5/17/2018 UPDATE ON ANTIRETROVIRAL THERAPIES Dr. Alftan D. Dyson, PharmD, BCACP, AAHIVP Director of Pharmacy Services Medical Advocacy and Outreach (MAO) Disclosures ■ Janssen Therapeutics- Community Speaker’s Bureau ■ Viiv Healthcare- Pharmacy Advisory Board Learning Objectives ■ Identify newly approved ART regimens and discuss appropriate use of these agents ■ Describe new approaches for treating PLWH 1
5/17/2018 KNOWING THE PAST TO UNDERSTAND THE PRESENT AND PLAN FOR THE FUTURE ABC/3TC, TDF/FTC (‘04) TAF/FTC, RPV + TAF + FTC Lopinavir +Ritonavir DTG + ABC FDC RPV, RPV + +3TC (‘16) Darunavir, TDF +FTC (‘14) ABC + AZT +3TC STR EFV (‘11) +TDF +FTC (‘06) AZT + 3TC Enfuvirtide, ELV + COBI + Atazanavir, TDF + FTC ELV + COBI + RAL, SELZ FTC (‘03) EFV, ABC (‘98) (‘12) TAF + FTC, ATZ (‘09) DTG, RPV AZT Approved + COBI, DRV + (‘17) COBI DTG TDF (‘01) Ritonavir (‘13) (‘96) HIV-1 Discovered AIDS Reported 1981 1984 1987 1990 1995 2000 2005 2010 2015 NOW Beyond… Initial ART Selection A. Boosted DRV plus tenofovir/FTC B. DTG/ABC/3TC C. DTG plus tenofovir/FTC D. EVG/c/tenofovir/FTC E. RPV/tenofovir/FTC F. RAL HD/tenofovir/FTC G. I like something else H. It depends NEW OPTIONS FOR INITIAL TREATMENT 2
5/17/2018 Bictegravir/TAF/FTC ■ Indications: Indications: Indications: Indications: – Initial treatment in adults with HIV infection – Replacement therapy in persons who have achieved virologic suppression (<50 copies per mL) for at least 3 months and have no history of treatment failure or known resistance to its components ■ Pharmacology and dosing: Pharmacology and dosing: Pharmacology and dosing: Pharmacology and dosing: – One-pill, once a day, with or without food – Half-life 17.3 hours – Excretion- feces 60.3%, urine 35%; Not recommended if CrCL <30 mL/minute ■ Drug resistance: Drug resistance: Drug resistance: Drug resistance: – Active in vitro against HIV isolates that carry some integrase resistance mutations – Efficacy in people with prior INSTI failure or resistance is unknown https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210251s000lbl.pdf, http://www.gilead.com/~/media/files/pdfs/medicines/hiv/descovy/descovy_pi.pdf?la=en Bictegravir/TAF/FTC ■ Drug Drug- -Drug Interactions: Drug Interactions: Drug Drug - - Drug Interactions: Drug Interactions: – Contraindications: Rifampin; Dofetilide Contraindications: Contraindications: Contraindications: – Special considerations: Special considerations: Special considerations: Special considerations: – Medications or oral supplements containing polyvalent cations; 2 hours before antacids, simultaneously with food with Ca++ or FeSO4 supplements – Metformin AUC increased 39%; assess risk vs. benefit ■ Side effects: Side effects: Side effects: Side effects: – Diarrhea, nausea and headache – Inhibition of tubular secretion � increase in serum creatinine (median 0.1 mg/dL) https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210251s000lbl.pdf, http://www.gilead.com/~/media/files/pdfs/medicines/hiv/descovy/descovy_pi.pdf?la=en Bictegravir/TAF/FTC: Treatment Naïve Trials -- -- 3.5% -- -- 3.5% 3.5% 3.5% Study 1489 1,2 (- ( - 7.9 to 1.0%) 7.9 to 1.0%) - ( ( 7.9 to 1.0%) - 7.9 to 1.0%) B/F/TAF (n=320) -0.6% (-4.8 to 3.6%) B/F/TAF (n=314) 100 92.9 100 ABC/3TC/DTG (n=315) 93.0 93.0 89.4 92.4 92.4 92.4 92.4 93.0 93.0 ABC/3TC/DTG (n=315) 80 80 Proportion of Participants, % Proportion of Participants, % Proportion of Participants, % Proportion of Participants, % 60 60 40 40 20 20 6.7 6.7 6.7 6.7 6.3 5.8 4.4 4.4 4.4 4.4 4.4 2.5 2.5 2.5 2.5 1 1 1 1 1.2 0 0 HIV-1 RNA HIV-1 RNA No HIV-1 RNA HIV-1 RNA No HIV-1 RNA HIV HIV HIV HIV- - -1 RNA 1 RNA 1 RNA - 1 RNA ≥ 50 c/mL ≥ 50 c/mL < 50 c/mL Data < 50 c/mL < 50 c/mL < 50 c/mL < 50 c/mL Data BIC non-inferior to DTG- containing regimen in terms of virologic suppression at Week 48 1,2 Gallant J et al, Lancet 2017; Sax P et al Lancet 2017 3
5/17/2018 Bictregravir (BIC) ■ Unboosted Integrase Inhibitor (INSTI) ■ High genetic barrier to resistance ■ Low potential for drug-drug interactions ■ Co-formulated with TAF/FTC A.C. ■ 32 y/o AAF diagnosed with HIV 3 years ago after ex-husband passed away from AIDS- related illness. Tx naïve, “doesn’t like taking pills.” Urged to come in by new partner who is not HIV-infected. ■ PMH: HTN- previously on medication, but took it intermittently and finally stopped completely ~ 5 months ago. Depression- untreated ■ SH: Single mother with 3 small children (6mo,2y,8y); some assistance from family members; Works as a manager at a fast food restaurant, works all shifts; limited transportation; no tob, ETOH, or illicit drug use. 4
5/17/2018 Bictegravir/TAF/FTC: Virologically Suppressed Switch ■ Randomized switch studies in virologically suppressed persons: – Switching to BIC/FTC/TAF non-inferior to continuing boosted PI 1 or a DTG, ABC, 3TC-containing regimen 2 1 Daar E et al IDWeek2017; 2 Molina J-M et al, CROI 2018 abstract 22 K.B. ■ 20 y/o AAM presents for initial visit after being diagnosed 2 weeks ago. He decided to get tested after he learned that his current partner has been living with HIV since 2006. He goes on to share that since his diagnosis, he and his partner now communicate more regularly about HIV. His partner has been helping him learn about different treatment options, and suggested K.B. start with one pill, but stay away from “the one that causes weird dreams.” You also learn that K.B.’s partner had problems with adherence on ”that one.” ■ PMH: No history ■ SH: In a monogamous relationship now, currently a junior in college studying music, smokes ½ ppd, social drinker, lives off fast food Doravirine (DOR) ■ New NNRTI ■ Active in vitro against HIV that is resistant to first-generation NNRTI (K103N, Y181C, G190A, E138K, K103N/Y181C) 1 ■ Metabolized by CYP3A4, but not an inhibitor or inducer ■ Not impacted by PPIs ■ No specific food requirements 1 Lai AAC 2014;58:1652-1663 5
5/17/2018 DRIVE-AHEAD: DOR/3TC/TDF in Treatment-Naïve PLWH Doravirine/3TC/Tenofovir DF (n=364) Phase 3 Efavirenz/FTC/Tenofovir DF (n=364) Double-blind, Randomized 1:1, 96 Wk Week 0 48 96 HIV RNA ≥1000 copies/mL Primary Endpoint Stratified by: HIV RNA <50 copies/mL • HIV RNA (</> 100K) and Doravirine/3TC/TDF Efavirenz/FTC/TDF • Hepatitis B/C co-infection 100 Difference (%): 91% 91% 3.5 (-2.0, 9.0) 84% 81% 81% 81% • Primary outcome: HIV RNA <50 copies/mL (FDA snapshot algorithm) 80 • Non-inferior efficacy � DOR (84%); EFV (81%) Patients (%) 60 • Virologic failures in DOR arm (6%) � Primary NNRTI resistance: (1.6%) � Primary NRTI resistance (1.4%) 40 • Superior safety profile for neuropsychiatric events and lipids 20 0 DOR/3TC/FDF and DOR submitted Jan 2018, PDUFA Oct 2018 Overall ≤ 100K >100K ITT (n=277/258) (n=69/73) (n=364/364) HIV RNA (copies/mL) (Observed Failure Approach) Squires KE, et al. J Int AIDS Soc . 2017;20(suppl 4):110-111. Abstract TUAB0104LB; Orkin C et al, CROI 2018, abstract 491 DRIVE with DORAvirine ■ DRIVE DRIVE DRIVE DRIVE- -AHEAD - - AHEAD AHEAD AHEAD – DOR/3TC/TDF vs. EFV/FTC/TDF ■ DRIVE- DRIVE -FORWARD FORWARD DRIVE DRIVE - - FORWARD FORWARD – DOR vs. DRV/r (non-inferior, lipids) ■ DRIVE DRIVE DRIVE DRIVE- - -SHIFT - SHIFT SHIFT SHIFT – Switch to DOR/3TC/TDF AMBER: PI-based STR for Initial Therapy ■ Phase 3 randomized, double-blind study designed to assess safety and efficacy of DRV/c + 3TC/TAF vs. DRV/c + 3TC/TDF ■ Primary endpoint: non-inferiority of STR vs. control to achieve vial suppression (VL < 50 copies/mL) at 48 weeks D/C/F/TAF (N= 362) Control (N= 363) 100 91.4% 88.4% 80 Patients (%) 60 40 AE leading to D/C- Rash @ 2% One- M184V 20 8.3% 4.4% 3.3% 4.1% 0 Virologic VL > 50 c/mL No virologic data response (VL <50 c/mL) Orkin EACS 2017 6
5/17/2018 Early Initiation/Rapid Start/TNT ■ No, we need resistance testing before initiating treatment. ■ Yes, my preferred regimen is Boosted DRV/tenofovir/FTC. ■ Yes, my preferred regimen is DTG/ABC/3TC. ■ Yes, my preferred regimen is DTG/tenofovir/FTC. ■ No, I prefer to schedule to patient for a visit later to begin treatment. ■ What, people do that? Challenging Tradition: 2-drug Therapies Nukes getting Nuked? ■ Initial therapy – LPV/r + 3TC (GARDEL) – DRV/r + RAL (NEAT001) – DTG + 3TC (PADDLE; ACTG A5353; GEMINI-1,2) – DRV/r +3TC (ANDES) ■ Switch therapy – LPV/r + 3TC/FTC (OLE) – ATV/r + 3TC (SALT, ATLAS-M) – DRV/r + 3TC (DUAL) – DRV/r + RPV – DTG + RPV – DRV/r + DTG (DUALIS)* – DTG + 3TC (LAMIDOL, ASPIRE, TANGO*) * Currently being studied 7
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