icon-folder.gif   Conference Reports for NATAP  
  50th ICAAC
Boston, MA
September 12-15, 2010
Back grey_arrow_rt.gif
Top Integrase Polymorphisms Do Not Confer
Resistance to S/GSK1349572 or Raltegravir

  50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 12-15, 2010, Boston
Mark Mascolini
Two naturally occurring amino acid substitutions (polymorphisms) in the HIV-1 integrase gene that are seen frequently in people with no integrase inhibitor experience conferred no resistance to raltegravir or to the experimental agent S/GSK1349572 (called 572 for short) in a series of studiers [1]. Earlier work by French researchers found high rates of L101I (46%), T124A (24.5%), and L101I plus T124A (10%) in people with no integrase inhibitor experience [2]. The new findings by Shionogi/GlaxoSmithKline may allay some concern that prevalent natural polymorphisms in integrase inhibitor-naive people could jeopardize response to these drugs.
The investigators scrutinized 2997 integrase sequences cataloged in the Los Alamos National Laboratory database before clinical use of integrase inhibitors began. This analysis revealed a high degree of genetic conservation across the 288 amino acid residues of HIV-1 integrase. Of these 288 sites, 169 (59%) varied by less than 1%. There were 34 sites with greater than 10% variation spread across the gene. The most highly polymorphic sites were position 101 (40%) and 124 (39%). At these two positions, by far the most frequent polymorphisms were L101I (60%) and T124A (61%).
Next the Shionogi/GSK team turned to data from a phase 2 trial that compared three doses of 572 (2, 10, and 50 mg) and placebo in a 10-day monotherapy trial [3]. Median viral load fell 1.5 log with 2 mg, 2.0 log with 10 mg, and 2.5 log with 50 mg. In an analysis that adjusted for dose response differences, the investigators assessed viral load responses on day 11 in 35 people whose virus carried polymorphisms at positions 101 or 124. All patients had multiple other amino acid substitutions, and the researchers did not attempt to factor out the potential impact of those substitutions. Observed median changes in viral load were all below 0.3 log, a change consistent with random variation and suggesting that no polymorphism examined favored a substantial increase or decrease in viral load.
The investigators then determined whether susceptibility to 572 or raltegravir in people with these polymorphisms differed from the group median fold change in susceptibility. It did not. Average fold changes in susceptibility were 0.79 to 572 and 0.89 to raltegravir. No single polymorphism yielded a fold change greater than assay variability.
Finally, the researchers created site-directed mutants incorporating L101I, T124A, both polymorphisms, and other substitutions that arose in serial passage studies of 572. Fold change in susceptibility to 572 ranged from 0.91 for L101I plus T124A to 2.5 for the nonpolymorphic mutation S153Y. Average fold changes in susceptibility to 572 and raltegravir were 1.4 and 1.2 with L101I and 0.95 and 0.82 with T124A.
1. Vavro C, Underwood M, Madsen H, et al. Polymorphisms at position 101 and 124 in the HIV-1 integrase gene: lack of effects on susceptibility to S/GSK1349572. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 12-15, 2010. Boston. Abstract H-935.
2. Marcelin AG, Malet I, Fabeni L, et al. Resistance-associated mutations to integrase inhibitor S/GSK1349572 in HIV-1 integrase inhibitor-na´ve and raltegravir-experienced patients. 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 554. http://www.retroconference.org/2010/PDFs/554.pdf
3. Lalezari J, Sloan L, Dejesus E, et al. Potent antiviral activity of S/GSK1349572, a next generation integrase inhibitor (INI), in INI-naive HIV-1-infected patients. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 19-22, 2009. Cape Town. Abstract TUAB105.