Liens d Intérêt Evalutation de Nouveaux Antirétroviraux. RPV PK Parameter. AUC inf 116 (98.6, 137) 109 (92.2, 129) 93.8 (79.

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1 14/3/215 Liens d Intérêt Evalutation de Nouveaux Antirétroviraux L exemple de la Rilpivirine Jean-Michel Molina Université de Paris Diderot, Sorbonne Paris Cité Hopital Saint-Louis, Paris Participation à des réunions de conseils pour les laboratoires Gilead, BMS, ViiV, Merck, Janssen, et Tobira, Subventions de recherche: Laboratoires Merck et Gilead 1 2 Background Overview of Rilpivirine Trials in ARV naïve patients Phase 3 Pooled ECHO/THRIVE Week 96 Phase 3 Star Trial Trials in ARV experienced patients (switch) Switch from PIs (Spirit) Switch from Background Rilpivirine () is an NNRTI with the following attributes: Anti-HIV-1 activity, EC 5 =.3ng/mL 1 No teratogenicity in preclinical studies 2 Half-life of ~ 5 hours 3 Food increases s bioavailability by approximately 6% should be taken with a meal 4 No significant drug interaction with TDF 5 or FTC 6 >99.7% protein-bound in vitro 7 Metabolised primarily via the CYP3A pathway Eviplera ( + TDF/FTC) or Edurant () 3 1. Azijn H, et al. AAC 21;54: Hoetelmans R, et al. IAS 25. Rio de Janeiro, Brazil. #WePe3.3C15 2. Desmidt M, et al. EACS 29. Cologne, Germany. #PE7.1/4 6. Mathias A, et al. IAC 21. Vienna, Italy. #LBPE17 3. Eviplera (emtricitabine/rilpivirine/tenofovir disoproxil fumarate). 7. Janssen PA, et al. J Med Chem 25;4:191 9 Summary of Proeuct Characteristics. November 211. Lachau-Durand S, et al. EACS 29. Cologne, Germany. #PE7.1/3 4. Crauwels H, et al. IWCPHT 2. New Orleans, LA. #P32 4 Mean plasma concentration (ng/ml) Effect of Food Type on Mean PK Profile Time (hours) Crauwels HM, et al. IWCPHT 2. New Orleans, LA. #P32 Standard breakfast (533 kcal) High-fat breakfast (92 kcal) Fasting conditions ( kcal) Nutritional drink (3 kcal) Taking with food increases exposure by 57% compared to fasting. AUC was similar when administered after a high-fat or standard breakfast. 5 Study treatments Single dose of the FTC//TDF with standard meal (54 kcal, 21 g fat) Single dose of the FTC//TDF under fasting conditions Single dose of the FTC//TDF with light meal (39 kcal, 12 g fat) PK Parameter Effect of food on the PK of FTC//TDF GMR (%) 9% CI Standard/Fasting GMR (%) 9% CI Light/Fasting GMR (%) 9% CI Light/Standard AUC inf 116 (9.6, 137) 19 (92.2, 129) 93. (79.2, 111) AUC last 119 (11, 142) 113 (95.4, 135) 94.9 (79.9, 113) C max 126 (15, 153) 134 (111, 163) 16 (7.6, 129) Relative to fasting conditions, exposures were modestly higher following light meal or standard meal exposures were narrowly outside the lack of food effect bounds for the light meal versus standard meal comparison Administration of FTC//TDF with a light meal or standard meal results in a modest increase in and TFV exposures versus fasting conditions Ramanathan, et al. HIV ; Glasgow. Poster 1

2 14/3/215 Drug Interactions: Contra-indications Drug that may decrease plasma concentrations 1. Drugs that increase gastric ph PPIs (esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole) Alternative #1: H 2 blocker given at least 12h before or 4h after Alternative #2: Antacids given 2h before or 4h after 2. CYP3A4 inducers Anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin) Antimycobacterials (rifabutin, rifampin, rifapentine) St. John s Wort (Hypericum perforatum) System glucocorticoid dexamethasone (more than a single dose) Teratogenicity Preclinical Safety Objectives: to assess the potential effects of oral on embryo-foetal development in rats and rabbits did not show teratogenic potential in rat and rabbit models at exposures 13- to -times higher than those seen in HIV-1-infected patients receiving 25mg qd at steadystate These animal data suggest that further studies of in women of child bearing potential are warranted Desmidt M, et al. EACS 29. Cologne, Germany. #PE7.1/4 : high and sustained virologic response rate over 96 weeks in Phase II study ECHO and THRIVE Phase 3 Studies Study Designs Randomized, double-blind, double-dummy, multicenter, 96-week study 1 25mg qd (n=93) 15mg qd (n=91) 75mg qd (n=95) 6mg qd (n=9) ECHO (TMC27-C29) 69 patients 25mg qd + TDF/FTC qd + placebo qd (n=346) Virologic responders (%, 95% CI) % 72% 71% 71% Viral load <5 copies/ml to Week 96 (ITT-TLOVR algorithm) ARV-naïve HIV RNA > 5, c/ml No NNRTI RAMs Sensitivity to the NRTIs 67 patients THRIVE (TMC27-C215) 6mg qd + TDF/FTC qd + placebo qd (n=344) 25mg qd + 2 NRTIs + placebo qd (n=34) 6mg qd + 2 NRTIs + placebo qd (n=33) Time (weeks) = rilpivirine ; = efavirenz; ITT-TLOVR = intent-to-treat time-to-loss-of-virologic-response ; CI = confidence interval Primary objective: to demonstrate non-inferiority (12% margin) vs. in confirmed virologic response (viral load [VL] <5 copies/ml, ITT-TLOVR) at Week 4 From 39 NNRTI RAMs based on list of 44 1 ; Based on Virco TYPE HIV-1 test; Tambuyzer L et al. Antivir Ther 29;14:13 9 Pozniak A, et al. AIDS 21;24: Cohen et al AIDS 212, Molina Lancet 211, Cohen Lancet Pooled ECHO and THRIVE Demographics and Baseline Characteristics Baseline parameter N=66 N=62 Female, % Median age, years Race, % Caucasian Black Asian Other races/not stated Efficacy results Median log 1 VL, copies/ml (min max) 5 (2 7) 5 (3 7) % viral load <1K copies/ml 54 4 Median CD4 cell count, cells/mm3 (min max) 249 (1 ) 26 (1 1,137) Hepatitis B or C co-infection, % 7 9 Background regimen (THRIVE) was balanced between treatment groups TDF/FTC 6%; AZT/3TC 3%; ABC/3TC 1% Adapted from Cohen C et al. IAS 211. Rome. Poster TULBPE

3 14/3/215 Pooled ECHO & THRIVE (wk 96 FTC/TDF Dataset) HIV RNA <5 copies/ml ITT-TLOVR Responders (%, 95% CI) Time (weeks) +FTC/TDF was non-inferior to +FTC/TDF at weeks 4 & 96 Mean change in CD4 cell count from baseline (NC=F) 4 weeks : +193 vs. : +12 cells/mm 3 96 weeks : +226 vs. : +222 cells/mm 3 Favours Favours Difference (95% CI) in response rates ( ) 77% 77% Adapted from Nelson M et al. EACS 211. Belgrade. Poster LBPE7.3/7 Eviplera SPC. November % 2% Patients (%) Pooled ECHO and THRIVE: ITT-TLOVR outcome at Week 96 by baseline VL 4. ( 1.7, 9.7) 4 N =36 1K N =329 Patients (%) >1K Responders 7 75 Non responders N = (-12, 1.5) N =353 Discontinued due to other reasons Discontinued due to AE/death Responses by baseline CD4 cell count were ( 2 cells/mm 3 ): 2% vs 79%, ( 5 <2 cells/mm 3 ): 71% vs 75% and (<5 cells/mm 3 ): 56% vs 69% VF eff Pooled ECHO and THRIVE: Wk 96 FTC/TDF Dataset VL <5 c/ml by Baseline Viral Load (Snapshot) VL <5 c/ml (%), Difference (95%CI) (-3.9, 9.1) (-31., 1.).5 (-4.5, 5.5) 3.6 (-7., 9.) / / / 2 Overall 1K >1K to 5K >5K Baseline HIV-1 RNA, copies/ml +FTC/TDF was non-inferior to +FTC/TDF in the overall analysis and in baseline viral load strata of 1, and 1,1-5, copies/ml by Snapshot analysis 25 / 255 Nelson M, et al. EACS 211. Belgrade, Serbia. #LBPE7.3/ / / / / 72 n / N 15 Patients (%) Pooled ECHO and THRIVE: ITT-TLOVR outcome at Week 96 by self-reported M-MASRI adherence 2.2 ( 6., 2.4) 1 4 N =552 N =499 Adherent (>95%) Patients (%) 1 M-MASRI = Modified Medication Adherence Self-Report Inventory (-22.7, 5.3) Responders* *Responders = patients with viral load <5 copies/ml, ITT-TLOVR algorithm; Lost to follow-up, non-compliance, withdrew consent, ineligible to continue, sponsor's decision; VF eff determined by TLOVR in the ITT population: confirmed response before Week 96 and confirmed rebound (rebounders) at or before Week 96, or no response before Week 96 (never suppressed) Difference (95% CI) in response rates (-) Non responders N =7 N =1 Suboptimally adherent ( 95%) Discontinued due to other reasons Discontinued due to AE/death VF eff Pooled ECHO & THRIVE (wk 96 FTC/TDF Dataset) Virologic Outcome* by Baseline VL SNAPSHOT % N=55 Pooled 1, N=546 N=2 N=255 Resistance Virologic Response (VL <5 c/ml) Virologic Failure Virologic Failure leading to discontinuation *ITT Snapshot analysis uses last viral load value in the Week 96 window (9 13 weeks) Adapted from Nelson M et al. EACS 211. Belgrade. Poster LBPE7.3/7 17 3

4 14/3/215 Pooled ECHO/THRIVE: Week 4 Full Dataset Incidence of Treatment-emergent a NNRTI and N(t)RTI RAM in Virologic Failures by Baseline Viral Load Category Incidence, n (%) (N = 66) (N = 62) All virologic failure with genotypic data b n = 62 n = 2 NNRTI RAM 39 (63) 15 (54) N(t)RTI RAM 42 (6) 9 (32) NNRTI and N(t)RTI RAM 37 (6) (29) Baseline viral load 1K c/ml ( n=36), (, n =33) n = 16 n =12 NNRTI RAM 61.6% (3) 51.5% (42) N(t)RTI RAM 71.9% (44) 2.6% (17) NNRTI and N(t)RTI RAM 51.4% (31).3% 1 () Baseline viral load >1K c/ml c/ml (, n=31), (, n=352) n = 46 n = 16 NNRTI RAM % (72) 1 2.% (63) N(t)RTI RAM 3511% (76) 72% (44) NNRTI and N(t)RTI RAM 321% (7) 72% (44) Virologic failures with NNRTI RAMs (%) Pooled ECHO & THRIVE (wk 4 Full Dataset) Treatment-emergent* NNRTI RAMs Any mg qd (n=62) 6mg qd (n=2) 1 E13K K11E H221Y V19I Y11C V9I K13N V16M Y1C Among VFs with emerging NNRTI RAMs, 46%, 31% and 23% had 1, 2, or 3 NNRTI RAMs, respectively, at failure Non-clade B VFs (n=13, including clade C) did not exhibit any distinctive pattern of NNRTI RAMs *Not present at screening or baseline and present at time of failure while on treatment Occurring in 5% of VF with available resistance data Most frequent NNRTI RAMS a Not present at screening or baseline and present at time of failure while on treatment. b At time of failure. Rimsky L, et al. IWHHC 211; Los Cabos, Mexico. Abstract Adapted from Eron J et al. ICAAC 21. Boston. Abstract H-11 2 Pooled ECHO & THRIVE (wk 4 Full Dataset) Treatment-emergent IAS-USA N(t)RTI RAMs 1 Virologic failures with N(t)RTI RAM (%) mg (n=62) 6mg qd (n=2) Any M14V M14I M14I/V K65R Most frequent N(t)RTI RAMs* 5 7 Safety and tolerability 1/62 VFs and 12/2 VFs failed with wild-type virus 37/62 VFs and 6/2 VFs had both treatment-emergent NNRTI and N(t)RTI RAMs Adapted from Eron J et al. ICAAC 21. Boston. Abstract H Pooled ECHO & THRIVE (wk 96 FTC/TDF Dataset) Adverse Events % N=55 N=546 P-value Any serious AEs Grade 2-4 treatment-related AEs <.1 Any treatment-related neurologic AE* <.1 Somnolence Dizziness 26 <.1 Disturbance in attention Any treatment-related psychiatric AE* <.1 Abnormal dreams/nightmares Any treatment-related rash 5 16 <.1 Discontinued due to AEs Rash Depression Pregnancy FTC/TDF demonstrated a more favourable overall safety profile, with significantly less discontinuations due to AEs Fewer discontinuations for rash with +FTC/TDF (p=.3) Majority of AEs occurred in the first year In Year 2, the incidence of treatment-related grade 2-4 AEs was 2.5% (+FTC/TDF) and 3.7% (+FTC/TDF) Adapted from Nelson M et al. EACS 211. Belgrade. Poster LBPE7.3/7 23 Pooled ECHO and THRIVE: Wk 96 FTC/TDF Dataset Laboratory Abnormalities % N=55 N=546 Significantly less Grade 3-4 and 2-4 adverse events (AEs) with +FTC/TDF P-value Grade Grade Most common Grade 2-4 AEs with -Hypophosphatemia -Pancreatic amylase -Hyperglycemia Serum creatinine -Grade 1 -Grade 2-4 -Mean change, mg/dl Bilirubin -Grade 1 -Grade 2-4 Grade 3 or 4 liver laboratory abnormalities were low and similar (<5%) in both groups, but there was a higher percentage of discontinuations due to these abnormalities with +FTC/TDF (1.1%) compared to +FTC/TDF (.4%) Nelson M, et al. EACS 211. Belgrade, Serbia. #LBPE7.3/

5 14/3/215 mmol/l Pooled ECHO and THRIVE: Wk 96 FTC/TDF Dataset Lipid Changes Over 96 Weeks +FTC/TDF +FTC/TDF TC* LDL* HDL* TG* *P<.1 for all comparisons ( vs. ) using Wilcoxon rank-sum test +FTC/TDF +FTC/TDF +FTC/TDF +FTC/TDF Subjects receiving +FTC/TDF had significantly less treatment-emergent lipid abnormalities compared with subjects receiving +FTC/TDF over 96 weeks +FTC/TDF produced minimal changes in TC, LDL, and TG levels from baseline through 96 weeks of treatment 43% 49% Total Cholesterol 72% 73% LDL 36% 33% 21% 19% 19% 14% 7%.2% 7% % of Subjects P<.2 for all comparisons by individual grades ( vs. ) using Fisher s exact test Total Cholesterol mmol/l Grade : < 5.2 Grade 1: > Grade 2: > Grade 3: > 7.7 LDL Grade : Grade 1: Grade 2: Grade 3: mmol/l < 3.4 > > > 4.9 2% 1% 5% Pooled ECHO and THRIVE: Conclusions at Week 96 showed sustained overall efficacy that was similar to over 96 weeks (7% overall response in each group) Suboptimal adherence was associated with reduced responses in both groups Response was numerically higher in the group with baseline VL 1K The effect of suboptimal adherence and higher baseline viral load on VF eff was more apparent with than with At Week 4 the overall VF res rate was higher with than, however, beyond Week 4 there were similar increases in VF res for both groups showed lower incidences than of Grade 2 4 overall AEs Dizziness, abnormal dreams/nightmares and rash (any grade) Discontinuations due to AEs (mainly rash and dizziness) Grade 2 to 4 lipid abnormalities From Week 4 to 96, there were no new safety concerns with either NNRTI was efficacious and well tolerated in a large and diverse group of treatment-naïve patients + TDF/FTC approved in Europe in naïve patients with <1. cp/ml Adapted from Nelson M, et al. EACS 211. Belgrade, Serbia. #LBPE7.3/7 25 At least possibly related to treatment STaR Study: Single-Tablet Regimen Emtricitabine/Rilpivirine/Tenofovir DF is Non-Inferior to Efavirenz/Emtricitabine/Tenofovir DF in ART-Naïve Adults Week 4 Results Calvin Cohen, David Wohl, Jose Arribas, Keith Henry, Jan van Lunzen, Mark Bloch, William Towner, Edmund Wilkins, Hui Wang, Kirsten White, Danielle Porter, Bill Guyer, Todd Fralich Eleventh International Congress on Drug Therapy in HIV Infection Glasgow, Scotland 15 November 212 Clinical trial number: GS-US Clinical Trials.gov: NCT ARV-naive HIV-1 RNA >25 c/ml Sensitivity to, FTC,, TDF (N=76) Stratified by HIV RNA ( or >1, c/ml) Primary endpoint: Secondary endpoints: Cohen 212 Glasgow STAR Study Design n=394 n=392 /FTC/TDF 4 Weeks Primary Endpoint 96 Weeks Efficacy of the 2 s by proportion with HIV-1 RNA <5 c/ml at Week 4 (FDA Snapshot analysis); non-inferiority margin of 12% Safety and efficacy of the 2 s by proportion with HIV-1 RNA <5 c/ml at Week 96 (FDA Snapshot analysis) Change in CD4 cell count at Weeks 4 and 96 Genotype/phenotype resistance at time of virologic failure Baseline Demographics and Characteristics Virologic Suppression and CD4 Change at Week 4 FDA Snapshot Analysis ITT Population /FTC/TDF FTC//TDF is non-inferior to /FTC/TDF Median age, years (IQR) 37 (29, 45) 35 (2, 45) Male % 93% 93% White % 6% 67% Black % 25% 24% Latino ethnicity % 15% 19% Mean CD4 cell count, cells/mm 3 (SD) 396 (1) 35 (17) HIV-1 RNA, log 1 c/ml, (SD) 4. (.7) 4. (.6) 1, c/ml, n (%) 26 (66%) 25 (64%) >1, to 5, c/ml, n (%) 9 (25%) 117 (3%) >5, c/ml, n (%) 36 (9%) 25 (6%) Proportion of Participants, % Virologic Virologic Failure Suppression (HIV-1 RNA <5 copies/ml) /FTC/TDF 13 No W4 Data 95% CI for Difference Favors /FTC/TDF Favors % 12% CD4 count change (cells/mm 3 ): +2 vs /FTC/TDF +191 (p=.34) 5

6 14/3/215 Virologic Suppression by FDA Snapshot Analysis Stratified by Baseline HIV-1 RNA 1, c/ml HIV-1 RNA <5 c/ml (%) /FTC/TDF /26 24/25 17/ /142 <1K >1K Baseline HIV-1 RNA copies/ml 95% CI for Difference Favors /FTC/TDF Favors < 1K > 1K compared to /FTC/TDF Superior for subjects with baseline HIV-1 RNA <1, c/ml Non-inferior for subjects with baseline HIV-1 RNA >1, c/ml Virologic Suppression at Week 4 FDA Snapshot Analysis by Baseline HIV-1 RNA HIV-1 RNA < 5 c/ml (%) / 26 /FTC/TDF / 25 1/ 9 96/ / 36 2/ 25 1K >1-5K * * >5K Baseline HIV-1 RNA copies/ml * Post hoc analyses; analyses for non-inferiority only pre-specified for 1, c/ml and >1, c/ml Virologic Failure at Week 4 FDA Snapshot Analysis by Baseline HIV-1 RNA Resistance Analysis Through Week 4 Virologic Failure (%) Baseline HIV-1 RNAcopies/mL Virologic failure: Week 4 HIV-1 RNA >5 copies/ml, or discontinued study drug due to lack of efficacy, or discontinued study drug due to other reasons and last available HIV-1 RNA >5 copies/ml *ECHO/THRIVE: Two Phase III double-blinded, double dummy, mulitcenter 96 week studies in treatment-naïve HIV-1 infected subjects randomized to receive either (25mg) or (6mg) in combination with 2 NRTIs (ECHO, FTC/TDF; THRIVE, Investigator s choice [FTC/TDF, n=46; 3TC/AZT, n=24; 3TC/ABC, n=6]). In the pooled TVD subset analysis (N=196), +TVD was non-inferior to +TVD (HIV-1 RNA <5 c/ml [3%, 1%]) STaR ECHO/THRIVE TVD Subsets* /FTC/TDF +FTC/TDF +FTC/TDF Overall 1K >1-5K >5K STaR* ECHO/THRIVE TVD Subset /FTC/TDF +FTC/TDF +FTC/TDF (n=394) (n=392) (n=55) (n=546) Subjects with Resistance Data 5% 2% 11% 3% Subjects with Resistance to ARVs 4% 1% 7% 2% Any Primary NNRTI-R 4% 1% 6% 2% Key NNRTI-R E13K/Q (2%) K13N (.3%) E13K/Q (4%) K13N (1%) Y11C/I (2%) Y11C/I (1%) K11E (1%) K11E (1%) Any Primary NRTI-R 4%.3% 7% 1% Key NRTI-R M14V/I (4%) M14I (.3%) M14V/I(6%) M14V/I (1%) K65R/N (1%) K65R/N (1%) K65R/N (.4%) Within Baseline (BL) HIV-1 RNA 1, copies/ml at BL 2% 1% 2% 1% >1, 5, copies/ml at BL 5% 9% 2% >5, copies/ml at BL 19% 4% 21% 7% The s used in STaR, compared to the components of the regimens used in ECHO and THRIVE, demonstrated less emergent resistance All Grades Treatment-Emergent Adverse Events * of Importance (n=394) Psychiatric Events, n (%) 62 (16%) 147 (3%) p<.1 Events >5% of subjects, either arm Abnormal Dreams 23 (6%) 96 (25%) Depression 26 (7%) 35 (9%) Anxiety, nervousness 2 (5%) 34 (9%) *prespecified evaluation for common adverse events, US Efavirenz Prescribing Information 1 (.3%) suicide occurred in the /FTC/TDF arm, day 36 of study /FTC/TDF (n=392) Nervous System Events, n (%) 117 (3%) 19 (51%) p<.1 Events >5% of subjects, either arm Dizziness, vertigo, balance disorder 3 (%) 1 (26%) Insomnia 3 (1%) 55 (14%) Somnolence 1 (3%) 27 (7%) Headache 49 (12%) 53 (14%) Adverse Events Leading to Discontinuation of Study Drug Discontinuations* Due to Adverse Event (AE), n (%) AE leading to discontinuation in >1 subject in either arm Nervous System Events (n=394) Dizziness Abnormal Dreams or Nightmare Insomnia 1 (.3%) Psychiatric Disorders Depression, Anxiety or Depressed Mood Suicidal Ideation GI, General, Skin Disorders Diarrhea Fatigue Pyrexia Toxic Skin Eruption *per safety population /FTC/TDF (n=392) 1 (2.5%) 34 (.7%) P<.1 23 (6%) 96 (25%) 5 (1.3%) 6 (1.5%) 3 (.%) 9 (2.3%) 2 (.5%) 2 (.5%) 2 (.5%) 2 (.5%) 2 (.5%) 6

7 14/3/215 Changes from Baseline to Week 4 in Fasting Lipids Star Conclusions Mean Changes from BL, mmol/l (mg/dl) Mean Baseline Values, mmol/l TC LDL TG HDL.57 (+22).3.3 (+1) (+1).36 (+14).9.21 (+).5 (-) -.9 p<.1 for all comparisons between treatment groups using ANOVA Change in TC:HDL at Week 4 was -.2 in both arms TC - total cholesterol, LDL - low-density lipoprotein, TG - triglycerides, HDL - high-density lipoprotein (+) (+2) /FTC/TDF Overall, /TDF/FTC was non-inferior to /FTC/TDF through 4 weeks for the primary endpoint of virologic suppression Superior when baseline HIV-1 RNA 1, copies/ml Non-inferior when baseline HIV-1 RNA >1, copies/ml Overall, low and similar rates of virologic failure occurred for (%) and /FTC/TDF (6%) Similar rates observed for virologic failure with baseline HIV-1 RNA 1, c/ml ( 5%, /FTC/TDF 3%) and for >1, to 5, c/ml ( 1%, /FTC/TDF 9%); low rates of resistance Higher rates of virologic failures for baseline HIV-1 RNA >5, c/ml ( 25%, /FTC/TDF 16%); resistance rate higher for (19% vs /FTC/TDF 4%) is well-tolerated compared to /FTC/TDF Significantly fewer nervous system and rash adverse events Significantly fewer discontinuations due to adverse events Significant differences for change in lipids TC, LDL, and TG favoring HDL favoring /FTC/TDF Similar change to TC:HDL ratio for both arms Switch Studies Switch d vers (GS 111) Phase 2b, open-label, multicentre, 4-week study of immediate switch from /FTC/TDF to FTC//TDF in stable, virologically controlled subjects Stable on /FTC/TDF x 3 months -Desire to switch due to tolerability issues -VL <5 c/ml wks -No genotypic resistance -egfr > 5mL/min N=5 FTC//TDF Week Primary endpoint: % of subjects with HIV-1 RNA <5 c/ml at Week 12 post-switch - ITT population FDA Snapshot Analysis Secondary endpoints: Safety of FTC//TDF over 24 & 4 wks HIV-1 RNA <5 c/ml at Week 24 and Week 4 Pharmacokinetics of after switching ITT = intent to treat Cohen C, et al. EACS 211. Belgrade, Serbia. Oral #LBPS1/4 4 Primary Endpoint: HIV-1 RNA <5 copies/ml at Wk 12 (FDA Snapshot Analysis ITT Population) % HIV-1 RNA < 5c/mL 1% % 6% 4% 2% % Cohen C, et al. EACS 211. Belgrade, Serbia. Oral LB #PS1/4 1% 49/49 FTC//TDF 1 subject withdrew consent before dosing 41 Primary Endpoint: Switch IP to : Spirit Study Design Switching boosted PI to Rilpivirine In-combination with Truvada as an Multicenter, international, randomized, open-label, Phase 3b, 4-week study Stable PI + RTV + 2 NRTI 6 months with HIV-1 RNA <5 c/ml On 1st or 2nd regimen No prior NNRTI use No known resistance to study agents (N=476) 2:1 PI + RTV +2 NRTIs 24 weeks 4 weeks Primary Endpoint Secondary Endpoint Non-inferiority (12% margin) of to PI+RTV+2 NRTIs by FDA snapshot analysis HIV RNA <5 copies/ml at 24 weeks 1 Secondary Endpoints: Proportion of subjects on who have HIV1 RNA <5 copies/ml at Week 4 Change in fasting lipid parameters and CD4 cell count at 24 1,2 and 4 weeks Safety and tolerability to PI+RTV+2NRTIs at 24 1 and 4 weeks Proportion of subjects who have HIV1 RNA <5 copies/ml (missing = excluded) through Week 4 1. Palella F, et al. IAC 212; Washington, DC. Oral TUAB14 2. Tebas P, et al. LIPO 212; Washington, DC. #1 42 7

8 14/3/215 Baseline Characteristics Antiretroviral Therapy at Screening (n=476) N = 317 PI+RTV+ 2NRTIs N = 159 Median age, years (IQR) 42 (35, 4) 43 (36, 49) Male 6% 91% White race 76% 7% Black race 19% 14% Latino ethnicity 16% 2% Median time since first ART, years (IQR) 2.9 (1.9, 4.4) 2.6 (1.7, 4.) Mean CD4 cell count, cells/mm 3 (SD) 576 (237) 6 (259) FTC/TDF 1% NRTI 3TC/ABC 13% % Subjects 3TC/ZDV 3.4 ABC 1.1 FTC. 3TC. TDF.6 d4t.2 ZDV.2 ATV 37% FPV % RTV-boosted PI LPV 33% DRV 2% % Subjects SQV APV TC: lamivudine; d4t: stavudine; ABC: abacavir; APV: amprenavir; ATV: atazanavir; DRV: darunavir; FPV: fosamprenavir; FTC: emtricitabine; LPV: lopinavir; RTV: ritonarvir; SQV: saquinavir; TDF: tenofovir disoproxil fumarate; ZDV: zidovudine Includes all treated subjects. 2 subjects enrolled on /FTC/TDF instead of a boosted PI (protocol violation) 44 Virologic Suppression at Weeks 24 and 4 FDA Snapshot Analysis ITT Population Treatment Response Among -treated Subjects with Pre-Existing K13N Proportion of Subjects, % Switching to was non-inferior* to remaining on PI+RTV+2NRTIs for 24 weeks. Similar rates of virologic suppression were also seen with 4 weeks of treatment with Virologic Suppression (HIV-1 RNA <5 c/ml) 1 (immediate switch, Day 1 to W24) 9 PI+RTV+2NRTIs (delayed, Day 1 to W24) (delayed switch, W24 to W4) Virologic Failure No Data Virologic Suppression (immediate switch, Day 1 to W4) 2.5 Virologic Failure CD4 mean change (cells/mm 3 ): Week 24: immediate switch +2, PI+RTV+2NRTIs +32 (p=.2), delayed switch -7 Week 4: immediate switch +1.2 No Data Subjects with Pre-existing K13N, n Snapshot Outcome, n (Immediate, D1 to W24) N = 317 (Delayed, W24 to W4) N = 152 (Immediate, D1 to W4) N = 317 (Total, D1 to W4) N = Virologic Suppression Virologic Failure 1 a 1 a No Data in Window 1 b 1 b a Failed with resistance, pre-existing K13N and V179I and acquired M14V, E13K, and V1V/I while on study drug b Missing data, suppressed at prior visit on study drug -treated subjects with pre-existing K13N had a high response rate * Primary endpoint, delta 3. (-1.6, 9.1) Grade 3 or 4 Adverse Events and Laboratory Abnormalities Changes from Baseline in Fasting Lipids Grade 3 or 4 Adverse Events Grade 3 or 4 Laboratory Abnormalities N = 317 (Immediate switch, at W4) PI+RTV +2NRTIs N = 159 (at W24) N = 152 (Delayed switch, at W24) 1 (5.7%) 11 (6.9%) 12* (7.9%) 2 (.%) 1 (11.3%) Adverse events and laboratory abnormalities occurring in 1% of subjects: * creatine kinase increase ALT, AST, creatine kinase, hematuria 23 (15.2%) Mean Changes from BL, mmol/l (mg/dl) TC LDL TG HDL.3 (-1) (-1) (-2) (3) (-2) (-4) (-24) (-25) (-25) (-16) -.41 (-14) (-16) (-53) -.6 (immediate, D1-W24) PI+RTV+2NRTIs (D1-W24) (delayed, W24-W4) (immediate, D1-W4) (-) -.9 (-64) -.72 AST, bilirubin, creatine kinase, triglycerides ALT, AST, creatine kinase, glycosuria Switching to resulted in improvement in fasting lipids, including TC, LDL, TGs, and TC:HDL ratio at Week 24 and maintained through Week 4 47 TC - total cholesterol, LDL - low-density lipoprotein, TG - triglycerides, HDL - high-density lipoprotein 4

9 14/3/215 Change in TC:HDL ratio from Baseline Conclusions Change in TC:HDL ratio TC:HDL ratio (immediate, D1-W24) PI+RTV+2NRTIs (D1-W24) (delayed, W24-W4) (immediate, D1-W4) Through 24 weeks, switching to was non-inferior to remaining on PI+RTV+2NRTIs (93.7% versus 9.9%) In the delayed switch arm, virologic suppression was maintained through 24 weeks with (92.1%) In the immediate switch arm, virologic suppression was maintained through 4 weeks after switching to (9.3%) Lower rate of virologic failure observed in subjects switching to (.9%) compared to remaining on PI+RTV+2NRTIs (5.%) at Week 24 Low rate of virologic failure (1.3%) was also seen in the delayed switch arm Through 4 weeks, maintained a low rate (2.5%) of virologic failure Resistance development was infrequent with switching to Switching to resulted in improvement in fasting lipids, including TC, LDL, TGs, and TC:HDL ratio at Week 24 and was maintained through Week 4 TC - total cholesterol, HDL - high-density lipoprotein