ABSTRACT
La resistencia a los antirretrovirales (ARV) es un problema de salud pública. Con el uso de inhibidores de la integrasa (INSTI) en pediatría, también comienzan a aparecer resistencias. El objetivo de esta comunicación es describir 3 casos con resistencia a los INSTI. Se describen 3 pacientes pediátricos con transmisión vertical del virus de la inmunodeficiencia humana (VIH). Iniciaron ARV de lactantes y preescolares, con mala adherencia al tratamiento, cursaron con diferentes planes secundarios a comorbilidades asociadas y fallas virológicas por resistencia. Los 3 casos clínicos describen la rápida aparición de resistencia frente a la falla virológica y el compromiso de los INSTI. La adherencia debe ser supervisada para detectar precozmente el aumento de la viremia. La falla virológica en un paciente tratado con raltegravir obliga a un rápido cambio de esquema ARV, ya que continuar utilizándolo podría favorecer nuevas mutaciones y resistencia a los INSTI de segunda generación.
Antiretroviral (ARV) drug resistance is a public health issue. Resistance has also been observed in the case of integrase strand transfer inhibitors (INSTIs) used in pediatrics. The objective of this article is to describe 3 cases of INSTI resistance. These are the cases of 3 children with vertically-transmitted human immunodeficiency virus (HIV). They were started on ARVs as infants and preschoolers, with poor treatment adherence, and had different management plans due to associated comorbidities and virological failure due to resistance. In the 3 cases, resistance developed rapidly as a result of virological failure and INSTI involvement. Treatment adherence should be monitored so that any increase in viremia can be detected early. Virological failure in a patient treated with raltegravir forces to a rapid change in ARV therapy because its continued use may favor new mutations and resistance to second-generation INSTIs.
Subject(s)
Humans , Male , Female , Child, Preschool , Child , Adolescent , HIV Infections/drug therapy , HIV-1/genetics , HIV Integrase Inhibitors/therapeutic use , HIV Integrase Inhibitors/pharmacology , Anti-HIV Agents/therapeutic use , Uruguay , Raltegravir Potassium/therapeutic use , Raltegravir Potassium/pharmacology , MutationABSTRACT
A quantitative structure-activity relationship (QSAR) study has been performed on integrase (IN) inhibition activity of a large series of N-methyl pyrimidones [Gardelli et al. (2007) J Med Chem 50, 4953-4975)] having varying heterocyclic ring substitution at 2-position of pyrimidone ring. The activity is found to be significantly correlated with surface tension and molar volume of the molecules. The whole series of compounds is divided into two subsets: a training set and a test set. A significant correlation is obtained for the training set, which is then used to predict the activity of compounds in the test set. The predicted activities of compounds in the test set are found to be very close to their observed activities. The predicting ability of the correlation obtained is judged by leave-one-out jackknife procedure. The correlation shows the effective role of the surface tension and molar volume of the molecules. From the correlation obtained, the integrase inhibition activities are predicted for some new prospective compounds.
Subject(s)
HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacology , Humans , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Quantitative Structure-Activity RelationshipABSTRACT
This review will summarize the role of integrase in HIV-1 infection, the mechanism of integrase inhibitors and resistance with an emphasis on raltegravir (RAL), the first integrase inhibitor licensed to treat HIV-1 infection.