The Art of Antiretroviral Therapy Annie Luetkemeyer, MD Medical - PDF document

12/13/19 The Art of Antiretroviral Therapy Annie Luetkemeyer, MD Medical Management of AIDS and Hepatitis, 2019 1 Disclosure Research grant support to UCSF related to HIV treatment from: • Gilead • Merck • Viiv 2 1

12/13/19 2019: What to start in “most patients” CLASS REGIMEN INSTI BIC/TAF/FTC INSTI DTG/ABC/3TC INSTI DTG/TAF/FTC INSTI* RTG/TAF/FTC* *HHS Guidelines only 3 When one size doesn’t fit all • Rapid start • High HIV RNA, low CD4 cell count • Switching- when to consider newer regimens & what to when drug resistance present • Abacavir and tenofovir sparing regimens • Extensive resistance 4 2

12/13/19 Case #1 : RAPID ART Start 48 year old man, new diagnosis of HIV, when admitted to hospital with community acquired pneumonia • CD4 + 275, HIV RNA 80,000 copies • HIV genotype and HLA-B*5701 both pending • Comorbidities • HTN • Hyperlipidemia • Mild renal insufficiency, eGFR = 50 5 ARS: What do you recommend? 1) Start BIC/TAF/FTC now 2) Start DTG/3TC 3) Start DTG/RPV 4) Start DTG/ABC/3TC 5) Wait for HIV Genotype to return New HIV diagnosis, CD4 275, HIV RNA 80K, No HIV genotype yet, mild renal insufficiency 6 3

12/13/19 ARS: What do you recommend? 1) Start BIC/TAF/FTC now 2) Start DTG/3TC -> DTG monotherapy if 3TC resistance 3) Start DTG/RPV -> NO ART start data 4) Start DTG/ABC/3TC-> NO HLA-B*5701 5) Wait for HIV Genotype to return New HIV diagnosis, CD4 275, HIV RNA 80K, No HIV genotype yet, mild renal insufficiency 7 RAPID ART Start: Take homes • DO start ART ASAP: Both DHHS & IAS-USA guidelines recommend ART initiation as soon as possible after diagnosis, if the patient is open to starting • DON’T wait for genotype/HLA-B5701 results (but DO send!) • DON’T start two-drug regimens without resistance data to guide you! 8 4

12/13/19 Case #2: High HIV RNA & Low CD4 + 58 year old man, new diagnosis of HIV with CD4 + 110, HIV RNA 425,000. • No evidence of opportunistic infection • Genotype = wild type • HLA-B*5701 negative • Renal insufficiency due to poorly controlled diabetes and hypertension, eGFR=50 9 Which tenofovir-sparing ART regimen is an option with a high viral load & low CD4 + cell count ? 1) Dolutegravir/rilpivine 2) Dolutegravir/3TC 3) Atazanavir/r plus ABC/3TC 4) DTG/ABC/3TC 5) Darunavir/r plus Raltegravir CD4 + 110, VL 425K, eGFR=50 HIV genotype = wild type 10 5

12/13/19 Which tenofovir-sparing ART regimen is an option with a high viral load & low CD4 + cell count? 1) Dolutegravir/rilpivine 2) Dolutegravir/3TC 3) Atazanavir/r plus ABC/3TC 4) DTG/ABC/3TC 5) Darunavir/r plus Raltegravir CD4 + 110, VL 425K, eGFR=50 HIV genotype = wild type 11 DHHS guidelines AVOID with CD4 + < 200 Rilpivirine-containing regimens Higher rates of virologic failure DRV/r + RAL observed AVOID with HIV RNA > 100,000 Rilpivirine-containing regimens Higher rates of ABC/3TC + EFV virologic failure ABC/3TC + ATV/r observed DRV/R + RAL 12 6

12/13/19 Gemini Studies: DTG/3TC vs DTG+TDF/FTC in treatment-naïve Caveats • CD4 + < 200 • W48 HIV RNA not < 50: 2 drug: 79% (50/63) vs 3 drug 93% (51/55) • However, few failures due to HIV VL >50- 2 drug: 3 vs 3 drug: 1 • Excluded VL > 500,000 at screening Take home: Caution with DTG/3TC with very high viral load & low CD4 + until more data. Cahn Lancet 2019, 393(10167):143-155 13 Case #3: ART of the Switch 38 year male body builder, travels extensively to compete, currently on his first regimen of BIC/TAF/FTC. • CD4 + 450, HIV RNA suppressed • Baseline genotype = wildtype He is distressed by reports of weight gain with INSTI’s and TAF and would like to change regimens. He has been reading about ART options and has the following requests: 1) One pill daily 2) No food requirement 3) Absolutely cannot be associated with weight gain 14 7

12/13/19 ARS:Which of these regimens meets his requirements? 1) Dolutegravir/Rilpivirine 2) Doravirine/TDF/3TC 3) Dolutegravir/3TC 4) Elvitegravir/cobicistat/TAF/FTC 5) BIC/TAF/FTC (current regimen) Suppressed on BIC/TAF/FTC, HIV = wild type Requests: ü single pill ü no food requirement ü no reported association with weight gain 15 Which of these regimens meets his requirements? 1) Dolutegravir/Rilpivirine 2) Doravirine/TDF/3TC 3) Dolutegravir/3TC 4) Elvitegravir/cobicistat/TAF/FTC 5) BIC/TAF/FTC (current regimen) Suppressed on BIC/TAF/FTC, HIV = wild type Requests: ü single pill ü no food requirement ü no reported association with weight gain 16 8

12/13/19 Food requirement ART • INSTI’s: BIC, DTG, RAL Can be taken without • NNRTI: DOR regard to food • All cobi- and ritonavir- boosted PI’s Take with food • NNRTI’s: RIL INSTI: ELV/cobi • NNRTI: Efavirenz Take on empty stomach • DHHS Guidelines 7/2019 17 Doravirine • NNRTI approved in 8/2018 • Both as stand alone pill & DOR/TDF/3TC FDC • Can be given without regard to food or acid suppression • Active against NNRTI mutations K103N, Y181C, G190A • 2 treatment naïve studies & 1 switch study www.i-Base.com (unbranded) 18 9

12/13/19 DRIVE-AHEAD: DRIVE FORWARD: DOR + TDF/3TC equivalent to EFV/FTC/TDF DOR + 2 NRTI equivalent to DRV/r + 2 NRTI 100 DOR/3TC/TDF (n = 364) DOR + 2 NRTIs (n = 383) 100 84 84 81 EFV/FTC/TDF (n = 364) 80 DRV/RTV + 2 NRTIs (n = 383) 80 80 Patients (%) Patients (%) 60 60 Treatment difference: 3.5% Treatment difference: 3.9% (95% CI: -2.0% to 9.0%) (95% CI: -1.6% to 9.4%) 40 40 20 20 13 11 11 10 9 7 5 5 0 0 HIV-1 RNA HIV-1 RNA No Data in No Data < 50 c/mL ≥ 50 c/mL Window 19 DRIVE-AHEAD: DRIVE FORWARD: DOR + TDF/3TC equivalent to EFV/FTC/TDF DOR + 2 NRTI equivalent to DRV/r + 2 NRTI 100 DOR/3TC/TDF (n = 364) 100 DOR + 2 NRTIs (n = 383) 84 84 81 EFV/FTC/TDF (n = 364) 80 DRV/RTV + 2 NRTIs (n = 383) 80 80 Patients (%) Patients (%) 60 60 Treatment difference: 3.5% Treatment difference: 3.9% (95% CI: -2.0% to 9.0%) (95% CI: -1.6% to 9.4%) 40 40 20 20 13 11 11 10 9 7 5 5 0 0 HIV-1 RNA HIV-1 RNA No Data in No Data < 50 c/mL ≥ 50 c/mL Window DOR + 2 DRV/RTV + 2 DOR/3TC/TDF EFV/FTC/TDF Outcome NRTIs NRTIs (n = 364) (n = 364) (n = 383) (n = 383) PROTOCOL DEFINED FAILURE 34 (9) 43 (11) 34 (9) 28 (8) n (%) Successful resistance analysis 15 20 34 33 § DOR resistance 2 -- 6 -- § NRTI resistance 2 1 5 5 § PI resistance -- 0 NA NA § EFV resistance NA NA -- 13 20 10

12/13/19 Doravine Switch study: DRIVE-SHIFT • Suppressed x ≥ 6 months • PI/r or PI/c, ELV/c, NNRTI plus 2 NRTI • No prior HIV virologic failure & DOR/3TC/TDF resistance exclusionary • Randomized to 24 weeks of continued therapy vs DOR/3TC/TDF then all on DOR/3TC/TDF x 24 weeks • DOR/3TC/TDF 90.8% vs No switch 94.6% • 7 with protocol defined failure after switch, none with DOR resistance. • 23 with baseline non-DOR NNRTI resistance switched, 21 suppressed (2 discontinued) Johnson JAIDS 2019 81(4): 463 21 Doravirine PRO’s CONS • No data in patients with • No food requirement virologic failure or more heavily treatment • Data to support use in experienced treatment naïve • NNRTI & NRTI resistance at • Vs.EFV/TDF/FTC time of failure- lower • Vs. DRV/r + 2 NRTI barrier to resistance • One switch study with • No long term data - what equivalence side effects will be • NOT a PI or INSTI discovered? Coformulated with TDF not TAF 22 11

12/13/19 Case #4: NRTI free Switch 67 year old woman, HIV well controlled on DRV/c/TAF/FTC with excellent adherence. • Known baseline M184V • HLA-B*5701(+) • Osteoporosis, on a bisphosphonate You would like to change her off of tenofovir-containing ART given her osteoporosis & abacavir-containing regimens not an option 23 ARS: Which 2 drug regimen is not recommended as an ABC/TDF sparing option in the current DHHS guidelines? 1) Dolutegravir/3TC 2) Darunavir/r + Raltegravir 3) Darunavir/r + 3TC 4) Cabotegravir/Rilpivirine 24 12

12/13/19 ARS: Which 2 drug regimen is not recommended as an ABC/TDF sparing option in the current DHHS guidelines? 1) Dolutegravir/3TC 2) Darunavir/r + Raltegravir 3) Darunavir/r + 3TC 4) Cabotegravir/Rilpivirine ( under FDA review) 25 NRTI-sparing Switch options 3TC-containing DTG/3TC LAMIDOL, ASPIRE, TANGO DRV/r +3TC DUAL GESIDA, DUALIS ATV/r + 3TC ATLAS-M, SALT 3TC- sparing DTG/RPV SWORD DTG + DRV/r DUALIS 26 13

12/13/19 NRTI-sparing Switch options 3TC-containing DTG/3TC LAMIDOL, ASPIRE, TANGO Known DRV/r +3TC M184V DUAL GESIDA, DUALIS ATV/r + 3TC ATLAS-M, SALT 3TC- sparing DTG/RPV SWORD DTG + DRV/r DUALIS 27 Switch to DTG/RPV: SWORD • HIV suppressed x > 6 months on 1 st or 2 nd ART regimen (NNRTI, PI, INSTI + 2 NRTI) • Virologic failure • 3 DTG/RIL: 1 with resistance testing available • Mutations: No INSTI, 1 NNRTI K101K/R, resuppressed on DTG/RIL Llibre. Lancet. 2018;391:839. Libre. Lancet. 2018;391:839. 28 14