely used for the treatment of chronic hepatitis B
Despite the introduction of Hepatitis B virus (HBV) vaccination programs in the last decade, hepatitis B remains a largely disseminated disease, with an estimated 350 million people chronically infected around the world, and over 2 billion people who have already been infected with the virus
HBV genotype G is distinct from the genomes of the other seven genotypes in that it possesses a 36-nt insertion at the 5' end of the core (C) gene and translational stop codons at positions 2 and 28 in the pre-C region, preventing hepatitis B e antigen (HBeAg) synthesis [4]
Summary
Lamivudine is an oral nucleoside analogue widely used for the treatment of chronic hepatitis B. Hepatitis B virus (HBV) isolates have been classified into eight genotypes (A to H) with distinct geographical distributions. HBV genotype G is distinct from the genomes of the other seven genotypes in that it possesses a 36-nt insertion at the 5' end of the core (C) gene and translational stop codons at positions 2 and 28 in the pre-C region, preventing HBeAg synthesis [4]. Despite these stop codons, patients infected with genotype G have been found positive for hepatitis B e antigen (HBeAg) [14]. When searched for, genotype G has not been identified in several countries, and seems to be an extremely rare genotype in Japan [16]
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