12/8/18 Outline of talk • Review new antiretroviral medications recently approved, including single pill combinations St State of of th the Art t on on ART • Two new medications here or close for very experienced patients • Review new paradigms in HIV medicine Medical Management of AIDS, CME course • Two drug therapy • Switches December 6, 2018 • Barriers to resistance • Predictors of doing well on 2-drug therapy Monica Gandhi MD, MPH • (Injectables) Medical director, Ward 86 HIV Clinic • (No financial disclosures) =Division of HIV, Infectious Diseases, and Global Medicine Case #1 ARS: AR S: What t is th the regimen you ou wou ould ch choos oose for this patient? fo • 52 yo man diagnosed with HIV 30 years ago • AZT/3TC then AZT/3TC/nevirapine then TDF/FTC + efavirenz in 1. BIC/TAF/FTC 2002 (and single pill combination in 2007) 2. DRV/cobi/TAF/FTC • Had off-and-on problems with adherence and viral load Genotype shows detectability over time with emergence of M184V, K103N, Y181C, 3. DRV/cobi/TAF/FTC + doravirine Y181C, K103N, D67N and switched to RAL/ETR/TDF/FTC in 2008 (declined PI) M184V, D67N in the 4. DTG/RPV + DTG extra dose RT gene; N155H in • Pt liked regimen and initially did well but then low-grade viremia 5. DRV/cobi/TAF/FTC + DTG BID recently, admits to missed doses – usually low-grade but when the integrase gene >500 copies/mL, able to genotype and shows K103N, M184V, 6. DRV/cobi/TAF/FTC + DTG daily D67N in the RT gene; N155H in the integrase gene • Pt finally agrees to regimen change but ideally wants once daily
12/8/18 Bictegravir/TAF/FTC approved February 8, 2018 ARS: AR S: What t are th the 4 4 mos ost t rece centl tly-ap approved HIV HI V me meds ds (all in n 2018)? PROS CONS • Data only in naives • INSTI-based 1. Bictegravir/TAF/FTC, fostemsavir, dolutegravir/TAF/FTC, ibalizumab and switch mandated • Well tolerated to date no historical genotype 2. Fostemsavir, ibalizumab, bictegravir/TAF/FTC, doravirine (±TDF/3TC) • Single pill with resistance 3. Doravirine (±TDF/3TC), DRV/cobi/TAF/FTC, bictegravir/TAF/FTC, • Small pill • Do not yet know ibalizumab • TAF/FTC as backbone signature mutations 4. DRV/cobi/TAF/FTC, cabotegravir, doravirine (±TDF/3TC), so no pre-testing (e.g. • Can’t use bictegravir bictegravir/TAF/FTC no HLA-B5701) nor TAF with rifampin 5. Fostemsavir, ibalizumab, doravirine, bictegravir • Limited real-world data Gallant J. Lancet HIV 2017; Sax P. Lancet HIV 2017; Molina J. CROI 2018; Daar E. Lancet HIV 2018; Andreatta K CROI 2018 B/F/TAF Phase 3 Efficacy through Weeks 48 to 96 Archived genotype resistance and bictegravir switch Study Population Comparator Efficacy Resistance DTG/ABC/3TC (96 weeks data ID • We do not know signature mutations of BIC (In vitro data for DTG suggested 1489 Naïve Non-inferior 0 week 2018) R263K/G188R were major mutations, clinical data from VIKING identified Q148 1 ) DTG+FTC/TAF (96 week data HIV • Switch studies (1844, 1878) – excluded patients with h/o historical resistance to 1490 Naïve Non-inferior 0 Drug Therapy, Glasgow 2018) TDF/(3)FTC/ABC/DTG (71% had historical genotypes) 1844 Suppressed DTG/ABC/3TC Non-inferior 0 • Retrospectively performed Archive genotypes on some patients in the 1844, 1898 switch studies (collected whole blood at baseline visit) 2,3 0 to INSTI but 1 1878 Suppressed Boosted PI + 2 NRTIs Non-inferior L74V in PI arm • We don’t archive in clinical care 0 to INSTI but 1 1961 E/C/F/(TAF or TDF) Suppressed Non-inferior M184V in (women) ATV+RTV + FTC/TDF ELV/cobi arm Have data from 2 naïve studies and switch studies in suppressed patients but no data among patients with baseline resistance yet (have some data with archive Genosure sequencing, but not used in clinical practice like historical genotype data). Real-world practice will help define Glasgow analysis similar but looked at M184V only (15% in archived genotypes) this, as will trials in patients with resistance like SAILING, VIKING with DTG) 1 Castagna JID 2014; 2 Andreatta K CROI 2018; 3 Andreatta K Gallant J. Lancet HIV 2017; Sax P. Lancet HIV 2017; Molina J. CROI 2018; Daar E. Lancet HIV 2018; Kotyo CROI 2018; Wohl D; ID week 2018 7 Glasgow 2018 LB4; Andreatta K CROI 2018; Andreatta. Glasgow 2018
12/8/18 Bottom line on BIC/TAF/FTC Case #1 (continued) § Potent INSTI-based single pill combination (potent, well-tolerated) with TAF/FTC backbone § You think about DRV/cobi/TAF/FTC + DTG BID but the patient § Patients without resistance : Naïve studies and switch REALLY does not want BID studies indicate non-inferior to DTG or PI-based § Also, he tells you firmly that he is “addicted to Maalox” and regimens without h/o resistance or virologic failure will never change that § Patients with resistance : Will need post-marketing surveillance data to understand potency in face of underlying NRTI resistance or prior INSTI mutations (had SAILING 1 and VIKING 2 studies, respectively, for dolutegravir prior to approval for these indications) 1 Cahn P. Lancet 2013; 2 Castagna A. JID 2014 Cations and INSTIs AR ARS: S: Is it t ok okay to o co-ad administer al aluminum an and DT DTG? RAL à 400mg and 600mg HD formulation – Space out from Ca/Fe supplements (RAL first); 1. No, never don’t give with antacids– WAIT 2. Yes, but you must space them out for CATS (no acid) ELV–> Space out from all x 2 3. Yes, if you take with food hours (ELV first) – WAIT for CATS 4. Oh no- cations and INSTIs! What is it again? DTG and BIC à Can take with Ca or Fe supplement with meal; space out from antacids– FEED YOUR CATS (wait for acid) Mathias. Glasgow 2018. Abstr P260; Song J. Clinical Pharm. 2015
12/8/18 Single pill PI-based Combination ( Symtuza ™) DRV/cobi/TAF/FTC approved July 12, 2018 EMERALD: Switch to DRV/Cobi/FTC/TAF PROS CONS 763 • DRV has the highest • PI-based and has cobi genetic barrier to booster resistance of ARVs • DRV trough with • First PI single pill DRV/cobi lower than • 10mg of TAF so no with DRV/RTV 378 more 25mg TAF with • Use a PI when you • Objective: Assess efficacy (non-inferiority) and safety of switching to DRV/cobi need a PI only, not D/C/F/TAF vs. continuing boosted-PI + F/TDF regimens in suppressed pts • Works against NRTI- 1st-line • Key inclusion criteria: resistant virus – On stable bPI + F/TDF regimen for at least 6 months Orkin et al, Lancet HIV, 2018; Eron J. ID Week 2018 (EMERALD) – Viral load (VL) <50 for ≥2 months before screening – Previous ART virologic failure (VF) allowed Orkin et al, Lancet HIV, 2018 and package insert; Eron et al. CROI 2018 abs 502; Kakuda T et al. JAC 2014; Orkin C. – Absence of history of VF on DRV, and if historical genotype available, absence of DRV RAMs Glasgow 2018 EMERALD: D/C/F/TAF Switch (Week 48 & 96) Bottom line on DRV/cobi/TAF/FTC Most rebounders (12/19 week 48 and 14/24 week 96) • Switch was non-inferior § DRV-based regimens are listed as alternative on resuppressed (<50) • Not strict criteria for switch study DHHS and IAS-USA guidelines but indicated when – 58% had ≥5 prior ARV regimens non-adherence suspected – 15% had prior VF § Patients without resistance : Used when non- – No DAMs but could have resistance to TDF or 3TC adherence or variable adherence is of concern – (Bictegravir switches – genotypic resistance to given high genetic barrier to resistance. Of note, TDF/TAF/3TC/ABC excluded; SWORD or STRIIVING DRV trough with DRV/cobi lower than with DTG switch -resistance to any class excluded) DRV/RTV 1 – In few failures, NO resistance to any study drugs emerged § Patients with resistance : Good data from EMERALD study 2 on efficacy of DRV/cobi/TAF/FTC • D/C/F/TAF safe- no benefit in renal even in setting of lots of prior experience (only biomarkers, but was benefit in bone Per package insert: 7 subjects had h/o TDF- associated resistance mutations; 53 had h/o excluded DAMS; allowed TDF, 3TC resistance) biomarkers 3TC (mainly M184). All suppressed 1 Kakuda T. JAC 2014; 2 Orkin Lancet HIV 2018 (darunavir package insert) Orkin et al, Lancet HIV, 2018; Eron J CROI 2018; Eron J ID week 2018
Recommend
More recommend
