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

RESISTANCE TO THE HIV-INTEGRASE INHIBITOR RALTEGRAVIR: ANALYSIS OF PROTOCOL 005, A PHASE II STUDY IN PATIENTS WITH TRIPLE-CLASS RESISTANT HIV-1 INFECTION

Antivir Ther. 2007; 12:S10 (abstract no. 8)

DJ Hazuda, MD Miller, BY Nguyen and J Zhao for the P005 Study Team
Merck Research Labs, North Wales PA 19454, USA

Raltegravir (RAL; MK-0518) is an integrase strandtransfer inhibitor (InSTI) from the hydroxypyrimidinone carboxamide class. Although structurally distinct from the diketo acids and naphthyridines, RAL is mechanistically similar and shares important chemical features with other InSTIs. RAL has demonstrated robust efficacy in treatment-experienced and treatment-naïve patients (Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. THLB0214; ICAAC 2006 Abstract # H-1670b; Conf Retroviruses Opportunistic Infect 2007 Feb 25-28;14 (Abstract # 105a/bLB). RAL resistance has been studied in vitro and is currently being evaluated in these clinical trials. Merck Protocol 005 is a Phase II dose-ranging study in HIV-1 patients failing therapy with PI, NNRTI and NRTI resistance. At week 24, 70% (95% CI: 54–83) to 71% (95% CI: 56–84) of patients on RAL and optimized background therapy (OBT) achieved HIV-1 RNA <400 copies/ml compared to 16% (95% CI: 7–30) of patients receiving placebo plus OBT (non-completers = failure). In the 38 RAL patients with virological failure (defined as not achieving >1 log₁₀ decrease in HIV RNA and HIV RNA <400 copies/ml at Wk 16 or viral relapse), RAL resistance has been analysed by sequencing integrase and evaluating all mutations identified relative to baseline as site-directed mutants for their effects on susceptibility to RAL (and other InSTIs), and viral replication capacity in single-cycle HIV-1 infectivity assays. Mutations in integrase were identified in 35 of the 38 RAL failures. RAL resistance was associated with two genetic pathways defined by mutations at either N155(H) or Q148 (H, R or K), which reduce susceptibility by 10–25-fold, respectively. Both in vitro and in vivo, the evolution of additional mutations resulted in high level resistance (N155 plus L74M, E92Q, G163R or Q148H/R/K plus E138K, G140S/A). While certain secondary mutations appear to moderate replication defects associated with specific N155 or Q148 mutations, all secondary changes studied resulted in increased resistance. These results suggest a single mutation may not have been sufficient to confer complete resistance in patients with these viruses. HIV-1 variants with N155 or Q148 mutations exhibited cross resistance to diverse InSTIs consistent with a mechanism that affects binding of the common pharmacophore within the integrase active site.

2007-06-12
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