Clinical considerations in switching antiretroviral therapy

Transcription

1 Clinical considerations in switching antiretroviral therapy David Jilich Department of Infctious Diseases, 1st Faculty of Medicine, Charles University in Prague and Na Bulovce Hospital 4th CEE Meeting on Viral Hepatitis and HIV October 11, 2018

2 Dislosures DJ has recieved honoraria for Advisory Board participation by Gilead Sciences, GSK ViiV and travel grants by Gilead Sciences

3 rg/files/guidelines_9.0- english.pdf

4 Reasons for switching toxicity intolerance DDI s comorbidities (e.g. liver or renal failure) aging/risk factors (cardiovascular, diabetes, etc.) incovenience/simplification (pill burden, bid) patient s wish/preference (STR) specific populations (drug users, pregnant women, etc.)

5 Reasons for switching (DORIVIR Study) 12,5 % 17,3 % 42,3 % 27,8 % n=104 toxicity inconvenience DDI s other Palacios et al. 2018

6 TDF vs. TAF GI TRACT PLASMA Tenofovir (TFV) Parent Nucleotide DIANION TFV TFV HIV TARGET CELL Tenofovir disoproxil fumarate (TDF) Tenofovir alafenamide (TAF) ESTER TDF 300 mg TAF 10mg T 1/2 = 0.4 min T 1/2 = 90 min TFV HIV TFV AMIDATE 91% lower TFV levels minimize renal and bone effects while maintaining high potency for suppressing HIV T 1/2 based on in-vitro plasma data 1. Lee W, et al. Antimicr Agents Chemo 2005;49(5): ; 2. Birkus G, et al. Antimicr Agents Chemo 2007;51(2):543 50; 3. Babusis D, et al. Mol Pharm 2013;10(2):459 66; 4. Ruane P, et al. J Acquir Immune Defic Syndr 2013; 63:449 5; 5. Sax P, et al. JAIDS 2014;67(1):52 8; 6. Sax P, et al. Lancet 2015 [Epub ahead of print]

7 Median (IQR) change from BL (ml/min) Studies 104 & 111 (w144) egfr BL, ml/min E/C/F/TAF E/C/F/TDF p < Week -24 * p-values calculated using 2-sided Wilcoxon rank-sum test to compare treatment groups. Arribas J et al. CROI Seattle, WA. Poster #453;

8 Intolerance Raffi F et al. J Antimicrob Chemother 2014; 69:

9 Intolerance Raffi F et al. J Antimicrob Chemother 2014; 69:

10 Lipid profiles in 48w (DOR vs. DRV/r) Molina et al. CROI 2017 Abstract 45LB

11 DDI s RAL DTG EVG/c

12 Cobicistat vs. Ritonavir Chemical structure Cobicistat Ritonavir Enzymatic inhibition CYP3A4 CYP2D6 (slabá) P-gp CYP3A4 CYP2C8 CYP2C9 CYP2D6 P-gp Enzymatic induction None CYP2B6 CYP2C9 CYP2C19 UGT1A4 P-gp Anti-HIV activity No Yes Co-administration with other antiretrovirals Yes Yes with limitations Influence of lab markers Increases serum creatinine concentration without decreasing renal function, increases lipids Increases serum lipids CYP = cytochrome P450; P-gp = P-glycoprotein; UGT = uridine 5 -diphosphoglucuronosyltransferase. Shah B, et al. Pharmacotherapy. 2013;33(10):

13 1 3 Non-boosted agents RAL EVG DTG BIC

14 DDI s in HIV/HCV co-infected persons www-hep-druginteractions.org

15 Study 1717 (Platelet Substudy) Phase 3, randomised, double-blinded, active-controlled study ABC/3TC + Third Agent HIV-1 RNA <50 c/ml for 6 months No CD4 criteria Estimated CrCL 50 ml/min No single-tablet regimen allowed sgpvi (n=545) 1:1 n=280 n=276 TAF/FTC QD Continue Third Agent ABC/3TC QD Continue Third Agent Platelet Substudy (n=61) From 4 sites in Dublin and London Week Objectives of platelet substudy and ggpvi analysis: Measure platelet reactivity using aggregometry at baseline, Week 4, Week 12 1 Collagen, TRAP, ADP, epinephrine, arachidonic acid Measure platelet surface markers at baseline and Week 12 1 GPVI, CD42b [GP1bA], P-selectin [CD62P] Measure soluble GPVI through Week 48 (whole Study 1717 population, n=545) 2 1. Mallon P, et al. CROI Boston, MA. Oral 80 ADP, adenosine diphosphate; GPVI, glycoprotein VI; TRAP, thrombin receptor-activating peptide 12

16 Průměrná % změna solubilního GPVI Solubile GPVI (Study 1717) TAF/FTC ABC/3TC TAF/FTC, n= ABC/3TC, n= Week In TAF/FTC arm, solubile GPVI significantly increases within 48 weeks Mallon P, et al. CROI Boston, MA. Poster 677LB

17 Pill burden (past vs. present)

18 Pill size (plays a role ) B/F/TAF (721 mg) E/C/F/TAF (1082 mg) DTG/ABC/3TC (1750 mg)

19 Dual therapy (in Europe) 18 Chart Title EU5 France Germany Italy Spain UK IPSOS, HIV Heathy Living 2018, poster 006

20 Female populations specifics

21 Female populations specifics

22 Female population specifics

23 Summary Switch strategy should be: individualized optimalized