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Home / Publications / 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

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

  • Authors: Alcaro S, Alteri C, Antinori A, Artese A, Beheydt G, Bertoli A, Ceccherini-Silberstein F, Costa G, d’Arminio Monforte A, Girardi E, Gori C, Orchi N, Parrotta L, Perno CF, Santoro MM, Svicher V, Theys K, Vandamme AM
  • Publication Year: 2013
  • Journal: Journal of Antimicrobial Chemotherapy
  • Link: http://www.ncbi.nlm.nih.gov/pubmed/23687186

Objetives

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 from 1997 to 2011 was 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.

Results

The number of HIV-1 B-infected patients with at least one protease-compensatory mutation increased over time (from 86.4% prior to 2001 to 92.6% after 2009, P = 0.02). 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).

Conclusions

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.

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About GHTM

GHTM is a R&D Unit that brings together researchers with a track record in Tropical Medicine and International & Global Health. It aims at strengthening Portugal's role as a leading partner in the development and implementation of a global health research agenda. Our evidence-based interventions contribute to the promotion of equity in health and to improve the health of populations.

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