16th International HIV Drug Resistance Workshop 12-16 June 2007, Barbados

RESISTANCE AND CROSS-RESISTANCE TO FIRST GENERATION INTEGRASE INHIBITORS: INSIGHTS FROM A PHASE II STUDY OF ELVITEGRAVIR (GS-9137)

Antivir Ther. 2007; 12:S11 (abstract no. 9)

DJ McColl¹, S Fransen², S Gupta², N Parkin², N Margot¹, S Chuck¹, AK Cheng¹ and MD Miller^1
1Gilead Sciences, Inc, Foster City, CA, USA; ²Monogram Biosciences, Inc, South San Francisco, CA, USA

BACKGROUND: Elvitegravir (EVG, GS-9137) is an HIV-1 integrase inhibitor (INI) that is being developed for the treatment of HIV-1 infection. The integrase genotypes and phenotypes of viral isolates from protocol-defined virological failures (VF) in an EVG Phase II clinical trial (GS-US-183- 0105) are described.

METHODS: Patients (n=278) were randomized to 20 mg, 50 mg or 125 mg once-daily doses of ritonavir-boosted EVG, or comparator-boosted PI (CPI/r), plus optimized NRTIs ±T-20. Darunavir and tipranavir were added in some patients at week 16. Integrase genotyping and phenotyping for VF patients from the EVG 125 mg arm (n=30) was performed using the experimental PhenoSense and GeneSeq INI assays (Monogram Biosciences). Susceptibility to EVG and MK-0518 (raltegravir, RAL), both synthesized by Gilead and provided in blinded fashion to Monogram, was analysed. Viral replication capacity (RC) was characterized.

RESULTS: Patients were highly treatment-experienced (median of three TAMs and 10 PI-R mutations at baseline). Patients receiving EVG 125 mg had rapid viral load declines; those with ≥one active drug(s) in the background therapy had durable responses (mean decline in HIV-1 RNA of 2.1 log₁₀ copies/ml at week 24). Baseline and post-baseline INI genotypes and phenotypes were obtained on 28/30 VF patients. Baseline EVG IC₅₀ fold-change values ranged from 0.91–2.53-fold. The most common integrase mutations that developed were E92Q, E138K, Q148R/K/H, N155H (each observed in 11/28, 39%), S147G (9/28, 32%) and T66I/A/K (5/28, 18%). Mutations at integrase codons E92, E138, Q148 and N155 were previously reported to have been selected by RAL in vivo. Virus from VF samples showed a mean EVG FC of >151-fold (range 1.02–301) and RAL FC >28-fold (range 0.78->256), providing evidence for cross-resistance between these two INIs. RC declined from a median of 108% at baseline to 54% at VF.

CONCLUSIONS: A variety of integrase mutations were observed following VF in patients treated with EVG, some of which have also been associated with resistance to RAL. Development of integrase mutations was associated with reduced susceptibility to both EVG and RAL in most subjects, suggesting potential cross-resistance between these drugs. Emergence of integrase mutations was also associated with reduced viral RC.

2007-06-12
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