Antiretroviral Therapy in 2016

Antiretroviral Therapy in 2016 Joel Gallant, MD, MPH Southwest CARE Center Santa Fe, NM University of New Mexico School of Medicine Johns Hopkins University School of Medicine

Disclosures Consulting, Advisory Boards, and DSMBs Bristol-Myers Squibb Gilead Sciences Janssen Therapeutics Merck & Co. ViiV Healthcare Research Support AbbVie Bristol-Myers Squibb Gilead Sciences Janssen Therapeutics Merck & Co. Sangamo BioSciences ViiV Healthcare

When to Start

START: Immediate vs Deferred Therapy for Asymptomatic, ART-Naive Pts International, randomized trial Study closed by DSMB following interim analysis HIV+, ART-naive adults with CD4 > 500 (N = 4685) Immediate ART ART initiated immediately following randomization (n = 2326) Deferred ART Deferred until CD4 350, AIDS, or event requiring ART (n = 2359) Composite 1 o endpoint: Serious AIDS-related (AIDS-related death or AIDSdefining event) or non-aids related event (non-aids related death, CVD, end-stage renal disease, decompensated liver disease, non-aids defining cancer) Median follow-up: 3.0 yrs; med. baseline CD4: 651; med. baseline VL: 12,759 Med. CD4 at initiation of ART for deferred group: 408 Lundgren J, et al. N Engl J Med. 2015

Cumulative Percent With Event START: 57% Reduced Risk of Serious Events or Death With Immediate ART 1.8% vs 4.1% in deferred vs immediate arms experienced serious AIDS or non-aids related event or death: HR = 0.43 (95% CI: 0.30 to 0.62); P <.001 10 8 6 Deferred ART 4 2 Immediate ART 0 0 6 12 18 24 30 36 42 48 54 60 Month Lundgren J, et al. N Engl J Med. 2015

START: Primary Endpoint Components With Immediate vs Deferred ART Endpoint Immediate ART (n = 2326) Deferred ART (n = 2359) N Rate/100 PY N Rate/100 PY Serious AIDS-related event 14 0.20 50 0.72 Serious non-aids related event 29 0.42 47 0.67 All-cause death 12 0.17 21 0.30 Tuberculosis 6 0.09 20 0.28 Kaposi s sarcoma 1 0.01 11 0.16 Malignant lymphoma 3 0.04 10 0.14 Non-AIDS defining cancer 9 0.13 18 0.26 CVD 12 0.17 14 0.20 HR (95% CI)* 0.28 (0.15-0.50) 0.61 (0.38-0.97) 0.58 (0.28-1.17) 0.29 (0.12-0.73) 0.09 (0.01-0.71) 0.30 (0.08-1.10) 0.50 (0.22-1.11) 0.84 (0.39-1.81) P Value <.001.04.13.008.02.07.09.65 Lundgren J, et al. N Engl J Med. 2015

Cumulative % With Event START: Cancer Events With Immediate vs Deferred ART Cancer Event, n Immediate ART (n = 2326) Deferred ART (n = 2359) Total 14 39 Kaposi s sarcoma 1 11 Lymphoma, NHL + HL 3 10 Prostate cancer 2 3 Lung cancer 2 2 Anal cancer 1 2 Cervical or testis cancer 1 2 Other types* 4 9 10 8 6 4 2 0 Time to Cancer Event Rate/100 PY: immediate, 0.20; delayed, 0.56 HR (immediate vs delayed): 0.36 (95%CI: 0.19 to 0.66, P =.001) 0 12 24 36 48 60 Months Deferred ART Immediate ART *Immediate ART: squamous cell carcinoma, plasma cell myeloma, bladder cancer, fibrosarcoma. Deferred ART: gastric adenocarcinoma, breast cancer, ureteric cancer, malignant melanoma, myeloid leukemia, thyroid cancer, leiomyosarcoma, liver cancer, squamous cell carcinoma of head and neck. Lundgren J, et al. N Engl J Med. 2015

Percent of Follow-up Time START: Primary Endpoint Events By Latest CD4 Count Latest CD4 > 500 Immediate ART No. of Pts with Events (Rates/100 PY) Deferred ART No. of Pts with Events (Rates/100 PY) Immediat e ART Deferred ART 60 50 2 3 6 11 20 (4.7)(0.8)(0.4)(0.6)(0.6) 5 34 34 9 14 (1.8)(2.0)(1.5)(0.6)(1.1) % of Primary Events 88% (37/42) 59% (57/96) 40 30 Rate/100 PY 0.6 1.1 20 10 0 Latest CD4 Count Lundgren J, et al. N Engl J Med. 2015

When to Start: DHHS Guidelines, January 2016 ART recommended for all HIV+ individuals to reduce risk of disease progression. Strength and evidence for recommendation vary by pretreatment CD4 count (AI) ART recommended for HIV-infected individuals for prevention of HIV transmission (AI) US DHHS Guidelines, January 2016

When to Start?: Guidelines AIDS/ symptoms CD4 <200 CD4 200-350 CD4 350-500 CD4 >500 US DHHS YES YES YES YES YES IAS-USA YES YES YES YES YES EACS YES YES YES YES YES BHIVA (UK) YES YES YES YES YES WHO YES YES YES YES YES

What to Start

DHHS Guidelines, January 2016 What to Start Recommended regimens Boosted PI-based INSTI-based Alternative regimens NNRTI-based DRV/r + FTC/TDF RAL + FTCTDF EVG/COBI/FTC/TDF DTG + FTC/TDF DTG/3TC/ABC EVG/COBI/FTC/TAF EFV/FTC/TDF RPV/FTC/TDF (VL <100,000; CD4 >200) PI-based ATV/c + FTC/TDF (CrCl >70) ATV/r + FTC/TDF (DRV/c or DRV/r) + 3TC/ABC DRV/c + FTC/TDF (CrCl >70) DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents, January 2016

The 5 most common initial regimens we ll now be using in the U.S. INSTI-based PI-based NNRTI-based EVG/COBI/FTC/TAF (Genvoya) DTG + FTC/TAF (Tivicay + Descovy) DTG/3TC/ABC (Triumeq) DRV/c + FTC/TAF (Prezcobix + Descovy) RPV/FTC/TAF (Odefsey)

Drugs I left out INSTI PI NNRTI NRTI RAL ATV LPV/r EFV AZT Disadvantages Twice daily (for now) Lower resistance barrier than DTG Jaundice Nephrotoxicity Cholelithiasis Nephrolithiasis More GI effects than DRV Gastric acid requirement Higher pill burden More GI effects More metabolic effects CNS side effects Rash Resistance Twice daily dosing Toxicity Advantages Tolerability Few drug interactions The only PI that can be given without boosting An option for patients with DRV rash Low cost Low cost Low cost

Proportion (%) with <50 c/ml SINGLE: Dolutegravir + ABC/3TC vs. EFV/TDF/FTC 100 90 DTG+ABC/3TC: 88% 80 70 60 50 WK 48 difference in response (95% CI): +7.4% (+2.5% to +12.3%); p=0.003 EFV/TDF/FTC: 81% 40 30 20 10 0 DTG 50 mg + ABC/3TC QD EFV/TDF/FTC QD BL 2 4 8 12 16 24 32 40 48 Week DTG + ABC/3TC QD superior to EFV/TDF/FTC at Wk 48 (1 o endpoint) Walmsley S, et al. N Engl J Med 2013;369:1807-18

STRIIVING: Switch to DTG/ABC/3TC Ongoing randomized, open-label phase IIIB study Primary endpoint: VL < 50 at Wk 24 Wk 24 Wk 48 VL < 50 on stable ART 6 mos; no previous virologic failure; HLA-B*5701 negative (N = 551) Baseline ART* (n = 277) DTG/ABC/3TC (n = 274) DTG/ABC/3TC (n = 277) *Containing 2 NRTIs plus NNRTI, PI, or INSTI. PI NNRTI INSTI TDF/FTC BL ART use, % 42 31 26 77 Trottier B, et al. ICAAC 2015.

STRIIVING: Study Disposition at Wk 24 Screened (N = 841) Randomized and treated DTG/ABC/3TC (n = 274) Randomized and treated Baseline ART (n = 277) 87% completed (n = 239) 13% of subjects withdrawn (n = 35) Adverse event 10 (4%) Lack of efficacy (virologic failure) 0 Protocol deviation 15 (5%) Stopping criteria met 0 Lost to follow-up 3 (1%) Investigator discretion 3 (1%) Withdrew consent 4 (1%) Trottier B, et al. ICAAC 2015. 88% completed (n = 244) 1 with missing information 12% of subjects withdrawn (n = 32) Adverse event 0 Lack of efficacy (virologic failure) 0 Protocol deviation 17 (6%) Stopping criteria met 0 Lost to follow-up 3 (1%) Investigator discretion 3 (1%) Withdrew consent 9 (3%)

VL < 50 (%) STRIIVING: Virologic Outcomes at Wk 24 Switch noninferior to maintaining baseline ART No protocol-defined virologic failure 3 pts in DTG/ABC/3TC arm (1%) and 4 pts in BL ART arm (1%) had VL 50-100 through Wk 24 Primary Efficacy Analysis: ITT-Exposed and Per Protocol Populations 100 80 60 40 20 0 88 93 93 85 Virologic Success Trottier B, et al. ICAAC 2015. DTG/ABC/3TC (ITT-E, n = 274) Baseline ART (ITT-E, n = 277) DTG/ABC/3TC (PP, n = 220) Baseline ART (PP, n = 215) 1 1 < 1 2 Virologic Nonresponse 14 10 6 5 No Virologic Data Baseline ART DTG/ABC/3TC ITT-E Population -3.4-9.1 2.3-12 -8-4 0 4 8 PP Population -0.3-4.9 4.4-12 -8-4 0 4 8 12 12

STRIIVING: Adverse Events and Treatment Satisfaction 10 pts discontinued for AEs in DTG/ABC/3TC arm vs 0 in baseline ART arm Greater increase in treatment satisfaction score from baseline to Wk 24 in DTG/ABC/3TC arm vs baseline ART arm: adjusted mean difference: 2.4 (P <.001) Trottier B, et al. ICAAC 2015. AEs in 10 Pts Who Withdrew* Grade Insomnia 2 Diarrhea, flatulence, rash Abdominal pain, anxiety, nausea, body ache Euphoric mood Headache Abdominal cramps, chills, diarrhea, dizziness, headache Pruritus 2 Abdominal pain, diarrhea, flulike syndrome, profuse sweating, change in body odor Fatigue, malaise, depression Nasal congestion Worsening fatigue Nausea Alopecia 1 Fatigue 1 Homicide 1 2 1 2 2 1 2 1 2 3 N/A *None serious AEs except homicide. Not drug related.

TAF vs. TDF: Mechanism of Action GI TRACT PLASMA RENAL TUBULAR CELL LYMPHOCYTE TDF (tenofovir disoproxil fumarate) 300 mg TFV TFV HIV TAF (tenofovir alafenamid e) 25 mg 91% lower plasma TFV RENAL TUBULAR CELL 1. Lee W et al. Antimicr Agents Chemo 2005;49:1898-906; 2. Birkus G, et al. Antimicr Agents Chemo 2007;51:543-50; 3. Babusis D, et al. Mol Pharm 2013;10:459-66; 4. Ruane P, et al. JAIDS 2013;63:449-5; 5. Sax P, et al. JAIDS 2014;67:52-8; 6. Sax P, et al. Lancet 2015;385:2606-15.

Patients, % GS 104/111: E/C/F/TAF noninferior to E/C/F/TDF at week 48 100 80 60 92 Δ +2.0% (95% CI: -0.7% to +4.7) 90 TAF/FTC/EVG/COBI (n = 866) TDF/FTC/EVG/COBI (n = 867) Results similar across all baseline virologic and demographic subgroups 7 pts in TAF arm and 5 pts in TDF arm with NRTI resistance at VF 1 in TAF arm and 2 in TDF arm with combined M184V/I + K65R 40 5 pts in TAF arm and 3 pts in TDF arm with INSTI resistance at VF n = 20 0 800 784 Virologic Success* 4 4 4 6 Virologic Failure No Data *VL < 50 as defined by FDA Snapshot algorithm Discontinued for AE, death, or missing data. Sax P, et al. Lancet 2015;385:2606-15.

GS-109: Switching From TDF- to TAF-based Regimens in Virologically Suppressed Pts Randomized, active-controlled, open-label study Primary Endpoint Wk 48 Pts with VL < 50 ( 96 wks) and egfr > 50 ml/min on stable TDF-based regimen for 48 wks (N = 1436) EVG/COBI/FTC/TAF QD (n = 959) Continue previous TDF-based regimen (n = 477) Continue through Wk 96 Primary endpoint: proportion of patients with VL < 50 after 48 wks Mills A, et al. Lancet Infect Dis 2016;16:43-52

Wk 48 VL < 50, % GS-109: Switching to E/C/F/TAF from TDFbased regimens 100 Primary Endpoint EVG/COBI/FTC/TAF P <.001 P =.02 P =.02 97 93 96 90 97 92 TDF-Based Regimen P = NS 98 97 80 60 40 20 n/n = 0 932/ 959 444/ 477 All Prior Regimens 241/ 251 112/ 125 Prior EFV/TDF/FTC 390/ 402 183/ 199 Prior Boosted ATV + TDF/FTC 301/ 306 149/ 153 Prior EVG/COBI/ FTC/TDF Mills A, et al. Lancet Infect Dis 2016;16:43-52

GS 1089: Switch from F/TDF to F/TAF Randomized, double-blind, double-dummy, active-controlled study n=333 F/TAF (200/10 or 200/25 mg)* QD F/TDF Placebo QD VL <50 on F/TDF + Third Agent egfr 50 ml/min Continue Third Agent F/TDF (200/300 mg) QD n=330 F/TAF* Placebo QD Continue Third Agent BL Wk 48 Wk 96 Primary Endpoint Secondary * F/TAF Dose: 200/10 mg with boosted PIs 200/25 mg with unboosted third agents HIV-1 RNA <50 c/ml Endpoint Gallant J, et al. Lancet HIV 2016;3:e158-65

VL <50, % GS 1089: Efficacy at Week 48 (Snapshot) Virologic Outcome Treatment Difference (95% CI) F/TDF F/TAF 1.3-2.5 5.1 Non-success 10% 0 +10% Gallant J, et al. Lancet HIV 2016;3:e158-65

TAF: Renal safety

GS104/111: E/C/F/TAF vs. E/C/F/TDF: Renal Safety Mean (SD) Change from Baseline egfr* 20 E/C/F/TAF E/C/F/TDF 10 0-10 -20-6.6-11.2 p <0.001 0 12 24 36 48 Time (Weeks) Events n (%) Sax P, et al. Lancet 2015;385:2606-15. Renal adverse events leading to discontinuation E/C/F/TAF n=866 E/C/F/TDF n=867 0 4 (0.5) Tubulopathy/Fanconi syndrome 0 0

Median % Change from Baseline (Q1, Q3) GS 104/111: TAF vs. TDF: Quantitative Proteinuria Urine [protein]:creatinine Ratio Protein (UPCR) Albumin (UACR) RBP Beta2- microglobulin 75 50 76 133 168 51 E/C/F/TAF E/C/F/TDF 25 20 7 9 24 0-25 -3-5 p <0.001 for all -50-32 Baseline 44 mg/g 44 mg/g 5 mg/g 5 mg/g 64 μg/g 67 μg/g 101 μg/g 103 μg/g Sax P, et al. Lancet 2015;385:2606-15

GS 1089: Switch from F/TDF to F/TAF Changes in egfr M e d ia n (Q 1, Q 3 ) c h a n g e e G F R * (m L /m in ) 2 0 F /T A F (n = 3 3 3 ) F /T D F (n = 3 3 0 ) 1 0 0 8.4 ml/min 2.8 ml/min p <0.001-1 0 0 1 2 2 4 3 6 4 8 W e e k s * egfr calculated with Cockcroft-Gault equation Gallant J, et al. Lancet HIV 2016;3:e158-65

Median % change GS 1089: Switch from F/TDF to F/TAF Change in Renal Biomarkers at Week 48 Urine Protein to Creatinine Ratio Protein Albumin RBP β2m F/TAF F/TDF All differences between treatments statistically significant (p <0.001) RBP, retinol-binding protein; β2m, β2-microglobulin. Gallant J, et al. Lancet HIV 2016;3:e158-65

Median Change from Baseline GS-112: Switching to E/C/F/TAF in patients with kidney disease (egfr 30-60) Multicenter, open-label phase III trial, N=242 (158 on TDF, 84 on non-tdf-based regimen) Changes in egfr to Wk 48 10 Total TDF Non-TDF 0-0.6 +0.2-1.8-1.8* -1.5-2.7* -10 Baseline: 56 58 53 54 56 50 *P < 0.05. egfr CG ml/min egfr CKD-EPI Cr ml/min/1.73m 2 Pozniak A, et al. J Acquir Immune Defic Syndr. 2016;71:530-7

TAF: Bone safety

Mean % Change From BL GS104/111: E/C/F/TAF vs. E/C/F/TDF Bone mineral density changes TAF/FTC/EVG/COBI (n = 866) TDF/FTC/EVG/COBI (n = 867) n n 2 0-2 -4-6 0 0 0 24 48 0 24 48 =845 =850 P <.001 P <.001 2 Wk 797 816 784 773-1.30-2.86 0-2 -4-6 836 848 Wk 789 815 780 767-0.66-2.95 Sax P, et al. Lancet 2015;385:2606-15

Median % Change (spine) in BMD (Q1, Q3) GS-109: Switch from TDF to TAF Changes in bone density (spine) Hip BMD similarly increased for pts treated with Genvoya 4 3 2 1 0-1 -2-3 EVG/COBI/FTC/TAF TDF-Based Regimen Baseline Week 24 Week 48 1.79-0.28 P <.001 Mills A, et al. Lancet Infect Dis 2016;16:43-52

Mean % change (95% CI) GS 1089: Switch from F/TDF to F/TAF: Bone density changes Spine Hip 4 4 2 1.5 p <0.001 2 1.1 p <0.001 0-0.2 0-0.2 F/TAF, n F/TDF, n B L 2 4 4 8 Weeks 321 310 300 320 310 306 B L 2 4 4 8 Weeks 321 309 300 317 305 303 3% BMD increase at Week 48 F/TAF 30.3% 16.7% p<0.001 F/TDF 13.7% 8.6% p=0.003 Gallant J, et al. Lancet HIV 2016;3:e158-65 35

What to Start: My Choices (no baseline resistance) Regimen PROS CONS EVG/COBI/FTC/TAF DTG/3TC/ABC DTG + FTC/TAF DRV/c + FTC/TAF RPV/FTC/TAF Single tablet Advantages of TAF Single tablet High resistance barrier Few drug interactions Advantages of DTG Advantages of TAF No PI resistance with failure Advantages of TAF Single tablet Excellent tolerability Advantages of TAF Drug interactions Potential for INSTI resistance HLA B*5701 testing MI risk? ABC: more AEs than TDF 2-pill regimen 2-pill regimen More side effects than with INSTIs Meal requirement VL, CD4 requirement Avoid acid-reducing agents

Choosing ART in special populations Adherence concerns: DRV/c + FTC/TAF DTG/ABC/3TC (?) Baseline genotype pending: Avoid NNRTI-based regimens HCV coinfection: INSTI + either FTC/TAF or 3TC/ABC HBV coinfection: FTC/TAF-based regimens Pregnancy: Consult perinatal guidelines

New Drugs and Treatment Strategies

LATTE-2: IM Cabotegravir + Rilpivirine for Long-Acting Maintenance Therapy Multicenter, open-label phase IIb study Primary endpoints: VL <50 by FDA snapshot, PDVF, and safety at maintenance Wk 32 ART-naïve pts with CD4 > 200 (N = 309) Induction Phase* Wk 16: RPV PO added CAB 30 mg PO QD + ABC/3TC Wk 20 Maintenance Phase Wk 32 primary analysis; Wk 1 dose selection Wk 96 CAB 400 mg IM + RPV 600 mg IM Q4W (n = 115) CAB 600 mg IM + RPV 900 mg IM Q8W (n = 115) CAB 30 mg PO + ABC/3TC PO QD (n = 56) *Pts with VL < 50 from Wk 16 to Wk 20 continued to maintenance phase. 6 pts discontinued for AEs or death in induction analysis. Margolis DA, et al. CROI 2016. Abstract 31LB.

VL <50 (%) LATTE-2: Maintenance Wk 32 Virologic Efficacy (ITT-Maintenance Exposed) Virologic efficacy of Q4W and Q8W IM regimens similar to oral regimen No INSTI, NNRTI, or NRTI resistance mutations detected 100 80 60 40 20 0 95 94 91 Virologic Success IM CAB + RPV Q4W (n = 115) IM CAB + RPV Q8W (n = 115) Oral CAB + ABC/3TC (n = 56) < 1 4 4 5 < 1 5 Virologic Nonresponse No Virologic Data Treatment Differences (95% CI) Oral -4.8 Q8W IM 3.7 12.2-12 -10-8 -6-4 -2 0 2 4 6 8 10 12-5.8 Q4W 2.8 11.5-12 -10-8 -6-4 -2 0 2 4 6 8 10 12 Margolis DA, et al. CROI 2016. Abstract 31LB.

LATTE-2: Safety Through Maintenance Wk 32 Most frequent ISRs were pain (67%), swelling (7%), and nodules (6%) AEs, % ISR events/injection: 0.53 99% of ISRs grade 1/2; none grade 4 Proportion of pts reporting ISRs decreased with time from 86% on Day 1 to 33% at Wk 32; 1% of pts withdrew for ISRs Drug-related grade 3/4 AEs (excluding ISRs) Pooled CAB + RPV IM Arms (n = 230) Oral CAB + ABC/3TC (n = 56) 3 0 Serious AEs 6 5 AEs leading to withdrawal 3 2 Margolis DA, et al. CROI 2016. Abstract 31LB.

Pts (%) LATTE-2: Wk 32 Pt Satisfaction With Maintenance Therapy vs Oral Induction How satisfied are you with your current treatment? How satisfied would you be to continue with your present form of treatment? More Neutral Less More Neutral Less 100 80 3 1 3 29 100 80 2 1 1 29 60 40 60 40 20 0 97 96 71 Q8W (n = 106) Q4W (n = 100) Oral CAB (n = 49) 20 0 98 98 71 Q8W (n = 106) Q4W (n = 100) Oral CAB (n = 49) Margolis DA, et al. CROI 2016. Abstract 31LB.

MK-1439-007: Doravirine + TDF/FTC vs EFV + TDF/FTC In Treatment-Naive Pts Doravirine: investigational NNRTI with activity against common NNRTI resistance mutations, QD dosing, no PPI drug drug interactions, improved CNS safety vs EFV in early studies Part 2 of 2-part randomized, double-blind phase II study Primary endpoint: VL < 40 c/ml at Wk 48 Wk 48 Wk 96 ART-naive HIV+ pts with VL 1000, CD4 100 (N = 132)* DOR 100 mg QD + TDF/FTC (n = 66) EFV 600 mg QD + TDF/FTC (n = 66) *42 pts receiving DOR 100 mg QD + TDF/FTC and 43 pts receiving EFV 600 mg QD + TDF/FTC in part 1 of this study were included in this analysis. Gatell JM, et al. CROI 2016. Abstract 470.

VL < 40 (NC = F), % (95% CI) MK-1439-007: Primary Endpoint 100 Doravirine 100 mg Efavirenz 600 mg 81.5 78.7 80 73.1 77.8 72.9 77.8 63.0 60 57.5 47.2 40 42.1 Wk 48 VL < 40 c/ml n/n (%) Doravirine 84/108 (77.8) 27.8 26.9 Efavirenz 85/108 (78.7) 20 15.7 Difference (95% CI): -1.1 (-12.2 to 10.0) 6.5 12.0 0 3.7 0 4 8 12 16 20 24 28 32 36 40 44 48 Gatell JM, et al. CROI 2016. Abstract 470. Treatment Wk

MK-1439-007: Clinical Adverse Events Clinical AEs, % Gatell JM, et al. CROI 2016. Abstract 470. DOR + TDF/FTC (n = 108) EFV + TDF/FTC (n = 108) Difference, DOR EFV (95% CI) 1 AE 87.0 88.9-1.9 (-10.9 to 7.1) Serious AEs 6.5 8.3-1.9 (-9.5 to 5.6) Death 0 0 D/c for AEs 2.8 5.6-2.8 (-9.2 to 3.0) Drug-related AEs* 31.5 56.5-25.0 (-37.3 to 11.8) Diarrhea 0.9 6.5 Nausea 7.4 5.6 Dizziness 6.5 25.9 Headache 2.8 5.6 Abnormal dreams 5.6 14.8 Insomnia 6.5 2.8 Nightmares 5.6 8.3 Sleep disorder 4.6 6.5 *Specific AEs occurring in 5% of pts included.

PADDLE: All Pts Virologically Suppressed by Wk 8 of DTG + 3TC Included 4 pts with VL > 100,000 at BL HIV-1 RNA (copies/ml) Pt # Screen BL Day 2 Day 4 Day 7 Day 10 Wk 2 Wk 3 Wk 4 Wk 6 Wk 8 Wk 12 Wk 24 1 5584 10,909 3701 383 101 71 < 50 < 50 < 50 < 50 < 50 < 50 < 50 2 8887 10,233 5671 318 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 3 67,335 151,569 37,604 1565 1178 266 97 53 < 50 < 50 < 50 < 50 < 50 4 99,291 148,370 11,797 3303 432 179 178 55 < 50 < 50 < 50 < 50 < 50 5 34,362 20,544 4680 1292 570 168 107 < 50 < 50 < 50 < 50 < 50 < 50 6 16,024 14,499 3754 1634 162 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 7 37,604 18,597 2948 819 61 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 8 25,071 24,368 6264 1377 Not done 268 105 < 50 < 50 < 50 < 50 < 50 < 50 9 14,707 10,832 Not done 516 202 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 10 10,679 7978 5671 318 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 11 50,089 273,676 160,974 68,129 3880 2247 784 290 288 147 < 50 < 50 < 50 12 13,508 64,103 3496 3296 135 351 351 84 67 < 50 < 50 < 50 < 50 13 28,093 33,829 37,350 26,343 539 268 61 < 50 < 50 < 50 < 50 < 50 < 50 14 15,348 15,151 3994 791 198 98 < 50 61 64 < 50 < 50 < 50 < 50 15 23,185 23,500 15,830 4217 192 69 < 50 < 50 < 50 Not done < 50 < 50 < 50 16 11,377 3910 370 97 143 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 17 39,100 25,828 11,879 1970 460 147 52 < 50 < 50 < 50 < 50 < 50 < 50 18 60,771 73,069 31,170 2174 692 358 156 < 50 < 50 < 50 < 50 < 50 < 50 19 82,803 106,320 35,517 2902 897 352 168 76 < 50 < 50 < 50 < 50 < 50 20 5190 7368 3433 147 56 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 Figueroa MI, et al. EACS 2015. Abstract 1066.

Switch From Suppressive ART to DTG Monotherapy 97% maintained virologic suppression at Wk 24 [1] Reasons for switch improved in most pts from BL to 24 wks [1] T-scores unchanged in 2 pts with osteoporosis In single pt with renal disease, egfr from 59 ml/min at BL to 52 ml/min/ at Wk 24; urine protein:creatinine ratio from 330 to 146 mg/mg Reason for Switch Pts at Risk, n Outcome Improved/ Avoided, n DDIs 13 13 GI In separate symptoms study of switch from suppressive ART 11 to DTG monotherapy, 89% of pts 9 maintained virologic suppression 24 wks after switch Dyslipidemia [2] 9 9 High Framingham score 3 3 1. Rojas J, et al. EACS 2015. Abstract 1108. 2. Katlama C, et al. EACS 2015. Abstract 714.

Evolution of Integrase Mutations in 2 DTG Monotherapy Switch Studies All 4 pts with virologic failure had history of INSTI use before switch 1 pt had previous RAL failure but no INSTI resistance VL at VF, c/ml INSTI Resistance by Timepoint (Detection Source) Day 0 Wk 4 Wk 12/13 Wk 24 155 [1] - None (DNA) - 118R (DNA) 469 [2] L74I (DNA) - 291 [2] 2220 [2] L74I, E92Q (RNA) R: EVG RAL None (DNA) - - None (DNA) None (RNA) None (DNA) - 155H (RNA) R: EVG RAL E138K / G140A, Q148R (RNA) R: DTG EVG RAL 1. Rojas J, et al. EACS 2015. Abstract 1108. 2. Katlama C, et al. EACS 2015. Abstract 714.

More in the pipeline Ibalizumab: entry inhibitor monoclonal antibody binds CD4 being studied for treatment and prevention BMS 663068 1 : entry inhibitor Blocks attachment by binding to gp120 BMS 955176 2 : maturation inhibitor Disrupts processing of gag protein Trial in naïve pts planned GS9883: integrase inhibitor Unboosted Potential for coformulation with TAF/FTC 1. Lalezari J et al. CROI 2014, Abstract 86. 2. Hwang C et al. CROI 2015, Abstract 114LB

Reasons to consider switching therapy in suppressed patients Older PIs: Reduce pill burden Decrease metabolic effects Decrease GI side effects Older NRTIs: d4t, ddi: SWITCH! (toxicity) AZT: consider switch (toxicity, side effects, simplification) Nevirapine: Reduce pill burden Not toxicity (most toxicity occurs with initiation) Efavirenz: CNS side effects No TAF-based coformulation TDF: If price the same, no advantage of TDF over TAF

Recent switch studies in suppressed pts Trial From To Outcome GS-123 TDF/FTC + RAL EVG/COBI/FTC/TDF GS-264 TDF/FTC/EFV RPV/FTC/TDF Strategy-NNRTI TDF/FTC + NNRTI EVG/COBI/FTC/TDF Strategy-PI TDF/FTC + PI/r EVG/COBI/FTC/TDF SPIRIT 2 NRTI + PI/r RPV/FTC/TDF SPIRAL 2 NRTI + PI/r (exp d pts) 2 NRTI + RAL SALT ATV/r + 2 NRTI ATV/r + 3TC OLE LPV/r + 2 NRTIs LPV/r + 3TC GS-109 TDF-based ART EVG/COBI/FTC/TAF STRIIVING Suppressive ART DTG/ABC/3TC ATLAS-M ATV/r + 2 NRTIs ATV/r + 3TC GS-119 Salvage regimen EVG/COBI/FTC/TAF + DRV LATTE CAB or EFV + 2 NRTIs CAB + RPV GS-1089 TDF/FTC + 3 rd agent TAF/FTC + 3 rd agent SWITHCMRK 2 NRTI + LPV/r (exp d pts) 2 NRTI + RAL HARNESS 2 NRTI + 3 rd Agent ATV/r + RAL Adapted from David Wohl

SWITCHMRK: Prior failure predicts failure Inferior efficacy of RAL appeared driven by more failure among pts with previous virologic failure Outcome SWITCHMRK1 SWITCHMRK 2 RAL (n = 174) LPV/r (n = 174) RAL (n = 176) LPV/r (n = 178) Patients without previous virologic failure VL < 50 at Wk 24, % 85.1 85.8 92.5 93.5 Treatment difference, % (95% CI) -0.7 (-9.9 to 8.6) -1.0 (-8.5 to 6.3) Patients with previous virologic failure VL < 50 at Wk 24, % 72.3 89.7 79.7 93.8 Treatment difference, % (95% CI) -17.3 (-33.0 to -2.5) -14.2 (-26.5 to -2.6) Eron JJ, et al. Lancet. 2010;375:396-407.

Switching: Caveats Know the treatment and resistance history Avoid switching from high barrier to lower barrier agents when you don t

Switching and simplifying therapy Horizontal Switches : switch to drug with equal or higher resistance barrier RTV COBI (boosters) Switches within INSTI class EFV or NVP RPV or ETR LPV/r or ATV/r DRV/r ABC or AZT TDF/TAF Vertical Switches : switch to drug with lower resistance barrier Most drug discontinuations Boosted PI NNRTI Boosted PI INSTI Boosted PI any STR DRV/r twice daily once daily TDF TAF