State of the art of ART Medical Management of AIDS December 7, 2017 - PDF document

No disclosures “State of the art” of ART Medical Management of AIDS December 7, 2017 Monica Gandhi MD, MPH Professor of Medicine, Division of HIV, Infectious Diseases and Global Medicine, UCSF Medical Director, “Ward 86”, San Francisco General Hospital Outline Ascent of the integrase inhibitor • Raltegravir once daily • Dolutegravir’s limitations • Darunavir/ritonavir- DHHS demotion deserved? • Bictegravir coming • Drug drug interactions Ascent of the integrase inhibitors 2-drug starts or simplifications New single pill combinations In all of the rush, remember cobicistat ≠ ritonavir New: Doravirine, monoclonal Abs 1

ONCEMRK: Raltegravir 1200mg daily ~ Dolutegravir: 400mg BID in naives Good drug but difficult year Cahn P. Lancet HIV 2017; Di Perri G, . EACS 2017. Abstract BPD1/3 Raltegravir HD (600mg) approved 5/17 (96 week data) DOMONO: Switch to DTG monotherapy ARS: How does DTG compare to PIs Single center Netherlands- as monotherapy after suppression? RCT of taking patients with virologic suppression (<50, 1. Both show acceptable rates of maintaining never CD4 <200 or viral load virologic suppression after switching to >100K) and switching to monotherapy DTG monotherapy versus 2. DTG better at maintaining suppression than continuing ART boosted PIs 24 weeks- VF ~same, study 3. Boosted PIs better at maintaining suppression continues than DTG 48 weeks: Of 77 patients on #451LB 4. Rates of virologic suppression after switch to DTG monotherapy, 8 with either monotherapy strategy unacceptably high VF (92% vs 98%, p 0.03) (but more resistance likely with DTG) 2

“Pathways of Resistance in Subjects Failing DOMONO: Switch to DTG monotherapy Dolutegravir” (Redomo study, abstract 42) Of 8 patients, 6 could get integrase inhibitor Clinic settings in Barcelona, Munich, genotyping – 3 had new INSTI resistance (50%) Montreal –simplifying to monotherapy without evidence (10440 pts) DTG bi or tri therapy (1082) 10% DTG monotherapy (122) 1.17% VF 64 (6%; 95% CI 5-7%) VF 11 (9%, 95% CI 6-18%) OR VF mono 1.58 (0.73-3.13) • 5/11, DTG was first INSTI • 8/11 had been suppressed 9/11 with INSTI for >3 years No INSTI resistance resistance (multiple • Adherence <95% in 4/11 pathways, 155, 18, • Weeks (median, IQR) from VF 92, 148) until genotype 5 (3-14) MOBIDIP: Monotherapy switch to boosted PI Adverse effects with DTG in real- 3% world cohorts and switch studies 24.8% Increased number of neuropsychiatric, CNS, GI side effects in women and older Ciaffi et al. 9/2017 individuals in real-world cohorts Some switch trials show surprisingly high rates of AEs Pts with virologic suppression randomized to monotherapy (133) de Boer M. AIDS. 2016; Hoffmann C. with DTG switch (13% more in HIV Med. 2017; Solasi C. 18 th Clinical or boosted PIs (LPV or DRV)+3TC (132) – study d/c’d 48 wks. Pharm HIV Workshop 2017; Kheloufi STRIIVING and SWORD) VF in 3% of boosted PI/3TC and 24% with monotherapy – no AIDS 2017; Menard AIDS 2017; Peñafiel JAC 2017; Yagura BMC ID 2017 (Figure resistance testing performed Associated with PK levels of DTG from CROI 2017#426); Trottier Antiviral Meta-analysis of 13 studies shows 8% more VF with boosted PI Therapy 2017; Llibre JM et al. CROI like with EFV 2017; Abstract 44LB.; Walmsley S et al, monotherapy vs triple but very little resistance (Arribas HIV Med 2015) IDWeek 2017, Abstract 1382 . 3

DHHS Guidelines for the Use of Antiretroviral ARS: Was change in DHHS guidelines Agents in Adults and Adolescents Living with HIV October 17, 2017 re: darunavir based on new clinical evidence? 1. Yes, darunavir is inferior to INSTIs, shouldn’t be in “drugs for everybody” Table 2. No, don’t think this change was indicated, DRV/r is complicated but so is DTG, EVG/cobi and RAL Darunavir/r DHHS demotion deserved? Bictegravir Agree with ATV/r demotion • WAVES trial (ELV/cobi > ATV in women, mainly tolerability, failures with PI resistance); A5257 trial (RAL>ATV/, mainly New INSTI to be combined with TAF/FTC tolerability); ARIA trial (DTG >ATV in women, potency) Two naïve trials and one switch trial Wk 48 DRV/r complicated Bictegravir/FTC/TAF* • FLAMINGO (DTG>DRV/r) and A5257 (RAL>DRV/r) mainly driven ART-naive, HLA-B*5701–negative (n = 314) GS1489 by tolerability but RAL failures in A5257 with INSTI resistance pts with eGFR CG ≥ 50 mL/min Dolutegravir/ABC/3TC † (N = 629) and DRV/r doesn’t fail with resistance (n = 315) (opinion) My bottom line ( opinion ): Wk 48 § GS-1490: randomized, double-blind, active-controlled phase III trial [2] • DTG and DRV/r both have AEs, low resistance when supported, GS1490 Bictegravir/FTC/TAF* DTG more resistance when alone; RAL well-tolerated but more ART-naive pts with (n = 320) resistance; EVG/cobi fails with resistance and cobi affects eGFR CG ≥ 30 mL/min Dolutegravir + FTC/TAF ‡ (N = 645) tolerability - I would have kept DRV/r up in table with INSTIs (n = 325) Gallant J. Lancet HIV 2017; Sax P Lancet HIV 2017 4

Bictegravir naïve studies Two Bictegravir naïve trials GS-1489 1 GS-1490 2 Baseline Characteristic BIC/FTC/TAF DTG/ABC/3TC BIC/FTC/TAF DTG + FTC/TAF (n = 314) (n = 315) (n = 320) (n = 325) 31 (18-71) 32 (18-68) 33 (18-71) 34 (18-77) Median age, yrs (range) Male, % 91 90 88 89 Median HIV-1 RNA, log 10 4.42 (4.03- 4.43 (3.95- 4.51 (4.04-4.87) 4.45 (4.03-4.84) copies/mL (IQR) 4.87) 4.90) § HIV-1 RNA > 100,000 17 16 21 17 copies/mL, % Bictegravir noninferior to dolutegravir Median CD4+ cell count, 443 (299- 440 (289- 450 (324-608) 441 (297-597) cells/mm 3 (IQR) 590) 591) More nausea with DTG in naïve trials § CD4+ cell count < 200 11 10 14 10 cells/mm 3 , % Otherwise, same side effects, no changes in lipids, no resistance with either in failures 1 Gallant J. Lancet HIV 2017; 2 Sax P Lancet HIV 2017 Gallant J. Lancet HIV 2017; Sax P Lancet HIV 2017 B/F/TAF switch study B/F/TAF switch study Abstract 67504 Abstract 67504 • Phase 3 Randomized, Controlled Trial of Switching to Fixed-Dose Bictegravir/Emtricitabine/Tenofovir Alafenamide (B/F/TAF) from Boosted Protease Inhibitor-Based Regimens in Virologically Suppressed Adults: Week 48 Results • Bictegravir noninferior to SBR (92.1% vs 88.9% VS)- excluded those with ABC/3TC/TAF/TDF resistance in past • Better lipids with bictegravir; no changes in other AEs except more HA with bic; more bili with ATV; 1 case of ABC-resistance on DRV/r/ABC/3TC Jurgen K. ID Week San Diego 2017 5

ARS: Besides the efficacy, what do Drug-drug interactions with bictegravir we know about bictegravir at this HIV Pharmacology June 2017; CROI 2017; ID week 2017 • Both DTG and BIC point given its imminent release? metabolized by UGT1A1 and CYP3A4- BIC ½ by each, but DTG more by UGT1A1 and 3 rd 1. Should have fewer side effects than dolutegravir pathway also involved • BIC increases metformin 2. Can use with TB therapy (like DTG) but less (39 vs Voriconazole 79% AUC) 3. Higher barrier to resistance than dolutegravir Rifabutin • 75% reduction in BIC 4. We know its resistance pathways with rifampin (must BID Atazanavir Atazanavir Rifampin Rifampin DTG with rifampin) 5. Smaller pill than DTG/ABC/3TC • No dose adjustment required in moderate liver or renal insufficiency Bictegravir ARS: What do we know about cations and integrase inhibitors? WHAT WE DON’T KNOW WHAT WE KNOW • Do not know extent of drug- • Noninferior to DTG drug interactions – may be • Will be available in single pill more or less than with DTG combination with TAF/FTC • Do not know side effects in • Smaller pill than 1. Raltegravir 400mg okay to co-administer with real-world populations DTG/ABC/3TC calcium • Do not know its major • No food requirements 2. Dolutegravir okay to co-administer with resistance pathways or which • Need to space out from mutations matter calcium with meal cations • Do not know genetic barrier • Can’t co-administer with 3. Elvitegravir not okay to co-administer with to resistance yet (in vitro is rifampin calcium not in vivo) • Increases tubular secretion of • Do not know how food will creatinine like DTG 4. A, B and C affect (meals increase DTG) 5. Simple algorithm eludes me so I avoid all • Don’t know pregnancy safety • Don’t know if can co- integrase inhibitors with all cations administer with Ca, Fe with meals like with DTG 6

Making it simple: Cations and INSTIs TWO DRUG STARTS RAL à 400mg ok with Ca but not 600mg; no with Mg, Dr. Havlir discussed Al à ”NO CATS” Switches of SWORD ELV and BIC –> Space out (RPV/DTG), LATTE-2 from all x 2 hours (with food) (Cabotegravir/RPV), – “WAIT FOR CATS” LAMIDOL DTG à Can take with Ca or Fe with meal; space out (DTG/3TC), from Al, Mg à “KFC BUT EMERALD WAIT for MA” (DRV/cobi/FTC/TAF) ARS: What are the two drug ARS: What are the two drug combinations you would consider combinations you would consider starting in naïve patients? starting in naïve patients? 1. DRV/ritonavir (cobi) + DTG: phase 3 – DUALIS- in 1. DRV/ritonavir (cobi) + DTG progress) 2. DRV/ritonavir (cobi) + 3TC 2. DRV/ritonavir (cobi) + 3TC: will discuss 3. DTG + 3TC 3. DTG + 3TC: will discuss 4. DRV/ritonavir (cobi) + RAL 4. DRV/ritonavir (cobi) + RAL: phase 3 (NEAT study. Raffi Lancet 2014) with more resistance in dual 5. DRV/ritonavir (cobi) + TAF (or TDF) therapy failures 6. Data not yet convincing for any of these to 5. DRV/ritonavir (cobi) + TAF (or TDF): not studied me 6. Data not yet convincing for any of these to me 7