Benefit of therapeutic drug monitoring of protease inhibitors in HIV‐infected patients depends on PI used in HAART regimen – ANRS 111 trial

Abstract

As a result of high inter-patient variability, and efficacy-concentration and toxicity-concentration relationships, optimization of HIV-protease inhibitor (PI) doses based on plasma concentrations could be beneficial. During a 48-week open prospective non-randomized interventional study of 115 protease inhibitor-naïve patients initiating an indinavir/ritonavir- or lopinavir/ritonavir-, or nelfinavir-containing therapy, protease inhibitor dose was modified when plasma trough concentrations (C(trough)) at weeks 2, 8, 16 and 24 were outside predefined optimal concentration ranges. Failure of the strategy was defined as the proportions of patients with HIV-RNA above 200 copies/mL from weeks 24 to 48 and/or experiencing grades 2, 3 or 4 PI-related adverse events during the study; proportion of patients with last C(trough) measurement outside the concentration range was determined at each visit. Virological failure and/or occurrence of adverse event were observed in 37/94 assessable patients (39%; 95% CI: 29.4-50.0). In the on-treatment analysis, failure of the strategy was noted in 16% of indinavir/r- or lopinavir/r-treated patients (8/51; 95% CI: 7.0-28.6; virological failure: 2; adverse event: 6) but in 44% of nelfinavir-treated patients (11/25; 95% CI: 24.4-65.1; virological failure: 10; adverse event: 1); C(trough) concentrations outside the range were less frequent at the last measurement than at W2 (41% vs. 66%; P < 0.05), with proportions of 35% for indinavir/r- or lopinavir/r-treated patients, but 57% for nelfinavir-treated patients. The proposed strategy of therapeutic drug monitoring may be beneficial to indinavir/r- and lopinavir/r-treated patients, but failed to move concentrations into the predefined range and to produce the expected virological success for nelfinavir-treated patients.

Maximum Likelihood Estimation of Long-Term HIV Dynamic Models and Antiviral Response

“…Using likelihood ratio test to compare the efficacy of the three studied PI, we found a significant difference in the efficacy of nelfinavir compared to lopinavir or indinavir. This is in agreement with the results of the trial (Duval et al, 2009) in which virological failure was found in 33% of patients treated with nelfinavir and only in 5% of patients treated by indinavir or lopinavir.…”

“…Plasma HIV-1-RNA were measured by Roche monitored with a LOQ of 50 copies/ml. The results of this trial are reported in Duval et al (2009). The proportion of virological failure was higher in the nelfinavir group and similar for indinavir and lopinavir, although lopinavir is supposed to be a more potent PI now widely used.…”

“…A second objective was to propose and apply statistical approaches for studying model selection in this context. We applied this approach to data obtained in patients of the clinical trial COPHAR2–ANRS 111 (Duval et al, 2009) initiating an antiviral therapy with two nucleoside analogs, reverse transcriptase inverse (RTI) and one protease inhibitor (PI). We analyzed simultaneously the HIV viral load decrease and the CD4 increase based on a long‐term HIV dynamic system.…”

Joint Population Pharmacokinetic Analysis of Zidovudine, Lamivudine, and Their Active Intracellular Metabolites in HIV Patients

“…The COPHAR2-ANRS 111 trial is a multicenter, noncomparative pilot trial of early therapeutic drug monitoring in HIV-positive patients naïve for PI-containing HAART (16). Patients received a combination of two NRTIs plus one PI as antiretroviral therapy.…”

Dynamical models of biomarkers and clinical progression for personalized medicine: The HIV context

“…This could initially be applied to all antiviral drugs, with a view to focus subsequently on more -targetable‖ drugs. This was already done by Duval et al [124], who showed that, among…”