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  EHDRW
6th European HIV Drug Resistance Workshop
Budapest, Hungary
March 26-28, 2008
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Single Mutations at Raltegravir Failure Suggest Low Resistance Barrier
 
 
  6th European HIV Drug Resistance Workshop
March 26-28, 2008
Budapest, Hungary
 
Mark Mascolini
 
Close study of 3 people in whom a raltegravir-based salvage regimen failed correlated viral rebound with emergence of a single mutation in 2 of them, a finding suggesting to the investigators that this integrase inhibitor has a low barrier to resistance [1]. (From Jules Levin: Despite this assertion, the percent undetectable in raltegravir studies of very treatment-experienced patients is good and so is the durability of the viral response; so I remain unconvinced that there is a low genetic barrier). Continued raltegravir treatment after failure led to evolution of further mutations in HIV integrase. And soon after mutations emerged, they got archived in blood cells.
 
Clinicians and virologists at Hopital Europeen Georges Pompidou in Paris searched for integrase mutations in 3 of 17 people whose raltegravir-containing salvage combination failed. These 17 patients got raltegravir in an expanded-access program with an avergae viral load of 4.26 log (between 10,000 and 20,000 copies) and an average CD4 count of 34. To itemize integrase mutations when raltegravir failed, Charlotte Charpentier and colleagues sequenced the entire integrase gene isolated from plasma and peripheral blood mononuclear cells (PBMCs) and analzyed clones derived from virus of 1 person.
 
Earlier research identified Q148K/R/H and N155H as primary integrase inhibitor mutations conferring resistance to both raltegravir and elvitegravir, the investigational Gilead integrase inhibitor [2,3]. In the new study Q148R emerged upon raltegravir failure in patients 1 and 3, but T66A plus E92Q evolved in patient 2. Ongoing treatment after viral rebound resulted in the following mutation patterns:
 
· Patient 1. Q148R at week 4 followed by G140S, Q148H, and N155H
· Patient 2. T66A and E92Q at week 16 followed by L74I
· Patient 3. Q148R at week 11 followed by G140S
 
The Pompidou investigators suggested that evolution of a single mutation at the time of virologic rebound confirms a low genetic barrier of resistance to raltegravir.
 
Clonal analysis of virus from patient 1 indicated that two primary integrase mutations--Q148R and N155H--evolved on distinct viral genomes. This patient's viral clones showed three distinct mutations patterns: 4 of 34 clones (12%) had Q148R, 9 of 34 (26%) carried N155H, and 20 of 34 (59%) bore G140S plus Q148H.
 
Direct sequencing of PBMCs from all 3 patients disclosed similar resistance profiles in paired plasma and PBMC samples. Mutations appeared simultaneously in plasma and in PBMC HIV DNA in 2 patients. In the third person mutations could be detected in PBMCs 35 weeks after they emerged in plasma. This fast archiving of resistant virus in blood cells suggests that, once mutations emerge, they may persist at low levels in cells and compromise treatment with other integrase inhibitors that have a similar resistance profile.
 
The Pompidou researchers stressed that maintaining raltegravir therapy after virologic failure can lead to pile-ups of added mutations, and that virus harboring two critical mutations, Q148R and N155H, can coexist on separate genomes in the same patient.
 
References
1. Charpentier C, Karmochkine M, Laureillard D, et al. Drug resistance profiles of HIV integrase gene in patients failing raltegravir-salvage therapy. 6th European HIV Drug Resistance Workshop. March 26-28, 2008. Budapest. Abstract 48.
2. Hazuda DJ, Miller MD, Nguyen BY, Zhao J. Resistance to the HIV-integrase inhibitor raltegravir: analysis of protocol 005, a phase II study in patients with triple-class resistant HIV-1 infection. Antiviral Ther. 2007;12:S10. Abstract 8.
3. McColl DJ, Fransen S, Gupta S. Resistance and cross-resistance to first generation integrase inhibitors: insights from a Phase II study of elvitegravir (GS-9137). Antiviral Ther. 2007;12:S11. Abstract 9.