12/13/19 Disclosures • Research grant support from National Institutes for Health (NIH), Centers for Antiretroviral Therapy Initiation: Disease Control (CDC) & President’s Emergency Plan for AIDS Relief (PEPFAR) – From Guidelines to Practice: ART 101 Medical Management of AIDS & Hepatitis – For work ongoing in East Africa related to HIV care models December 12, 2019 – This disclosure is unrelated to this presentation Vivek Jain, M.D., M.A.S. Associate Professor of Medicine Division of HIV, Infectious Diseases & Global Medicine San Francisco General Hospital, University of California, San Francisco 1 2 1
12/13/19 Goals Outline • Working proficiency in selecting initial ART regimens • Review of Guideline regimens • Nucleotide reverse transcriptase inhibitors (NRTI's): • Review DHHS first line & alternate regimens – tenofovir, TAF, abacavir – Pros and cons, considerations, choices – Many updates from last year (4 new drugs FDA approved in 2018) • Integrase strand transfer inhibitors (INSTI's): – dolutegravir, bictegravir, elvitegravir, raltegravir • Will not focus on: • Protease inhibitors (PI's): – HIV drug resistance – ART switching in virally suppressed patients – darunavir, atazanavir – ART for pediatric or pregnant patients – Drugs still in development (but not yet FDA approved) • Non-nucleotide reverse transcriptase inhibitors (NRTI's): – There's lots at this conference on all of the above, but we will focus on ART initiation – rilpivirine, doravirine • 2-drug ART regimens: • 45 minutes… lots to cover! – DTG/3TC, DTG/RPV 3 4 2
12/13/19 Outline DHHS Guidelines • Review of Guideline regimens • Available for download at: • Nucleotide reverse transcriptase inhibitors (NRTI's): • https://aidsinfo.nih.gov/guidelines/html/1/adu – tenofovir, TAF, abacavir lt-and-adolescent-arv/0 • Integrase strand transfer inhibitors (INSTI's): – dolutegravir, bictegravir, elvitegravir, raltegravir • Protease inhibitors (PI's): – darunavir, atazanavir • Non-nucleotide reverse transcriptase inhibitors (NRTI's): – rilpivirine, doravirine • 2-drug ART regimens: – DTG/3TC, DTG/RPV 5 6 3
12/13/19 US DHHS Guidelines: 1 st LineTherapy U.S. DHHS Guideline Update: October, 2018 Most recent version: July, 2019 Initial Regimens Initial Regimens “for Most People” “in Certain ClinicalSituations” BIC /TAF/FTC EVG /cobi + (TDF/FTC orTAF/FTC) * If reproductive potential, consult guidance * If reproductive potential, consult guidance Recommended regimens are those with These regimens are effective and tolerable, but have DTG /ABC/3TC RAL / ABC /3TC demonstrated durable virologic efficacy, favorable some disadvantages when compared with the regimens Only if HLB57-01 negative Only if HLAB57 negative and VL<100,000 tolerability and toxicity profiles, and ease of use. listed above, or have less supporting data from * If reproductive potential, consult guidance * If reproductive potential, consult guidance randomized clinical trials. However, in certain clinical DTG + (TDF/FTC orTAF/FTC) ( DRV /RTV or DRV/cobi) + (TDF/FTC orTAF/FTC) situations, one of these regimens may be preferred. * If reproductive potential, consult guidance RAL + (TDF/FTC orTAF/FTC) ( DRV /RTV or DRV/cobi) + ABC/3TC * If reproductive potential, consult guidance Only if HLB57-01 negative ( ATV /RTV or ATV/cobi) + (TDF/FTC orTAF/FTC) ( ATV /RTV or ATV/cobi) +ABC/3TC Only if HLAB57 negative and VL<100,000 DOR /TDF/FTC or (DOR +TAF/FTC) Adapted Footnotes: a 3TC may be substituted for FTC, or vice versa. ABC/3TC, TDF/3TC, TDF/FTC, TAF/FTC are available as tablets, and as part of single tablet regimens. Cost, access, and availability of of STRs can influence choice of 3TC vs FTC. EFV + (TDF/FTC orTAF/FTC) b TAF and TDF are two forms of tenofovir approved by the FDA. TAF has fewer bone and kidney toxicities than TDF, while TDF is associated with lower lipid levels. Safety, cost, and access are among the factors to consider when choosing between these drugs. c RAL can be given as 400 mg BID or 1200 mg (two 600-mg tablets) once daily. RPV + (TDF/FTC orTAF/FTC) Adapted from: US DHHS ART Guidelines – July, 2019 Update US DHHS ART Guidelines – October 28, 2018 Update Only if VL<100,000 & CD4+>200 http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf 7 8 4
12/13/19 FDA-Approved ARVs, 2019 Shorter List of ARVs, 2019 NRTI (nucleoside analogs) Protease Inhibitors NRTI (nucleoside analogs) Protease Inhibitors • Tenofovir alafenamide TAF • Darunavir DRV • Tenofovir alafenamide TAF • Darunavir DRV • Tenofovir TDF • Atazanavir ATV • Tenofovir TDF • Ritonavir RTV • Abacavir • Cobicistat • Abacavir ABC • Ritonavir RTV ABC Cobi • Emtricitabine FTC • Cobicistat Cobi • Emtricitabine FTC • Lamivudine 3TC • Lopinavir LPV • Lamivudine 3TC • Stavudine D4T • Fosamprenavir FPV • Didanosine DDI • Amprenavir APV • Zalcitabine DDC • Tipranavir TPV NNRTI (non-nucleosides) • Zidovudine ZDV • Nelfinavir NFV • Rilpivirine RPV • Saquinavir SQV NNRTI (non-nucleosides) • Indinavir IDV • Rilpivirine RPV Integrase Inhibitors CCR5 Inhibitors • Etravirine ETR • Bictegravir BIC • Doravirine DOR • Maraviroc MVC • Dolutegravir DTG • Efavirenz EFV Fusion Inhibitors • Elvitegravir EVG • Nevirapine NVP • Raltegravir RAL • Delavirdine DLV • Enfuvirtide T-20 Integrase Inhibitors Monoclonal Antibody • Bictegravir BIC • Ibalizumab IBA • Dolutegravir DTG • Elvitegravir EVG • Raltegravir RAL 9 10 5
12/13/19 Basic Initial Regimen Composition Outline Previously: Currently: • Review of Guideline regimens NNRTI • Nucleotide reverse transcriptase inhibitors (NRTI's): EFV RPV – tenofovir, TAF, abacavir INSTI or 2x NRTI • Integrase strand transfer inhibitors (INSTI's): 2x NRTI BIC DTG RAL + TAF/FTC PI – dolutegravir, bictegravir, elvitegravir, raltegravir TDF/FTC + or or • Protease inhibitors (PI's): r/ATV r/DRV or TDF/FTC – darunavir, atazanavir ABC/3TC PI or or • Non-nucleotide reverse transcriptase inhibitors (NRTI's): ABC/3TC r/DRV INSTI – rilpivirine, doravirine • 2-drug ART regimens: RAL EVG DTG – DTG/3TC, DTG/RPV 11 12 6
12/13/19 NRTI’s: Tenofovir-based Meds NRTI’s: TDF/FTC (Truvada) TDF/FTC (Truvada): evidence supporting renal concerns? TAF/FTC (Descovy) TDF/FTC (Truvada) Large meta- RenalConcerns BoneConcerns analysis Renal Profile Slow, small including RCTs: smalldifference, magnitude TDF better? Decrease in perhaps 3-4 Decrease in decrement mL/min eGFR eGFR over Other bone density? in eGFR Cooper CID 2010 time? over time? Bone Profile Generalized decrease in renal function Japanese cohort with larger decline in TDF > Other agents; difference small eGFR with TDF vs.ABC Modest loss in Y1, less after that Nishijima AIDS 2014 Risk of better? -10 eGFR after 6Y TDF vs -9 Concomitant tubular Laprise CID 2013 Issues: controversial topic increase toxicity/ • observational study vs. RCT risk of Fanconi’s Small risk of Lipid Profile • baseline eGFR fracture? Initial case A known syndrome? proximal • low body weight reports low-level worse? tubular toxicity/ • other renal risks 2002-2004 risk; forms • use of r/PI Fanconi’s the basisof • other nephrotoxic meds syndrome? monitoring 13 14 7
12/13/19 NRTI’s: TDF/FTC (Truvada) NRTI’s: TAF/FTC (Descovy) TAF (tenofovir alafenamide) TDF/FTC (Truvada): evidence for bone concerns? Oral TAF prodrug TAF taken into cells, processed to circulates in create tenofovir-diphosphate Hip BMD Spine BMD plasma (TFV-DP , the active drug) •Decrement in bone Similar non-inferiority of TAF when Virologic non-inferiority of TAF to density after paired with cobi/DRV TDF when paired with cobi/EVG ARTinitiation • TAF/FTC/cobi/DRV noninferior to Genvoya (TAF/FTC/cobi/EVG) •Then TDF/FTC+cobi/DRV: noninferior to Stribild stabilization (AMBER Study) (TDF/FTC/c/EVG) (Study 104/111): ACTG 5202 Study: McComsey, JID,2011 • at Week 48: 91% VS [TAF] vs. 88% [TDF] • at Week 96: 85% VS [TAF] vs. 84% [TDF] • at Week 48: 92% VS [TAF] vs. 90% [TDF] • Clinical significance of a 2-4% loss of BMD unclear… • at Week 96: 87% VS [TAF] vs. 85% [TDF] • at Week 144, 84.2% [TAF] vs. 80.0% [TDF] • No apparent evidence that this translates to higher risk of fracture… Eron JJ et al., AMBER Study: AIDS, 2018 Orkin, C. et al., AMBER Study: HIV Drug Therapy Glasgow, Oct. 2018 Similar AE profile, lipid effects Week 48 data: Sax PE et al., Study 104/111: Lancet, 2015 Week 96 data: Wohl D et al., Study 104/111: JAIDS, 2016 Week 144 data: Arribas J et al., Study 104/111: JAIDS, 2017 15 16 8
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