HIV-1 resistance patterns to integrase inhibitors in antiretroviral-experienced patients with virological failure on raltegravir-containing regimens

Abstract

Diverse genetic profiles can be associated with VF on raltegravir-containing regimens, including the dynamics of replacement of mutational profiles. Pharmacokinetic parameters could be involved in this genetic evolution.

Population Pharmacokinetic Analysis and Pharmacogenetics of Raltegravir in HIV-Positive and Healthy Individuals

“…However, some recent evidence suggests a possible role of drug concentration, in addition to virological parameters, in the efficacy and induction of virological resistance to RAL (12,14). In accordance with results of the QD Merck study (35), our simulations of 400 mg BID compared to 800 mg QD indicate that a higher percentage of patients would exhibit C min under the protein-adjusted IC 95 with the 800-mg QD regimen than with 400 mg BID, which might put patients at risk of virological failure, in particular those with a high viral load, as reported by Eron et al (14).…”

“…However, the rather high intrapatient variability might limit its effectiveness. Based on some evidence about pharmacokinetic and pharmacodynamic relationships (12,14) and on the good correlation between RAL intracellular concentrations and plasma concentrations (16,28), there is a need to further explore the relationship between efficacy and pharmacokinetic exposure and the potential role of concentration monitoring. Better-standardized studies based upon more extensive sampling on a better-defined population would circumvent some of the limitations inherent to observational studies.…”

MK-0536 Inhibits HIV-1 Integrases Resistant to Raltegravir

“…These structures show that INSTIs act as interfacial inhibitors (20) by forming a network of molecular interactions with IN, its viral DNA substrate and the metal ion cofactors (Mg 2ϩ ) (6,8,11). These structures revealed why elvitegravir (EVG; Gilead Science) is effective against the RAL-specific mutation Y143R (2,18). The oxadiazole moiety of RAL participates in a stacking interaction with the tyrosine 212 (Y212) aromatic ring of PFV IN (Fig.…”

Multiple Genetic Pathways Involving Amino Acid Position 143 of HIV-1 Integrase Are Preferentially Associated with Specific Secondary Amino Acid Substitutions and Confer Resistance to Raltegravir and Cross-Resistance to Elvitegravir

“…However, longitudinal evaluations have demonstrated that RAL-resistant viruses with substitutions at position 148 or 155 may be replaced by variants with Y143 substitutions upon continued RAL treatment (25)(26)(27). In a majority of cases, Y143 substitutions comprise C and R, both of which can confer significant reductions in RAL susceptibility (17,18,25,27).…”