Absence of Hepatitis B Resistance Mutants before Introduction of Oral Antiviral Therapy

Introduction. The aim of this study was to assess whether hepatitis B virus drug resistant mutations antedated the widespread use of nucleos(t)ide analogues in treatment na？ve patients. A number of reports have suggested that drug resistant mutants can be detected in apparently treatment na？ve patients. Study. Fifty deidentified serum samples collected from 1986 to 1992 from patients with replicative chronic HBV infection at the University of Miami were genotyped and tested for resistance mutations using a line probe assay InnoLiPA HBV DR v2/v3. Serum HBV DNA was measured. All patients had documented chronic HBV infection with a detectable viral load, HBeAg seropositivity, and absence of HIV infection. Results. Of the 50 individuals included, 86% were male, mean age was 40？±？12 years, and mostly genotype A. The mean HBV DNA was 126？pg/mL (range 6.4 to 557.0). No mutations were identified. Conclusions. The absence of drug induced mutations in these sera collected several years prior to the introduction of oral antiviral therapy suggests that these mutations do not occur in treatment na？ve populations. Detection of drug resistance in an apparently treatment na？ve subject suggests either unrecognized prior antiviral therapy or infection by an inoculum from a treatment experienced patient. 1. Introduction Infection with hepatitis B virus (HBV) remains a frequent etiology of cirrhosis and hepatocellular carcinoma with estimated 360 million individuals with chronic infection worldwide [1]. Although vaccination will ultimately reduce the disease burden due to HBV, antiviral therapy can favorably alter its natural history [2]. Goals of therapy include suppression of HBV replication to delay progression of liver disease reducing the risk of hepatic decompensation and hepatocellular carcinoma as well as infectivity to other individuals. Although standard interferon alpha was licensed for the treatment of chronic HBV infection over two decades ago more widespread therapy became feasible with the advent of well-tolerated oral antiviral nucleoside and nucleotide agents. However, shortly after the introduction of the first nucleoside analogue, lamivudine, treatment induced mutations in the viral genome were identified. These mutations resulted in reduced antiviral efficacy and diminished clinical benefit. Subsequently adefovir, a nucleotide analogue, efficacious in presence of lamivudine induced mutations was licensed, but its use was also associated with emergence of genomic antiviral resistance. Antiviral resistance has also been identified with more recently