ARV Update: 2016 and Beyond Antonio E. Urbina, MD Associate Professor of Medicine Icahn School of Medicine Mount Sinai Hospital

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1 ARV Update: 2016 and Beyond Antonio E. Urbina, MD Associate Professor of Medicine Icahn School of Medicine Mount Sinai Hospital Disclosures Scientific Advisory Panels: Gilead, Thera technologies, Merck, VIIV Clinical Research: BMS, VIIV Overview ART has become simpler, safer and better tolerated For last 19 months, no cases of MTCT in New York State The durability of the regimens has increased and virologic failure with emergent resistance has become less common. Most patients with MDR HIV are currently suppressed on more complex, and perhaps fragile or cumbersome regimens. Therefore more new agents are still needed. For other patients adherence to oral ART presents a substantial challenge. Long acting agents, and new delivery systems for ART will be needed Narrowing the Gap in Life Expectancy for HIV+ versus HIV Subjects Kaiser cohort data from evaluating life expectancy between HIV+ (n=25,768; 46% on ART at BL) and HIV (n=257,600) subjects Mortality rate of 1,827 vs. 326 per 100,000 person years, respectively Abridged life tables were used to estimate years of life remaining at age 20 Even with early ART initiation, a life expectancy gap remains between HIV+ and HIV subjects. Mitigation of risk factors, like smoking, may further reduce the survival disparity. Marcus J, et al, CROI Boston, MA. Oral 54 Expected years of life remaining at age 20 (95% confidence interval) HIV+ HIV Difference P value Overall ( ) <0.001 HIV+ and initiated ART with CD ( ) < No hepatitis B or C ( ) < No drug/alcohol abuse ( ) < No smoking ( ) <

2 START Trial: Impact on Cancer Results: Immediate vs. deferred ART initiation and the risk of any type cancer, infection related and infection unrelated cancers in the START study Model A A: univariable, estimated in a Cox Any type cancer Model B proportional hazards model with a single treatment indicator (n=53) Model C Model D B: adjusted for baseline covariates; age, gender, race, geographical region, smoking, BMI, hepatitis B/C, CD4 cell count and Model A baseline log 10 HIV RNA Infection related Model B cancer C: adjusted for latest HIV RNA, modelled as Model C <200 copies/ml vs HIV RNA >200 copies/ml (n=53) Model D D: adjusted for latest CD4 cell count and latest HIV RNA (<200 copies/ml) Model A Infection unrelated Model B cancer Model C (n=53) Model D START Trial: Increased Quality of Life with Immediate ART Initiation Change from Baseline Current Health (Visual Analog Scale, 0 100) Immediate ART Deferred ART Months from Randomization Change from Baseline General Health (SF 12 v2, Scaled 0 100) Months from Randomization % reduction in risk of infection related cancers (KS, HL & NHL,HPV) Factors associated with risk of Infection related cancers Age Baseline HIV RNA risk: high income country Borges A, et al. 23rd CROI; Boston, MA; February 22 25, Abst No of Participants: No of Participants: Imm,: 2091 Imm,: Def.: Def.: Lifson A, et al. 23rd CROI; Boston, MA; February 22 25, Abst BC Cohort: Trends in Drug Class Resistance in Recent Treatment Era HIV Drug resistance/1000 ART Treated Persons* Review of resistance testing results in British Columbia since 2009 Significant decline in detected PI an RT resistance; despite increase in use of integrase inhibitors, rate of resistance remains very low Declining prevalence of drug resistant strains, and low prevalence of integrase inhibitor resistance, to date Lepik K, et al. 23rd CROI; Boston, MA; February 22 25, Abst. 492LB Prevalence of Drug Resistance RT, PI resistance/1000 ART treated INI resistance/1000 ART treated Decreasing prevalence of RT, PI resistance, trend p<0.001, R Increasing prevalence of INI resistance, trend p<0.001, R Year U.S. Clinics: Changes in Viral Load Over Time Percent of Subjects % CFAR Network of Integrated Clinical Systems (CNICS) Cohort 29,467 Participants at 8 HIV Clinics Percentage of Suppressed Viral Load Over Time Calendar Year OR Std Err 95% CI P value Integrase Use [ ] <0.01 Male [ ] <0.01 Age (per year) [ ] <0.01 Race (White=Ref) Black [ ] <0.01 Hispanic [ ] 0.27 Other/Missing [ ] 0.06 Years from Baseline [ ] <0.01 Simoni J, et al. 23rd CROI; Boston, MA; February 22 25, Abst % 2

3 Case # 1 DG is a 47 year old WM, HIV+ (dx d 2004), nadir CD4 count 400 with PMHx hypogonadism and hyperlipidemia. Patient is on emtricitabine/rilpivirine/tdf (Complera ) and reports excellent adherence. He presents to you on 4/2016 for HIV f/u after transferring care. Labs done that day reveal viral load of 9,026, + RPR 1:16 and testosterone >1200 Repeat testing confirms elevated viral load and you perform a resistance test Case # 1 Given the results of the Genosure Prime, you decide to switch patient to: 1. emtricitabine/tdf (Truvada ) + DTG (Tivicay ) 2. emtricitabine/tdf (Truvada ) + darunavir/cobi (Prezcobix ) 3. abacavir/lamivudine/dtg (Triumeq ) 4. emtricitabine/elvitagravir/cobi/taf (Genvoya ) + darunavir (Prezista ) Case # 2 TM is a 59 year old male with PMHx long standing HIV/AIDS, hyperlipidemia, GERD, BPH, osteoporosis, HTN on delavirdine, (Rescriptor, 3 tabs twice daily), LPV/r (Kaletra, 2 tabs twice daily) and raltegravir (Isentress, 1 tab twice daily). He presents to you after transferring care and would like to discuss alternative ARV options. 3

4 Genosure Archive Case # 2 Given the results of the Genosure Archive, you decide to switch the patient to: 1. DTG (Tivicay ) + rilpivirine (Edurant ) 2. DTG (Tivicay ) + darunavir/cobi (Prezcobix ) 3. emtricitabine/elvitagravir/cobi/taf (Genvoya ) + darunavir (Prezista ) 4. DTG (Tivicay ) + darunavir/cobi (Prezcobix ) + etravirine (Intelence ) Basics of ARV Management Treatment Naive Perform genotyping on everyone prior to initiating ARVs If patient in AHI or if you want to start prior to results of resistance testing then: Use either DRV/r, DRV/c or DTG with TDF/FTC Treatment Experienced Best to get resistance testing within 4 weeks of being on ARVs Wild type virus can outgrow the minor variants Familiarize yourself with the various resistant tests from Monogram Genotypic testing +/ integrase Phenotypic +/ integrase Tropism Archive, genotypic testing 4

5 Recommendations for Resistance Testing DHHS Guidelines: Genotypic testing is recommended at baseline Genotypic testing is recommended at first and second failures in patients with suboptimal virologic response or virologic failure Addition of phenotypic to genotypic testing is generally preferred for persons with known or suspected complex drugresistance mutation patterns, particularly to protease inhibitors In persons failing integrase based regimens, genotypic testing for integrase resistance should be considered Trofile testing should be performed prior to use of entry inhibitor (maraviroc) Genotype or Phenotype or Both? Genotype can identify resistance when mutations are present only as mixtures, therefore can give an early warning sign that resistance is on the horizon Phenotype directly measures virus vs. drug Is a true measure of susceptibility Both tests in combination may provide the most complete picture of resistance 1 This approach may be most useful in patients who are more treatment experienced Parkin, et al. JAIDS 31: , 2002 Patient Case: History GenoSURETM Integrase Results The patient is a 48 year old man who has been HIV positive since the mid 1990s. He has been on multiple regimens over the years due to virologic breakthrough or adverse events. For the past several years, his virus has been well controlled. However, he recently failed his raltegravir containing regimen (RAL/TDF/FTC) with a viral load of 20,000+ copies/ml, which was confirmed on two separate samples. 5

6 Genosure Archive Sequencing the integrated proviral HIV 1 DNA present in infected cells of individuals with undetectable plasma HIV 1 RNA levels can provide information about resistance associated mutations acquired in the past and archived in the HIV 1 reservoir. Circulating peripheral blood mononuclear cells (PBMCs) are a source of cellular proviral DNA that can be used for genotyping to detect previously transmitted or emergent drug resistance mutations in virologically suppressed patients. Proviral DNA sequencing may be a valuable tool when used in combination with or in the absence of historical RNA genotype data to guide regimen switching in the setting of virologic suppression. GenoSure Archive SM Process 3X HIV Pol SCOPE Cohort UCSF well established cohort of HIV+ patients Patients for this study were selected using the following criteria: Documented history of drug resistance Achieved durable virologic suppression PBMC aliquots available during a period of ART induced suppression Majority of these patients initiated ART prior to 2001 PBMC samples from 48 patients were used in this study Cellular DNA was extracted from 4.5 million PBMC/sample for use in the GenoSure Archive assay J. Toma 1, et. al. Drug Resistance Profiles Derived from HIV 1 DNA in ARV Suppressed Patients Correlate with Historical Resistance Profiles Obtained from HIV 1 Plasma RNA 6

7 SCOPE Cohort GenoSure Archive Demonstrates an 85% Sensitivity to Detect Major Resistance Associated Variants J. Toma 1, et. al. Demographics N or Mean % or Range Male 42 89% Female 5 11% Age CD4 Nadir CD4 at testing Tx History Years aviremic prior to testing Number of ARV regimens ART Resistance NRTI Resistance 43 90% NNRTI Resistance 24 50% PI Resistance 32 67% One Class Resistance 7 15% Two class Resistance 16 33% Three class Resistance 20 42% *Demographic information was incomplete for one patient J. Toma 1, et. al. All Variants NRTI NNRTI PI Sensitivity 85% 89% 82% 77% 95% CI (80 89%) (83 94%) (67 91%) (66 85%) False Neg. Rate 15% 11% 18% 23% * * * * * * * * NRTI NNRTI Protease Note: Low prevalence of resistance variants at some positions resulted in large confidence intervals *No variants present in the historical genotypes J. Toma 1, et. al. GenoSure Archive Accurately Represents Historically Wildtype Variants All Variants NRTI NNRTI PI NPV 97% 96% 98% 96% 95% CI (95 97%) (93 97%) (96 99%) (94 98%) False Omission Rate 3% 4% 2% 4% NRTI NNRTI Protease Mechanism of Action Tenofovir Disoproxil Fumarate and Tenofovir Alafenamide GI TRACT TFV TDF TAF RENAL TUBULAR CELL PLASMA LESS PLASMA STABILITY 91% LESS PLASMA TFV 1 TFV TFV GREATER PLASMA STABILITY RENAL TUBULAR CELL OAT 1 & 3 TFV OAT 1 & 3 TFV 1. Sax P, et al. Lancet 2015 OAT, organic anion transporter; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; TFV, tenofovir. LYMPHOCYTE TFV TAF 25 mg results in >90% lower TFV plasma levels HIV Wohl D, et al. CROI Boston, MA. #681 7

8 Study Design Efficacy at Week 48 (Snapshot) Randomized, double blind, double dummy, active controlled study F/TAF QD Virologically Suppressed (< 50 c/ml) F/TDF + Third Agent egfr 50 ml/min n=333 n=330 F/TDF Placebo QD Continue Third Agent F/TDF QD F/TAF Placebo QD Continue Third Agent HIV-1 RNA <50 c/ml, % Virologic Outcome Treatment Difference (95% CI) F/TDF F/TAF F/TAF Dose: 200/10 mg with boosted Pis 200/25 mg with unboosted third agents BL Wk 48 Wk 96 Primary Endpoint Secondary HIV-1 RNA <50 c/ml Endpoint Virologic Success Virologic Failure No Virologic Data 10% 0 +10% Gallant J, et al. CROI Boston, MA. #29 Gallant J, et al. CROI Boston, MA. #29 Changes in egfr from Baseline Change in Renal Biomarkers at Week 48 Urine Protein to Creatinine Ratio Protein Albumin RBP β2m 8.4 ml/min 2.8 ml/min p <0.001 Median % change F/TDF F/TAF All differences between treatments statistically significant (p <0.001) Participants who remained on TDF continued to have increased proteinuria while those who switched to TAF had decreased proteinuria * egfr calculated with Cockcroft Gault equation Gallant J, et al. CROI Boston, MA. #29 RBP, retinol binding protein; β2m, β2 microglobulin Gallant J, et al. CROI Boston, MA. #29 8

9 Change in Bone Mineral Density through Week 48 Fasting Lipid Results F/TAF F/TDF Mean % change (95% CI) F/TAF, n F/TDF, n Spine 1.5 p < Weeks Hip 1.1 p < Weeks Median value (mg/dl) p < Week 48 Baseline p < p= p= p= % BMD increase at Week 48 F/TAF 30% 17% p<0.001 F/TDF 14% 9% p=0.003 Total LDL HDL Triglycerides TC: HDL Ratio Cholesterol F/TAF F/TDF Patients initiating lipid-lowering agents 4% 4% Gallant J, et al. CROI Boston, MA. #29 Gallant J, et al. CROI Boston, MA. #29 Basics of ARV Management Initial Regimens: Recommended New Agents TAF containing ARVs: 1. elvitegravir/cobicistat/emtricitabine/ TAF (10 mg) [Genvoya ] 2. emtricitabine/rilpivirine/taf 25 mg [Odefsey ] 3. emtricitabine/taf (25 mg) [Descovy ] Cobicistat ARVs: ATZ/cobi [Evotaz ] DAR/cobi [Prezcobix ] Fine tuning experienced patients If possible, switch off all D drugs like stavudine and didanosine Consider switching off efavirenzcontaining regimes for CNS/psychiatric, lipo atrophic or elevated TGs Consider switching off older PIs like saquinavir, indinavir and LPV/r INSTI based DTG/ABC/3TC; only if HLA-B*5701 negative (AI) DTG (QD) + TDF/FTC (AI) EVG/COBI/TDF/FTC; only if pre-art CrCl >70 ml/min (AI) EVG/COBI/TAF/FTC; only if pre-art CrCl 30 ml/min (AI) RAL + TDF/FTC (AI) PI based DRV/r (QD) + TDF/FTC (AI) Note: 3TC can be used in place of FTC and vice versa; TDF: caution if renal insufficiency January

10 Initial Regimens: Alternative Initial Regimens: Other NNRTI based EFV/TDF/FTC (BI) RPV/TDF/FTC; only if pre-art HIV RNA <100,000 copies/ml and CD4 >200 cells/µl (BI) PI based ATV/c + TDF/FTC; only if pre-art CrCl >70 ml/min (BI) ATV/r + TDF/FTC (BI) (DRV/c or DRV/r) + ABC/3TC; only if HLA- B*5701 negative (BIII for DRV/c, BII for DRV/r) DRV/c + TDF/FTC; only if pre-art CrCl >70 ml/min (BII) Note: 3TC can be used in place of FTC and vice versa; TDF: caution if renal insufficiency INSTI based RAL + ABC/3TC; only if HLA-B*5701 negative (CII) NNRTI based EFV + ABC/3TC; only if HLA-B*5701 negative and pre-art HIV RNA <100,000 copies/ml (CI) a PI based (ATV/c or ATV/r) b + ABC/3TC; only if HLA- B*5701 negative and pre-art HIV RNA <100,000 copies/ml (CIII for ATV/c and CII for ATV/r) LPV/r (QD or BID) c + ABC/3TC; only if HLA- B*5701 negative (CI) LPV/r (QD or BID) c + TDF/FTC (CI) Notes: 3TC can be used in place of FTC and vice versa a. Consider alternative to EFV in women who plan to become pregnant or are not using effective contraception. b. ATV/r should not be used in patients who take >20 mg omeprazole per day. c. QD LPV/r is not recommended in pregnant women. January January Initial Regimens: Other (2) Other Regimens when TDF or ABC cannot be used DRV/r + RAL; only if pre-art HIV RNA <100,000 copies/ml and CD4 >200 cells/µl (CI) LPV/r (BID) + 3TC (BID) (C1) Novel ARV Studies January

11 GARDEL: Dual ART With LPV/RTV + 3TC vs Triple ART With LPV/RTV + 2 NRTIs Randomized, open-label phase III noninferiority trial Primary endpoint: HIV-1 RNA < 50 c/ml (ITT-e, FDA snapshot analysis) Pts with virologic response at Wk 48 offered extension to Wk 96 Stratified by HIV 1 RNA ( vs > 100,000 c/ml) ART-naive pats with HIV-1 RNA > 1000 copies/ml; no NRTI/PI resistance; HBsAg negative (N = 426) Cahn P, et al. EACS Abstract 961. Wk 24 interim analysis Wk 48 primary analysis Lopinavir/Ritonavir 400/100 mg BID + Lamivudine 150 mg BID (n = 217) Lopinavir/Ritonavir 400/100 mg BID + Investigator Selected NRTIs in FDC* (n = 209) *ZDV/3TC: 54%; TDF/FTC: 37%; ABC/3TC: 9% Wk 96 extension analysis GARDEL: Dual ART Noninferior to Triple ART at Wk 48 and Wk 96 Safety and tolerability also similar between treatment arms Pts (%) Wk: 96 Virologic Success Wk 48 difference: +4.6% (95% CI: -2.2 to 11.8; P =.171) Wk 96 difference: +5.9% (95% CI: -2.3 to 14.1; P =.165) Virologic Nonresponse D/C due to AE or Death Dual ART Triple ART Cahn P, et al. EACS Abstract 961. Cahn P, et al. Lancet Infect Dis. 2014;14: D/C for Other Reasons ATLAS-M: Switch From Suppressive ATV/RTV + 2 NRTIs to ATV/RTV + 3TC Randomized, multicenter, open-label phase IV trial Primary endpoint: absence of treatment failure at Wk 48, defined as ART modification for any reason and/or virologic failure Pts receiving stable ATV/RTV + 2 NRTIs ( 3 mos) with HIV-1 RNA < 50 c/ml and CD4+ > 200 cells/mm 3 ( 6 mos), and no previous virologic failure (N = 266) Wk 24 interim analysis Di Giambenedetto S, et al. EACS Abstract 867. Wk 48 primary endpoint Switch to ATV/RTV 300/100 mg + 3TC 300 mg QD (n = 133) Continue ATV/RTV 300/100 mg QD + 2 NRTIs (n = 133) Wk 96 planned follow up ATLAS-M: Virologic Efficacy and Safety Through Wk 48 Switch to ATV/RTV + 3TC noninferior and superior (post hoc) to continuing ATV/RTV + 2 NRTIs in ITT, S=F analysis Pts Free of Treatment Failure (%) ATV/RTV + 3TC ATV/RTV + 2NRTIs BL W4 W12 W24 W36 W48 Significantly greater increases in TC (P <.01), LDL (P <.05), and HDL (P <.01) with ATV/RTV + 3TC vs ATV/RTV + 2 NRTIs at Wk 48 Mean change in egfr at Wk 48: +2 ml/min with ATV/RTV + 3TC vs -4 ml/min with ATV/RTV + 2 NRTIs (P <.001) Di Giambenedetto S, et al. EACS Abstract 867. Treatment Difference (95% CI) ATV/RTV + 2 NRTIs ATV/RTV + 3TC

12 PADDLE: Dolutegravir + Lamivudine in Treatment-Naive Pts Open label, single arm phase IV exploratory trial Primary endpoint: HIV 1 RNA < 50 copies/ml at Wk 48 (ITT e, FDA snapshot analysis) Treatment-naive pts with HIV-1 RNA ,000 copies/ml; CD4+ cell count 200 cells/mm 3 ; HBsAg negative (N = 20) Figueroa MI, et al. EACS Abstract First Cohort Dolutegravir 50 mg QD + Lamivudine 300 mg QD (n = 10) Second cohort to be enrolled following confirmation of first cohort success at Wk 8 Second Cohort Dolutegravir 50 mg QD + Lamivudine 300 mg QD (n = 10) PADDLE: All Pts Virologically Suppressed by Wk 8 of DTV + 3TC Included 4 pts with HIV-1 RNA > 100,000 copies/ml 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 , < 50 < 50 < 50 < 50 < 50 < 50 < , < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < , ,569 37, < 50 < 50 < 50 < 50 < , ,370 11, < 50 < 50 < 50 < 50 < ,362 20, < 50 < 50 < 50 < 50 < 50 < ,024 14, < 50 < 50 < 50 < 50 < 50 < 50 < 50 < ,604 18, < 50 < 50 < 50 < 50 < 50 < 50 < 50 < ,071 24, Not done < 50 < 50 < 50 < 50 < 50 < ,707 10,832 Not done < 50 < 50 < 50 < 50 < 50 < 50 < 50 < , < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < , , ,974 68, < 50 < 50 < ,508 64, < 50 < 50 < 50 < ,093 33,829 37,350 26, < 50 < 50 < 50 < 50 < 50 < ,348 15, < < 50 < 50 < 50 < ,185 23,500 15, < 50 < 50 < 50 Not done < 50 < 50 < , < 50 < 50 < 50 < 50 < 50 < 50 < 50 < ,100 25,828 11, < 50 < 50 < 50 < 50 < 50 < ,771 73,069 31, < 50 < 50 < 50 < 50 < 50 < , ,320 35, < 50 < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 Figueroa MI, et al. EACS Abstract Cross Study PK Comparison: Comparable Viral Decay in Dual and Triple Dolutegravir based ART Simplification from a Complex DRV Based MTR to 2 Tab E/C/F/TAF + DRV Phase 3, multi-centered, randomized, open label, active-controlled Change in Viral Load from baseline (Log10) PADDLE 2 SPRING 1 SINGLE 2.2 pvl change at each time point (Mean ±Standard error of the mean) Week pvl Change at Each Timepoint (Mean=standard Error of the Mean) Change in Viral Load from baseline (Log10) PADDLE SPRING SINGLE Week pvl Change at Each Timepoint (Mean=standard Error of the Mean), Normalized per Baseline pvl N=89 Switch to E/C/F/TAF + DRV QD Treatment HIV Suppressed Naïve Patients 2:1 Study DRV-Based 102 and MTR 103 egfr 50 ml/min Continue DRV-Based MTR N=46 Key inclusion criteria HIV 1 RNA <50 c/ml for 4 months No HBV infection Week 24 Week 48 Week 144 Primary Endpoint Resistance on historical genotype 2 class resistance DRV dose: 800 mg once daily No Q151M, T69ins in RT, signature DRV R or INSTI R Permissive: M184V/I, K65R, 3 TAMs Primary Endpoint Efficacy of simplification to E/C/F/TAF + DRV vs continuation of a complex DRV-based MTR by FDA Snapshot analysis (HIV-1 RNA < 50 copies/ml at Week 24) Secondary Endpoints Intensive PK in a subset of subjects Efficacy by HIV-1 RNA <50 or <20 copies/ml at Week 48 Safety and tolerability through Week 48 Sued O, et al. 23rd CROI; Boston, MA; February 22 25, Abst Huhn G, et al. ID Week San Diego, CA. Oral # ClinicalTrials.gov Identifier: NCT

13 Baseline Characteristics E/C/F/TAF + DRV, n=89 DRV MTR, n=46 Median age, years Male 82% 61% Black or African descent 39% 57% Median CD4 count, cells/μl Median egfr CG, ml/min Hyperlipidemia / HTN / DM / CVD 46% / 34% / 8% / 7% 28% / 37% / 11% / 4% Prior ARV regimens Median number pills per day pills per day 40% 37% Regimen with at least BID dosing 65% 65% TDF / ABC / other NRTIs 61% / 11% / 12% 54% / 11% / 13% RAL 56% 50% Resistance 2 class / 3 class resistance 70% / 26% 74% / 20% M184V/I 85% 78% K65R 20% 30% NNRTI R / PI R 89% / 38% 87% / 28% MTR=multiple tablet regimen Huhn G, et al. ID Week San Diego, CA. Oral # Intensive PK Sub Study Pharmacokinetics of EVG, DRV, TAF, and TFV Mean (95%CI) Concentration [ng/ml] EVG Concentration Time (h) E/C/F/TAF + DRV IC 95 (45 ng/ml) DRV Concentration Time (h) E/C/F/TAF + DRV IC 50 (55 ng/ml) EVG C trough >10 fold above protein binding adjusted IC 95 (45 ng/ml) DRV C trough >22 fold above protein binding adjusted IC 50 (55 ng/ml) TAF exposures in efficacious range demonstrated in E/C/F/TAF Studies TFV exposure (mean [%CV] AUC: 367 [33] ng*h/ml) well below levels observed following TDF containing regimens COBI adequately boosted EVG and DRV, providing exposures established for efficacy MTR=multiple tablet regimen 50 Huhn G, et al. ID Week San Diego, CA. Oral #726 Virologic Outcomes at Week 24 and 48 Subjects (%) Treatment Difference E/C/F/TAF + DRV (n=89) (95% Confidence Interval) DRV MTR (n=46) DRV MTR E/C/F/TAF + DRV p=0.23 Week p=0.004 Week Treatment Satisfaction Scores at Weeks 24 and 48 Patient Reported Outcomes: HIV Treatment Satisfaction (HIV-TSQ) Questionnaire Mean Baseline E/C/F/TAF + DRV HIV-TSQ Score* DRV MTR Mean change Week 24 Worsening Improvement p <0.001 W24 W48 W24 W48 W24 W48 Virologic Success Virologic Failure No Virologic Data (HIV-1 RNA < 50) E/C/F/TAF + DRV was statistically superior to DRV-based MTRs at Week 48 - At Week 48, significantly higher virologic success rate at the more stringent cutoff (HIV-1 RNA <20 copies/ml) with E/C/F/TAF + DRV compared with DRV MTR (90% vs 72%, p=0.012). - Emergent resistance through Week 48: 0 E/C/F/TAF + DRV vs 1 DRV MTR (M184V/I + K65R). - Discontinued due to other reasons: E/C/F/TAF + DRV (1 investigator s discretion, 1 withdrew consent) vs DRV MTR (3 withdrew consent, 2 lost to follow-up). Huhn G, et al. ID Week San Diego, CA. Oral # Week 48 p <0.001 Simplification to 2-tablet E/C/F/TAF + DRV was associated with more treatment satisfaction at Weeks 24 and 48 than DRV + MTR *ANCOVA HIV-TSQ at baseline 0 6 response range, n=10 questions, higher score=better satisfaction in recent weeks; HIV-TSQ (change) post-baseline: -3 3 response range, higher=better satisfaction; From ANCOVA model (treatment as fixed effect; baseline total HIV-TSQ score as covariate). Huhn G, et al. ID Week San Diego, CA. Oral #

14 Conclusions Simplification from ~5 pills to 2 pills per day regimen of E/C/F/TAF + DRV resulted in: Statistically superior rates (94% vs 76%) of HIV suppression at Week 48 Appropriate COBI boosting of EVG and DRV based on exposures established for efficacy The 2 tablet E/C/F/TAF + DRV regimen was safe and well tolerated Significant declines in proteinuria and tubular proteinuria; stable egfr More treatment satisfaction at Weeks 24 and 48 Virologically suppressed adults on complex DRV based MTRs with 2 and 3 class MDR HIV including M184V/I and K65R in RT may benefit from regimen simplification to E/C/F/TAF +DRV Huhn G, et al. ID Week San Diego, CA. Oral # CDC Proof of Concept Study: FTC/TAF for PrEP Treatment arm (n=6) Placebo arm (n=6) FTC/TAF PrEP Protects Macaques from Rectal SHIV Infection FTC/TAF prevents rectal SHIV infection in macaques to a degree similar to that previously found with FTC/TDF but with a substantially reduced TFV dose 1 FTC/TAF protected 100% of macaques (N=6) challenged with SHIV in a similar, pre clinical trial 2 24h SHIV +2h FTC/TAF 24h SHIV +2h PBO Percent protected SHIV challenges (weeks, n) SHIV challenge repeated weekly for up to 19 weeks FTC/TAF Placebo FTC/TAF should not be used for PrEP in humans until a planned clinical study is completed 1. Massud I, et al. CROI Boston, MA. # Heneine W, et al. CROI Denver, CO. #32LB 100% 0% HIV 1 Life Cycle Maturation Maturation inhibitor Release Assembly/ cleavage Budding Lataillade et al. CROI 2015, Abstract 114LB. 14