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Nucleoside and nucleotide analogues (NAs) have transformed the management of chronic hepatitis B virus (HBV) infection. Lamivudine was the first to be licensed for this purpose. Unfortunately, monotherapy was associated with a high rate of virological breakthrough due to selection of HBV with specific polymerase mutations.1 This makes it unsuitable for use in most circumstances, though low cost and widespread availability maintain its popularity in many countries. Adefovir was next to be licensed. Though less prone to the selection of drug-resistant species, many treated patients exhibited a partial response, and persistent serum HBV DNA positivity was frequently observed for those with high pre-treatment titres.2 Many patients with treatment failure due to lamivudine resistance were ‘rescued’ by switching to adefovir. It was then noted that the risk for selection and emergence of adefovir resistance mutations was greater in the lamivudine pre-treated cohort than had been observed during adefovir treatment of nucleoside treatment-naïve patients.3 This was the first evidence that the outcome of HBV antiviral treatment might be compromised by the prior unsuccessful use of NAs. Subsequently, telbivudine, entecavir and tenofovir were licensed. The resistance profile of telbivudine is disappointing.4 However, both entecavir and tenofovir are potent antivirals and with little or no selection of resistant species during prolonged therapy.5–7 Thus, a number of expert guidelines recommend either entecavir or tenofovir for first-line oral treatment of treatment-naïve patients with chronic HBV.8 9 Cost and availability have determined that many patients have had exposure to both lamivudine and adefovir, and a proportion of these have clinically significant levels of viral replication (ie, levels likely to be associated with progressive liver damage). Emerging data are examining the impact of prior lamivudine and adefovir exposure on response to tenofovir or entecavir.
For instance, in this issue of Gut, …