Poster Dolutegravir in the French Named Pa5ent Program* in Integrase HIV-‐2 Resistant Infected Pa5ents 572 Diane Descamps,1-‐3 Gilles Peytavin,1,2,4 Florence Damond,1-‐3 Roland Tubiana,5 Pauline Campa,6 Marie-‐Aude Khuong-‐Josses,7 Claudine Duvivier,8 Marina Karmochkine,9 Tuna Lukiana,10 Sophie Matheron1, 2, 11 Diane Descamps +33140256150 [email protected] 1IAME, UMR 1137, Univ Paris Diderot, Sorbonne Paris Cité, F-‐75018, Paris, France; 2 IAME, UMR 1137, INSERM, F-‐75018 Paris, France; 3AP-‐HP, Hôpital Bichat-‐Claude Bernard, Laboratoire de Virologie, F-‐75018 Paris, France; 4AP-‐HP, Hôpital Bichat,-‐Claude Bernard, Laboratoire de Pharmaco-‐Toxicologie, F-‐75018 Paris, France; 5AP-‐HP, Hôpital PiSé-‐Salpêtrière, Service des Maladies InfecSeuses et Tropicales F-‐75013 Paris, France; 6AP-‐HP, Hôpital Saint-‐Antoine, Service des Maladies InfecSeuses et Tropicales F-‐75011 Paris, France; 7 Hôpital Delafontaine, Service des Maladies InfecSeuses et Tropicales, Saint-‐Denis, France; 8 AP-‐HP, Hôpital Necker, Service des Maladies InfecSeuses et tropicales, Centre d’InfecSologie Necker-‐Pasteur, F-‐75015, Paris, France; 9AP-‐HP, Hôpital Européen Georges Pompidou, Service d’Immunologie Clinique, F-‐75015, Paris, France; 10 ViiVhealthcare, F-‐78163, Marly le Roi, France; 11AP-‐HP, Hôpital Bichat-‐Claude Bernard, Service des Maladies InfecSeuses et Tropicales, F-‐75018 Paris, France. Table 1. Pa5ents characteris5cs and immuno-‐virological response to dolutegravir containing regimens at M3 and M6 Pts Age (Years) Introduc5on Dura5on of Gender known HIV-‐2 (M/F) infec5on (Years) DTG containing ARV Regimens GSS Dolutegravir (DTG) is a second genera5on integrase inhibitor (INSTI), ac5ve in pa5ents harboring first-‐genera5on INSTI resistant virus DTG has shown in vitro ac5vity on HIV-‐2 isolates In France, DTG was available before the market authorisa5on in a named pa5ent program (NPP / ATUn*) in salvage therapy We report preliminary safety and efficacy data of DTG containing regimens in HIV-‐2 infected pa5ents with virological failure. Methods 1 2 3 4 5 6 7 8 9 10 11 12 13 53 43 52 48 53 54 69 51 50 33 58 64 51 M M M M M M M F F M M M F 9 15 9 22 13 10 20 20 2 11 24 15 22 ZDV/3TC/DRV/r/FOSC TDF/FTC/LPV/SQV/r ZDV/ABC/3TC/DRV/SQV/r/FOSC ZDV/3TC/DRV/r/FOSC DRV/r/MVC/FOSC 3TC/DRV/r/MVC/FOSC ZDV/3TC/DRV/r/MVC DRV/SQV/r DRV/r/MVC ABC/DRV/r TDF/ddI/DRV/r ABC/3TC/DRV/r TDF/FTC/DRV/r 3 2 3 1 2 2 2 1 1 2 3 2 1 Baseline Month 3 Results Month 6 Plasma RNA (c/ml) CD4 (/mm3) Plasma RNA (c/ml) CD4 (/mm3) Plasma RNA (c/ml) CD4 (/mm3) 46760 23120 1280 3096 26060 138400 9544 3050 18630 800 3998 21199 5741 439 85 100 53 157 62 138 171 355 77 27 97 200 456 <40 <40 376 <40 11440 1119 <40 <40 <40 5407 1450 6083 324 181 132 76 157 45 168 157 342 109 NA 34 207 3170 <40 <40 807 <40 9991 6715 <40 323 NA 4795 20206 3995 450 NA 140 46 320 174 118 159 616 NA NA NA NA NA: non available Table 2. Baseline paaerns of protease, RT and integrase associated muta5ons and tropism Genotypic Sensi5vity Score (GSS) was: GSS =3 (n=3), GSS =2 (=6) and GSS =1 (n=4). Baseline pakerns of protease, RT and integrase associated muta5ons and tropism are depicted on Table 2. Available integrase genotypic resistance pakerns were: Y143C/G/H/R (n=5), Q148K/R/S (n=2), N155H (n=4). At M3 and M6 plasma HIV-‐2 RNA was undetectable in 6/10 and 4/11 pa5ents respec5vely, and median CD4 cells count was 158/mm3 (101-‐188) and 166/mm3 (135-‐353). All pa5ents (4/4) with integrase resistance pakern Y143C/G/H/R (n=5) had an undetectable plasmaHIV-‐2 RNA at M6 (n=4, one missing data). Dolutegravir plasma concentra5ons (C12h) are presented on Figure 1. Despite the small number of samples, DTG C12h in pa5ents with plasma HIV-‐2 RNA < 40 copies/ml were above than those with detectable plasma HIV-‐2 viral load at Month 6. PR RT INI discon5nua5on. Figure 1. Dolutegravir Plasma concentra5ons (ng/ml) according to plasma HIV-‐2 RNA at Month 6 Tropism 1 10I, 46L, 47A, 71I, 84V, 89V, 90M 65R 155H X4 2 3 53L, 54L, 71I 10I, 47A, 71I, 84V, 90M NA 184V 97A, 143C/G 97A, 143H/R, 157Q X4 X4 4 54M, 71I, 82F, 90M 65R, 70R, 151M 72I, 155H X4 5 6 7 8 9 10I, 50V, 71I, 82F, 89V, 90M 54M, 71I, 82F, 89V, 90M 54M, 71I, 84V, 90M 50V, 54L, 71I, 90M 10I, 50V, 54M, 71I 67N, 115F, 151M, 184V 65R, 67M, 151M, 184V 65R, 69S, 184V, 65R, 151M,184V 65R, 70R, 115F, 184V 97A, 143G 92Q, 155H, 157Q 140S, 148R 72I, 97A, 143R 92Q, 155H R5 R5 NA R5 X4 10 11 12 13 71I 54M, 71I, 82F, 90M 10I, 50V, 89V 15V, 54M 184V 67N, 184V, 215Y 184V, 215Y 65R, 151M, 184V 72I, 97A, 143R 147G NA 140S, 148K X4 X4 X4 X4 Conclusions 9000 DTG Plasma C12h (ng/ml) Pts NA: non available *Authorisa5on for Temporary Use by name prescrip5ons were in the NPP. Median dura5on of HIV-‐2 known infec5on was 15 years (10-‐20) and median follow up was 9 months (min: 3 -‐ max: 15). HIV-‐2 groups were: A (n=9), B (n=3) and H (n=1) . HIV-‐2 tropism was genotypically predicted as CCR5 in 3 pa5ents. Baseline median plasma HIV-‐2 RNA and CD4 cells count values were 9,544 cp/mL (3,096-‐23,120) and 100 cells/mm3 (77-‐171), respec5vely. Op5mized background ARV regimens, included: DRV/r (n=12), SQV/r (n=2), MVC (n=3) associated with NRTIs. Dual boosted PI regimens consis5ng in DRV/SQV/r and LPV/SQV/r were administered in two pa5ents (pts 2 and 3). Five pa5ents received in addi5on foscarnet induc5on treatment (FOSC), 4 of whom with ZDV, and one received in induc5on FOSC with ZDV just before DTG instaura5on (pa5ent 8). One pa5ent died from progressive mul5focal leukoencephalopathy at M4. No other serious clinical or biological events led to DTG Data from all HIV-‐2 infected pa5ents with virological failure to raltegravir, receiving DTG 50 mg bid with op5mized background an5retroviral (OB ARV) regimens were collected from the NPP. Plasma HIV-‐2 RNA was performed at 5me of DTG ini5a5on (baseline), Month 3 (M3) and M6. Cumula5ve genotypic resistance tests (current and historical) were interpreted according to the last version of ANRS algorithm (v23). DTG plasma concentra5ons were measured, on the same samples than plasma HIV-‐2 RNA, using Ultra Performance Liquid Chromatography combined with tandem mass spectrometry (UPLC-‐MS/MS) (Waters Corpora5on Milford, MA, USA) (LOQ < 5 ng/ml) [Jung et al, 2007]. Demographic, biological and therapeu5c characteris5cs were recorded. Medians (IQR) were presented. Pa5ents baseline characteris5cs are summarized in Table 1. A total of 13 HIV-‐2 infected pa5ents (10 males and 3 females) with a median age of 51 years (50-‐54) and having received 16 previous ARV 8000 These preliminary results demonstrated that DTG-‐containing 7000 6000 5000 5,436 ng/ml (3,987-‐6,730) 4000 2,687 ng/ml (1,377-‐4,740) 3000 2000 Larger pa5ent numbers and longer follow-‐up are needed to confirm these findings. 1000 0 Plasma HIV-‐2 RNA N C12h N pa5ents regimens provide a substan5al efficacy rate for salvage therapy in heavily ARV-‐experienced HIV-‐2–infected pa5ents with virus harboring resistance to first-‐genera5on INSTIs. < 40 copies/ml 10 3 > 40 copies/ml 17 7 21st Conference on Retroviruses and Opportunis5c Infec5ons; March 3-‐6, 2014; Boston, MA Reference Jung BH, Rezk NL, Bridges AS, Corbek AH, Kashuba AD. Simultaneous determina5on of 17 an5retroviral drugs in human plasma for quan5ta5ve analysis with liquid chromatography-‐tandem mass spectrometry. Biomed Chromatogr 2007; 21:1095-‐1104 Acknowledgments, We acknowledge the Agence Na5onale de Recherche sur le SIDA et les Hépa5tes virales (ANRS) and ViiV Healthcare
© Copyright 2024 ExpyDoc
