Background:  The hepatitis B virus (HBV) genome is comprised of 4 overlapping genes that encode a number of complex and multifunctional proteins. Long-term therapy with nucleos(t)ide analogs can lead to resistant HBV mutants, which over time may become the dominant species. The HBV polymerase overlaps the envelope gene, which encodes the hepatitis B surface antigen (HBsAg), in such a way that selection of drug-resistance mutations may affect HBV antigenicity or viral secretion. While escape to vaccines might occur in the first instance, the second situation may account for occult HBV infections.

Methods:  We identified at our institution 62 patients (43 HBV/HIV co-infected and 19 HBV mono-infected) who had been exposed to anti-HBV drugs, despite having detectable serum HBV DNA. HBV DNA was analyzed for mutations in the RT and HBsAg genes using polymerase chain reaction (PCR) and sequencing.

Results:  Main characteristics of the study population are recorded in the table. Their median time under lamivudine (3TC), tenofovir (TDF), and adefovir (ADV) was 39, 13, and 22 months, respectively. In HBV-mono-infected patients “a” determinant and “c” terminal mutations were detected in the HBs gene, mainly in patients infected with HBV genotype D. In contrast, “c” terminal mutations were mostly detected in HBV/HIV-co-infected patients. In a multivariate analysis, the “a” determinant mutations were found to be HBV genotype-dependent; whereas “c” terminal mutations selected by antiviral agents were not.

Conclusions:  Mutations in the HBV surface antigen following exposure to 3TC are significantly more frequent in HBV genotype A than D, whereas naturally occurring vaccine escape mutants are more frequent in HBV-mono-infected patients with genotype D. HBV genotyping should be performed before starting therapy with anti-HBV active drugs in HBV/HIV-co-infected patients and 3TC (and emtricitabine [FTC]) because single anti-HBV agents should be avoided. The circulation of HBV-encoding envelope mutations selected by antiviral agents requires further investigation to determine whether they may represent a public health concern.