Slides General Resources for HIV ART

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: 1st 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. c RAL can be given as 400 mg BID or 1200 mg (two 600-mg tablets) once daily. US DHHS ART Guidelines – October 28, 2018 Update 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 Organizational comments: (ATV/cobi or ATV/RTV) + (TDF/FTC or TAF/FTC) • BIC/TAF/FTC new in 2018... • DOR added to second line in 2018... (ATV/cobi or ATVRTV) + ABC/3TC • 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 moved out of first line in 2018… DOR/TDF/FTC or (DOR + TAF/FTC) • Guidelines don’t really emphasize TAF vs. TDF much… EFV + (TDF/FTC or TAF/FTC)

Adapted from: US DHHS ART Guidelines – October 28, 2018 Update RPV + (TDF/FTC or TAF/FTC) 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 • Etravirine ETR CCR5 Inhibitors • Doravirine DOR • Maraviroc MVC • Efavirenz EFV • Nevirapine NVP Fusion Inhibitors • Delavirdine DLV • Enfuvirtide T-20

Integrase Inhibitors Monoclonal Antibody • Bictegravir BIC • Ibalizumab IBA • Dolutegravir DTG • Elvitegravir EVG • Raltegravir RAL ARVs in Common Use, 2018

NNRTI (non-nucleosides) New FDA Approvals in 2018 • 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 PI TAF/FTC TDF/FTC + or or or r/ATV r/DRV TDF/FTC + ABC/3TC PI or or ABC/3TC r/DRV INSTI

RAL EVG DTG NRTI’s NRTI’s: Tenofovir-based Meds

TDF/FTC (Truvada) TAF/FTC (Descovy)

Renal Concerns Bone Concerns Renal Profile

Decrease in Decrease in better? eGFR over bone density? time? Bone Profile

Risk of better? tubular Concomitant toxicity/ increase Fanconi’s risk of Lipid Profile syndrome? fracture? worse? NRTI’s: TDF/FTC (Truvada)

TDF/FTC (Truvada): evidence supporting renal concerns?

Large meta- analysis Slow, small including RCTs: magnitude small difference, TDF perhaps 3-4 decrement Other mL/min eGFR 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 proximal Initial case A known • low body weight reports low-level tubular toxicity/ 2002-2004 risk; forms • other renal risks Fanconi’s the basis of • use of r/PI syndrome? monitoring • other nephrotoxic meds 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: (Study 104/111 Data through 144 weeks) • eGFR, urine prot./creat., RBP/creat., b2M/creat.

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 NRTI’s: TAF/FTC (Descovy)

Evidence for improved bone profile? à (Study 104/111 Data through 144 weeks)

Less drop in BMD Smaller rise in PTH Less drop in BMD

Arribas J et al., JAIDS, 2017 Less decline in bone density through 96 weeks: Similar data from AMBER Study: Smaller decrease in hip bone density: • Less bone density decline with TAF: -0.7% [ECF-TAF] vs. -3.3% [ECF-TDF] (p<0.001) Hip Spine Fem neck D/C/F/TAF +0.21% -0.68% -0.26% Smaller decrease in spine bone density: -1.0% [ECF-TAF] vs. -2.8% [ECF-TDF] D/C TDF/FTC -2.73% -2.38% -2.97% (p<0.001) Eron JJ et al., AMBER Study: AIDS, 2018 NRTI’s: TAF/FTC (Descovy)

Smaller pill size Compelling for some patients; less important to other patients

TAF/FTC Stribild

TDF/FTC Genvoya NRTI’s: TAF/FTC (Descovy)

Lipid profile Drug interactions

Lipid change from baseline to 144 weeks Rifamycins is worse in TAF vs. TDF: Induce CYP3A4, P-gp, and BRCP

TAF TDF Inhibit OATP1B1, OATP1B3

Total chol. é31 é13 Net effect of this unknown Do not co-administer rifamycins with TAF HDL é6 é2

LDL é19 é6 TAF with cobicistat

TG é20 é12 TAF a substrate of CYP3A4, P-gp, OATP1B1, and OATP1B3 Arribas J et al., JAIDS, 2017 Cobi inhibits these à boosts TAF levels Note: TDF associated with favorable lipid profile; TAF is a move away from Thus, TAF dose with cobi is 10mg not 25mg this favorable profile TAF and TDF Summary

TDF/FTC (Truvada) TAF/FTC (Descovy) Renal Concerns Bone Concerns Renal Profile better? Decrease in Decrease in eGFR over bone density? time? Bone Profile

better? Risk of tubular Concomitant toxicity/ increase Lipid Profile Fanconi’s risk of syndrome? fracture? worse?

Consider eGFR, proteinuria, osteoporosis, and need for rifamycins in this decision… NRTI’s: ABC/3TC (Epzicom)

ABC/3TC (Epzicom):

ABC Hypersensitivity Cardiovascular Concerns

Polymorphism of HLAB57-01 allele Enhanced platelet reactivity? 4-8% of overall population positive; Theoretical Basic 2-4% among African Americans basis for Platelet aggregation? biology ABC binds to HLA molecule, concern Promotes ischemic CV disease? triggering HS reaction Controversial

• Database studies are equivocal • Do not clearly demonstrate MI risk Fully discriminative HLA- B57-01 If positiveàABC contraindicated à Testing If negative ABC safe Issues: controversial topic • observational studies vs. RCTs Guideline Language: “Increase in • other CV risks: accounted for? CV events is associated with ABC use in some, but not all, cohort studies” • risks from other ARVs? • duration of follow-up? • what outcomes assessed? NRTIs for Patients with HBV

• For Hepatitis B positive patients: – TDF/FTC: • 2 active agents: good choice

– TAF/FTC: • 2 active agents • also FDA approved for HBV+ patients; good choice

– ABC/3TC: • only the 3TC is active • if using ABC, typically combine with entecavir Take Home Points: Summary of NRTI Choices

• TAF vs. TDF: – Check current renal function, presence of proteinuria – Consider current bone density status – Think about drug interactions with TAF • ABC: – Test for HLAB57-01 allele variant – Gauge level of cardiovascular risk/concern • Also: – Ascertain Hepatitis B status and factor this into plan – Consider tablet size, co-formulation options • Minor point: – Consider lipids Integrase Inhibitors Integrase Inhibitors: Overview

• Dominant class of ART: goal is for all patients to be considered for INSTI

• Dolutegravir continues to be in wide use – Part of single tablet regimen Triumeq – Also available separately • Bictegravir FDA approved in 2018 – Only available as part of single tablet Biktarvy • Elvitegravir (E/C/F/TAF, and E/C/F/TDF) – Both Genvoya and Stribild moved from 1st to 2nd line • Raltegravir remains on 1st line list Integrase Inhibitor Overview

Dolutegravir (DTG) Tivicay (DTG 50mg)

• Highly potent, highly SINGLE Study: DTG+ABC/3TC vs. EFV/TDF/FTC efficacious • 144-week viral suppression 71% vs. 63% (superior) • High genetic barrier to SPRING-2 Study: DTG + (ABC/3TC or TDF/FTC) vs. resistance RAL + (ABC/3TC or TDF/FTC) • 50mg QD dosing, no • 96-week viral suppression 82% vs. 78% (non-inferior) booster FLAMINGO Study: DTG+ (ABC/3TC or TDF/FTC) vs. • Available as part of DRV/RTV + (ABC/3TC or TDF/FTC) Triumeq, or separately • 96-week viral suppression 71% vs. 63% (non-inferior)

• Need BID if using with EFV, or with rifampin Dolutegravir (cont’d)

Notes/Caution:

• DTG alone only for eGFR>30 • Side effects à discontinuation • DTG as Triumeq only for eGFR>50 initially thought to be <2-3% in first • Inhibits OCT2 à inhibits tubular year Curtis et al., HIV Clin Trials. 2014 creatinine secretion, éCr will rise • Headache, insomnia increasingly 0.1-0.3 recognized • 15% (85/556) Amsterdam patients •Decreased absorption when stopped DTG: polyvalent cations given (Ca+2, 6% (sleep), 4% (GI), 4% (malaise), 3% (psychological) Mg+2, Fe+3, e.g.) à space DTG 2h 2% joint/tendon/muscle, 2% before or 6h after these neurologic de Boer et al. AIDS 2016 • Hypersensitivity/skin reactions • Caution: boosts metformin levels uncommon (<1%) Integrase Inhibitor Overview (cont’d)

Bictegravir (BIC) Biktarvy (BIC 25mg/TAF 10mg/FTC 200mg)

• Highly potent, highly Trial 1489: Biktarvy vs. Triumeq efficacious • 48-week viral suppression 92% vs 93% • VS similar in VL<100K, VL 100K-400K and • High genetic barrier to VL>400K resistance

• 25mg dose as part of Trial 1490: Biktarvy vs. TAF/FTC + DTG single tablet Biktarvy • 48-week viral suppression 89% vs 93% (TAF/FTC/BIC) Sax PE et al., Lancet, 2017 Gallant, J et al., Lancet, 2017 • No booster Bictegravir (cont’d)

Cautions:

• Inhibits tubular secretion of • Do no co-administer with rifampin creatinine: raises Cr by 0.1mg/dL (reduces BIC and TAF) • Only for eGFR>30 • Not for liver disease Child-Pugh C • Boosts metformin levels

• Substrate of CYP3A: so any inducer • Caution for patients with HBV of CYP3A will decrease BIC levels when discontinuing: risk of HBV • Vice versa for inhibitors of CYP3A flare • Same for inducer or inhibitor of UGT1A1 • Antacids with Al/Mg/Ca: take BIC 2h before • TAF component is a substrate of P- • Fe/Ca supplements: take with BIC gp and BCRP… so inducers can and food reduce TAF, inhibitors can increase TAF… Integrase Inhibitors (cont’d)

Elvitegravir (EVG)

• Well-tolerated, strong efficacy • Hypersensitivity rare • 150 mg QD dosing • 1/866 patients had rash in EVG • Requires cobicistat (150mg QD) studies • Lower genetic barrier to resistance

Stribild (TDF 300/FTC 200/cobi 150/EVG 150)

Genvoya (TAF 10/FTC 200/cobi 150/EVG 150)

Raltegravir (RAL) Isentress (RAL 400 BID) Isentress HD (RAL 600 x 2 QD) • Very well-tolerated, good • Hypersensitivity reaction (rare, potency/efficacy mild) • 400mg BID dosing • Even rarer: DRESS syndrome • Can dose at 1200mg QD Ripamonti et al. AIDS 2014 (noninferior to 400mg BID) • No boosting required • Lower genetic barrier to resistance Integrase Inhibitor Drug Interactions

• There are a lot of these… recommend using interactions website/checker, and consultation with ID specialists to review these • EVG most problematic because of cobicistat… • DTG, BIC, RAL are all less problematic… • Key to remember (and look up): antacids, cations (Mg/Al/Ca), metformin, rifamycins, steroids (dex)

• Screen your patient for these, and good to document (esp. if on EVG) in your notes for others: – ”patient on INSTI for HIV: consult pharmacy team before starting antacids, anticoagulants, antiepileptics, antidepressives, metformin, rifamycins, cations, or steroids.” Dolutegravir and Pregnancy

• Dolutegravir in preliminary/emerging data has been associated with low rate of neural tube defects

• Guidelines: “preliminary data suggest that there is an increased risk of neural tube defects (NTDs) in infants born to people who were receiving DTG at the time of conception” – “negative pregnancy test result should be documented prior to initiating DTG in antiretroviral therapy (ART)-naive individuals of childbearing potential – DTG is not recommended for those who are pregnant and within 12 weeks post-conception – DTG is also not recommended for those of childbearing potential who are planning to become pregnant or who are sexually active and not using effective contraception – For those who are using effective contraception, use of a DTG-based regimen can be considered after discussing the risks and benefits of this drug with the patient”

• It is not yet known whether other INSTIs pose a similar risk of NTDs (i.e., a class effect). Integrase Inhibitor Overview

Dolutegravir Bictegravir Raltegravir Elvitegravir

Frequency QD (ART-naïve or INSTI- QD 1200mg QD QD naïve) or 400mg BID BID: with CYP3A4 or UGT1A1 inducers, or with INSTI mutations

Genetic High High Lower Lower barrier to resistance

Single tablet Yes, Triumeq Yes, Biktarvy No Yes, Genvoya or regimen Stribild option?

Key side Nausea, diarrhea/GI disturbance, headache, insomnia effects

Increased CK, myositis, Myositis, increased myositis, hyperlipidemia hypersensitivity, CK (4%) hypersensitivity, hepatotoxicity hepatotoxicity, SJS/TEN Take Home Points: Summary of INSTI Choices

• Priority: – Consider/prioritize offering an INSTI to all patients ahead of PI or NNRTI based regimen – Try to avoid cobicistat boosting where possible • DTG: – Daily, well tolerated, best if any history of resistance – Part of co-formulated Triumeq – Watch developing data on pregnancy • BIC: – Daily, well tolerated, no data on patients with resistance • Also/always: – Consider drug drug interactions, tablet size Protease Inhibitors Protease Inhibitor Overview

• Darunavir (DRV/r) • Highest potency; fewer side effects than other PIs; well tolerated Norvir: RTV 100 Prezista: DRV 800 • 800mg QD dosing (if no DRV mutations) – concomitantly administer either RTV 100mg QD or cobicistat 150mg QD Prezista: DRV 600 • 600mg BID dosing (when DRV mutations present) – concomitantly administer RTV 100mg BID (don’t use cobicistat for boosting)

• Side effects: overall low RTV 100 • As with most PI’s: GI side effects, skin rash (sulfa moiety) – usually self limited, dyslipidemia, rare hepatotoxicity Prezcobix: • Advise take with food DRV 800/cobi 150

• Unlike ATV: no hyperbilirubinemia; no spacing apart from H2-blockers; PPI’s are ok • Moved from first line to second line in 2017 Symtuza: DRV 800/cobi 150/ TAF/FTC Trial Data Supporting D/C/F/TAF

• Darunavir/cobi/TAF/FTC (800/150/10/200) – AMBER Study (ART-naïve adults, randomized to D/C/F/TAF (n=362) vs. DRV/cobi + FTC/TDF (n=363) to W48 (double blind phase III non-inferiority trial, -10% margin) – D/C/F/TAF: 91.4% VS at Week 48 vs. DRV/cobi + TDF/FTC: 88.4% VS (+2.7%, 95% CI -1.6% to +7.1%; non-inferior) AMBER: Eron JJ et al., AIDS, July 2018

– EMERALD Ph. 3 switch study (in virally suppressed adults) also showed non-inferior maintenance of VS with D/C/F/TAF vs. control EMERALD: Orkin, C et al., Lancet HIV, 2017 Protease Inhibitors (cont’d)

RTV 100 ATV 300 • Atazanavir (ATV/r) • Good potency, generally well-tolerated, 300mg QD (+ RTV 100mg QD) • Least effect on lipids of PI’s • ↑bilirubin: sometimes cosmetic, sometimes beyond • GERD: in ART-naïve patients: – H2 blockers: give ATV 400QD 2h before or 10h after H2; give ATV300/RTV100 anytime – PPI: use omeprazole 20 or equivalent (maximum) 12h before ATV • Recommend take with food Recommend against combining ATV with PPI • Not in first line recommended list Take Home Points: Summary of PI Choices

• Priorities: – As noted earlier, prioritize PIs below/after INSTIs in most/all patients – With ritonavir or cobicistat booster, must carefully check all drug interactions • Darunavir: – Daily (for most patients), well tolerated – Part of co-formulated Symtuza • Atazanavir, Lopinavir, others: – Older, and most patients should be modernized away from these • Also/always: – Consider drug drug interactions, tablet sizes NNRTI’s NNRTI Overview

Rilpivirine • Potency similar to EFV • Lower efficacy when • Lacks CNS side effects VL>100K or CD4<200 (RPV) • Less lipid effects • Requires 400 cal. meal

Edurant: RPV 25 • H2 blocker: give 12h before or 4h after RPV Odefsey: RPV 25/ • PPI: avoid TAF 25/FTC 200 • In second line list Doravirine • FDA approved 2018: ART-naïve • Low rates of headache, • Good potency nausea, diarrhea (DOR) • Has TDF in combination pill • Metabolized by CYP3A; • Don’t combine with Pifeltro: DOR 100 • Pifeltro: No dose adjustment for rifampin (rifabutin ok if renal failure or liver disease use DOR 100 BID) Delstrigo: DOR 100/ • In second line list TDF 300/FTC 300 • Delstrigo: only for eGFR>50 NNRTI Overview (cont’d)

Efavirenz • Potency well • Caution with depression established • Rare suicidality (EFV) • QD • CNS side effects: insomnia, dreams Sustiva: EFV 600 • Lipid effects • In second line list Etravirine • Potency similar to EFV • BID drug (200mg BID) • Less lipid effects (data support 400mg QD) (ETV) • In second line list

Intelence: ETR 200 x2 Take Home Points: Summary of NNRTI Choices

• Priorities: – As noted earlier, prioritize NNRTIs below/after INSTIs in most/all patients – Lower genetic barrier to resistance • Efavirenz: – Older med; should modernize regimen in most patients • Rilpivirine: – Part of co-formulated Odefsey; calorie requirement, and some drug interactions • Etravirine, Doravirine: – Can make sense in certain situations Single Tablet Regimens Single Tablet Co-Formulations