Lack of a Clinically Significant Pharmacokinetic Interaction between Etravirine and Raltegravir Using an Original Approach Based on Drug Metabolism, Protein Binding, and Penetration in Seminal Fluid: A Pharmacokinetic Substudy of the <scp>ANRS</scp>‐163 <scp>ETRAL</scp> Study

Lê, Minh Patrick; Valantin, Marc‐Antoine; Assoumou, Lambert; Soulié, Cathia; Mestre, Soizic Le; Weiss, Laurence; Yazdanpanah, Yazdan; Molina, Jean‐Michel; Bouchaud, Olivier; Raffi, François; Reynes, Jacques; Cálvez, Vincent; Marcelin, Anne‐Geneviève; Costagliola, Dominique; Katlama, Christine; Peytavin, Gilles; Duvivier, Claudine; Goujard, Cécile; Jeantils, Vincent; Salmon, Dominique; Simon, Anne; Verdière, Nathalie; Morlat, Philippe; Poizot‐Martin, Isabelle; Allavena, Clotilde; Naqvi, Alissa; Bernard, Louis; Chidiac, Christian; Hamdoud, Karima

doi:10.1002/phar.2242

Cited by 4 publications

(4 citation statements)

References 27 publications

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“…Although the alcohol consumption is one of the main factors associated with non-adherence, it should to be taken with cautious in the context of the ANRS-165 ETRAL study as the total etravirine and raltegravir plasma concentrations were adequate in most patients, favoring virologic efficacy and confirming good treatment adherence (> 95%). 2,17 In conclusion, the dual regimen raltegravir/etravirine represents an effective option for patients in a context of suppressed viraemia. The emergence of mutations in case of VF in this trial was similar to that seen in other NNRTI plus INI dual regimen studies.…”

Section: Discussionmentioning

confidence: 94%

“…1 Furthermore, there was no clinically significant pharmacokinetic interaction between etravirine and raltegravir and both etravirine and raltegravir plasma concentrations were adequate in most patients of this study. 2 The aim of this analysis was to describe in details the virological rebounds (VR) defined as at least one plasma viral load (pVL) > 50 copies/mL in terms of : 1) resistance by Ultra Deep Sequencing (UDS), 2) HIV cell-associated HIV DNA changes and 3) seminal VL in the ETRAL ANRS-163 study. Furthermore, the potential factors associated with the VR were evaluated.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of viral rebounds on dual etravirine/raltegravir maintenance therapy (ANRS-163 ETRAL trial)

Soulié

Assoumou

Sayon

et al. 2020

Journal of Antimicrobial Chemotherapy

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Background The ANRS-163 ETRAL trial, a switch study to an etravirine 200 mg/raltegravir 400 mg twice-daily regimen in 165 patients with HIV-1 infection, showed durable efficacy until Week 96. The aim of this work was to investigate in detail the virological rebounds (VRs), defined as at least one plasma HIV viral load (VL) >50 copies/mL. Methods Quantification of HIV-DNA level was assessed at baseline, Week 48 and Week 96 (n = 157). VLs were measured in seminal plasma at Week 48 (n = 26). Genotypic resistance testing by ultra-deep sequencing (UDS) for reverse transcriptase (RT) and integrase regions was performed at baseline and at the time of VR. Results In this study, 19 patients experienced VR, with 2 patients having virological failure (VF; two consecutive VLs >50 copies/mL). For the first patient with VF, UDS detected minority resistant variants only in RT (K103N, 9.6%; Y181C, 4.9%) at baseline. Some RT variants became dominant at VF (K101E, 86.3%; Y181C, 100.0%; G190A, 100.0%) and others emerged in integrase (Y143C, 2.4%; Q148R, 6.2%; N155H, 18.8%). For the second patient with VF, neither RT nor integrase mutations were detected at baseline and VF. Median HIV-DNA level was similar at baseline, Week 48 and Week 96 (2.17, 2.06 and 2.11 log10 copies/106 cells, respectively). Only one patient had a detectable seminal HIV VL (505 copies/mL). Conclusions The dual etravirine/raltegravir regimen as maintenance therapy was effective and the emergence of mutations in cases of VF was similar to that seen in other dual-regimen studies. No HIV-DNA level modification was evidenced by Week 96.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Characterization of viral rebounds on dual etravirine/raltegravir maintenance therapy (ANRS-163 ETRAL trial)

Soulié

Assoumou

Sayon

et al. 2020

Journal of Antimicrobial Chemotherapy

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“…Plasma concentrations of etravirine and raltegravir were determined by ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS; Waters Acquity UPLC-TQD, Milford, MA). 8 The limit of quantification was <5 ng/ml for both drugs, and interpretation was based on the corresponding in vitro protein-adjusted 95% inhibitory concentration (PBIC95) for wild-type (WT) HIV-1: 116 ng/ml for etravirine 9 and 15 ng/ml for raltegravir. 10 Etravirine and raltegravir C24h were considered to be adequate if above the respective PBIC95.…”

Section: Data Collectionmentioning

confidence: 99%

“…Results of pooled C24h of etravirine and raltegravir over the study period are presented as median (interquartile range [IQR]) values and compared with the historical data of q12h regimen. 8…”

Section: Data Collectionmentioning

confidence: 99%

Once-daily etravirine/raltegravir (400/800 mg q24h) dual therapy maintains viral suppression over 48 weeks in HIV-infected patients switching from a twice-daily etravirine/raltegravir (200/400 mg q12h) regimen

Palich

Allavena

Peytavin

et al. 2020

Journal of Antimicrobial Chemotherapy

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Background Etravirine/raltegravir dual therapy has been shown to be highly effective as a twice-daily (q12h) regimen in suppressed HIV-infected patients enrolled in the ANRS-163 study. Objectives As a once-daily (q24h) regimen is easier for daily life, we aimed to evaluate the capacity of etravirine/raltegravir (400/800 mg) q24h to maintain viral suppression in patients on etravirine/raltegravir q12h. Methods Patients on a suppressive etravirine/raltegravir q12h regimen for at least 96 weeks were switched to etravirine/raltegravir q24h in this prospective, multicentre, open-label, single-arm study. Primary outcome was the rate of virological failure (VF: confirmed pVL >50 copies/mL, single pVL >400 copies/mL or single pVL >50 copies/mL with ART change) at Week 48 (W48). Secondary outcomes included treatment strategy success rate (no VF and no treatment discontinuation), regimen tolerability, plasma drug concentrations and resistance profile in the case of VF. Results A total of 111 patients were enrolled, with a median (IQR) age of 57 years (52–62), CD4 count of 710 cells/mm3 (501–919) and viral suppression for 7.9 years (5.9–10.7). Two patients experienced viral rebound at W24 and W48, leading to a VF rate of 2.0% (95% CI 0.5–7.8) at W48, associated with INSTI resistance in one case. Both had past NNRTI mutations. Ten patients discontinued treatment for adverse events (n = 2), investigator or patient decisions (n = 3), lost to follow-up (n = 3), death (n = 1) or pregnancy (n = 1). Overall, the strategy success rate was 89% (95% CI 81.5–93.6) at W48. In a subgroup of 64 patients, median (IQR) plasma C24h concentrations were 401 ng/mL (280–603) for etravirine and 62 ng/mL (31–140) for raltegravir. Conclusions Switching patients virally suppressed on etravirine/raltegravir q12h to the same regimen but given q24h was highly effective in maintaining virological suppression in HIV-infected patients.

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Membrane Transporters and Carriers in Human Seminal Vesicles

Malinowski

Grzegółkowski

Piotrowska

et al. 2022

JCM

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Seminal vesicles play an important role in the male reproductive system, producing seminal fluid and thus adequate environment for sperm. However, mechanisms underlying secretory functions of the seminal vesicles’ epithelium have not been defined yet. The aim of the present study was to characterize expression and immunolocalization of selected membrane transporters and carriers in the seminal vesicles. The study included biopsy specimens collected from non-affected parts of seminal vesicles from 53 patients of Caucasian origin subjected for prostatectomy. RT-PCR was used to define expression of 15 genes coding for ABC-family and 37 genes encoding 37 SLC-family transporters/carriers. Immunohistochemistry was used to define localization of 6 transporters. In the seminal vesicles, the following membrane transporters and carriers were defined: ABCA1, ABCB1, ABCB5, ABCB6, ABCC1, ABCC2, ABCC3, ABCC4, ABCC5, ABCC6, ABCG2, SLC01C1, SLC02B1, SLC04A1, SLC04C1, SLC10A1, SLC15A1, SLC15A2, SLC16A1, SLC16A3, SLC19A1, SLC22A1, SLC22A3, SLC22A11, SLC22A18, SLC22A4, SLC22A5, SLC28A1, SLC2A9, SLC33A1, SLC47A1, SLC47A2, SLC51A, SLC51B, SLC7A5, SLC7A6. Age-dependent expression was evidenced for ABCB1, ABCG2, SLC04C1, SLC15A1, SLC16A1, SLC22A11, SLC22A18, SLC47A1 and SLC47A2. ABCG2, P-gp, MRP1, MRP3, MCT1 and LAT1 were localized in the apical membrane and P-gp in the basolateral membrane of the seminal vesicle epithelium. The expression of the membrane transporters and carriers in the seminal vesicle epithelium confirms its secretory and barrier functions.

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Lack of a Clinically Significant Pharmacokinetic Interaction between Etravirine and Raltegravir Using an Original Approach Based on Drug Metabolism, Protein Binding, and Penetration in Seminal Fluid: A Pharmacokinetic Substudy of the ANRS‐163 ETRAL Study

Cited by 4 publications

References 27 publications

Characterization of viral rebounds on dual etravirine/raltegravir maintenance therapy (ANRS-163 ETRAL trial)

Characterization of viral rebounds on dual etravirine/raltegravir maintenance therapy (ANRS-163 ETRAL trial)

Once-daily etravirine/raltegravir (400/800 mg q24h) dual therapy maintains viral suppression over 48 weeks in HIV-infected patients switching from a twice-daily etravirine/raltegravir (200/400 mg q12h) regimen

Membrane Transporters and Carriers in Human Seminal Vesicles

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