International cohort analysis of the antiviral activities of zidovudine and tenofovir in the presence of the K65R mutation in reverse transcriptase

Abstract

A K65R mutation in HIV-1 reverse transcriptase can occur with the failure of tenofovir-, didanosine-, abacavir-, and, in some cases, stavudine-containing regimens and leads to reduced phenotypic susceptibility to these drugs and hypersusceptibility to zidovudine, but its clinical impact is poorly described. We identified isolates with the K65R mutation within the Stanford Resistance Database and a French cohort for which subsequent treatment and virological response data were available. The partial genotypic susceptibility score (pGSS) was defined as the genotypic susceptibility score (GSS) excluding the salvage regimen's nucleoside reverse transcriptase inhibitor (NRTI) component. A three-part virologic response variable was defined (e.g., complete virologic response, partial virologic response, and no virologic response). Univariate, multivariate, and bootstrap analyses evaluated factors associated with the virologic response, focusing on the contributions of zidovudine and tenofovir. Seventy-one of 130 patients (55%) achieved a complete virologic response (defined as an HIV RNA level of <200 copies/ml). In univariate analyses, pGSS and zidovudine use in the salvage regimen were predictors of the virologic response. In a multivariate analysis, pGSS and zidovudine and tenofovir use were associated with the virologic response. Bootstrap analyses showed similar reductions in HIV RNA levels with zidovudine or tenofovir use (0.5 to 0.9 log(10)). In the presence of K65R, zidovudine and tenofovir are associated with similar reductions in HIV RNA levels. Given its tolerability, tenofovir may be the preferred agent over zidovudine even in the presence of the K65R mutation.

FIG. 1.

Bootstrap analyses with 1,000 replicates for change in log₁₀ viral load by medication category, controlling for baseline viral load, partial genotypic susceptibility score, and number of new medications in salvage regimen. (a) Bootstrap analysis for change in log₁₀ viral load for new zidovudine (AZT), controlling for baseline viral load, partial genotypic susceptibility score, and number of new medications in the salvage regimen. (b) Bootstrap analysis for change in log₁₀ viral load for recycled zidovudine, controlling for baseline viral load, partial genotypic susceptibility score, and number of new medications in the salvage regimen. (c) Bootstrap analysis for change in log₁₀ viral load for new tenofovir, controlling for baseline viral load, partial genotypic susceptibility score, and number of new medications in salvage regimen. (d) Bootstrap analysis for change in log₁₀ viral load for continued tenofovir, controlling for baseline viral load, partial genotypic susceptibility score, and number of new medications in salvage regimen. TDF, tenofovir disoproxil fumarate. Point estimates for the change in log₁₀ viral load (95% confidence intervals) for each medication category are as follows: −0.6 (−1.4, 0.1) (a), −0.5 (−1.2, 0.2) (b), −0.9 (−1.6, −0.3) (c), and −0.5 (−1.0, 0.1) (d).