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5th International Workshop on HIV Drug Resistance & Treatment Strategies4-8 June 2001, Scottsdale, Arizona |
OBJECTIVES: Tenofovir is a nucleotide analogue HIV reverse transcriptase (RT) inhibitor, and its oral prodrug (tenofovir DF) is in Phase III clinical trials. We wished to determine the range of tenofovir susceptibility in vitro of HIV isolates from untreated individuals, and the cross-resistance profile of tenofovir in a large panel of clinically derived recombinant isolates.
METHODS: The distribution of tenofovir susceptibility in nearly 1000 treatment-naïve HIV-infected individuals from the USA, Canada, Europe and South Africa was determined using the Virco Antivirogram assay. In addition, phenotypic susceptibility to tenofovir and other RT inhibitors was determined in a panel of nearly 5000 consecutive clinical isolates.
RESULTS: More than 97.5% of treatment-naïve individuals (two standard deviations) had tenofovir susceptibility <3-fold above the wild-type control. Therefore, a biological cut-off for tenofovir was set at threefold for the Antivirogram. The clinically derived panel of 5000 samples showed a broad range of drug susceptibilities, including 69% having >10-fold decreased susceptibility to at least one antiretroviral drug class, 43% to two classes, and 16% to all three classes. Specifically, 40, 17 and 49% of samples had >10-fold reduced susceptibility to lamivudine, zidovudine, or at least one NNRTI, respectively. Large decreases in tenofovir susceptibility were rare, with 4 and 1% of samples having >5-fold or >10-fold decreases in tenofovir susceptibility, respectively. Over 88% of these 5000 samples were within the threefold normal range for tenofovir. Among samples with reduced susceptibility to lamivudine, zidovudine, stavudine, didanosine or abacavir (beyond their biological cut-off), 85, 71, 62, 72 and 76%, respectively, remained within the normal range for tenofovir. Correspondingly, correlation coefficients of linear regression plots of tenofovir susceptibility compared to other RT inhibitors were relatively low (r2<0.4) for all drugs.
CONCLUSIONS: The normal range for biological variability in tenofovir susceptibility among treatment-naïve patients is threefold in the Antivirogram assay. In a clinical panel of nearly 5000 HIV samples representing predominantly treatment-experienced patients, reduced susceptibility to tenofovir beyond the normal range was infrequent and <10-fold in 99% of cases. Reduced tenofovir susceptibility was not closely associated with resistance to any licensed NRTI or NNRTI. These results suggest that the majority of treatment-naïve and treatment-experienced patients have HIV that could be susceptible to tenofovir DF therapy.
PRESENTING AUTHOR: MD Miller
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