David Cluck, PharmD, BCPS, AAHIVP Associate Professor of Pharmacy Practice Office 326 Phone

Transcription

1 David Cluck, PharmD, BCPS, AAHIVP Associate Professor of Pharmacy Practice Office 326 Phone

2 Recall newly approved antiretrovirals and their respective place in therapy Discuss emerging data on new antiretrovirals that are likely to be approved for clinical use

3 Parallel, randomized, double-blind, active-controlled phase III studies Primary endpoint: HIV-1 RNA < 50 c/ml at Wk 48 (FDA Snapshot) Stratified by HIV-1 RNA, CD4+ cell count, geographic region Wk 48: Primary Endpoint Wk 144 Treatment-naive HIV-infected pts with HIV-1 RNA 1000 copies/ml, egfr 50 ml/min (N = 1733) *150/150/200/10 mg once daily. 150/150/200/300 mg once daily. EVG/COBI/FTC/TAF* single-tablet regimen (n = 866) EVG/COBI/FTC/TDF single-tablet regimen (n = 867) Arribas JR, et al. CROI Abstract 453. Sax PE, et al. Lancet. 2015;385:

4 Arribas JR, et al. CROI Abstract 453. Sax PE, et al. Lancet. 2015;385:

5 Pts (%) Wk: E/C/F/TAF (n = 866) E/C/F/TDF (n = 867) Treatment Difference Wk 48: 2.0% (95% CI: -0.7% to 4.7%) Wk 144: 4.2% (95% CI: 0.6% to 7.8%; P =.02) Virologic Virologic No Data Success Failure Efficacy similar across pt subgroups, trending toward or significantly better with TAF in each group By baseline HIV-1 RNA, baseline CD4+ cell count, adherence, age, sex, race, region Virologic failure with resistance by Wk 144: 1.4% in each arm Arribas JR, et al. CROI Abstract 453. Sax PE, et al. Lancet. 2015;385:

6 Rate of discontinuation for AEs higher with TDF vs TAF regimen 3.3% vs 1.3% (P =.01) Spine and hip BMD loss greater with TDF vs TAF regimen 6 discontinuations for bone AEs in TDF arm vs 0 in TAF arm TC, LDL, and HDL increases greater with TAF vs TDF regimen, but no difference in TC:HDL ratio Rates of lipid-modifying therapy initiation similar: 5.5% vs 5.8% Renal Events Leading to Discontinuation, n Proximal renal tubulopathy Cr elevation or egfr decrease E/C/F/TAF (n = 866) E/C/F/TDF (n = 867) Renal failure 0 2 Nephropathy 0 1 Proteinuria 0 1 Bladder spasm 0 1 Total 0 12 Arribas JR, et al. CROI Abstract 453.

7 Randomized, noninferiority phase III trial of RAL 800 mg QD (n = 382) vs RAL 400 mg BID (n = 389), both with TDF/FTC [1] RAL QD inferior to RAL BID at Wk 48 in ITT (NC = F) analysis Lower RAL trough levels associated with higher risk of failure in QD arm but not in BID arm HIV-1 RNA < 50 c/ml (NC = F) / / 389 Wk 48 : -5.7 (95% CI: to -0.83; P for noninferiority =.044) RAL 800 mg QD (n = 382) RAL 400 mg BID (n = 389) More resistance at failure in QD arm Parameter, n Pts with VF* and HIV-1 RNA > 400 c/ml RAL QD (n = 382) *Failure included both failure to suppress and rebounders. Most patients with VF and RAL resistance had 2 mutations associated with resistance to RAL. PK studies of 2 new RAL formulations administered as 1200-mg once daily showed promise in healthy patients [2] RAL BID (n = 388) Resistance data available FTC resistance only 11 2 Integrase inhibitor and FTC resistance 9 2 No evidence of resistance Eron J, et al. Lancet Infect Dis. 2011;11: Krishna R, et al. EACS 2013, Abstract PE10/17.

8 Multicenter, double-blind, randomized phase III trial Stratified by HIV-1 RNA (> vs 100,000 c/ml), HBV and/or HCV coinfection Wk 48 Wk 96 ART-naive adults with HIV-1 RNA 1000 c/ml, no BL resistance to study agents (N = 802) RAL 1200 mg QD* + Placebo 400 mg BID + TDF/FTC (N = 533) RAL 400 mg BID + Placebo 1200 mg QD + TDF/FTC (n = 269) *Administered as two 600-mg tablets. Follow-up for 14 days HIV-1 RNA < 40 c/ml at Wk 48 (primary endpoint; FDA snapshot) 89% with RAL QD vs 88% with RAL BID QD dose noninferior at Wk 48: treatment difference of 0.5% (95% CI: -4.2% to 5.2%) Noninferiority maintained at Wk 96: 82% with RAL QD vs 80% with RAL BID (treatment difference of 1.4%; 95% CI: -4.4% to 7.3%) Di Perri G, et al. EACS Abstract BPD1/3..

9 HIV-1 RNA < 40 c/ml at Wk 96,* % Age 34 yrs > 34 yrs Sex Male Female Race Asian Black White Ethnicity Hispanic/Latino Non-Hispanic/ Latino Viral subtype B Non-B RAL 1200 mg QD (n = 533) Di Perri G, et al. EACS Abstract BPD1/3. RAL 400 mg BID (n = 269) HIV-1 RNA < 40 c/ml at Wk 96, % BL HIV-1 RNA, c/ml 100,000 > 100,000 BL CD4+ cell count, cells/mm > 200 Hepatitis status HBV and/or HCV positive Both HBV/CV negative Concomitant PPI/H 2 blocker use Yes No RAL 1200 mg QD (n = 533) RAL 400 mg BID (n = 269) *No statistically significant differences between treatment arms across subgroups. Median age of 34 yrs.

10 Randomized, open-label, multicenter phase III trials Primary endpoint: HIV-1 RNA < 50 copies/ml at Wk 48 (ITT- E snapshot) HIV-infected pts with HIV-1 RNA < 50 c/ml for 12 mos while receiving first or second ART regimen with 2 NRTIs + INSTI, NNRTI, or PI; no previous VF; HBV negative (N = 1024) Switch to DTG + RPV (n = 513) Continue Baseline ART (n = 511) Wk 52 Wk 148 Continue DTG + RPV Switch to DTG + RPV DTG + RPV 70% to 73% of pts receiving TDF at baseline Llibre JM, et al. CROI Abstract 44LB.

11 Pts (%) HIV-1 RNA < 50 c/ml DTG + RPV (n = 513) Baseline ART (n = 511) Treatment difference: -0.2% (95% CI: -3.0% to 2.5%) < 1 1 Virologic Nonresponse 5 4 No Data 1 pt with confirmed criteria for virologic withdrawal at Wk 36 in DTG + RPV arm had K101K/E Documented nonadherence at VF Resuppressed with continued DTG + RPV No INSTI resistance Wk 48 Llibre JM, et al. CROI Abstract 44LB.

12 Mean (µg/l) DTG + RPV Baseline ART 100 Baseline Baseline Wk 48 Wk P <.001 Bone-specific alkaline phosphatase P < Osteocalcin Procollagen 1 N-terminal propeptide Bone Turnover Marker P < AE rates generally similar between treatment arms through Wk 52 Numerically higher rate of drug-related grade 1/2 AEs with switch: 17% vs 2% Numerically higher rate of withdrawal for AEs with switch: 4% vs < 1% No notable change in serum lipid values from baseline to Wk 48 in either treatment arm Llibre JM, et al. CROI Abstract 44LB.

13 Comparison of VF rates among HIV-infected pts initiating ART from August 2013 to March 2017 at 8 CNICS sites (N = 5177) Proportion Without VF Kaplan-Meier Time to VF* DTG Other INSTI DRV Yrs *VF: HIV-1 RNA > 400 c/ml at 6 mos after initiating ART. Cox models adjusted for age, CD4+ cell count, days from last HIV-1 RNA, CNICS site, sex, HBV, HCV, HIV risk factor, and race. Pts All pts Other INSTI DTG DRV DTG Tx-naive pts Other INSTI DTG DRV DTG Events, n ahr for VF of DTG vs Comparator (95% CI) ( ) ( ) ( ) ( ) Nance R, et al. IDWeek Abstract 1688.

14 Randomized comparison of switch to DTG 50 mg QD monotherapy (immediate switch) vs continued baseline ART for 24 wks followed by switch to DTG 50 mg QD monotherapy (delayed switch) in virologically suppressed pts with no previous VF At Wk 24, DTG monotherapy noninferior to continued baseline ART for maintained HIV-1 RNA < 200 c/ml After 24 wks, all pts allowed to switch to DTG QD monotherapy Study d/c early because of high VF rate after 48 wks of DTG monotherapy VF in 8/77 pts with DTG monotherapy vs 3/152 pts on combination ART in concurrent nonrandomized control group (P =.03) Among 6 VF cases with resistance data in DTG monotherapy group, 3 developed INSTI resistance Wijting I, et al. CROI Abstract 451LB.

15 International, multicenter retrospective study evaluated virologically suppressed pts switched from combination ART to DTG 50 mg QD monotherapy Pts with history of VF on INSTI and INSTI resistance excluded 11 of 122 pts switched to DTG monotherapy experienced VF 9 of 11 had genotypic INSTI resistance at VF INSTI resistance pathways varied: 92Q/155H (n = 1); 97A/155H (n = 1); 155H/148R (n = 1); 118R (n = 2); 148K (n = 1); 148H (n = 2); 148R (n = 1) Blanco JL, et al. CROI Abstract 42.

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17 Probability Treatment with EFV associated with increased risk of suicidality Absolute risk is small EFV EFV-free HR: 2.28 (95% CI ; P =.006) 47 events/5817 PY (8.08/1000 PY) 15 events/4099 PY (3.66/1000 PY) Wks to Suicidality Mollan K, et al. IDWeek Abstract Risk of attempted or completed suicide also associated with EFV (HR: 2.58; 95% CI: 0.94 to 7.06; P =.06) EFV also associated with increased risk of death from injury, substance use, or unknown causes Careful attention should be paid to cause of death in all clinical trials Multivariate Analysis of Factors Associated With Suicidality in ACTG Clinical Trials Variable HR (95% CI) PValue Randomly assigned EFV 2.15 ( ).01 Age category, yrs < ( ) 1.69 ( ) 1.00 (reference) Hx IDU 2.18 ( ).02 Psychiatric hx or psychoactive rx 3.90 ( ) <

18 Doravirine: next-gen NNRTI, unique resistance profile, low DDI potential, no food or PPI effects Multicenter, randomized, double-blind phase III trial Primary endpoint: HIV-1 RNA < 50 copies/ml at Wk 48 Stratified by HIV-1 RNA > 100,000 c/ml, baseline NRTI Wk 48 Wk 96 HIV-infected pts with HIV-1 RNA 1000 copies/ml within 45 days of Day 1; no previous ART; no resistance to study drugs (N = 769) DOR 100 mg QD + FTC/TDF or ABC/3TC QD + Placebo for DRV + RTV (n = 385) DRV 800 mg + RTV 100 mg QD + FTC/TDF or ABC/3TC QD + Placebo for DOR (n = 384) 14-day follow-up Molina JM, et al. CROI Abstract 45LB.

19 Pts (%) DOR + 2 NRTIs (n = 383) DRV + RTV + 2 NRTIs (n = 383) HIV-1 RNA < 50 c/ml Treatment difference: 3.9% (95% CI: -1.6% to 9.4%) Virologic Nonresponse Wk No Data Efficacy similar in both arms regardless of baseline HIV-1 RNA or CD4+ cell count No drug resistance detected in pts with PDVF through Wk 48 in either arm n = 1 pt with noncompliance discontinued at Wk 24, developed DOR and FTC resistance Molina JM, et al. CROI Abstract 45LB.

20 AE, % DOR (n = 383) DRV + RTV (n = 383) 1 AE Treatment-related AE Serious AE 5 6 Discontinuation for AE 2 3 AEs of clinical interest Rash* Neuropsychiatric *Discontinued due to rash: n = 2 in DOR arm; n = 1 in DRV + RTV arm. No discontinuation for neuropsychiatric conditions. Fasting Lipid Δ From BL to Wk 48, mg/dl DOR (n = 383) DRV + RTV (n = 383) LDL-c* Non-HDL-c* Cholesterol Triglyceride HDL-c *P <.0001 for DOR vs DRV + RTV. Molina JM, et al. CROI Abstract 45LB.

21 Bictegravir: investigational QD INSTI, active against most INSTI RAVs, low DDI potential, half-life ~ 18 hrs, no food requirement with dosing, primarily metabolized by CYP3A4 and UGT1A1 Randomized, double-blind, active-controlled phase II trial Primary endpoint: HIV-1 RNA < 50 copies/ml at Wk 24 Wk 24 Wk 48 HIV-infected pts with HIV-1 RNA 1000 copies/ml; CD cells/mm 3 ; no previous ART; HBV and HCV negative (N = 98) BIC + FTC/TAF QD + Placebo for DTG QD (n = 65) DTG + FTC/TAF QD + Placebo for BIC QD (n = 33) Open-label extension Sax PE, et al. CROI Abstract 41. Sax PE, et al. Lancet HIV. 2017;[Epub ahead of print]. Zhang H, et al. CROI Abstract 40.

22 No drug resistance detected in either arm through Wk 48 BIC + FTC/TAF (n = 65) DTG + FTC/TAF (n = 33) Pts (%) Treatment difference: 2.9% (95% CI: -8.5% to 14.2%) Treatment difference: 6.4% (95% CI: -6% to 18.8%) 20 0 Virologic Success 3 6 Virologic Failure 0 0 No Data 20 0 Virologic Success 2 6 Virologic Failure 2 3 No Data Wk 24 Wk 48 Sax PE, et al. CROI Abstract 41.

23 Any Grade AE Occurring in 5% in Either Arm, % BIC + FTC/TAF (n = 65) DTG + FTC/TAF (n = 33) Diarrhea Nausea 8 12 Headache 8 3 URTI 8 0 Fatigue 6 6 Arthralgia 6 6 Chlamydial infection 6 3 Back pain 6 0 Furuncle 5 6 Flatulence 2 6 Gastroenteritis 2 6 Costochondritis 0 6 Hemorrhoids 0 6 Pruritus 0 6 Grade 2-4 Lab Abnormality 5% in Either Arm, % BIC + FTC/TAF (n = 64*) DTG + FTC/TAF (n = 32*) Creatine kinase 13 9 AST 9 3 Hyperglycemia 8 13 ALT 6 0 LDL 6 9 Amylase 5 6 Hematuria 3 6 Glycosuria 2 6 *Pts with 1 post-bl laboratory assessment, excluding those not specified for all pts. Difficult to conclude on safety from small study, but 4 fully enrolled phase III trials now evaluating efficacy, safety, tolerability of coformulated BIC/FTC/TAF Sax PE, et al. CROI Abstract 41.

24 Randomized, open-label, multicenter phase III trial HIV-1 RNA 50 c/ml at Wk 48 (primary endpoint; FDA snapshot) 1.7% in both arms; Wk 48 treatment difference showed noninferiority of switch: 0% (95% CI: -2.5% to 2.5%) Wk 48 Pts with HIV-1 RNA < 50 c/ml for 6 mos while receiving boosted DRV or ATV + 2 NRTIs (ABC/3TC or FTC/TDF); egfr 50 ml/min (N = 577) Switch to BIC/FTC/TAF (n = 290) Continue Boosted PI + 2 NRTI Regimen (n = 287) HIV-1 RNA < 50 c/ml at Wk 48 (secondary endpoint): 92.1% BIC/FTC/TAF; 88.9% cont. baseline ART (difference: 3.2%; 95% CI: -1.6% to 8.2%) Daar ES, et al. IDWeek Abstract LB-4.

25 No treatment-emergent resistance detected in BIC/FTC/TAF arm Lipid parameters significantly improved with BIC/FTC/TAF vs continued baseline ART Change from baseline to Wk 48: TG, -6 vs +4 mg/dl (P =.002); cholesterol:hdl ratio, -0.2 vs 0 (P =.033) AE Associated With D/c, n BIC/F/TAF (n = 290) Continue Baseline ART (n = 287) Any AE 2 1 Acetabular fracture/acute kidney injury 0 1 Rash 1 0 Schizophrenia 1 0

26 AMBER: randomized, double-blind phase III trial [1] Treatment-naive pts with HIV-1 RNA 1000 c/ml; susceptible to DRV, FTC, and TVF (N = 725) EMERALD: randomized, open-label phase III trial [2,3] DRV/COBI/FTC/TAF (n = 362) DRV/COBI + FTC/TDF (n = 363) Wk 48 Wk 48 Pts with HIV-1 RNA < 50 c/ml for 2 mos while receiving boosted PI + FTC/TDF for 6 mos; no previous VF on DRV; egfr 50 ml/min (N = 1141) Switch to DRV/COBI/FTC/TAF (n = 763) Continue Boosted PI + FTC/TDF (n = 378) 1. Orkin C, et al. EACS Abstract PS8/2. 2. Orkin C, et al. IDWeek Abstract 1689b. 3. Orkin C, et al. Lancet HIV. 2017;[Epub ahead of print].

27 Pts (%) Wk 48 Virologic Efficacy Treatment difference: 2.7% (95% CI: -1.6% to 7.1%) Virologic Success* 4.4 (n = 16) *Primary endpoint: HIV-1 RNA < 50 c/ml by FDA snapshot. Orkin C, et al. EACS Abstract PS8/2. DRV/COBI/FTC/TAF (n = 362) DRV/COBI + FTC/TDF (n = 363) 3.3 (n = 12) HIV-1 RNA 50 c/ml 1 treatment-emergent resistance mutation (M184I/V) observed in DRV/COBI/FTC/TAF arm Similar low rates of grade 3/4 AEs between treatment groups Lower rate of AE-related d/c for DRV/COBI/FTC/TAF vs DRV/COBI + FTC/TDF (1.9% vs 4.4%) Hip/spine BMD changes more favorable with DRV/COBI/FTC/TAF Significantly higher egfr by serum creatinine (P <.0001) and cystatin c (P =.001) with DRV/COBI/FTC/TAF

28 Pts (%) Treatment difference: 1.2% (95% CI: -1.7% to 4.1%) Virologic Success* Wk 48 Virologic Efficacy DRV/COBI/FTC/TAF (n = 763) Continue Boosted PI + FTC/TDF (n = 378) Treatment difference: 0.4% (95% CI: -1.5% to 2.2%) Virologic Rebound *HIV-1 RNA < 50 c/ml (FDA Snapshot). Primary endpoint: confirmed HIV-1 RNA 50 c/ml or premature d/c with last HIV-1 RNA 50 c/ml. Orkin C, et al. IDWeek Abstract 1689b. Orkin C, et al. Lancet HIV. 2017;[Epub ahead of print]. Arribas JR, et al. EACS Abstract BPD2/8. No PI or NRTI resistance mutations (viral rebound with resistance data: n = 1 DRV/ COBI/FTC/TAF; n = 3 control) Similar low rates of grade 3/4 AEs, d/c for AEs between treatment groups Significant improvements in hip/spine BMD for DRV/COBI/FTC/TAF vs control Similar egfr by serum creatinine between groups (P =.092); increased egfr by cystatin c with DRV/COBI/ FTC/TAF (P =.034) In post-hoc subanalysis, bone and renal parameters improved with switch regardless of sex, age, preexisting diabetes or HTN

29 Ibalizumab: humanized mab to conformational epitope on CD4 receptor that blocks postattachment HIV entry into CD4+ T-cells without altering normal cell function Single-arm, open-label phase III trial Primary endpoint: 0.5 log 10 HIV-1 RNA decrease at Day 14 Pts with HIV-1 RNA > 1000 copies/ml; on ART 6 mos, on stable ART 8 wks; resistant to 1 ARV from 3 classes, sensitive to 1 ARV for OBR (N = 40) Control Period: Day 0-7 Ibalizumab 2000 mg IV Day 7 (loading dose) Continue Failing ART Days 0-14 Primary Endpoint: Day 14 Ibalizumab 800 mg IV Day 21, Q2W (maintenance dose) Switch to OBR Day 14 Wk 25 53% with resistance to all drugs from 3 classes; 68% with INSTI resistance Lewis S, et al. CROI Abstract 449LB.

30 Primary endpoint: 83% with 0.5 log 10 HIV-1 RNA decrease at Day 14 vs 3% at end of control period (P <.0001) 60% with 1.0 log 10 HIV-1 RNA decrease Mean decrease by Day 14: 1.1 log 10 Wk 24 Virologic Outcome Ibalizumab + OBR 1.0 log 10 HIV-1 RNA decrease, % log 10 HIV-1 RNA decrease, % 48 HIV-1 RNA < 50 copies/ml, % 43 HIV-1 RNA < 200 copies/ml, % 50 Mean HIV-1 RNA decrease from 1.6 baseline, log 10 9 pts reported 17 serious AEs 1 drug-related serious AE (IRIS) resulted in discontinuation 9 other pts discontinued Death (n = 4; liver failure, Kaposi sarcoma; end-stage AIDS, lymphoma) Consent withdrawal (n = 3) Lost to follow-up (n = 2) No cases of anti-ibalizumab antibodies Lewis S, et al. CROI Abstract 449LB.

31 Fostemsavir: prodrug of investigational attachment inhibitor temsavir BRIGHTE: ongoing randomized, double-blind, placebo-controlled phase III trial with openlabel extension (N = 371 treated pts) Includes nonrandomized cohort with same eligibility criteria (except no remaining ARV classes and no remaining fully active approved drugs) given FTR 600 mg BID + OBR during open-label extension (n = 99) Randomized 3:1 Day 8 Primary analysis Day 9 Start OLE Wk 24 Wk 96 HIV-infected pts experiencing failure of current ART, HIV-1 RNA 400 c/ml, with 1-2 remaining ARV classes ( 1 fully active available agent/class), not able to construct viable regimen with remaining agents (n = 272) FTR 600 mg BID + failing regimen (n = 203) PBO BID + failing regimen (n = 69) FTR 600 mg BID + OBR FTR 600 mg BID + OBR Until rollover study, marketing approval, or additional option available Kozal M, et al. EACS Abstract PS8/5.

32 Primary endpoint: adjusted* mean HIV- 1 RNA log 10 change at Day 8 in randomized ITT-E population FTR vs PBO: vs (difference: ; 95% CI: to ; P <.0001 ) Wk 24 viral suppression by snapshot Randomized cohort (N = 272): HIV-1 RNA < 40 c/ml: 54% HIV-1 RNA < 200 c/ml: 71% Nonrandomized cohort (N = 99): HIV-1 RNA < 40 c/ml: 36% Most common grade 2-4 tx-related AEs were nausea, diarrhea, headache, vomiting, fatigue, asthenia Wk 24 Safety Event, n (%) Randomized Cohort (n = 270) Nonrandom. Cohort (n = 99) All Treated Pts (N = 371) Any event 243 (90) 93 (94) 338 (91) Grade 2-4 txrelated AE AE leading to d/c 49 (18) 19 (19) 68 (18) 12 (4) 9 (9) 21 (6) Serious AE 73 (27) 37 (37) 112 (30) Tx-related serious AE 6 (2) 3 (3) 9 (2) Death 8 (3) 9 (9) 17 (5) *Mean adjusted by HIV-1 RNA on Day 1. Per Levene s test of homogeneity of variance. 12 out 17 deaths from AIDS-related events; 1 death from recurrent atypical mycobacterial infection due to IRIS. Kozal M, et al. EACS Abstract PS8/5.

33 Dose-ranging, randomized phase IIb study Primary endpoint: HIV-1 RNA < 50 c/ml at Wk 48 At Wk 96: 76% of pts receiving CAB + RPV had HIV-1 RNA < 50 copies/ml ART-naive pts, HIV-1 RNA 1000 c/ml (N = 243) Wk 24 Induction Phase* CAB 10 mg QD + 2 NRTIs (n = 60) CAB 30 mg QD + 2 NRTIs (n = 60) CAB 60 mg QD + 2 NRTIs (n = 61) EFV 600 mg QD + 2 NRTIs QD (n = 62) Wk 48: Primary Endpoint Maintenance Phase CAB 10 mg QD + RPV 25 mg QD CAB 30 mg QD + RPV 25 mg QD CAB 60 mg QD + RPV 25 mg QD Wk 96 *Pts with HIV-1 RNA < 50 c/ml at Wk 24 continued to maintenance phase. FTC/TDF or ABC/3TC. Wk 144: Ad Hoc Open-Label Phase CAB 30 mg QD + RPV 25 mg QD Margolis DA, et al. CROI Abstract 554LB. Margolis DA, et al. Lancet Infect Dis. 2015;15:

34 Ad hoc analysis through Wk 144 of open-label phase Serious AEs: 9%; d/c for AEs: 3% PDVF in 9 pts (ITT-E) 6 during induction/maintenance 3 during open-label (Wks ) 2 of 3 had emergent mutations: n = 1 with V151V/I (IN); n = 1 with K101E + M230M/L (NNRTI) 1 pt without PDVF developed E138K + V108V/I (NNRTI) Treatment Outcomes at Wk 144 (Snapshot), n (%) CAB Subtotal* (ITT-E) (n = 181) CAB Subtotal* (ITT-ME) (n = 160) HIV-1 RNA < 50 c/ml 122 (67) 122 (76) HIV-1 RNA 50 c/ml Previous change in ART No virologic data in window D/c for AE or death D/c for otherreasons On study with missing data in window 18 (10) 3 (2) 41 (23) 8 (4) 27 (15) 6 (3) 13 (8) 2 (1) 25 (16) 4 (3) 15 (9) 6 (4) PDVF 9 (5) 6 (4) *CAB 10 mg + CAB 30 mg + CAB 60 mg. Margolis DA, et al. CROI Abstract 442. Margolis DA, et al. CROI Abstract 554LB. Margolis DA, et al. Lancet Infect Dis. 2015;15:

35 Agent MoA or Formulation Phase Dosing/ Administration Implications GS-CA1 [1] HIV capsid inhibitor Preclinical Extended release, suitable for SC of solid depot formulation Potent ART with orthoganol resistance profile to existing ART; potential for long-acting formulation due to low aqueous solubility, high stability GS-9131 [2] NRTI Preclinical Potential for once daily dosing Potent ART active against NRTI RAMs K65R, L74V, M184V alone or in combination; minimal loss of susceptibility with 4 or more TAMs MK-8591 [3] Nucleoside Reverse Transcriptase Translocation Inhibitor (NRTTI) I 10 mg QW PO; potential for extended duration Comparable MK-8591 levels in animal rectal, vaginal tissue to TDF levels in tissues of human subjects highlights potential prophylaxis utility GS-PI1 [4] PI Preclinical Potential for unboosted, QD dosing Potent ART with high barrier to resistance, including < 2-fold loss in potency against major PI RAMs, and 10- fold to 40-fold longer in vivo half life vs ATV or DRV NANO-EFV, NANO-LPV [5] Oral, lower dose SDN I nefv: 50 mg QD, 21 d nlpv/rtv: 200/100 mg BID, 7 d Enhanced oral bioavailability suggests can reduce EFV, LPV dose by ~ 50% while maintaining PK 1. Tse WC, et al. CROI Abstract White KL, et al. CROI Abstract Grobler J, et al. CROI Abstract Link JO, et al. CROI Abstract Owen A, et al. CROI Abstract 39.

36 Agent TMC278 LA [1] MoA or Formulation LA injectable RPV (IM) Phase Dosing/ Administration Implications II 1200 mg IM Q8W Potential as injectable, long-acting PrEP Elsulfavirine [2] Prodrug of new NNRTI VM1500A IIb Combined therapy: 20 mg elsulfavirine + FTC/TDF PO QD Less toxic alternative to EFV for initial ART UB-421 [3] Anti-CD4 receptor mab II 10 mg/kg QW IV or 25 mg/kg Q2W IV Possible ART alternative for maintenance therapy in virologically suppressed pts 1. Bekker L-G, et al. CROI Abstract 421LB. 2. Murphy R, et al. CROI Abstract 452LB. 3. Wang C-Y, et al. CROI Abstract 450LB.