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16th International HIV Drug Resistance Workshop12-16 June 2007, Barbados |
CLONAL ANALYSIS OF SAMPLES FROM VIROLOGICAL RESPONDERS RECEIVING RACIVIR IN THE RCV 201 STUDY
Antivir Ther. 2007; 12:S26 (abstract no. 24)
A De La Rosa1, Robert Lloyd Jr2 and MJ Otto1
1Pharmasset, Inc, Princeton, NJ, USA; 2Research Think Tank, Alpharetta, GA, USA
BACKGROUND: Racivir [RCV, (±)-,β-2′,3′-dideoxy-3′- thia-5-fluorocytosine; (±)-FTC], is a 50:50 mixture of enantiomers with potent anti-HIV/HBV activity and an excellent in vitro and in vivo safety profile. The RCV 201 study was designed to determine the activity of RCV in patients infected with HIV harbouring the M184V mutation. Forty-two subjects were randomized to receive either blinded RCV (n=26) in place of lamivudine or to continue with blinded lamivudine (n=16) for 28 days. All patients enrolled in the study had virus harbouring the M184V mutation at day 0. In addition, the majority of patients had virus with additional NNRTI or thymidine analogue associated mutations (TAMs). In a subset of patients (n=11), RCV demonstrated antiviral activity (>0.5 log10 viral load decline) by day 28. Six of these patients achieved undetectable viral loads (<400 copies/ml) by day 28. Clonal genotypic analysis of samples at day 0 and day 28 were performed to determine whether the M184V mutation was present on the same genome as the NNRTI mutations or TAMs in responding patients.
METHODS: HIV-1 population and clonal genotypic analyses were performed for day 0 and day 28 plasma samples from RCV virological responders (n=11). Twenty-five clones from each sample were sequenced and resolved using the Tower Sequencing Platform and OpenGene™ (Siemens Diagnostics) sequencing system. Combined sequences for each patient isolate (n=25 clones) plus the original population sequence were aligned in columnar form with identified mutations as compared to a LAI/Bru reference using MuTanker™ (Research Think Tank, Inc.).
RESULTS: By clonal genotypic analysis, all virological responders (100%) had virus harbouring the M184V mutation at day 0. There were no new resistance-associated mutations observed in the clonal analysis samples from responders who were unable to achieve viral reduction below detectable levels (<400 copies/ml) at day 28. NNRTI mutations and TAMs were also found on these genomes.
CONCLUSIONS: RCV effectively reduced viral loads in responders harbouring the M184V mutation and fewer than three TAMs at day 28. Clonal genotypic analysis of virus from responders indicate that the M184V mutation was found on all clones in addition to multidrug resistance associated mutations observed with first-line therapy failure.
2007-06-12
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