17th International HIV Drug Resistance Workshop 10-14 June 2008, Sitges, Spain

RELEVANCE OF HIV GAG CLEAVAGE SITE MUTATIONS IN FAILURES OF PROTEASE INHIBITOR THERAPIES

Antivir Ther. 2008; 13(Suppl. 3):A53 (abstract no. 48)

J Verheyen¹, A Altmann², E Knops¹, E Schülter¹, N Sichtig¹, S Reuter³, G Fätkenheuer¹, H Pfister¹ and R Kaiser^1
1University of Cologne, Cologne, Germany; ²Max-Planck Institute for Informatics, Saarbrücken, Germany; ³University Clinic Düsseldorf, Germany

BACKGROUND: The evolution of HIV cleavage site (CS) mutations after exposure to protease inhibitors (PI) is generally acknowledged. However, the impact of CS mutations on PI resistance has been controversially discussed. They have been described as either resistance-conferring mutations and/or compensatory mutations. The analysis of HIV CS mutations in PI failures could help to increase knowledge about the relevance of CS mutations.

METHODS: We analysed 188 HIV genotypes of 154 patients in pol gene as well as in gag gene. All genotypes were obtained after at least 90 days (median: 458 days) of antiretroviral therapy with PIs. HIV genotypes were interpreted with HIV genotypic-resistance tools (ANRS, geno2pheno, HIVdb, HIV-Grade and Rega) and classified according the highest agreement. Prediction of lopinavir (LPV) therapy failure was performed with Random Forests using the International AIDS Society-USA list for protease (PR)/reverse transcriptase (RT) as well as CS mutations (431V/437V/449F) and evaluated by 10-fold cross-validation (control group: 102 successful LPV therapies with gag and pol genotypes).

RESULTS: HIV genotypes from PI failures harboured therapy-associated HIV CS mutations and resistance-associated PR mutations in comparable numbers (66% versus 71%, respectively). If genotypic PI resistance was predicted (n=71), therapy-associated CS mutations could be found in 90% (mainly 1 or 2). HIV gag CS mutations 128I, 431V, 437V, 449F, 451T, 452S and 453L accumulated in HIV classified PI-resistant compared to PI-susceptible samples (n=70). HIV interpretation tools gave conflicting results or predicted intermediate resistance in 47 of 188 (25%) HIV genotypes mainly harbouring therapy-associated CS-mutations (42/47). A rules-based system adapted from the HIV Stanford algorithm with weighted PR mutations and CS mutations (431V [15], 437V [10] and 449F [10]) for LPV resistance would have led in 14 of 24 HIV genotypes to a switch in predicted LPV resistance (intermediate resistance to full resistance). Additionally, predication of therapy outcomes for LPV therapies (n=78) slightly, but significantly, improved with Random Forests analysis (P<0.001) if CS mutations (431V/437V/449F) were considered.

CONCLUSION: Therapy-associated HIV CS mutations were frequently selected under PI therapies and PI-resistant viruses were rarely found without CS mutations. Furthermore, CS mutations were found in PI failures without predicted PI resistance probably pointing to an underestimated genotypic PI resistance. This is especially supported by the fact that outcomes of LPV therapies were predicted more exactly by bioinformatic methods using HIV pol and gag genes.

2008-06-10
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