Antiretroviral Therapy Initiation: From Guidelines to Practice: “ART 101” Medical Care of Vulnerable and Underserved Populations: CME Course February 28, 2019 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
Disclosures • Research grant support from National Institutes for Health (NIH), Centers for Disease Control (CDC) & President’s Emergency Plan for AIDS Relief (PEPFAR) – – For work ongoing in East Africa related to HIV care models – This disclosure is unrelated to this presentation
Goals • To create a working proficiency in selecting initial ART regimens for non-HIV specialists, including how and when to access specialists • Review DHHS first line & alternate regimens for HIV treatment – Pros and cons, considerations, choices – Many updates from last year (4 new drugs FDA approved in 2018) • Will not focus on: – In-depth ART pharmacology – HIV drug resistance – Optimizing ART regimens in virally suppressed individuals – 2-drug or “Nucleoside-sparing” regimens – ART for pediatric or pregnant patients – Drugs in development but not yet FDA approved • 50 minutes… lots to cover! • Reach out to your ID colleagues anytime for discussion and optimization on ART! • Take-home points summarized on the yellow slides
General Resources for HIV ART • HIV Warm Line/National Clinician Consultation Center: – http://nccc.ucsf.edu/, Telephone: (800) 933-3413, M-F, 6 a.m. – 5 p.m. Pacific time • For SF Health Network Providers: – Send eConsult to SFGH Infectious Diseases Clinic • HIV drug interactions checker – University of Liverpool: https://www.hiv-druginteractions.org/ • HIV drug resistance database/checker – Stanford University: – https://hivdb.stanford.edu/hivdb/by-mutations/
US DHHS Guidelines: 1 st Line Therapy Yellow = October 2018 updates Recommended regimens are those with These regimens are effective and tolerable, but have demonstrated durable virologic efficacy, favorable some disadvantages when compared with the regimens tolerability and toxicity profiles, and ease of use. listed above, or have less supporting data from randomized clinical trials. However, in certain clinical situations, one of these regimens may be preferred. 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. 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. US DHHS ART Guidelines – October 28, 2018 Update c RAL can be given as 400 mg BID or 1200 mg (two 600-mg tablets) once daily. http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
U.S. DHHS Guideline Update: October, 2018 Initial Regimens Initial Regimens “for Most People” “in Certain Clinical Situations” BIC /TAF/FTC EVG /cobi + (TDF/FTC or TAF/FTC) * If reproductive potential, consult guidance * If reproductive potential, consult guidance DTG /ABC/3TC RAL / ABC /3TC Only if HLB57-01 negative Only if HLAB57 negative and VL<100,000 * If reproductive potential, consult guidance * If reproductive potential, consult guidance DTG + (TDF/FTC or TAF/FTC) ( DRV /RTV or DRV/cobi) + (TDF/FTC or TAF/FTC) * If reproductive potential, consult guidance RAL + (TDF/FTC or TAF/FTC) ( DRV /cobi or DRV/RTV) + ABC/3TC * If reproductive potential, consult guidance Only if HLB57-01 negative ( ATV /cobi or ATV/RTV) + (TDF/FTC or TAF/FTC) Organizational comments: • BIC/TAF/FTC new in 2018... ( ATV /cobi or ATVRTV) + ABC/3TC • DOR added to second line in 2018... • DRV moved out of first line list in 2017… Only if HLAB57 negative and VL<100,000 • EVG/cobi/TAF/FTC and EVG/cobi/TDF/FTC DOR /TDF/FTC or (DOR + TAF/FTC) moved out of first line in 2018… • Guidelines don’t really emphasize TAF vs. EFV + (TDF/FTC or TAF/FTC) TDF much… RPV + (TDF/FTC or TAF/FTC) Adapted from: US DHHS ART Guidelines – October 28, 2018 Update Only if VL<100,000 & CD4+ >200
FDA-Approved ARVs, 2018 NRTI (nucleoside analogs) Protease Inhibitors • Tenofovir alafenamide TAF • Darunavir DRV • Tenofovir TDF • Atazanavir ATV • Abacavir ABC • Ritonavir RTV • Emtricitabine FTC • Cobicistat Cobi • Lamivudine 3TC • Lopinavir LPV • Stavudine D4T • Fosamprenavir FPV • Didanosine DDI • Amprenavir APV • Zalcitabine DDC • Tipranavir TPV • Zidovudine ZDV • Nelfinavir NFV • Saquinavir SQV NNRTI (non-nucleosides) • Indinavir IDV • Rilpivirine RPV CCR5 Inhibitors • Etravirine ETR • Doravirine DOR • Maraviroc MVC • Efavirenz EFV Fusion Inhibitors • Nevirapine NVP • Delavirdine DLV • Enfuvirtide T-20 Integrase Inhibitors Monoclonal Antibody • Bictegravir BIC • Ibalizumab IBA • Dolutegravir DTG • Elvitegravir EVG • Raltegravir RAL
ARVs in Common Use, 2018 NRTI (nucleoside analogs) Protease Inhibitors • Tenofovir alafenamide TAF • Darunavir DRV • Tenofovir TDF • Atazanavir ATV • Abacavir ABC • Ritonavir RTV • Emtricitabine FTC • Cobicistat Cobi • Lamivudine 3TC New FDA Approvals in 2018 NNRTI (non-nucleosides) • Rilpivirine RPV • 2/18: Bictegravir BIC • 3/18: Ibalizumab: monoclonal Ab IBA • 7/18: TAF/FTC/cobicistat/DRV Symtuza Integrase Inhibitors • 8/18: Doravirine DOR • Bictegravir BIC • Dolutegravir DTG • Elvitegravir EVG • Raltegravir RAL
Basic Initial Regimen Composition Previously: Currently: NNRTI EFV RPV INSTI or 2x NRTI 2x NRTI BIC DTG RAL + TAF/FTC PI TDF/FTC + or or r/ATV r/DRV or TDF/FTC ABC/3TC PI or or ABC/3TC r/DRV INSTI RAL EVG DTG
NRTI’s
NRTI’s: Tenofovir-based Meds TAF/FTC (Descovy) TDF/FTC (Truvada) Renal Concerns Bone Concerns Renal Profile better? Decrease in Decrease in eGFR over bone density? time? Bone Profile Risk of better? Concomitant tubular increase toxicity/ risk of Fanconi’s Lipid Profile fracture? syndrome? worse?
NRTI’s: TDF/FTC (Truvada) TDF/FTC (Truvada): evidence supporting renal concerns? Large meta- analysis Slow, small including RCTs: small difference, magnitude TDF perhaps 3-4 decrement mL/min eGFR Other in eGFR Cooper CID 2010 over time? 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 -10 eGFR after 6Y TDF vs -9 Laprise CID 2013 Issues: controversial topic • observational study vs. RCT Small risk of • baseline eGFR Initial case A known proximal • low body weight reports low-level tubular toxicity/ • other renal risks 2002-2004 risk; forms • use of r/PI Fanconi’s the basis of • other nephrotoxic meds monitoring syndrome?
NRTI’s: TDF/FTC (Truvada) TDF/FTC (Truvada): evidence for bone concerns? Hip BMD Spine BMD • Decrement in bone density after ART initiation • Then stabilization ACTG 5202 Study: McComsey, JID, 2011 • Clinical significance of a 2-4% loss of BMD unclear… • No apparent evidence that this translates to higher risk of fracture…
NRTI’s: TAF/FTC (Descovy) TAF (tenofovir alafenamide) • Plasma concentrations are Oral TAF prodrug TAF taken into cells, hydrolyzed/processed to create 90% lower than TDF circulates in tenofovir (TFV), then phosphorylated to create • Intracellular plasma tenofovir-diphosphate (TFV-DP , the active drug concentrations much higher Virologic non-inferiority to TDF/FTC (data through 144 weeks) Genvoya (TAF/FTC/cobi/EVG) noninferior Similar data from AMBER Study: to Stribild (TDF/FTC/c/EVG) • TAF /FTC/cobi/DRV noninferior to (Study 104/111): TDF /FTC+cobi/DRV: • at Week 48: 91% VS [TAF] vs. 88% [TDF] • at Week 48: 92% VS [TAF] vs. 90% [TDF] • at Week 96: 87% VS [TAF] vs. 85% [TDF] Eron JJ et al., AMBER Study: AIDS, 2018 • at Week 144, 84.2% [TAF] vs. 80.0% [TDF] 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
NRTI’s: TAF/FTC (Descovy) Evidence for improved renal profile? Smaller changes in proteinuria by 4 measurements: • eGFR, urine prot./creat., RBP/creat., b 2M/creat. (Study 104/111 Data through 144 weeks) Less decline in eGFR: • median drop in CrCl: -2.0 mL/min [ECF-TAF] -7.5 mL/min [ECF-TDF] (p<0.001) Fewer discontinuations due to renal dysfunction: • 0 discontinuations [TAF] • vs.12 discontinuations [TDF] Arribas J et al., JAIDS, 2017 Similar data from AMBER Study: • Less decline in eGFR with DCF/TAF vs. DRV/cobi+TDF/FTC • Smaller changes in proteinuria Eron JJ et al., AMBER Study: AIDS, 2018 Also note: Can use TAF for patients with eGFR ≥ 30 Sax PE et al., Lancet, 2015, Wohl D et al., JAIDS, 2016 , whereas TDF for patients with eGFR ≥ 60 Arribas J et al., JAIDS, 2017
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