BACKGROUND: The number of minor protease substitutions in wild-type virus at positions targeted during antiretroviral drug treatment, varies considerably between HIV-1 subtypes. Minor protease substitutions may impact the genetic barrier of resistance likely by modulating the fitness and resistance once relevant major substitutions are selected. Therefore, subtypes containing larger numbers of minor protease substitutions could have lower genetic barriers for drug resistance. In this study, the number of minor protease substitutions for every protease inhibitor was compared between subtypes using 1855 from antiretroviral-naive patients. METHODS: Identified were subtypes A to G, J, CRF01_AE and CRF02_AG. The most common clades were B (1299 sequences), followed by subtype C (n=209), G (86), and CRF02_AG (71). The particular minor substitutions considered relevant for protease inhibitors were obtained from the IAS-USA list of 2004. Tipranavir and amprenavir were not included in the analysis. The frequency of minor protease substitutions was compared between sequences of clade B and all individual non-B subtypes using Kruskal-Wallis and Mann-Whitney tests. RESULTS: Sequences belonging to non-B subtype had 20% (subtypes C, D and CRF01_AE) to 70% (G, J, CRF02_AG) more minor protease substitutions as compared to clade B (P<0.001). Non-B sequences contained relatively more often the K20R (generally >15% for most non-B sequences versus 2% in B; P<0.001), and M36I substitutions (>85% in all individual non-B subtypes and 17% in B; P<0.001). On the other hand, L63P (9-30% in all particular non-B versus 57% in B), and V77I (<15% in all individual non-B clades versus 27% in B) were found more frequently in subtype B sequences (P<0.001). Polymorphisms across subtypes were uncommon at positions 24, 32, 53, 54, 73 and 88. All particular non-B subtypes contained on average more minor substitutions specific for indinavir, nelfinavir, atazanavir and ritonavir (P<0.001). Conversely, subtype B sequences generally harboured more minor protease substitutions relevant for saquinavir, and lopinavir/ritonavir (P<0.001). CONCLUSION: Dissimilarities in the genetic barrier for protease inhibitor resistance are expected across subtypes. Studies are needed to investigate whether these may be clinically relevant. If confirmed, such differences should be taken into account in the initial choice of antiretroviral drug regimens.
Differences in the frequency of minor substitutions between HIV-1 subtypes and their potential impact on the genetic barrier for resistance to protease inhibitors / D.V. de Vijver, A.M. Wensing, G. Angarano, B. Asjo, C. Balotta, E. Boeri, R. Camacho, M.L. Chaix, D. Costagliola, E.L. de Coul, A. de Luca, I. Maljkovic, C. de Mendoza, I. Derdelinckx, Z. Grossman, O. Hamouda, A. Hatzakis, I.M. Hoepelman, R. Hemmer, A. Horban, K. Korn, C. Kucherer, T. Leitner, C. Loveday, E. Macrae, L. Meyer, C. Nielsen, V. Ormaasen, L. Perrin, D. Paraskevis, E. Puchhammer Stockl, L. Ruiz, M. Salminen, J.C.C. Schmit, F. Schneider, R. Schuurman, V. Soriano, G. Stanczak, M. Stanojevic, A.M. Vandamme, K. Van Laethem, M. Violin, K. Wilbe, S. Yerly, M. Zazzi, C.A.B. Boucher. - In: ANTIVIRAL THERAPY. - ISSN 1359-6535. - 10:4(2005), pp. S145-S145.
Differences in the frequency of minor substitutions between HIV-1 subtypes and their potential impact on the genetic barrier for resistance to protease inhibitors
C. Balotta;
2005
Abstract
BACKGROUND: The number of minor protease substitutions in wild-type virus at positions targeted during antiretroviral drug treatment, varies considerably between HIV-1 subtypes. Minor protease substitutions may impact the genetic barrier of resistance likely by modulating the fitness and resistance once relevant major substitutions are selected. Therefore, subtypes containing larger numbers of minor protease substitutions could have lower genetic barriers for drug resistance. In this study, the number of minor protease substitutions for every protease inhibitor was compared between subtypes using 1855 from antiretroviral-naive patients. METHODS: Identified were subtypes A to G, J, CRF01_AE and CRF02_AG. The most common clades were B (1299 sequences), followed by subtype C (n=209), G (86), and CRF02_AG (71). The particular minor substitutions considered relevant for protease inhibitors were obtained from the IAS-USA list of 2004. Tipranavir and amprenavir were not included in the analysis. The frequency of minor protease substitutions was compared between sequences of clade B and all individual non-B subtypes using Kruskal-Wallis and Mann-Whitney tests. RESULTS: Sequences belonging to non-B subtype had 20% (subtypes C, D and CRF01_AE) to 70% (G, J, CRF02_AG) more minor protease substitutions as compared to clade B (P<0.001). Non-B sequences contained relatively more often the K20R (generally >15% for most non-B sequences versus 2% in B; P<0.001), and M36I substitutions (>85% in all individual non-B subtypes and 17% in B; P<0.001). On the other hand, L63P (9-30% in all particular non-B versus 57% in B), and V77I (<15% in all individual non-B clades versus 27% in B) were found more frequently in subtype B sequences (P<0.001). Polymorphisms across subtypes were uncommon at positions 24, 32, 53, 54, 73 and 88. All particular non-B subtypes contained on average more minor substitutions specific for indinavir, nelfinavir, atazanavir and ritonavir (P<0.001). Conversely, subtype B sequences generally harboured more minor protease substitutions relevant for saquinavir, and lopinavir/ritonavir (P<0.001). CONCLUSION: Dissimilarities in the genetic barrier for protease inhibitor resistance are expected across subtypes. Studies are needed to investigate whether these may be clinically relevant. If confirmed, such differences should be taken into account in the initial choice of antiretroviral drug regimens.
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