TY - JOUR
T1 - Structural modifications induced by specific HIV-1 protease-compensatory mutations have an impact on the virological response to a first-line lopinavir/ritonavir-containing regimen
AU - Alteri, Claudia
AU - Artese, Anna
AU - Beheydt, Gertjan
AU - Santoro, Maria Mercedes
AU - Costa, Giosué
AU - Parrotta, Lucia
AU - Bertoli, Ada
AU - Gori, Caterina
AU - Orchi, Nicoletta
AU - Girardi, Enrico
AU - Antinori, Andrea
AU - Alcaro, Stefano
AU - Monforte, Antonella D Arminio
AU - Theys, Kristof
AU - Vandamme, Anne Mieke
AU - Ceccherini-Silberstein, Francesca
AU - Svicher, Valentina
AU - Perno, Carlo Federico
PY - 2013/10
Y1 - 2013/10
N2 - Objectives: This study evaluates the impact of specific HIV-1 protease-compensatory mutations (wild-type amino acids in non-B subtypes) on virological response to a first-line lopinavir/ritonavir-containing regimen in an HIV-1 subtype B-infected population. Patients and methods: The prevalence of protease-compensatory mutations from1997 to 2011was calculated in 3063 drug-naive HIV-1 B-infected patients. The role of these mutations on virological outcome is estimated in a subgroup of 201 patients starting their first lopinavir/ritonavir-containing regimen by covariation and docking analyses. The number of HIV-1 B-infected patients with at least one protease-compensatory mutation increased over time (from86.4% prior to 2001 to 92.6% after 2009, P1/40.02). Analysing 201 patients starting first-line lopinavir/ritonavir, the median time to virological failure was shorter in patients with at least one protease-compensatory mutation than in patients with no protease-compensatory mutations. By covariation and docking analyses, specific mutations were found to affect lopinavir affinity for HIV-1 protease and to impact virological failure. Specifically, the L10V+I13V+L63P+I93L cluster, related to fast virological failure, correlated with a decreased drug affinity for the enzyme in comparison with wild-type (ΔGmut=-30.0 kcal/mol versus ΔGwt=-42.3 kcal/mol). Our study shows an increased prevalence of specific protease-compensatory mutations in an HIV-1 B-infected population and confirms that their copresence can affect the virological outcome in patients starting a lopinavir/ritonavir-containing regimen.
AB - Objectives: This study evaluates the impact of specific HIV-1 protease-compensatory mutations (wild-type amino acids in non-B subtypes) on virological response to a first-line lopinavir/ritonavir-containing regimen in an HIV-1 subtype B-infected population. Patients and methods: The prevalence of protease-compensatory mutations from1997 to 2011was calculated in 3063 drug-naive HIV-1 B-infected patients. The role of these mutations on virological outcome is estimated in a subgroup of 201 patients starting their first lopinavir/ritonavir-containing regimen by covariation and docking analyses. The number of HIV-1 B-infected patients with at least one protease-compensatory mutation increased over time (from86.4% prior to 2001 to 92.6% after 2009, P1/40.02). Analysing 201 patients starting first-line lopinavir/ritonavir, the median time to virological failure was shorter in patients with at least one protease-compensatory mutation than in patients with no protease-compensatory mutations. By covariation and docking analyses, specific mutations were found to affect lopinavir affinity for HIV-1 protease and to impact virological failure. Specifically, the L10V+I13V+L63P+I93L cluster, related to fast virological failure, correlated with a decreased drug affinity for the enzyme in comparison with wild-type (ΔGmut=-30.0 kcal/mol versus ΔGwt=-42.3 kcal/mol). Our study shows an increased prevalence of specific protease-compensatory mutations in an HIV-1 B-infected population and confirms that their copresence can affect the virological outcome in patients starting a lopinavir/ritonavir-containing regimen.
KW - Antiviral
KW - Drug resistance
KW - Molecular modelling
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U2 - 10.1093/jac/dkt173
DO - 10.1093/jac/dkt173
M3 - Article
C2 - 23687186
AN - SCOPUS:84888354788
VL - 68
SP - 2203
EP - 2209
JO - Journal of Antimicrobial Chemotherapy
JF - Journal of Antimicrobial Chemotherapy
SN - 0305-7453
IS - 10
M1 - dkt173
ER -