Antiretroviral Therapy: Panel Discussion

disclosures Antiretroviral Therapy: Panel Discussion Medical Management of HIV December 9, 217 Panelists: Harry Lampiris, MD; Annie Luetkemeyer, MD; Carina Marquez, MD Moderator: Oliver Bacon, MD none Questions What to start in an ART-naïve, with/without labs What to start if M184V alone? INSTI resistance New uses for old(er) drugs (rilpivirine, atazanavir)? Using fewer than 3 drugs Initial ART in pregnant women How will might soon-to-arrive ARVS change your initial management Treatment modification for (multiple) comorbidities, deintensification Question: in the era of Test and Treat, what regimen would you choose for an ARV-naïve patient without resistance testing available? 1

Case 1. 24, female, newly HIV+ : Lab-based Ag/Ab (+), differentiation Ab(-), HIV RNA 1.2 million c/ml CD4, scr, HLA-B*571, genotype, INSTI genotype all pending. Urine HCG(-); has an IUD No comorbidities Case 1: panelists, which regimen(s) for ARVnaïve patient who wants test-and-treat? 1. Elvitegravir/cobi/FTC/TAF 2. Darunavir 8mg QD + ritonavir 1mg QD + FTC/(TAF or TDF) 3. Raltegravir 12mg QD + FTC/(TAF or TDF) 4. Dolutegravir/abacavir/3TC 5. Dolutegravir + FTC/(TAF or TDF) 6. Rilpivirine/FTC/(TAF or TDF) 7. Dolutegravir + 3TC Recommended initial ART regimens reclassified in DHHS OCT217 I. For most people with HIV INSTI + 2 NRTIs 1. DTG/ABC/3TC if HLA-B*571 negative 2. (DTG or RAL) + FTC/tenofovir 3. Elvitegravir/cobicistat/FTC/tenofovir Recommended initial ART regimens reclassified in DHHS OCT217 II. For certain clinical situations 1. Boosted PI + 2 NRTIs In general, DRV preferred over ATV No distinction between boosting agents (rtvvs cobi) 2 NRTIs can be (FTC or 3TC) + (tenofovir or ABC) ABC only if HLA-B*571 negative Boosted ATV + ABC/3TC only if HIV RNA<1, c/ml 2. NNRTI + 2 NRTIs 1. EFV + (FTC or 3TC) + tenofovir 2. RPV/FTC/tenofovir only if HIV RNA<1, c/ml and CD4>2 cells/mm3 3. INSTI + 2 NRTIs 1. RAL + ABC + (3TC or FTC) only if HLA-B*571 negative and HI RNA<1, c/ml 4. If TDF, TAF and ABC cannot be used 1. DRV/r + RAL 4mg BID only if HIV RNA<1, c/ml and CD4>2 cells/mm3 2. LPV/r BID + 3TC BID 2

Case 2 Question: (How) does presence of M184V affect your choice of initial ART? 3, MSM, lab-based Ag/Ab(+) differentiation Ab HIV-1(+) at his most recent PrEP visit 3 weeks ago. Had heard about French study and was taking Truvada before and after sex, with some of his partners. Stopped altogether after testing HIV(+) CD4 55 cells/mm3, HIV RNA 5, c/ml, scr.9, Hepatitis B sag(-), HLA-B*571(-) GT: M184M/V Case 2: Panelists, Choice of initial therapy with M184V? 1. Dolutegravir/abacavir/3TC 2. Elvitegravir/cobicistat/FTC/(TAF or TDF) 3. Elvitegravir/cobicistat/FTC/(TAF or TDF) + DRV 4. Dolutegravir + FTC/(TAF or TDF) 5. Darunavir 8mg QD + ritonavir 1mg QD + FTC/(TAF or TDF) 6. Darunavir/cobi + FTC/(TAF or TDF) DAWNING: DTG Effective Even With Partially Active Background Regimen Randomized, open-label phase IIIb study in which pts in resourcelimited settings with virologic failure on NNRTI + 2 NRTIs treated with DTG + 2 NRTIs or LPV/RTV + 2 NRTIs (N = 627) Pts could not have primary resistance to INSTIs or PIs; pts required to receive 1 fully active NRTI Baseline NRTIs: ZDV + 3TC, 4%; TDF + 3TC or FTC, 42%; TDF + ZDV, 12%; ABC + 3TC, 2% Pts (%) 1 8 6 4 2 n/n = HIV-1 RNA < 5 copies/ml, Wk 24 (ITT-E) 82 257/ 312 69 215/ 312 Overall* *Treatment difference: 13.8% (95% CI: 7.3% to 2.3%; P <.1) 74 45/ 61 2 55 35/ 64 DTG + 2 NRTIs LPV/RTV + 2 NRTIs 84 212/ 251 < 2 Fully Active NRTIs 73 18/ 248 Aboud M, et al. IAS 217. Abstract TUAB15LB. 3

Question(s): How do you interpret results of the GenoSure Archive assay when they suggest resistance in a patient with an undetectable VL? How comfortable are you with dolutegravir pseudomonotherapy? Case 3: 54 yo man, homeless, heterosexual but no sex in 25 years. Recently moved to SF from LA HCV ab(+) GT1a/1b; TC 153, H29, L62, TG312; scr.8, Sulfa allergy HIV(+) and on treatment since 1993. Prior regimens unknown, but reports having undetectable VL ever since since viral loads could be measured, and CD4 never <2. No h/o OIs. Current VL <2, CD4=816 Currently on DRV/ABC/3TC x 2 years I take it as many times a week as I can; records from LA clinic state he takes it 3x/week. He says will only take QD regimen. GenoSure Archive: NRTI: M41L, D67N, M184M/V, L21W T215Y; NNRTI: none; PI: K2R, M36I, I62V Case 3: Virologic suppression on DTG/ABC/3TC with ABC and 3TC resistance mutations by DNA testing 1. DTG/ABC/3TC (1 QD) 2. DTG + FTC/TAF (2 QD) 3. DRV/Cobi + DTG (2 QD) 4. DTG + RPV (2 QD) 5. E/C/F/TAF + DRV (2 QD) 6. Something else Question: What ARVs to use in the setting of resistance to INSTIs and NRTIs? GenoSure Archive: NRTI: M41L, D67N, M184M/V, L21W T215Y; NNRTI: none; PI: K2R, M36I, I62V; INSTI: none 4

Case 4: 31, MSM, HIV+ 27, BL HIV RNA > 1,; baseline GT= wild-type, HLA-B*571(-); nadir CD4 189 EFV/FTC/TDF ->rash-> ATV/r + FTC/TDF-> jaundice, total Bili 9. RAL + FTC/TDF with intermittent suppression until persistent viremia in 5/217: HIV RNA 4136 c/ml, CD4 244 cells/mm3 GT RT: M184V, K65R; PI: none; INSTI: G14S, Q148H. Trofile = R5 virus Audience: if you prescribe ART, have you encountered patients who developed INSTIresistance on Raltegravir or Elvitegravir? 1. Yes 2. No Case 4: panelists: which of the following would you include in a regimen for INSTI (G14S, Q148H) and NRTI (K65R, M184V) resistance: 1. dolutegravir 5mg BID 2. darunavir 6 BID + ritonavir 1 BID 3. darunavir 8 QD + ritonavir 1 QD 4. etravirine 2mg BID 5. etravirine 4mg QD 6. rilpivirine 25mg QD 7. FTC/TAF 1 tab QD 8. ABC/3TC 1 tab QD Question: What would you use/not use for initial ART in a woman diagnosed with HIV during pregnancy? Feel free to use coformulations if available 5

Case 5: initial ART for pregnant woman 32 y.o. woman, B-HCG(+) 6 months ago, LMP 7 months ago HIV+ by Ag/Ab and differentiation Ab 4 days ago Last (-)HIV test: 6 months ago Wants to keep pregnancy HIV RNA pending, GT pending, CD4 count 42 cells/mm3, HLA- B*571(-) CrCl>6ml/min Case 5: 1 st line ART for pregnant woman, rapid start, 3 rd trimester 1. Dolutegravir/abacavir/3TC 2. Dolutegravir + FTC/TAF 3. Raltegravir 4mg BID + FTC/TDF 4. Elvitegravir/cobi/FTC/TDF 5. Efavirenz/FTC/TDF 6. Atazanavir 3mg QD+ ritonavir 1mg QD + FTC/TDF QD 7. Darunavir 6mg BID + ritonavir 1mg BID + FTC/TDF Antiretroviral Agents and Pregnancy Preferred NRTI NNRTI PI Abacavir/lamivudine OR Emtricitabine*/tenofovir Alternative Zidovudine/LamivudineZi Efavirenz OR Rilpivirine plus preferred 2- NRTI Insufficient data in pregnancy Do not use in pregnancy Emtricitabine/tenofovir alafenamide (TAF/FTC) ABC/AZT/3TC as complete regimen; d4t, ddi Etravirine, Nevirapine *Or lamivudine. 1May be initiated after the first 8 weeks of pregnancy. Evidence of human fetal risk; Pregnancy Category D. Atazanavir/r 3 Darunavir/r plus preferred 2-NRTI Lopinavir/r plus preferred 2-NRTI Tipranavir, Fosamprenavir/ Indinavir/ Saquinavir/ Rttonavir alone, Nelfinavir Entry Inhibitor Maraviro c, T2 2Contraindicated with CD4+ counts >25/mm3 due to potential for liver toxicity. 3Theoretical concern for hyperbilirubinemia. 4Co-formulated with cobicistat/emtricitabine/tenofovir DF. Note: no data on use of cobicistat in pregnancy and can not be recommended for ART-naïve pregnant women at this time. DHHS. http://aidsinfo.nih.gov/contentfiles/perinatalgl.pdf. Revision October 16, 216. Integrase Inhibitor Raltegravir plus preferred 2- NRTI backbone Dolutegravir plus preferred 2-NRTI Elvitegravir/co bicistat 23 Tsepamo: Birth Outcomes When Initiating Firstline DTG vs EFV in Pregnancy Prospective cohort study in HIV-infected women in Botswana initiating ART with EFV/FTC/TDF vs DTG/FTC/TDF while pregnant (N = 5438) Adverse Birth Outcomes, n (%) Any Severe DTG (n = 845) 291 (34.4) 92 (1.9) Zash R, et al. IAS 217. Abstract MOAX22LB. EFV (n = 4593) 166 (35.) 519 (11.3) arr* (95% CI) 1. (.9-1.1) 1. (.8-1.2) Stillbirth 18 (2.1) 15 (2.3).9 (.6-1.5) Neonatal death (< 28 days) 11 (1.3) 6 (1.3) 1. (.5-1.9) Preterm birth (< 37 wks) Very preterm (< 32 wks) SGA (< 1th percentile weight) Very SGA (< 3rd percentile weight) 149 (17.8) 35 (4.2) 156 (18.7) 51 (6.1) 844 (18.5) 16 (3.5) 838 (18.5) 32 (6.7) *For DTG vs EFV; adjusted for maternal age, education, gravida. 1. (.8-1.1) 1.2 (.8-1.7) 1. (.9-1.2).9 (.7-1.2) Few first-trimester ART exposures (DTG, n = 116; EFV, n = 396); most second/third trimester Only 1 major congenital abnormality observed (skeletal dysplasia in EFV-exposed group) ABO risks similar when initiating first-line DTG vs EFV in pregnancy 6

Case 6: new drugs/strategies for first line in 218 Question: It s December 9, 218. How are you thinking about using new ARVs/treatment strategies for treatment-naïve patients? 51, newly confirmed HIV+ by CDC algorithm 2 weeks ago, last HIV(-) 2 years ago when he stopped PrEP ( wasn t having that much sex ) History of depression, not currently being treated Hypertension, controlled on Lisinopril HIV RNA 12, c/ml; CD4 count 375 cells/mm3; HLAB*571(-), genotype = wild-type egfr>6 TC 18 HDL 34 LDL 12 TG 2 Case 6: panelists, new drugs/strategies for initial therapy in 218 1. dolutegravir/abacavir/3tc (1 tab daily) 2. bictegravir/ftc/taf (1 tab daily) 3. doravirine/3tc/tdf (1 tab daily) 4. DRV/c/FTC/TAF (1 tab daily) 5. dolutegravir + 3TC (2 tabs daily) 6. dolutegravir/rilpivirine (1 tab daily) Question: How do you balance virologic efficacy and cardiovascular, renal comorbidities in treatment simplification? 7

Case 7: 58, HIV(+) since 199s peak HIV RNA >1, c/ml; nadir CD4 <5 cells/mm3 History of exposure to nevirapine, d4t, 3TC, nelfinavir, with periods of meth use, intermittent viremia, culminating in virologic failure with (list of mutations): Suppressed in 26 with unboosted ATV (due to hyperlipidemia, recurrent pancreatitis), TDF, 3TC, T-2. virus is mixed CCR5/CXCR4 tropic. TDF switched to ABC due to CKD in 28; CrCl currently 51. Lipids are TC167 H28 L??? TG783 on atorvastatin and fenofibric acid CV risk score: Currently suppressed on ATV 4 BID, RAL 4 BID, ABC/3TC Case 7: (how) would you modify his regimen 1. ATV BID + RAL BID + ABC 6 mg/3tc 3mg QD (no change) 2. DRV/r + DTG + 3TC 3. DRV/r + DTG + FTC/TAF 4. DTG + RPV 5. DTG + DRV/r 6. ATV/r + 3TC 7. EVG/cobi/FTC/TAF + DRV Thanks! D:A:D: Exposure to ATV/RTV or DRV/RTV and Risk of CVD Prospective analysis of pts followed from 29 to earliest CVD, last visit + 6 mos, or 2/1/216 (N = 35,711) 1157 pts (3.2%) developed CVD (MI, stroke, sudden cardiac death, invasive CV procedure) Cumulative exposure to DRV/RTV, but not ATV/RTV, associated with increased CVD risk in multivariate analysis: 59% risk increase per 5 yrs of DRV/RTV Association does not appear to be mediated through dyslipidemia, in contrast with first-generation PIs CVD Risk per 5 Yrs of ARV Exposure, IRR (95% CI) Model ATV/RTV DRV/RTV Univariate 1.25 (1.1-1.43) 1.93 (1.63-2.28) Multivariate Baseline adjusted* 1.3 (.9-1.18) 1.59 (1.33-1.91) Time-updated adjusted* 1.1 (.88-1.16) 1.53 (1.28-1.84) *Adjusted for: BMI, CKD, DM, CD4, dyslipidemia. CVD Incidence Rate Ratio (95% CI) 2.5 2. 1.5 1..5 Relationship Between 5-Yr Exposure to ARVs and CVD No exposure Univariate MV: BL adj model MV: Time-updated adj model ATV/RTV DRV/RTV Ryom L, et al. CROI 217. Abstract 128LB. 8

D:A:D: Cumulative Exposure to ARVs Associated With Increased CKD Risk CKD Risk by Yrs of ARV Exposure, Incidence Rate Ratio* (95% CI) Drug 1 Yr 5 Yrs TDF ATV + RTV LPV/ RTV 1.14 (1.1-1.19) 1.2 (1.13-1.26) 1.11 (1.6-1.16) Mocroft A, et al. Lancet HIV. 216;3:e23-e32. 1.94 (1.57-2.39) 2.44 (1.86-3.21) 1.66 (1.32-2.9) *Multivariate analysis. For each value, P <.1 Incidence Rate Ratio (95% CI) 1.5 1.4 1.3 1.2 1.1 1..9.8 P value (univariate) TDF <.1 P value <.1 (multivariate) ATV + RTV <.1 <.1 Univariate Multivariate LPV/RTV <.1 <.1 55 Clinic: Real-World Virologic Suppression by Regimen in Pts With M184V Mutation Retrospective cohort study using medical records of new pts presenting to University of Louisville outpatient HIV clinic from January 23 to July 216 HIV-1 RNA < 2 c/ml (%) Analysis of tx-naive (2%) or tx-experienced (98%) pts with M184V mutation: N = 1 pts, 167 regimens Regimens With < 3 Fully Active Drugs P =.13 P =.51 1 1 1 P =.11* 1 P =.4 84 85 78 8 8 72 8 69 69 71 6 HIV-1 RNA < 2 c/ml (%) 4 4 21 2 2 18/ 11/ 59/ 21/ 56/ 17/ 3/ 4/ 1/ 7/ n/n = 151 16 n/n = 86 25 72 2 14 5 14 7 < 3 3 PI INSTI PI INSTI PI INSTI RAL EVG Fully Active Drugs Overall HIV-1 RNA HIV-1 RNA < 1, c/ml 1, c/ml *Predefined noninferiority criteria not met for regimens with < 3 vs full active drugs. Kirkpatrick L, et al. IDWeek 217. Abstract 1372. 6 4/ 4 DTG EARNEST: Boosted PI + NRTIs Noninferior to Boosted PI + RAL Randomized, open-label phase III trial in which pts in sub-saharan Africa with virologic failure on NNRTI + 2 NRTIs treated with LPV/RTV + RAL, LPV/RTV + 2-3 NRTIs, or LPV/RTV monotherapy* (N = 1277) HIV-1 RNA < 4 copies/ml, Wk 144 [2] HIV-1 RNA < 5 copies/ml, Wk 96 [1] 1 Pts (%) 1 8 6 4 2 74 P <.1 73 LPV/RTV + 2/3 NRTIs (n = 426) LPV/RTV + RAL (n = 433) LPV/RTV monotherapy (n = 418) *Pts had no prior PIs; pts receiving monotherapy received 12 wks of LPV/RTV + RAL. Paton NI, et al. N Engl J Med. 214;371:234-247. Paton, NI, et al. ACHA 215. 44 Pts (%) 8 6 4 2 88 85 77 81 61 LPV/ 1 2-3 LPV/ RTV + RTV LPV/RTV + NRTI RAL (Number of Active NRTIs) Study 119: Switch to EVG/COBI/FTC/TAF + DRV in Treatment-Experienced Pts Multicenter, open-label, randomized phase III trial Primary endpoint: HIV-1 RNA < 5 copies/ml at Wk 24 Treatment-experienced pts, HIV-1 RNA < 5 c/ml for 4 mos on DRVcontaining ART, with history of drug resistance* and egfr 5 ml/min (N = 135) Wk 24 39% pts receiving 6 pills/day at baseline Switch to EVG/COBI/FTC/TAF + DRV 8 mg QD (n = 89) Baseline ART (n = 46) Wk 48 EVG/COBI/FTC/TAF + DRV 8 mg QD (n = 46) Huhn GD, et al. IDWeek 215. Abstract 726. Huhn GD, et al. J Acquir Immune Defic Syndr. 217;74:193-2. Wk 144 *Resistance to 2 ARV classes, including 3 thymidine analogue mutations and/or K65R, but not integrase inhibitors (unless currently receiving RAL, EVG, or once-daily DTG), and no DRV resistance. 9

Study 119: Virologic Suppression After Switch to EVG/COBI/FTC/TAF + DRV Wk 24 Virologic Efficacy Wk 48 Virologic Efficacy Summary Points 1 97 91 EVG/COBI/FTC/TAF + DRV Baseline ART 1 94 EVG/COBI/FTC/TAF + DRV Baseline ART Pts (%) 8 6 4 Treatment difference: 5.3% (95% CI: -3.4% to 17.4%; P =.23) Pts (%) 8 6 4 76 Treatment difference: 18.3% (95% CI: 3.5% to 33.%; P =.4) 2 HIV-1 RNA < 5 c/ml 2 1 9 Virologic Failure No Data 2 HIV-1 RNA < 5 c/ml 11 2 Virologic Failure 13 3 No Data Huhn GD, et al. J Acquir Immune Defic Syndr. 217;74:193-2. 1