StateoftheART in Antiretroviral Therapy Optimal Initial Regimens in

State-of-the-ART in Antiretroviral Therapy: Optimal Initial Regimens in 2016 Rajesh T. Gandhi, MD Director, HIV Clinical Services and Education Massachusetts General Hospital Boston, Massachusetts Thanks to Alice Pau, Roger Bedimo and Marilyn Shi for assistance with slides Washington, DC: August 23, 2016

Financial Relationships With Commercial Entities �Dr Gandhi has received grants paid to his institution from Gilead Sciences, Inc, EBSCO, Merck & Co, Inc, and Vii. V Healthcare. (Updated 08/15/16) Slide 2 of 44

Learning Objectives After attending this presentation, participants will be able to: �Identify optimal antiretroviral regimens for HIV-infected persons �Customize antiretroviral regimens for persons with specific comorbidities Slide 3 of 44

HIV: What to Start in 2016 • Choosing an Initial Regimen • Treatment Guidelines and Recent Changes • Four Controversies Slide 4 of 44

Reproductive Cycle of HIV and Sites of Action of Major Classes of Antiretroviral Medications Slide 5 of 44 Gandhi M, Gandhi RT. N Engl J Med 2014; 371: 248 -259.

Reproductive Cycle of HIV and Sites of Action of Major Classes of Antiretroviral Medications Fusion Inhibitors CCR 5 Antagonists Reverse Transcriptase Inhibitors (RTI) Nucleoside RTI (NRTIs) – tenofovir, abacavir, 3 TC, FTC Nonnucleoside RTI (NNRTIs) – efavirenz, rilpivirine Slide 6 of 44 Gandhi M, Gandhi RT. N Engl J Med 2014; 371: 248 -259. Protease inhibitors (PI) – darunavir/ritonavir or cobi; atazanavir/ritonavir or cobi Integrase strand transfer inhibitors (INSTI) – dolutegravir, raltegravir, elvitegravir/cobicistat

Antiretroviral Therapy 2016: >25 Options Nucleoside and nucleotide RTIs (NRTI) Non nucleoside NRTIs: (NNRTI) • Zidovudine, AZT • Delavirdine (DLV) • Abacavir, ABC • Nevirapine, NVP • Lamivudine, 3 TC • Efavirenz, EFV • Didanosine, dd. I • Etravirine • Stavudine, d 4 T • Rilpivirine • Tenofovir, TDF • Emtricitabine, FTC Fusion inhibitors: • AZT/3 TC • Enfuvirtide, ENF or T 20 • AZT/3 TC/ABC • ABC/3 TC • TDF/FTC Red – combination agents • TAF/FTC Single pill regimens CCR 5 receptor blocker • EFV/FTC/TDF • Maraviroc • RPV/FTC/TDF Integrase inhibitor (INSTI) • EVG/cobi/FTC/TDF • Raltegravir, RAL • DTG/ABC/3 TC • Elvitegravir, EVG • Dolutegravir, DTG Protease inhibitors (PIs): • Indinavir, IDV • Saquinavir, SQV • Nelfinavir, NFV • Amprenavir, APV • Atazanavir, ATV • Fosamprenavir, FPV • Lopinavir/ritonavir • Tipranavir • Darunavir/cobicistat • Atazanavir/cobicistat • EVG/cobi/FTC/TAF • Rilpivirine/FTC/TAF

Commonly Used Medications for HIV NRTIs • Abacavir (ABC)/3 TC • Tenofovir*/FTC * Tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) Slide 8 of 44 NNRTI: Rilpivirine (RPV)** (if VL <100 K, CD 4>200) Efavirenz (EFV)+ Boosted PI: ritonavir or cobicistat plus Darunavir (DRV/r or DRV/c) Atazanavir (ATV/r or ATV/c) Integrase inhibitor: Raltegravir (RAL) Elvitegravir (EVG)/cobicistat** Dolutegravir (DTG)++ **Coformulated with TDF/FTC and TAF/FTC; +Coformulated with TDF/FTC; ++Coformulated with ABC/3 TC

Choosing An Initial Regimen EFV DTG RPV EVG/cobi RAL DTG EFV EVG/cobi DTG ATV/r DRV/r RAL ATV/r Slide 9 of 44

Updated July 14, 2016 Recommended Regimens Integrase inhibitor + 2 Nucleoside RTI Dolutegravir/abacavir/3 TC Dolutegravir+TDF/FTC or TAF/FTC Elvitegravir/cobi/TDF (or TAF)/FTC Raltegravir +TDF/FTC or TAF/FTC Protease inhibitor + 2 Nucleoside RTI Darunavir/r +TDF/FTC or TAF/FTC Slide 10 of 44 http: //www. aidsinfo. nih. gov/Content. Files/Adultand. Adolescent. GL. pdf

What’s New in the DHHS Treatment Guidelines • TAF/FTC added as 2 -NRTI option in several Recommended and Alternative Regimens • Guidance on choosing between ABC, TAF and TDF-containing regimens added • LPV/r plus 2 -NRTI regimen removed from list of Other Regimens • TAF added as an option for HIV/HBV coinfected patients • TAF should be avoided in patients on rifamycins, e. g. those receiving rifampin-containing TB therapy Slide 11 of 44

July 12, 2016 Recommended Initial Antiretroviral Therapy Regimens Regimen DTG/ABC/3 TC DTG + TAF/FTC EVG/cobi/TAF/FTC RAL + TAF/FTC Rating Ala Ala Alll If TAF not available, TDF remains an effective and generally well-tolerated option. . Some clinicians may prefer to continue using TDF pending broader experience with TAF in clinical practice Slide 12 of 44

HIV: What to Start in 2016 • Four controversies: – Should all HIV-infected patients be treated, including elite controllers? – Should all newly-diagnosed HIV-infected patients be started on an integrase inhibitor (INSTI)-based regimen? – Should TAF replace TDF for all patients? – How should an ART regimen be chosen in patients with specific comorbidities or conditions? Slide 13 of 44

Controversy 1: Should all HIV-infected patients be treated, including elite controllers? Slide 14 of 44

When to START? HIV-infected adults CD 4 count >500 N=4685 Immediate ART (n=2326) Deferred ART (n=2359) (CD 4 Declined to <350 or AIDS-related event) • Primary endpoint: serious AIDS-related event, serious non–AIDS-related event, or death • May 2015: DSMB recommended offering ART to all participants • Median baseline CD 4 count 651. Deferred group: median CD 4 count at ART initiation, 408 • Median HIV RNA: ≈13, 000 (IQR ≈ 3, 000, 43, 000) Slide 15 of 44

Immediate ART Prevents AIDS- and Non-AIDS Related Events Number of Serious Events Number of Events 100 96 80 60 40 50 42 72% Reduction (P<0. 001) 47 39% Reduction (P=0. 04) 29 20 0 Deferred ART (n=2359) Immediate ART (n=2326) 57% Reduction (P<0. 001) 14 Composite Endpoint AIDSRelated Components (Serious Events) Non-AIDS Related • TB, KS, lymphoma — most common AIDSrelated events — all less frequent in immediate. ART group 1 • Cancer rates (combining AIDS/non-AIDS) lower in immediate-ART group 2 • Greatest benefit: age >50, VL >50, 000, CD 4: CD 8 <0. 5, Framingham score >10%3 Slide 16 of 44 1 Lundgren J, et al. INSIGHT START Study Group. N Engl J Med. 2015. 2 Borges et al, CROI 2016, #160; 3 Molina J et al, International AIDS Conference 2016, Abstract THAB 0201

DHHS and IAS–USA: ART recommended for all HIV+ individuals, regardless of CD 4 cell count CD 4 Cell Count Recommendation ≤ 350 -500 >500 AI AI: strong recommendation, data from randomized clinical trials WHO on Sept 30, 2015: “Treat-all” US DHHS Guidelines, January 2011. Slide 17 of 44

Earlier and earlier. . Data Supporting “Same Day” ART Initiation: San Francisco (Pilcher CD, JAIDS 2016); South Africa (Rosen S, PLo. S Medicine, 2016); Haiti (Koenig S, International AIDS Conf. , July 2016, WEA 0202) US DHHS Guidelines, January 2011. Slide 18 of 44

What about Elite Controllers (EC)? Reasons to not start ART • Drug toxicities • Risk of drug resistance if patient non-adherent • Cost of ARVs • No proof that ART prevents complications Slide 19 of 44

What about Elite Controllers (EC)? Reasons to not start ART • Drug toxicities • Risk of drug resistance if patient non-adherent • Cost of ARVs • No proof that ART prevents complications Landay A, AIDS 2014; Dinoso JB, CID 2008; Chun TW, JID 2013; Pereyra F AIDS 2012; Crowell TA, JID, 2015 Hatano H, PLo. S Pathogens, 2013; Kim CJ JAIDS, 2014 Slide 20 of 44 Reasons to start ART • EC have higher HIV RNA levels, immune activation and inflammation than ARTtreated patients – ongoing replication • EC have high rates of subclinical atherosclerosis • EC have higher hospitalization rates for CVD than ART-treated patients • EC may develop low CD 4 counts , low CD 4/CD 8 ratio • Treating EC increases CD 4 counts and CD 4/CD 8 ratio; decreases T cell activation

Should all EC be treated? • Some EC have “quiescent” phenotype – Higher CD 4 count – Lower HIV RNA (ultrasensitive assays) – Different transcriptional profile of immune activation & cytokine genes • Other EC have more “active” phenotype – Decreased CD 4 counts; elevated CD 8 counts; decreased CD 4: CD 8 ratio – Elevated CRP – Intermittently detectable virus Slide 21 of 44 Transcriptional profiling reveals distinct subgroups of EC • I recommend treatment to latter group, citing theoretic rationale, acknowledging uncertainty • More data needed on EC

Controversy 2: Should all newly diagnosed patients be started on an integrase inhibitor? Slide 22 of 44

What to Start Recommended Regimens Randomized controlled trials indicate INSTI-based Dolutegravir/abacavir/3 TC regimens are optimal for most patients with newly. Integrase inhibitor + 2 Dolutegravir+TDF/FTC or TAF/FTC diagnosed HIV Nucleoside RTI Elvitegravir/cobi/TDF (or TAF)/FTC Raltegravir +TDF/FTC or TAF/FTC Protease inhibitor + 2 Nucleoside RTI Slide 23 of 44 Darunavir/r +TDF/FTC or TAF/FTC http: //www. aidsinfo. nih. gov/Content. Files/Adultand. Adolescent. GL. pdf

Randomized controlled trials: INSTI vs. NNRTI • Dolutegravir + ABC/3 TC superior to EFV/TDF/FTC (SINGLE) • More discontinuations in EFV group (10% vs. 2%) Slide 24 of 44 Walmsley S et al, NEJM, 2013

Randomized controlled trials: INSTIs vs. PI • RAL superior to ATV/r & DRV/r (ACTG A 5257)1 • Dolutegravir superior to DRV/r (FLAMINGO)2 • EVG/cobi superior to ATV/r in women (WAVES)3 • DTG/ABC/3 TC superior to ATV/r + TDF/FTC in women (ARIA)4 1 Lennox Slide 25 of 44 ARIA: Wk 48 VL <50 J et al, Ann Int Med, 2014; 2 Clotet B et al, Lancet, 2014; 3 Squires K, et al. Lancet HIV, 2016; 4 C. Orell et al. International AIDS Conference, July 2016, Durban, South Africa. TUAC 1021

Which INSTI? • EVG vs. RAL − Treatment-experienced: both drugs comparable 1 • DTG vs. RAL − Treatment naïve (SPRING-2): both drugs comparable 2 − Treatment-experienced (SAILING): DTG superior to RAL 3 Slide 26 of 44 1. Elion R et al, JAIDS, 2013. 2 Raffi F et al, Lancet, 2013. 3 Cahn P et al, Lancet, 2013

INSTI RAL EVG/c DTG Slide 27 of 44 PROS CONS • Longest-track record • Fewest drug interactions • Twice daily (once daily formulation coming – ONCEMRK trial) • Not coformulated as part of single-pill regimen • Available in single-pill regimen with TDF/FTC, TAF/FTC • Most drug interactions (because of cobi) • Food requirement • Available in single-pill regimen with ABC/3 TC • High genetic barrier to resistance • Not coformulated with tenofovir • Largest pill size of single pill regimens • Drug interaction with metformin

ONCEMRK • 802 pts randomized (2: 1) – RAL 1200 mg QD + TDF/FTC – RAL 400 mg BID + TDF/FTC Wk 48 VL<40 (Snapshot) • RAL QD non-inferior to RAL BID – VL <40: 88. 9% vs. 88. 3% • Resistance – QD arm: 5 pts (0. 9%): RAL, FTC – BID arm: 3 pts had testing (2 no resistance, 1 failed testing) Slide 28 of 44 Cahn P et al, International AIDS Conference, 18 -22 July 2016, Durban, South Africa. Abstract FRAB 0103 LB

INSTIs: Limitations • In some trials, INSTIs comparable to (not better than) other agents: e. g. studies 102 & 103, EVG/cobi similar to EFV and ATV/r • Cations affect INSTI absorption (need to stagger dosing) • Adverse events: rhabdo with RAL; insomnia with DTG • Only INSTI single-pill regimen that contains tenofovir is with EVG/c, which has multiple drug interactions − New unboosted INSTI, GS-9883 (bictegravir), being developed for use in TAF/FTC-containing single-pill regimen 1, 2 Slide 29 of 44 1 Tsiang M, ASM Microbe 2016, PW-031; 2 Gallant J, ASM Microbe 2016, PW-030

Scenarios in which Alternative to INSTI Might be Chosen • Patient with uncertain adherence or need to start ART before resistance test available: – Boosted PI (DRV/r or DRV/c): high genetic barrier to resistance • Patient with low HIV RNA, high CD 4 count: – RPV/TDF/FTC, RPV/TAF/FTC: small pill, well-tolerated – RPV/TDF/FTC superior to EFV/TDF/FTC if VL <100, 0001 – Don’t use RPV if VL >100, 000, CD 4 <200 – Food requirement; avoid PPI; stagger H 2 blocker Cohen C et al, AIDS 2014 Slide 30 of 44 1

Scenarios in which Alternative to INSTI Might be Chosen • Patient with TB on rifampin-based regimen: – Most data with EFV/TDF/FTC – Rifampin has less effect on EFV concentrations than other ARVs – RAL, DTG can also be used (but at increased dose) Slide 31 of 44

Controversy 3: Should TAF replace TDF for all patients? Slide 32 of 44

Tenofovir alafenamide (TAF) • TAF: pro-drug of tenofovir that concentrates in cells, converted to tenofovir (TFV) • TAF: 90% lower plasma TFV levels compared to TDF (tenofovir disoproxil fumarate) • EVG/cobi/FTC/TAF compared to EVG/cobi/FTC/TDF for initial therapy: n=1733 Slide 33 of 44 Sax P et al, Lancet, 2015

TAF vs. TDF HIV-1 RNA <50 % • Virologic efficacy: E/C/F/TAF non-inferior 92 90 to E/C/F/TDF 1 100 E/C/F/TAF • TAF associated with: 80 E/C/F/TDF − Smaller decrease in e. GFR 60 (-6. 4 vs. -11 m. L/min) 40 − Less proteinuria 20 4 4 4 6 − Smaller decrease in bone mineral 0 Success Failure No Data density (BMD) − But greater increase in cholesterol, LDL, HDL, TGs • EVG/c/FTC/TAF approved for patients § D TC: +29 mg/d. L with Cr. CL down to 302 § D LDL: + 14 mg/d. L § D TC: HDL: same Slide 34 of 44 1 Sax P et al, Lancet, 2015; 2 Pozniak A et al, JAIDS, 2016

TAF/FTC Switch Study HIV RNA <50 at wk 48 • 663 patients with virologic suppression on TDF/FTC + 3 rd agent randomized to continue 94 93 TDF/FTC or switch to TAF/FTC (plus 3 rd agent) • TAF non-inferior to TDF in maintaining EVG/c/FTC/TAF – Nov. 2015 virologic suppression (initial therapy & switch studies) • TAF group: RPV/FTC/TAF – Mar. 2016 – increased e. GFR (+8. 4 vs. 2. 8 ml/min) (bioequivalence study) – improved proteinuria FTC/TAF (25 mg) – April 2016 – increased BMD (1. 1 -1. 5%) (switch studies) – But: increased cholesterol, LDL, TG; no Darunavir/c/FTC/TAF – phase III in TC: HDL Slide 35 of difference 44 Gallant J et al, Lancet HIV, 2016

Should TAF replace TDF? Reasons to choose TAF Reasons to choose TDF • TAF is virologically as effective as TDF. • Compared with TDF, TAF has more favorable effects on renal and bone markers. − Particularly important in patients who already have renal or bone disease or who are at high risk of these complications. • Compared with TAF, more and longer-term data with TDF, particularly in studies in treatment naïve patients. • More favorable lipid effects. • Renal and bone marker advantages of TAF not yet known to translate into better clinical outcomes. • TDF-regimens likely to be cheaper than TAF when TDF goes generic. • Cost of TAF- and TDF-regimens currently similar. Slide 36 of 44

TAF or TDF • When should you definitely use TAF over TDF? – Patient with osteoporosis or osteopenia – Patient with renal disease (e. GFR >30) or evidence for proximal tubular dysfunction (e. g. proteinuria) – Growing proportion of patients: “graying of the epidemic” • When should you definitely not use TAF? – Patient on rifamycin (may decrease TAF levels) – Pregnant women – For pre-exposure prophylaxis (Pr. EP) Slide 37 of 44

Controversy 4: How should an ART regimen be chosen in patients with specific conditions? ABC/3 TC DTG TDF/FTC RAL DTG TAF/FTC DRV/r ABC/3 TC EVG/cobi TAF/FTC TDF/FTC ATV/r EVG/cobi ABC/3 TC EFV

NRTI ABC/3 TC PROS • Not nephrotoxic • Single pill regimen with DTG (unboosted INSTI) CONS • Must confirm HLA-B 5701 negative • Some studies, but not all, show association with cardiac events • Greater nephrotoxicity than ABC and TAF • Larger decline in bone mineral density than with ABC or TAF TDF/FTC • Single pill regimens with EFV, RPV, EVG/c • Lowers lipids • Active vs. HBV TAF/FTC • More favorable effects on renal and • Less long-term data, particularly bone markers than TDF for initial therapy • Single pill regimens with EVG/c, RPV • Active vs. HBV Slide 39 of 44

Customizing ART Scenario Preferred Therapy Kidney Disease (e. GFR < 60) ABC + 3 TC or TAF/FTC (if Cr. Cl >30) (Avoid TDF, ATV/r, LPV/r: associated with kidney disease 1) High cardiac risk HBV Favor TDF or TAF TDF/FTC or TAF/FTC Pregnancy Osteoporosis/ osteopenia Slide 40 of 44 (Less data with TAF; HBV indication not yet included in its label) ABC/3 TC, TDF/FTC or AZT/3 TC plus RAL or ATV/r, DRV/r or EFV* *after first 8 wks Avoid TDF 1 Mocroft A et al, Lancet, 2016

ACTG A 5224 s: Spine BMD: TDF vs. ABC (in combination with EFV or ATV/r)1 TDF 2 ABC 0 -1. 3% -2 -3. 3% -4 -6 0 48 Weeks 96 Median change from baseline, % ABC and TAF Cause Less BMD Loss Than TDF GS studies: Spine BMD: TDF vs. TAF (in combination with EVG/cobi/FTC)2 TDF 2 TAF 0 -0. 96% -2 -2. 8% -4 -6 0 48 96 Weeks • Which causes more bone loss – ABC or TAF? No head trials yet • Randomized trial comparing ABC/3 TC/DTG to TAF/FTC/GS-9883 (ongoing) • In patients with osteoporosis or osteopenia: avoid TDF – use ABC or TAF Slide 41 of 44 1 Mc. Comsey GA, JID, 2011; 2 Wohl D, JAIDS, 2016

Customizing ART: Drug Interactions Scenario Preferred Therapy HCV Therapy Anticipated Often use raltegravir, dolutegravir: fewer drug interactions Acid-lowering therapy Avoid or caution with rilpivirine, atazanavir Stagger dosing of integrase inhibitors Cations CYP 3 A 4 metabolized medications Slide 42 of 44 Avoid or caution with PIs, cobi Useful site: http: //www. hiv-druginteractions. org

Drug Interactions: Exogenous Steroids • Injectable steroids: levels increased by PI, cobi – 10% of patients on PIs who received steroid injection developed clinical evidence of steroid excess or adrenal insufficiency 1 • Inhaled fluticasone 2 & budesonide 3: systemic levels increased by PI, cobi – Beclomethasone is safer alternative 4 1 Hyle 2 DHHS E et al, JAIDS, 2013 guidelines for use of antiretroviral agents in HIV-1 -infected adults and adolescents. http: //AIDSinfo. nih. gov 3 http: //www. fda. gov/For. Consumers/By. Audience/For. Patient. Advocates/HIVand. AIDSActivities/ucm 336367. htm Slide 43 of 44 4 Boyd S et al, JAIDS, 2013

HIV: What to Start in 2016 • Should all HIV-infected patients be treated? Yes. Data supporting same-day initiation. Case can be made for also treating elite controllers. • Should all HIV-infected patients be started on an INSTI-based regimen? Most should receive INSTI. Certain scenarios where other regimens may be preferred. • Should TAF replace TDF for all patients? In patients with bone or renal disease, TAF is particularly advantageous. • Choosing ART in pt with comorbidities? Customize based on effects on bone, kidney, CV disease, HBV/HCV; drug interactions. Slide 44 of 44

State-of-the-ART in Antiretroviral Therapy: Optimal Initial Regimens in 2016 Rajesh T. Gandhi, MD Director, HIV Clinical Services and Education Massachusetts General Hospital Boston, Massachusetts Thanks to Alice Pau, Roger Bedimo and Marilyn Shi for assistance with slides Washington, DC: August 23, 2016