State of the art of ART

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1 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 2-drug starts or simplifications New single pill combinations In all of the rush, remember cobicistat ritonavir New: Doravirine, monoclonal Abs Ascent of the integrase inhibitors 1

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

3 DOMONO: Switch to DTG monotherapy Of 8 patients, 6 could get integrase inhibitor genotyping 3 had new INSTI resistance (50%) Pathways of Resistance in Subjects Failing Dolutegravir (Redomo study, abstract 42) Clinic settings in Barcelona, Munich, 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 ( ) No INSTI resistance 5/11, DTG was first INSTI 8/11 had been suppressed for >3 years Adherence <95% in 4/11 Weeks (median, IQR) from VF until genotype 5 (3-14) 9/11 with INSTI resistance (multiple pathways, 155, 18, 92, 148) MOBIDIP: Monotherapy switch to boosted PI Pts with virologic suppression randomized to monotherapy (133) or boosted PIs (LPV or DRV)+3TC (132) study d/c d 48 wks. VF in 3% of boosted PI/3TC and 24% with monotherapy no resistance testing performed Meta-analysis of 13 studies shows 8% more VF with boosted PI monotherapy vs triple but very little resistance (Arribas HIV Med 2015) 3% 24.8% Ciaffi et al. 9/2017 Adverse effects with DTG in realworld cohorts and switch studies Increased number of neuropsychiatric, CNS, GI side effects in women and older individuals in real-world cohorts Some switch trials show surprisingly high rates of AEs with DTG switch (13% more in STRIIVING and SWORD) Associated with PK levels of DTG like with EFV de Boer M. AIDS. 2016; Hoffmann C. HIV Med. 2017; Solasi C. 18 th Clinical Pharm HIV Workshop 2017; Kheloufi AIDS 2017; Menard AIDS 2017; Peñafiel JAC 2017; Yagura BMC ID 2017 (Figure from CROI 2017#426); Trottier Antiviral Therapy 2017; Llibre JM et al. CROI 2017; Abstract 44LB.; Walmsley S et al, IDWeek 2017, Abstract

4 DHHS Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV October 17, 2017 ARS: Was change in DHHS guidelines 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? Agree with ATV/r demotion WAVES trial (ELV/cobi > ATV in women, mainly tolerability, failures with PI resistance); A5257 trial (RAL>ATV/, mainly tolerability); ARIA trial (DTG >ATV in women, potency) DRV/r complicated FLAMINGO (DTG>DRV/r) and A5257 (RAL>DRV/r) mainly driven by tolerability but RAL failures in A5257 with INSTI resistance and DRV/r doesn t fail with resistance My bottom line (opinion): DTG and DRV/r both have AEs, low resistance when supported, DTG more resistance when alone; RAL well-tolerated but more resistance; EVG/cobi fails with resistance and cobi affects tolerability - I would have kept DRV/r up in table with INSTIs GS1489 Bictegravir New INSTI to be combined with TAF/FTC Two naïve trials and one switch trial ART-naive, HLA-B*5701 negative pts with egfr CG 50 ml/min (N = 629) Bictegravir/FTC/TAF* (n = 314) Dolutegravir/ABC/3TC (n = 315) GS-1490: randomized, double-blind, active-controlled phase III trial [2] GS1490 ART-naive pts with egfr CG 30 ml/min (N = 645) Gallant J. Lancet HIV 2017; Sax P Lancet HIV 2017 Bictegravir/FTC/TAF* (n = 320) Dolutegravir + FTC/TAF (n = 325) Wk 48 Wk 48 4

5 Two Bictegravir naïve trials Bictegravir naïve studies Baseline Characteristic BIC/FTC/TAF (n = 314) GS GS DTG/ABC/3TC (n = 315) BIC/FTC/TAF (n = 320) DTG + FTC/TAF (n = 325) Median age, yrs (range) 31 (18-71) 32 (18-68) 33 (18-71) 34 (18-77) Male, % Median HIV-1 RNA, log 10 copies/ml (IQR) HIV-1 RNA > 100,000 copies/ml, % Median CD4+ cell count, cells/mm 3 (IQR) CD4+ cell count < 200 cells/mm 3, % 4.42 ( ) 4.51 ( ) 4.43 ( ) 4.45 ( ) ( ) 1 Gallant J. Lancet HIV 2017; 2 Sax P Lancet HIV ( ) 440 ( ) 441 ( ) Bictegravir noninferior to dolutegravir More nausea with DTG in naïve trials Otherwise, same side effects, no changes in lipids, no resistance with either in failures Gallant J. Lancet HIV 2017; Sax P Lancet HIV 2017 Abstract B/F/TAF switch study Abstract B/F/TAF switch study 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

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

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

8 ANDES study ANDES study: DRV/r + 3TC Initial Therapy GARDEL (phase 3) 1 had shown efficacy of LPV/r/3TC in naïve pts (and Argentina has fixed dose combo of DRV/r) Andes 2 VL <400 at wk 24: 95-97% Baseline VL >100K: high response rate Dual therapy non-inferior to triple therapy at wk 24 Both arms well-tolerated Patients (%) HIV RNA <400 Copies/mL (ITT) Darunavir/r +: Lamivudine Lamivudine + tenofovir DF Difference (%): -2.5 (-7.9, 2.9) 95% 97% 100% 100% Larger phase 4 trial underway x 48 weeks No resistance testing done 20 0 Overall (n=75/70) Baseline HIV RNA >100K Copies/mL (n=20/15) 1 Cahn P. Lancet ID 2014; 2 Cahn P. IAS 2017 Sued O, et al. J Int AIDS Soc. 2017;20(suppl 4):104. Abstract MOAB0106LB. A5353: DTG + 3TC in naives New single pill combinations PADDLE (20 pts, 48 weeks, DTG + 3TC, no failures) 1 A5353 Phase 2 single-arm, 52-week study (n=120) 2 HIV RNA 1000 to <500,000 copies/ml; no resistance; no HBV Age (30 years), male (87%), CD4 count ( cells/mm 3 ), HIV RNA ( log10 copies/ml) Primary efficacy outcome 90% achieved HIV RNA <50 copies/ml at week 24 (FDA snapshot algorithm), regardless of baseline HIV RNA level Virologic failure (n=3) was uncommon, associated with suboptimal adherence (did DTG plasma concentrations) BUT 1 virologic failure had emergent R263RK (DTG mutation) and M184V (3TC mutation) Concerned about lack of forgiveness to adherence in real world, GEMINI phase 3 ongoing Taiwo BO, et al. IAS Abstract MOAB0107LB; PADDLE: Cahn P. J Int AIDS Soc May 8

9 ARS: What are the brand names of the two single pill combinations for treatment of HIV coming soon? 1. Symuca and Juluza 2. Symtuza and Juluca 3. DoluRil and Darquad 4. Symcap and Juluca 5. Gesundheit Single pill PI-based Combination (Symtuza ) EMERALD: Switch to DRV/Cobi/FTC/TAF Objective: Assess efficacy (non-inferiority) and safety of switching to D/C/F/TAF vs. continuing boosted-pi + F/TDF regimens in suppressed pts Key inclusion criteria: On stable bpi + F/TDF regimen for at least 6 months Viral load (VL) <50 for 2 months before screening Previous ART virologic failure (VF) allowed Absence of history of VF on DRV, and if historical genotype available, absence of DRV RAMs Orkin et al, Lancet HIV, EMERALD: D/C/F/TAF Switch (Wk 48) Switch was non-inferior Lax criteria for switch study 58% had 5 prior ARV regimens 15% had prior VF No DAMs but could have resistance to TDF or 3TC Bictegravir switch - resistance to TDF/TAF/3TC/ABC excluded SWORD or STRIIVING DTG switch - resistance to any class excluded In few failures, NO resistance to any study drugs detected D/C/F/TAF safe- no benefit in Cr with TAF but because of cobi; better bones Week 48 efficacy Most rebounders (12/19 D/C/F/TAF and 4/8 control) resuppressed (<50) at Wk 48 Orkin et al, Lancet HIV, Amber study: Comparing SPC to TDF Randomized, double-blind phase III trial Treatment-naive pts with HIV-1 RNA >1000, susceptible to DRV, TDF, 3TC (N = 725) DRV/COBI/FTC/TAF (n = 362) DRV/COBI + FTC/TDF (n = 363) High rates of virologic suppression (91.4%) - 1 treatment-emergent resistance mutation (M184I/V) in SPC arm Lower rate of AE-related d/c for DRV/COBI/FTC/TAF vs DRV/COBI + FTC/TDF (1.9% vs 4.4%) Hip/spine BMD changes more favorable with SPC Significantly higher egfr by serum creatinine (P <.0001) and cystatin C (P =.001) with DRV/COBI/FTC/TAF Wk 48 Orkin et al. EACS. Milan, Italy Oct

10 Cobicistat ritonavir in a surreal world, apples are not apples ARS: Which of these is NOT true when comparing cobicistat to ritonavir? 1. Dolutegravir levels increase when combined with cobicistat compared to ritonavir 2. Darunavir/cobicistat does not seem to be as potent as darunavir/ritonavir in a clinical cohort 3. Cobicistat has fewer drug-drug interactions than ritonavir 4. Cobicistat combined with TDF is not as well tolerated as well as ritonavir combined with TDF More not less: Cobicistat has more drug-drug interactions than ritonavir 1) Switching from a RTV-boosted PI to a cobicistatboosted PI when paired with DTG leads to 100% increased DTG trough levels 2) Cobicistat increases dabitagran levels dangerously; ritonavir okay 3) Cobicistat increases drospirenone in the Yaz contraceptive whereas ritonavir does not 4) Cobicistat with TDF leads to such high TFV levels that there were high rates of discontinuation of TDF/FTC with cobi in Italian clinic 1 Gervasoni. JACC 2017; 2 Kakadiya. AAC 2017; 2 Majeed S. HIV Pharmacology Workshop Chicago 2017; 4 Cattaneo JAIDS 2017 Beware that darunavir/cobicistat may be less potent than darunavir/rtv Trough with DRV/cobi lower than DRV/RTV 1 (DRV decreases half-life of cobi 2 ) so former may be less forgiving than latter Clinical cohort 3 showed 5% failure with switch to DRV/cobi use with food and watch carefully after switch 1 Kaduda T. JAC 2014; 2 Eliot JAC 2017; Nugent. 16 th EAC. Milan. Oct Abstract P39 10

11 New anti-hiv drugs Drug class Name of drug Comments NNRTI Attachment inhibitor Maturation inhibitor Broadly neutralizing Ab Broadly neutralizing Ab Doravirine covered this am and in panels BMS or fostemsavir BMS VRC01, for prevention or treatment Ibalizumab, for treatment of MDR-HIV DRIVE-FORWARD (DRV/r vs DOR looks good 48 wks); DRIVE AHEAD (DOR/TDF/FTC vs EFV/TDF/FTC, DOR better tolerated Looks good in phase IIb; now in Phase III with heavily experienced pts (BRIGHTE study, EACS, 24 week good) Discontinued due to treatment emergent resistance and GI intolerability Bar et al. NEJM Nov 9, 2016 delays viral rebound but resistance Phase III data complete in MDR-HIV and FDA review pending Ibalizumabin Patients with Multi-Drug Resistant HIV Monoclonal Ab: binds CD4; blocks HIV entry IV infusion: loading dose, then every 2 wks Phase 3 open label study in 40 pts on a failing regimen with 3-class ARV resistance (highly experienced and resistant) Day 14: 83% had >0.5 log10 VL reduction; 60% had >1.0 log10 VL reduction Wk 24 results (ibalizumab + OBR): 43% had VL <50; 50% had VL <200 Mean VL decrease 1.6 log10 Expanded access: efficacy at wk 48 (n=27) All 15 patients with VL <50 at Wk 24 maintained viral suppression to Wk 48; another pt achieved VL <50 at wk 48 Under FDA review (filed May 2017) Emu et al, Abstract 1686, IDWeek 2017 Clinical pearls from talk Raltegravir once daily but low genetic barrier Never use dolutegravir as monotherapy, some side effects Bictegravir non-inferior to DTG but we don t know drug-drug interactions or how will stand up with resistance in background DRV/cobi/TAF/FTC coming out, seems good even with resistance in background Still should like darunavir/ritonavir, high genetic barrier, more forgiving than darunavir/cobi for patients with adherence issues Thank you to Drs. Diane Havlir, Meg Newman, Vivek Jain, Harry Lampiris, Annie Luetkemeyer, HIV Fellows Clinic, and to Jon Oskarsson, Mary Lawrence Hicks, Eva Mureithi 11