Adefovir dipivoxil is a nucleotide analogue currently in .e III trials in both drug-naïve and treatment-experienced individuals. Early work in vitro shows that resistance is linked almost exclusively to the development of two mutations, K65R and K70E, which lead, respectively, to 16- and 9-fold reductions in IC50 relative to wild-type isolates [1,2]. In vivo, resistance is quite slow to develop in adefovir-treated individuals. In a group of 29 patients receiving adefovir monotherapy for 12 weeks followed by adefovir with other agents for up to 12 months, only 2 cases of adefovir resistance were detected, both linked to the development of the K70E mutation [2]. In a larger study of adefovir intensification of ongoing therapy, only 2/175 patients developed the K70E mutation after 24 weeks of therapy [3]. The clinical correlation of this observation with respect to the durability of benefit that can be achieved from adefovir is not completely clear. In more recent trials including adefovir in complex regimens administered as first line therapy, there is no evidence of drug resistance in small numbers of patients followed for up to 20 weeks [4]. To date, there have been no reports of the emergence of the K65R mutation in adefovir-treated patients in vivo.

Adefovir appears to be especially active against viruses with high-grade resistance to 3TC, or to both AZT and 3TC. This has been confirmed using recombinant virus-based assays in vitro [5]. This phenomenon may be important in vivo, as shown in table 1. In patients receiving adefovir as single-agent intensification therapy, the best responses (over 24 weeks) were seen in those with 3TC-resistant viruses at baseline. In addition, a close correlation was observed between the adefovir phenotype at baseline and the virologic response over time. A formal analysis of the data has shown that a 5-fold reduction in adefovir susceptibility at baseline was associated with a poor therapeutic response [6]. It should be noted that the presence of high-grade AZT resistance (without the M184V mutation) leads to a significant decrease in adefovir susceptibility, which may reduce the efficacy of adefovir when used in salvage therapy.

Table 1. Efficacy of adefovir as intensification therapy (study 408) as a function of the baseline viral genotype and phenotypic susceptibility to adefovir [3].