Disclosures. Patient 1. Goals/Format 12/7/17. Antiretroviral Therapy Management:

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1 Disclosures Antiretroviral Therapy Management: Panel Discussion & Debate Medical Management of AIDS & Hepatitis December 8, 2017 Brad Hare, MD, 1 Annie Luetkemeyer, MD 2 Susa Coffey, MD, 2 Vivek Jain, MD 2 1 Kaiser Permanente, San Francisco Brad Hare: None Annie Luetkemeyer: Research support from ViiV Susa Coffey: None Vivek Jain: Research grant support from Gilead Sciences for work in East Africa related to methods of ART care delivery Research grant support from NIH, CDC, PEPFAR & 2 Division of HIV, Infectious Diseases & Global Medicine San Francisco General Hospital, University of California, San Francisco Goals/Format Patient 1 Explore three cases in ART management Elicit audience opinions Expert panel reflections 38 year old man, no medical history Being routinely tested for HIV every three months; last negative test 3 months ago, August 2017 In November 2017, HIV test is positive CD4=640 cells/ul, HIV-1 RNA = 31,000 c/ml HIV-1 genotype is sent, and still pending Patient expresses desire to initiate ART immediately (and you agree) 1

2 Audience Preliminary Vote Given the many options for ART, would you initiate TAF/FTC (Descovy) + dolutegravir (Tivicay)? (A) YES, I would give TAF/FTC + DTG. Case 1: Susa Coffey Yes, comfortable initiating TAF/FTC + dolutegravir (B) NO, I would recommend something else. Case 1: Starting DTG + TAF/FTC is appropriate. Pt with early HIV, CD4=640, VL=31,000; genotype is pending. Mountains of data and experience with DTG + 2 NRTIs in initial ART; preferred regimen If concern for transmitted resistance (R) How likely? How likely to impact this regimen in NEXT 2-3 WEEKS? TDR present in ~15%, NRTI mutation ~7% K65R rare, M184V ~4-5% Major INSTI mutations RARE Almost certainly has fully-active DTG and TAF, fully or perhaps partially effective FTC; this should be sufficient Menza TW et al, AIDS Case 1: Starting DTG + TAF/FTC is appropriate. Pt with early HIV, CD4=640, VL=31,000; genotype is pending. Assuming resistance to 1 NRTI, should still be effective Data for DTG + 1 fully- active NRTI Naives: DTG + 3TC: PADDLE, wk 48 VF in 1/20, no mutations ACTG 5353: wk 24 VL <50 in 90%; 89% if BL VL >100,000. VF with R in 1/120 (adherence issues) Treatment-experienced: DTG + 2NRTIs SAILING: subset on DTG + 2 NRTIs with resistance to 1-2 NRTIs-> Wk 48 NO VF if 0 or 1 fully-active NRTI (0/13) DAWNING: DTG + 2NRTIs (vs LPV/r + 2NRTIs) after VF with 1 st ART regimen->251 pts w/ 1 fully active NRTI, 84% w/ VL <50 at wk 48 (vs 73% of LPV/r); no IN or new RT mutations DAWNING Study Mean BL VL 4.21 log; >100K in 22% Cahn et al. J IAS Taiwo BO, IAS Demaest J, IAS Aboud M, et al. IAS Abstract TUAB0105LB. 2

3 Real-World Risk of Virologic Failure in Pts Starting DTG-Based vs DRV-Based ART DTG + TAF/FTC is a potent, simple, tolerable regimen Likelihood of transmitted resistance is very low, and risk of VF from transmitted resistance is even lower, esp. in next 2-3 weeks Much clinical experience from SFGH RAPID ART Patients who initiated DHHS Recommended ART from 8/13-3/17 at 8 CNICS sites (N = 5177) 1229 on DTG or DRV/r with ABC/3TC, TDF/FTC, or TAF/FTC Pts All pts ahr* for VF of DTG vs DRV (95% CI) DRV DTG 0.41 ( ) Tx-naive pts (1229) DRV DTG 0.32 ( ) Virologic failure: HIV-1 RNA > 400 c/ml at 6 mos after initiating ART. *Cox models adjusted for age, CD4+ cell count, days from last HIV-1 RNA, CNICS site, sex, HBV, HCV, HIV risk factor, and race. Case 1: Counterpoint: Brad Hare No, not comfortable initiating TAF/FTC + dolutegravir Would initiate another regimen Nance R, et al. IDWeek Abstract Modified from clinicaloptions.com Case 1 (BH) Patient diagnosed w/hiv in acute care setting, last tested negative 3 months ago, CD4=640, VL=31,000, but genotype is sent and pending do not have data. Would you start DescovyDTG or something else Transmitted drug resistance still occurs ARV Drug Class % with Major IAS-USA Mutations Most Common Mutations NRTI 8.9 A62V, M41L, M184V, K70R, D67N NNRTI 7.8 K103N, K101E, L100I, V108I, Y188C/L PI 3.2 M46I/L, V321, L90M, I84V, D30N Buchacz (CROI 2013, #615). HOPS Cohort Case 1 (BH) Patient diagnosed w/hiv in acute care setting, last tested negative 3 months ago, CD4=640, VL=31,000, but genotype is sent and pending do not have data. Would you start DescovyDTG or something else Transmitted drug resistance still occurs Clinical trials: Participants always have baseline genotypes to enter Reasonable clinical strategy: Start broad (still simple), wait for the data, and refine What s worse: 2-4 weeks of one extra drug, or a lifetime of generated resistance? 3

4 Final Audience Vote Given the many options for ART, would you initiate TAF/FTC (Descovy) + dolutegravir (Tivicay)? (A) YES, I would TAF/FTC + DTG. (B) NO, I would recommend something else. Patient 2 Audience Preliminary Vote 56 year old man, no medical co-morbidities Diagnosed with HIV in 2012; initially started TDF/FTC (Truvada) + ritonavir/darunavir and achieved virologic suppression. Switched Truvada to TAF/FTC (Descovy) in 2016; maintained RTV/DRV Continuous virologic suppression Would you recommend switching off the protease inhibitor and switching to an integrase inhibitor? Or stay with current protease inhibitor? (A) I would switch the PI to an INSTI. (B) I would continue the PI. 4

5 NO Protease inhibitors in Preferred initial ART Case 2: Annie Luetkemeyer Would switch to integrase-based regimen PI s associated with: Increase CVD (53% increase in D:A:D with DRV/r!) Dyslipidemia Metabolic derangement AND NO current single pill formulation, to boot! Ryom L, et al. CROI Abstract 128LB. Ryom L, et al. CROI Abstract 128LB. DHHS guidelines 10/17 NEAT-022: 50 yrs old or Framingham >10%, on PI/r + NRTI, suppressed x 6 months, no documented resistance/virologic failure Non-inferior to PI/r Improved lipid profile Improved Framingham score (both ATZ and DRV) Gatell TUAB1012 IAS 2017 What if preexisting resistance? GenosureArchive: Useful application SPIRAL study: 282 patients suppressed on PI/r x > 24 weeks, 40% with prior virologic failure RAL-based regimen equivalent to PI/r, virologic failure rare (1 vs. 3) DTG more potent than RAL DTG/3TC dual therapy thus far effective in several pilot switch studies and several pilot treatment initiation studies, thus: ütaf should have efficacy with DTG even if M184 and 1-2 TAMs present ütransmitted INSTI resistance still very rare. Can get an Genosure Archive if worried Martinez AIDS 2010;24:1697, DOLAM Blanco EACS 2017, Taiwo EACS 2017, Figueroa IAS 2017, ACTG 5353 Taiwo IAS

6 Genosure Archive: Cautionary tale Genosure showed RT T369 A/I/V PR L10/I, D60E, 162V, L63 S/C/T Historic genotype: RT M41L, D67N, L210W, T215Y, V106I, Y181V PR: L10I, M36I/M, M46L, I54V, L63S, I64V, V82A. Concordance of Archive with GT Singh ID Week 2016 Abstract paired samples, % concordance with historical GT was 92% for Protease Inhibitor resistance and 88% for reverse transciptase. Toma ICAAC 2015 Case 2 (BH) TAF/FTC + DRV/RTV, suppressed, and you don t have any GT info 56yo man no co morbidities, on ART x7 years, good adherence à switch off PI to integrase or stay on PI? Case 2: Counterpoint: Brad Hare If it s not broken, don t fix it Where are the data for DTG/TDF with M184V? ArchiveDNA test? Want convenience? Symtuza is on the way Would stay with PI-based regimen 6

7 Prevalence of Transmitted HIV Drug Resistance in US, Genotypic analysis of samples from newly diagnosed patients in CDC National HIV Surveillance System (N = 12,668) Cases (%) Ocfemia MC, et al. CROI Abstract 730. All cases with sequences Cases classified as recent infections Cases classified as long-standing infections 0 1 or more 1 class 2 class 3 class NNRTI NRTI PI Transmitted Drug Resistance Mutations 4.1 Pts (%) EMERALD: Switch From Boosted PI + FTC/TDF to DRV/COBI/FTC/TAF in Suppressed Pts Randomized, open-label, active-controlled phase III trial in which virologically suppressed pts continued a boosted PI + FTC/TDF regimen or switched to DRV/COBI/FTC/TAF single-tablet regimen (N = 1149) Treatment difference: 0.8% (95% CI: -1.7% to 3.3%) Virologic Success* *HIV-1 RNA < 50 copies/ml. Wk 24 Virologic Efficacy 0.5 (n = 4) Virologic Failure DRV/COBI/FTC/TAF (n = 763) Boosted PI + FTC/TDF (n = 378) Treatment difference: -0.3% (95% CI: -2.0% to 1.5%) 0.8 (n = 3) No Virologic Data Molina JM, et al. IAS Abstract TUAB0101. Virologic Rebound No PI or NRTI resistance associated mutations noted (n = 2 genotyped for each treatment group) Similar low rates of grade 3/4 AEs, d/c for AEs between treatment groups Significant improvements in hip/spine BMD for DRV/COBI/FTC/TAF vs control Similar egfr by serum creatinine between groups (P =.118); increased egfr by cystatin c with DRV/COBI/ FTC/TAF (P =.026) Slide credit: clinicaloptions.com Pts (%) AMBER: DRV/COBI/FTC/TAF vs DRV/COBI + FTC/TDF for Treatment-Naive Pts Treatment difference: 2.7% (95% CI: -1.6% to 7.1%) Wk 48 Virologic Efficacy Virologic Success* DRV/COBI/FTC/TAF (n = 362) DRV/COBI + FTC/TDF (n = 363) (n = 16) (n = 12) HIV-1 RNA 50 c/ml *Primary endpoint: HIV-1 RNA < 50 c/ml by FDA snapshot. 1 treatment-emergent resistance mutation (M184I/V) observed in DRV/COBI/FTC/TAF arm Similar low rates of grade 3/4 AEs between treatment groups 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 DRV/COBI/FTC/TAF Significantly higher egfr by serum creatinine (P <.0001) and cystatin c (P =.001) with DRV/COBI/FTC/TAF Final Audience Vote Would you recommend switching off the protease inhibitor and switching to an integrase inhibitor? Or stay with current protease inhibitor? (A) I would switch the PI to an INSTI. (B) I would continue the PI. Orkin C, et al. EACS Abstract PS8/2. Reproduced with permission. Slide credit: clinicaloptions.c 7

8 Patient 3 65 year old woman with: chronic kidney disease (egfr = 40 ml/min) severe osteoporosis (DEXA with T-score -3.1 in hip) coronary artery disease (recent exercise treadmill test positive for ischemia) and HTN: takes ASA 81mg QD, metoprolol 25mg QD, and lisinopril 5mg QD Diagnosed with HIV in 2016 (records unavailable) à started on TAF/FTC (Descovy) + dolutegravir (Tivicay) à virally suppressed since then You want to switch to a nucleoside-sparing ART regimen for medical reasons; patient also wants this Audience Preliminary Vote What type of NRTI-sparing regimen would you construct? (A) I would give a 2-drug NRTI-sparing regimen (B) I would give a 3-drug NRTI-sparing regimen Case 3: Susa Coffey Would use a 2-drug NRTI-sparing regimen 8

9 Case 3 switch to NRTI-Sparing 2-drug ART. 65 yo woman with CKD (egfr 40), severe osteopenia, CAD. On stable suppressive TAF/FTC + DTG, needs to switch to a NRTI-sparing regimen. Q1: 2 drugs vs 3 drugs? Q2: does 3TC/FTC count as a NRTI? we can go either way on this A good 2-drug regimen likely to be sufficient; she is an excellent candidate: She has proved her ability to adhere closely to ART Stable viral suppression Likely wildtype virus Case 3 switch to 2-drug regimen. 65 yo woman with CKD (egfr 40), severe osteopenia, CAD. On stable suppressive TAF/FTC + DTG, needs to switch to a NRTI-sparing regimen LOTS of good new data! DTG/RPV DTG + 3TC DTG + DRV/r DRV/r + 3TC HIV-1 RNA <50 c/ml, % Switch to DTG + RPV: SWORD 1/ Virologic outcomes, Week <1 1 0 Virologic Virologic a Adjusted for age success and baseline 3 rd agent. non-response DTG + RPV (n=513) CAR (n=511) 5 4 No virologic data N=1024, viral suppression 12 months, stable ART 6 mos DTG + RPV non-inferior to CAR, incl in subgroups (age, gender, race) VF in 2 in dual arm, 1 w/ K101K/E, resuppressed BMD improved on DTG/RPV after switch from TDF (DEXA substudy) DTG/RPV approved by FDA Nov 2017 (Juluca): switch from stable ART, VS, no VF, no resistance Llibre et al. CROI 2017; Seattle, WA. Abstract 44LB. McComsey G, IAS Switch to DTG + 3TC (and remember the Naive trials- Case 1) Study N Baseline Results Ref LAMIDOL Single arm, prospective, open label DTG/3TC vs DTG mono vs 3-drug RTC ASPIRE DTG/3TC vs current ART; RCT DTG/3TC vs historic control Prosp. open label Single arm, prospective, open label 104 VL <50 x 2 yrs, no R 91 VL <50 x 12 mos, no VF or resistance to 3TC or INI 89 VL <50 on any 3-d ART No VF, no R 183 DTG, 170 DRV, 141 ATV 72 (vs 86 control) VL <50, no VF with INI resistance 203 VL <50 6 mos, median 72 mos Wk 48: VL <50 101/ rebound to 77 c/ml, 1 LTFU, 1 interrupted. No IN resistance, 1 w/ L74V/L. Wk 24: DTG/3TC: 1 VF (low level VL, no resistance) DTG mono: 2 VF with INI R (this arm stopped) Wk 24: VL <50 in 93% vs 91% Wk 48: 91% vs 89% 1 VF in DTG/3TC, no R Up to 2 yrs VF: 3 (DTG), 6 (DRV), 4 (ATV) Wd 96: VL <50 in 97% in both gps Blips in 1 vs 6 VF: 0 (295 pt-yrs of f/u) d/c: 12 Retrospective % VL <50 Median 23 wks: VL <50 97% (82/84) 1 VL=55, 1 VL=239 Metaanalysis of 4 DTG/3TC studies 261 VL <50 VF in 1 DTG/3TC, no mutations Joly V, EACS Blanco JL, EACS Taiwo BO, EACS Borghetti, EACS Tau L, EACS Maggiolo F, EACS 2017; BMC ID DTG/3TC vs DRV/r/3TC vs ATV/r/3TC Retrosp. investigatorselected Hidalgo- Tenorio C, EACS Buzzi M, EACS 9

10 INSTI + PI/r or PI/r + 3TC: Switch(2) and Naïve(1) each INSTI + PI/r N Baseline Results Ref NEAT-001 RAL/DRV-r vs DRV/r/TDF/FTC Naive DTG + DRV/r Switch, single arm DTG + DRV/r Switch, retrosp. PI/r + 3TC N Baseline Results Ref DUAL DRV/r + 3TC vs DRV/r + 2 NRTIs RTC open label switch Metaanalysis of 4 PI/r + 3TC studies ANDES DRV/r + 3TC vs DRV/r + TDF/3TC RTC open label Naive 805 No resistance CD4 < VL <50 x >6 mo on DRV/r + 2 NRTIs, no R TDF/FTC in 75%, ABC/3TC 25% 1051 (525 on dual) 145 Median BL VL 4.6 log, >100,000 in 27% Noninferior 96 wks: VL <5 on 89% vs 93%, incr VF in RAL/DRV if VL >100K or CD4 <200 R: 5 with IN mutations, 1 K65R 27 Suppressed 48 wks: VL <50 in 25/27 (93%) 1 VF, no resistance % with VF Resistance to 1-5 ARV classes or hx VF w/o GT. 17% with DRV RAMS, 11% with INI RAMS 48 weeks: VL <50 in 91% (14 took ARVs BID) No new R mutations Wk 48: VL <50 in 89% vs 93% VF in n=4 vs w/ VL <200, 1 VF at BL, 1 VF during study No R either arm Wk 48 VL <50: PI/3TC noninferior (4% margin); no diffs by gender, HCV, or PI Wk 24: VL <400 in 95% vs 97% On treatment: 100% vs 99% 1 VF in 3-drug arm Raffi F, Lancet Navarro, J. EACS Capetti AF, BMC ID Pulido F, CID, Perez-Molina A, EACS Sued O, IAS Case 3 switch to 2-drug regimen Already on DTG let s keep it Prefer to avoid PIs ØLargest RTC: DTG + RPV ØAccumulation of data DTG + 3TC Case 3: Counterpoint: Annie Luetkemeyer: Too soon for 2 drug therapy here! The #1 goal for her is to maintain virologic suppression! This patient would not have qualified for SWORD, PADDLE, NEAT given her comorbidities DTG + 2 nd drug is one step away from DTG monotherapy Excellent data to support 3 drug regimens, including NRTI-sparing regimens Would stick with a 3-drug NRTI-sparing regimen Fagard IAS 2009, JAIDS 2012; 59(5);489 Tashima AIM 2015; 163(12);

11 Final Audience Vote What type of NRTI-sparing regimen would you construct? (A) I would give a 2-drug NRTI-sparing regimen Acknowledgements Monica Gandhi, MD Oliver Bacon, MD Thank you for participating! (B) I would give a 3-drug NRTI-sparing regimen 11