Effect of Pregnancy on Unbound Raltegravir Concentrations in the ANRS 160 RalFe Trial.

A population pharmacokinetic model was developed to explore the pharmacokinetics modification of unbound raltegravir during pregnancy. The RalFe ANRS160 study was a nonrandomized, open-label, multicenter trial enrolling HIV-infected pregnant women receiving a combined antiretroviral regimen containing 400 mg raltegravir twice daily. Biological samples were collected during the third trimester of pregnancy (between 30 and 37 weeks of gestational age) and at postpartum (4 to 6 weeks after delivery). A population pharmacokinetic model was developed with Monolix software. A total of 360 plasma samples were collected from 43 women during pregnancy and postpartum. The unbound raltegravir was described by a one-compartment model with a transit compartment with first-order absorption, evolving to bound raltegravir (by a linear binding to albumin) or metabolism to RAL-glucuronide or to a first-order elimination, with a circadian rhythm. During pregnancy, the absorption was decreased and delayed and the raltegravir elimination clearance and glucuronidation increased by 37%. Median total and unbound area under the curve from 0 to 12 h significantly decreased by 36% and 27% during pregnancy. Median total trough concentration (Ctrough) decreased significantly in the evening (28%); however, the median total Ctrough in the morning, unbound Ctrough in the morning, and unbound Ctrough in the evening showed a nonsignificant decrease of 16%, 1%, and 15%, respectively, during pregnancy compared to the postpartum period. This is the first study reporting the pharmacokinetics of unbound raltegravir during pregnancy. As unbound Ctrough did not significantly decrease during the third trimester, the pregnancy effect on raltegravir unbound concentrations was not considered clinically relevant. (This study has been registered at ClinicalTrials.gov under identifier NCT02099474.).

Dolutegravir and lamivudine maintenance therapy in HIV-1 virologically suppressed patients: results of the ANRS 167 trial (LAMIDOL).

OBJECTIVES: To evaluate the dolutegravir+lamivudine combination in virologically suppressed patients living with HIV. METHODS: The ANRS 167 LAMIDOL trial was an open-label, single arm, multicentre trial assessing once-daily dolutegravir (50 mg)+lamivudine (300 mg) in virologically suppressed HIV-1 patients on first-line triple-drug regimens. The main criteria for inclusion in the trial were plasma viral load (pVL) ≤50 copies/mL for ≥2 years, CD4 nadir >200 cells/mm3 and WT HIV prior to treatment initiation. From week -8 (W-8) to day 0 (D0) (Phase 1), the current third agent was switched to dolutegravir. From D0 to W48 (Phase 2), patients received once-daily dolutegravir+lamivudine, except if intolerant or if pVL >50 copies/mL during Phase 1. Virological failure was defined as pVL >50 copies/mL in two consecutive samples. The study was designed to show that the strategy had an efficacy of ≥80%, assuming a 90% success rate with a type I error of 5% and a power of 90%. RESULTS: In total, 104 of 110 patients enrolled in Phase 1 were included in Phase 2. These 104 patients were 86% male, 72% MSM and 87% CDC stage A. Their characteristics were (median): age 45 years, CD4 nadir 339 cells/mm3, baseline CD4 743 cells/mm3 and duration of viral suppression 4.5 years. The overall success rate at W48 was 97% (95% CI: 94%-100%), meeting the design expectation/assumption. Three therapeutic failures occurred: one virological failure at W4, one lost to follow-up at W32 and one interruption of therapeutic strategy at W40 after a blip (pVL 59 copies/mL but control pVL <50 copies/mL). Three viral blips occurred in two additional patients. Neither M184V nor integrase resistance mutations were detected after failure or blips. CONCLUSIONS: Dolutegravir+lamivudine is a promising maintenance therapy in HIV-1-infected patients with controlled virological suppression.

Signal detection on a patient cohort: A disproportionality analysis of the ANRS CO22 HEPATHER cohort to identify associations between direct acting antivirals and adverse events in patients with hepatitis C virus chronic infection.

PURPOSE: Our aim was to explore a signal detection method for early identification of potential adverse drug reactions (ADRs) in a patient cohort. METHODS: ANRS CO22 HEPATHER is a French multicentre prospective observational cohort started in 2012. The cohort includes patients with chronic hepatitis C virus (HCV) infection with reports of all adverse events (AEs) occurring in patients exposed to HCV drugs. We applied a disproportionality method, which calculated a measure of association, the Bayesian information component (IC), for each drug-AE pair. Information components were continuously updated and a positive drug-AE association was detected when the lower limit of an IC 95% credible interval (95% CI) exceeded 0. We illustrate how the method could result in timely detection of photosensitivity reaction with simeprevir use. RESULTS: By August 28, 2016, 6600 patients with HCV infection had been treated or were undergoing current HCV treatment, and 3464 experienced at least one AE for a total of 12 720 reported AEs. We detected 52 positive drug-AE associations, including 44 that were known ADRs based on the summary of product characteristics. The association between simeprevir and photosensitivity reaction was detected on June 4, 2014. At this date, 68 patients had received simeprevir and 6 photosensitivity reaction (4 during simeprevir treatment) had been reported for an estimated IC of 1.90, 95% CI, 0.20-3.61. CONCLUSIONS: The disproportionality method can help with early detection of potential ADRs in patient cohorts. Detected associations need to be confirmed by a review of clinical data.