XI International HIV Drug Resistance Workshop: Basic Principles and Clinical Implications Seville, Spain, 2–5 July 2002

BACKGROUND: In short monotherapy trials in treatment-naïve patients, the antiviral response to tenofovir DF therapy was greater than 1 log₁₀, whereas in intensification trials among treatment-experienced patients the HIV RNA response was –0.6 log₁₀ copies/ml. As 94% of the experienced patients had resistance mutations to nucleoside reverse transcriptase inhibitors, pre-existing resistance is a likely contributor to their decreased responses. Previous descriptive analyses have indicated that decreased responses are associated with the number and type of thymidine analogue-associated mutations (TAMs) at baseline.

METHODS: Studies 902 and 907 were placebo-controlled, randomized studies of tenofovir DF therapy when added to stable background antiretroviral therapy. 333 patients (222 tenofovir DF, 111 placebo) had baseline HIV genotypes. In multivariate regression models, the effects of individual TAMs (codons 41, 67, 70, 210, 215 or 219), other nucleoside-associated mutations, baseline HIV RNA, baseline CD4, duration of prior therapy, and number of concurrent antiretrovirals were assessed for their impact on HIV RNA response at week 24.

RESULTS: Two baseline TAM patterns were observed: mutations at positions 41-210-215 were highly correlated with one another (P <0.0001, Spearman correlation coefficients) as were mutations at positions 67-70- 219 (P <0.0001). Sixty-seven mutations also associated weakly with 41-210-215. These two patterns appear to represent two distinct pathways of TAM development. Baseline HIV RNA, baseline CD4, and treatment with tenofovir DF were significantly associated with HIV RNA responses. Adjusting for these covariates, ≥3 TAMs in the 41-210-215 pathway were significantly associated with reduced tenofovir DF responses (parameter estimates >0.37 log₁₀ copies/ml, P <0.0001). The K65R mutation was also associated with a significantly reduced response (n=6, P=0.006). However, multiple TAMs in the 67-70-219 pathway, which can include the T215F mutation, did not significantly affect tenofovir DF response relative to response in patients without TAMs (parameter estimate <0.13 log₁₀ copies/ml, P >0.15). Baseline M184V was marginally significant for an improved response (parameter estimate=–0.12 log₁₀ copies/ml, P=0.04). Overall, the genotypic results correlate well with in vitro tenofovir susceptibility results and show that the highest levels of in vitro resistance (>4-fold, n=12) is associated with K65R or multiple mutations in the 41- 210-215 TAM pathway inclusive of mutations at positions 39, 43, 44, 67, 68, 69, 75, 118, and 208 (mean 6.3 mutations). Site-directed recombinant viruses demonstrate reductions in tenofovir susceptibility associated with K65R or accumulations of mutations in the 41-210-215 pathway.

CONCLUSION: Multivariate regression analyses and in vitro susceptibility results confirm that the infrequent K65R mutation or multiple mutations in the 41-210-215 TAM pathway are associated with reduced responses to tenofovir DF therapy. Prior accumulation of ≥5 TAMs within this pathway is associated with the highest levels of resistance. Continued thymidine analogue therapy in the presence of replicating HIV probably results in progression of this resistance pathway.

PRESENTING AUTHOR: MD Miller

Download PDF of this abstract.

2002-07-02
14

Copyright © 2002 - International Medical Press Ltd. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the International Medical Press Ltd. 2-4 Idol Lane, London EC3R 5DD UK.