1st International Workshop on HIV Drug Resistance & Treatment Strategies 25-28 June 1997, St. Petersburg, Florida, USA

GENOTYPIC CHARACTERIZATION OF HIV-1 VARIANTS ISOLATED FROM AIDS PATIENTS TREATED WITH ADEFOVIR DIPIVOXIL (BIS-POM PMEA)

Antiviral Therapy 1997;2 (Suppl 5):15 (abstract no. 24)

AS Mulato, PL Lamy, W Li, MD Miller and JM Cherrington
Gilead Sciences, Foster City, CA 94404, USA

Adefovir dipivoxil (bis-POM PMEA), an oral prodrug of adefovir (PMEA), is currently in Phase III testing for the treatment of HIV infection. Previous in vitro experiments demonstrated that either a K65R or K70E HIV reverse transcriptase (RT) mutation could be selected in the presence of adefovir, conferring approximately a 10-fold decrease in susceptibility to adefovir. In a Phase II study, HIV RT genotypic analyses were performed on plasma samples obtained at baseline and during the 12 week clinical trial of adefovir dipivoxil monotherapy. Of the patients, 75% were nucleoside inhibitor-experienced. HIV RT nucleotides 1-900 were sequenced. RT genotypic analyses were performed on additional plasma samples obtained from a subset of patients in this same trial who opted to enrol into a subsequent 6 month maintenance phase of dosing during which concomitant antiretroviral therapies were permitted. Plasma HIV RNA decreased by a median 0.6 log from the maintenance phase baseline among the 30 patients completing 6 months of dosing. Among 31 patients analysed from the initial phase to date, one patient developed an M184V mutation at week 12 that was not present at baseline (this patient had a 2.0 log decrease in viral RNA and may have been taking lamivudine surreptitiously). Among 27 patients analysed from the 6 month maintenance phase to date, RT mutations were observed in four patients at month 6. All four patients had a decrease in viral load of ≥ 0.5 log at 6 months. Three of these patients were receiving concomitant therapy. One patient receiving monotherapy during the maintenance phase developed a K70E mutation, which was present as a 50% mixture of wild-type and mutant codons at months 3 and 6. Importantly, this patient experienced a sustained viral load decrease of 0.9 log at month 6. Recombinant viruses expressing this patient's baseline and month 6 RT genes were generated and the month 6 recombinant showed a 5-10-fold increase in IC₅₀ value for PMEA and lamivudine as compared to the baseline virus. These data are in agreement with previous findings using both an in vitro-selected PMEA-resistant virus expressing the K70E mutation and an HXB2D recombinant virus expressing only the K70E mutation in RT. These preliminary data from clinical samples suggest that HIV mutations associated with adefovir resistance do not arise readily during prolonged therapy. Recombinant viruses generated from the baseline and month 6 RT genes of the other three patients with genotypic changes in RT have been generated and are currently being analysed. Further work investigating the relationship between novel genotypes/phenotypes arising on adefovir dipivoxil therapy and virological response during treatment is ongoing.

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1997-06-25
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