Integrase Inhibitors in the Treatment HIV-Infection. Andrew Zolopa, MD Stanford University

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1 Integrase Inhibitors in the Treatment HIV-Infection Andrew Zolopa, MD Stanford University 1

2 IAS-USA 212 Guidelines Updated Recommendations When to start ART is now recommended for all patients, regardless of CD4 cell count Regimen simplification Coformulations of drugs and complete regimens increasingly used once daily are preferred for convenience and probable improved adherence Cost Generic ARVs may reduce program costs, but prescribers should not revert to older and more toxic drugs not recommended in the guidelines More complex regimens without coformulations raise adherence concerns and may increase out-of-pocket costs for patients Thompson MA, et al. JAMA 212;38:

3 EACS Guidelines: When to Start ARV Therapy In serodiscordant couples early initiation of ART as one aspect of the overall strategy to reduce HIV transmission to the seronegative partner should be considered and actively discussed Current CD4 + lymphocyte count Condition 35-5 >5 Asymptomatic HIV infection C D Symptomatic HIV disease (CDC B or C conditions) incl. tuberculosis R R Primary HIV infection C C Pregnancy (before third trimester) R R Conditions (likely or possibly) associated with HIV, other than CDC stage B or C disease: HIV-associated kidney disease R R HIV-associated neurocognitive impairment R R Hodgkin's lymphoma R R HPV-associated cancers R R Other non-aids-defining cancers requiring chemo- and/or radiotherapy C C Autoimmune disease otherwise unexplained C C High risk for CVD(>2% estimated 1 yr risk) or history of CVD C C Chronic viral hepatitis HBV requiring anti-hbv treatment R R HBV not requiring anti-hbv treatment C/R D HCV for which anti-hcv treatment is being considered or given R D HCV for which anti-hcv treatment not feasible R C C = CONSIDER. D = DEFER. R = RECOMMENDED. (October, 211)

4 Treatment as Prevention in British Columbia Expanded HAART Coverage Associated with Decreased New HIV Diagnosis Population based registry (British Columbia) of all individuals who have tested HIV+ with HIV RNA test between Number of Active HAART Participants p=.1 New HIV+ Diagnoses (All) p=.8 New HIV+ Diagnoses (IDU) p= Year Number of New HIV+ Diagnoses These results support the long term sustainability of BC s HAART expansion strategy, as it relates to its impact on reducing HIV and decreasing HIV new diagnoses. Montaner J, et al. IAC 212; Washington, DC. THPE13 4

5 Treatment as Prevention in British Columbia ART Resistance 1% 9% 8% 7% 6% 5% 4% Never Genotyped 3 Classes 2 Classes 1 Class Wild Type 3% 2% 1% % Despite increased HAART use, the prevalence of drug resistance steadily decreased with proportion of wild-type virus increased (3% in 2 to >65% in 211) Reduction in resistance is attributable to greater proportion of virologically suppressed patients accompanied with high adherence levels Montaner J, et al. IAC 212; Washington, DC. THPE13 5

6 Life Cycle of HIV: Targets for Antiretrovirals Mature virus Entry inhibitors TNX-355 CCR5 antagonists CXCR4 antagonists Maturation inhibitors Bevirimat Raltegravir Elvitegravir Integrase inhibitors PIs Reverse transcriptase inhibitors

7 TRIO Study: Combination of DRV/r, ETR and RAL (+/- nrtis, ENF) in Heavily-Experienced Patients Baseline Characteristics (n=13) Median (IQR) HIV RNA, log 1, copies/ml 4. ( ) CD4, cells/mm (132 35) Virologic Response (ITT, M=F) 1 9 CD4 Nadir, cells/mm 3 79 (25 169) Years ART prior to enrollment 13 (11 15) # mutations at screening Major PI 4 (3 5) NRTIs 5 (4 6) NNRTIs 1 ( 2) Additional ARVs (OBR) NRTIs 83% Enfuvirtide 12% % with HIV RNA <5 c/ml (95% CI) % (95% CI: 85% to 96%) Median CD4 count increase from baseline to week 48: 18 cells/mm 3 86% (95% CI: 85% to 96%) High rate of suppression; unclear role of OBR Weeks Yazdanpanah, et al. CID 29.

8 Without Active OBT Antiviral effect of Integrase Inhibitor (ELV GS-9137) is lost rapidly Mean Change From Baseline in HIV RNA log 1 Copies/mL p< GS mg W ith No Active Drugs in OBT (n=26) GS mg W ith >=1 Active NRTI or First Use of T-2 (n=47) Week *Data from Zolopa GS-9137 et al. 125 JID mg 21 patients after addition of a PI were excluded

9 IAS-USA 212 Guidelines Recommended and Alternative Initial ART in Adults* NNRTI Boosted PI RECOMMENDED EFV/FTC/TDF EFV + 3TC/ABC DRV + RTV + FTC/TDF ATV + RTV + FTC/TDF ATV + RTV + 3TC/ABC ALTERNATIVE RPV/FTC/TDF RPV + 3TC/ABC NVP + FTC/TDF or 3TC/ABC DRV + RTV + 3TC/ABC LPV/r + FTC/TDF or 3TC/ABC * EVG/COBI/FTC/TDF Integrase Inhibitor RAL (BID) + FTC/TDF RAL (BID) + 3TC/ABC RPV/FTC/TDF and EVG/COBI/FTC/TDF added as an alternative regimen ABC added to recommended ARVs with the following notations: Only with EFV or ATV + RTV HLA-B*571 screening is recommended before ABC administration to reduce the risk of hypersensitivity reaction For patients with HIV-1 RNA <1, c/ml Avoiding the use in patients with or at high risk of CVD might be considered * Avoiding the use of LPV/r (also applies to FPV+RTV) might be considered for patients with or at high risk of CVD New drug application has been filed with regulatory authorities. Approval decisions pending Thompson MA, et al. JAMA 212;38:

10 STARTMRK: Raltegravir vs. Efavirenz in Treatment-naïve Patients: Final 5-Year Double-Blind Results 689 Patients screened for study eligibility 123 Patients excluded 25% vrna <5 copies/ml 2% ARV drug resistance 282 Patients randomized to RAL group 284 Patients randomized to EFV group 1 Patient did not receive any study drug 281 Patients (99.6%) treated with RAL/TDF/FTC 282 Patients (99.3%) treated with EFV/TDF/FTC 2 Patients did not receive any study drug 71 Patients (25.2%) discontinued 6 due to lack of efficacy 14 due to adverse events 21 Patients (74.5%) completed entire 5-year study 98 Patients (34.5%) discontinued 1 due to lack of efficacy 28 due to adverse events 184 Patients (64.8%) completed entire 5-year study Rockstroh J, et al, 19th IAC; Washington, DC; July 22-27, 212; Abst. LBPE19.

11 STARTMRK: Outcomes at 5 Years ITT, NC=F Percent of Patients with HIV RNA Levels <5 Copies/mL Weeks % % CD4 Change: RAL +374 vs. EFV Number of Contributing Patients Raltegravir 4 mg bid Efavirenz 6 mg qhs Rockstroh J, et al, 19th IAC; Washington, DC; July 22-27, 212; Abst. LBPE19.

12 STARKMRK: Time to Discontinuation Due to Adverse Event Cumulative Discontinuation Rate Due to AE (%) Weeks log-rank p-value = Number of Contributing Patients Raltegravir 4 mg bid Raltegravir 4 mg bid Efavirenz 6 mg qhs Efavirenz 6 mg qhs Rockstroh J, et al, 19th IAC; Washington, DC; July 22-27, 212; Abst. LBPE19.

13 Quad Pivotal Phase 3 Trials Published in Lancet June 3, 212 Study GS-12 Study GS-13 Sax P, et al. Lancet 212; 379: DeJesus E, et al. Lancet 212; 379:

14 Study Design: 96 Weeks results (Study 12 and 13) (Zolopa et al; JAIDS 213; Rockstroh et al. JAIDS 213) Randomized, double-blind, double dummy, active-controlled study Treatment Naïve Patients with HIV-1 RNA 5 c/ml Any CD4 cell count, egfr 7 ml/min Study 12 (n=7) 1:1 STB QD ATR Placebo QHS ATR QHS STB Placebo QD Study 13 (n=7) 1:1 STB QD ATV/r + TVD Placebo QD ATV/r + TVD QD STB Placebo QD Week 48 Primary Endpoint Week 96 Secondary Endpoint Studies to be continued blinded through Week 192

15 Baseline Characteristics Study 12 and 13 - Week 96 Characteristic STB (n=71) ATR (n=352) ATV/r + TVD (n=355) Age (years), Mean Male 9% 9% 89% Non-White 34% 36% 22% Black or African Descent 25% 26% 13% Asymptomatic HIV Infection 82% 84% 83% HBV : HCV Seropositive 1% : 5% 3% : 4% 2% : 3% HIV-1 RNA (log 1 c/ml), Median > 1, c/ml 38% 33% 4% CD4 count (cells/mm 3 ), Mean % 42% 46% GFR (ml/min), Median (Cockcroft Gault) * Positive HBV surface antigen or HCV antibody

16 Efficacy Endpoint: HIV-1 RNA <5 c/ml* Study 12 and 13: STB (Combined) vs ATR Percentage of subjects (%) Virologic Success Virologic Failure No data in Window STB (n=71) ATR (n=352) 95% CI for Difference Favors ATR Wk 48 Wk 96 Favors STB.3 4.8% % % 12% * As defined by FDA Snapshot algorithm. Non Inferiority demonstrated if lower bound of CI higher than 12%

17 Efficacy Endpoint: HIV-1 RNA <5 c/ml* Study 12 and 13: STB (Combined) vs ATV/r + TVD Percentage of subjects (%) Virologic Success Virologic Failure No data in Window STB (n=71) ATV/r + TVD (n=355) 95% CI for Difference Favors ATV/r + TVD Favors STB Wk 48 Wk % % % 12% * As defined by FDA Snapshot algorithm. Non Inferiority demonstrated if lower bound of CI higher than 12%

18 HIV-1 RNA < 5 c/ml Through Week 96 (M=F) Study 13 Week 96 Subjects with HIV-1 RNA <5 c/ml (%) % 88% (P=.15) STB (n=353) ATV/r + TVD (n=355) 87% Week 85% (P=.6)

19 Difference in Efficacy by Subgroup at Week 96 Study 12 and 13 OVERALL Age <4 year 4 years Sex Male Female Race Favors Comparator Favors STB White Non-White Baseline HIV-1 RNA 1, c/ml >1, c/ml Baseline CD4 count 35 cells/mm 3 >35 cells/mm 3 Study Drug Adherence* <95% 95% * Pill count Differences in Percentages (95% CI)

20 Efficacy by HIV-1 RNA and CD4 Subgroups Study 12 and 13 - Week 96 Virologic Success * at Wk 96 (%) / / / 214 STB / 268 ATR ATV/r + TVD K >1K >35 35 HIV-1 RNA (c/ml) 96/ / / / / / 331 CD4 (cells/mm 3 ) 118/ / 163 * Virologic success (HIV-1 RNA <5 copies/ml) as defined by FDA Snapshot algorithm

21 Change from Baseline in CD4 Cells Study 12 and 13 - Week 96 Change in CD4 (cells/mm 3 ), Mean (95% CI) STB ATR ATV/r + TVD (P=.18) * +211 (P=.3) * (P=.95) * +261 (P=.26) * BL Week STB (n=) ATR (n=) ATV/r+TVD (n=) * Comparison vs STB

22 Subject Disposition Through Week 96 Study 12 and 13 STB Randomized and Treated (n=71) ATR Randomized and Treated (n=352) ATV/r + TVD Randomized and Treated (n=355) 15% Discontinued (n=12) 17% Discontinued (n=61) 15% Discontinued (n=55) Adverse event 4% 7% 6% Lost to follow-up 4% 5% 3% Lack of efficacy 1% 1%.3% Non-compliance 2% 2% 2% Withdrew consent 1% 2% 3% Investigator discretion 1% 1% Pregnancy 1%.3% Protocol violation.3% Death.1%.3%

23 Common Adverse Events (Grades 1-4) Study 12 and 13 - Week 96 STB (n=71) ATR (n=352) ATV/r + TVD (n=355) Adverse Event W48 W96 W48 W96 W48 W96 Diarrhea 22% +3% 19% +5% 27% +4% Nausea 2% +1% 14% +1% 19% +2% Rash events 17% +4% 28% +3% 18% +5% Upper respiratory infection 15% +6% 11% +6% 16% +4% Headache 15% +2% 1% +2% 12% +3% Fatigue 13% +1% 13% +2% 13% +3% Depression 8% +3% 11% +3% 7% +5% Insomnia 8% +2% 14% +2% 5% +2% Nasopharyngitis 7% +3% 5% +3% 8% +3% Abnormal dreams 9% +.1% 27% +1% 4% +.3% Sinusitis 6% +2% 8% +3% 5% +3% Dizziness 6% +1% 24% +1% 7% +1% Ocular icterus.3% 14% >1% of patients in any group

24 Common Gastrointestinal AEs (All Grades) Study 12 and 13 Week 96 STB (n=71) ATR (n=352) ATV/r + TVD (n=355) Patients with AE (%) Diarrhea Nausea Weeks Weeks Bar: Incident events Line: Ongoing events in the window (prevalence)

25 Common Neuropsychiatric AEs (All Grades) Study 12 and 13 Week 96 STB (n=71) ATR (n=352) ATV/r + TVD (n=355) Abnormal Dreams Dizziness Patients with AE (%) Weeks Weeks Bar: Incident events Line: Ongoing events in the window (prevalence)

26 Phase 3 GS-12 and 13: Quad vs. EFV/FTC/TDF or ATV+RTV Resistance Through Week 48 n (%) GS-12 1 Quad (n=348) GS-12 1 EFV/FTC/TDF (n=352) Subjects Analyzed for Resistance* 14 (4%) 17 (5%) Subjects with Resistance to ARV Regimen 8 (2%) 8 (2%) Primary Integrase RAM -E92Q, T66I, Q148R and/or N155H 7 (2%) Primary NNRTI or PI RAM -K13N, K11E, V18I, Y188Y/F/H/L and/or G19A Primary NRTI RAM -M184V/I -K65R 8 (2%) (2%) 2 (.6%) 2 2 GS-13 2 Quad (n=353) GS-13 2 ATV+RTV +FTC/TDF (n=355) 12 (3%) 8 (2%) 5 (1%) 4 (1%) 4 (1%) 4 1 * Subjects who experienced either suboptimal virologic response (two consecutive visits with VL 5 c/ml and <1 log 1 below baseline after Wk 8), virologic rebound (2 consecutive visits with VL either 4 c/ml after achieving VL <5, or >1 log 1 increase from nadir), or had VL 4 c/ml at their last visit. - - Development of resistance to one or more component of Quad (EVG, COBI, FTC, and TDF) regimen was infrequent (1-2%) RAM: resistance associated mutations 1. Sax P, et al. Lancet 212; 379: DeJesus E, et al. Lancet 212; 379:

27 Genotypic and Phenotypic Analysis of the QUAD Virologic Failures with Emergent Resistance Genotype Phenotype a INSTI Fold-Change vs WT Virology NRTI Patient Primary Secondary EVG TFV FTC 1 A62A/V K65R M184V Q148R G14C > >84 2 A62A/V K65R M184V E92Q H51H/Y L68V >89 3 K65R M184V E92Q S153A >18 4 ND T66T/I E92E/Q N155N/H E157E/Q 54 ND ND 5 M184V E92E/Q Q148Q/R N155H/N >18 6 M184V E92Q >121 7 M184V E92Q >76 8 M184V N155H >126 9 M184I E92Q >14 1 M184V Q148R > M184V T66T/I E92E/Q > K65K/R M184M/I M184V >88 PhenoSense PR/RT or IN (Monogram Biosciences). Phenotype above the defined assay cutoffs are colored red (FC above the biological or lower clinical cut-off) or green (at or below the cut-off). ND= no data due to assay failure. All patients with phenotypic resistance to a component of QUAD had a primary resistance-associated mutation RESEARCH

28 Temporal order of resistance appearance differs between EFV and RAL regimens: Results from STARTMRK 6% 5% 4% 3% 2% Percent of Patients EFV failures 1% RAL failures EFV or RAL Resistance Only EFV or RAL Resistance First EFV or RAL Simultaneous with FTC/3TC FTC/3TC Resistance First FTC/3TC Resistance Only % Miller et al. Antiviral Therapy 21

29 Emergent Resistance Through Week 96 Study 12 and 13 - Week 96 STB (n=71) ATR (n=352) ATV/r + TVD (n=355) Wk48 Wk96 Wk48 Wk96 Wk48 Wk96 Emergent Resistance, n 13 (2%) +3 (+.4%) 8 (2%) +2 (+1%) Primary INSTI-R 11 (2%) +3 (+.4%) 8 (2%) +2 (+1%) or NNRTI-R E92Q 8 +1 K13N 7 +2 or PI-R, n N155H 3 +2 K11E +3 Q148R 3 V18I 2 T66I 2 Y188F/H/L 1 +1 M23L +2 V9I +1 G19A 1 P225H +1 Primary NRTI-R, n 12 (2%) +3 (+.4%) 2 (1%) +1 (+.3%) M184V/I M184V/I 2 +1 K65R 4 +1 K65R 2 +1

30 QUAD Virologic Failures with EVG Resistance show RAL Cross-resistance (>biological cut-off) INSTI Virology Patient EVG > RAL Biological Cut-Offs: EVG 2.5; RAL 1.5 Mead fold change value for EVG was >67-fold Mean fold change value for RAL = 7.9-fold RESEARCH

31 Genotypic resistance patterns for Integrase Inhibitors Stanford Resistance database:

32 Changes in GFR from Baseline and from Week 4 Study 12 and 13 Week 96 GFR Change from BL (ml/min) (Cockcroft Gault) (Median [IQR]) GFR Change from Wk 4 (ml/min) (Cockcroft Gault) (Median [IQR]) STB ATR ATV/r + TVD Week Week

33 Healthy Volunteer Study COBI Alters Estimated GFR but Not Actual GFR Mean Change from Baseline (ml/min; Cockcroft-Gault) Estimated GFR Placebo COBI 15 mg Dosing 7 14 Day Iohexol-bsed GFR (ml/min) Actual GFR COBI Placebo n=12 n=12 Onset was within days of initiation and quickly reversed upon COBI discontinuation COBI effects were seen in estimated GFR but not actual GFR Cohen C, et al. CROI 21; San Francisco. Oral #58LB

34 Cobicistat and Ritonavir Inhibition of Creatinine by OCT2 and MATE1 transporters Proximal Tubule ATP ATP ATP Pgp BCRP MRP2 ATP-Binding Cassette N O N Creatinine NH 2 OCT2 MATE1 H + Dolutegravir Cimetidine Trimethoprim Ritonavir Cobicistat MATE2-K OCTN1 OCTN2 Solute Carrier Blood (Basolateral) Active Tubular Secretion Urine (Apical) Lepist E-I, et al. ICAAC 211. Chicago. # A1-1724

35 AEs Leading to Study Drug Discontinuation (DC) Study 12 and 13 Week 96 STB (n=71) ATR (n=352) ATV/r + TVD (n=355) Adverse Event* W48 W96 W48 W96 W48 W96 Renal events 1.% +.4%^.3% +.3%^ Fatigue.3%.3% +.3%.6% Nausea.3% 1.1% Hepatitis C.3% +.3% +.3% Pyrexia.3%.3% Burkitt s lymphoma.1% +.1% Diarrhea.3%.3% Rash events.1% 1.1% 1.1% * >1 patients in STB No cases of renal tubulopathy between W48 and W96 ^ 3 patients on STB and 1 on ATV/r+TVD with isolated Cr elevation without renal tubulopathy between W48 and W96

36 Cross Study Comparison Renal Adverse Events (AEs) in Treatment-Naive Prospective TDF Studies Depiction of data from multiple published clinical trials. Not all regimens have been compared head-to-head. Study (Third Agent) TDF Subjects (n) D/C due to Renal AE (%) Follow-up (weeks) TDF alone GS-12, 13 (TDF for HBV) STARTMRK (RAL or EFV) 563 NR 48 QDMRK (RAL) 77 NR 48 Unboosted Regimens GS-93 (EFV) GS-934 (EFV) ECHO/THRIVE (RPV or EFV) GS , 14 (EFV) ASSERT (EFV) ABT-73 (LPV/r) ARTEMIS (DRV + RTV or LPV/r) GEMINI (SQV + RTV or LPV/r) GS (ATV+RTV) 355.3% 48 GS , 13, 14 (Quad) 749.8% 48 Boosted Regimens CASTLE (ATV+RTV or LPV/r) 878 <1% 96 HEAT (LPV/r) 345 <1% 96 ARTEN (ATV+RTV or NVP) 569 <1% 48 ABT-418 (LPV/r) 19 <1% 96 ACTG 522 (ATV+RTV or EFV) 925 1% 96 BATON (ATV+RTV) 1 1% 48 GS , 114 (ATV+RTV or ATV+Cobi) % 48, 96 ALERT (FPV+RTV or ATV+RTV) % 48 Total 1, % NR: not reported 36

37 Changes in Bone Mineral Density Study 13 Week 96 4 Change in Hip BMD (%) Mean (95% CI) (n=12) 4 Change in Spine BMD (%) Mean (95% CI) (n=12) STB ATV/r + TVD (P=.11) (P=.69) Week STB ATV/r + TVD -3.3 (P=.21) (P=.49) Week STB (n=353) ATV/r + TVD (n=355) W48 W96 W48 W96 Fracture events, (n) 3 (1%) +1 (+.3%) 6 (2%) +8 (+2%)

38 Study 93E Change from Baseline in Spine and Hip BMD Through 1 Years 1,* 8 Mean BMD Change from BL, % Seven patients experienced bone fractures in TDF arm All were trauma-related None were considered related to TDF by site Principal Investigator -3.4% 2-3.3% 2-2.5% -2.9% Study Year Hip (n) Spine (n) * P.3 and P.31 at each visit by Wilcoxon Signed Rank test comparing change from baseline. 1. Adapted from Madruga J, et al. HIV1 21. Glasgow. #86 2. Data on file, Gilead Science 38

39 Change from Baseline in Fasting Lipids Study 12 and 13 Week 96 * STB vs ATR ^ STB vs ATV/r+TVD Median Change at Wk 96 (mg/dl) (P=.1) * (P=.64) * Total Cholesterol (P=.2) * (mmol/l) Median Change at Wk 96 (mg/dl) (P=.3)^ LDL HDL Triglycerides (mmol/l) STB ATR ATV/r + TVD No difference in change in TC to HDL ratio at Week 48 or 96

40 SPRING-2: Dolutegravir vs. Raltegravir in ARV-naïve Patients Phase III, randomized, double-blind, double-placebo, multicenter, parallel-group, non-inferiority study HIV ART-naive HIV-1 RNA 1 c/ml 1:1 Randomization Stratified by VL and NRTI Randomized phase DTG 5 mg QD+ RAL PBO BID + 2 NRTIs* DTG PBO QD + RAL 4 mg BID + 2 NRTIs* Nonrandomized phase DTG 5 mg QD open-label + 2 NRTIs *ABC/3TC or TDF/FTC Randomization Week 48 Week 96 Raffi F, et al. 19th IAC; Washington, DC; July 22-27, 212; Abst. THLBB4.

41 Study 145: Elvitegravir vs. Raltegravir in Treatment-experienced Patients Treatment Experienced and/or resistance to 2 or more ARV classes and VL > 1 c/ml on current regimen Randomized and Treated (n=712) EVG (n=354) RAL (n=358) 59% Continued (n=28) 41% Discontinued (n=146) 42% Discontinued (n=15) 58% Continued (n=28) Most common Reasons in >1 arm 39 Patient non-compliance 34 3 Withdrew consent Lost to follow-up Lack of efficacy Adverse event Protocol violation 14 Elion R, et al, 19th IAC; Washington, DC; July 22-27, 212; Abst. TUAB15.

42 Study 145: HIV-1 RNA <5 c/ml (ITT, TLOVR) at Weeks 48 and 96 95% CI for Difference Favors RAL Favors EVG W W Virologic Response Virologic Failure Others -1% 1% Elion R, et al, 19th IAC; Washington, DC; July 22-27, 212; Abst. TUAB15.

43 SPRING-2: Baseline Characteristics DTG 5 mg QD n=411 RAL 4 mg BID n=411 Age Median (years) Gender Male 85% 86% Race White 84% 86% African American/African heritage 12% 9% Baseline HIV-1 RNA Median (log 1 c/ml) >1, c/ml 28% 28% Baseline CD4 + Median (cells/mm 3 ) <2 cells/mm 3 13% 12% Hepatitis coinfection HBV 2% 2% HCV 1% 9% Investigator-selected dual NRTIs TDF/FTC 59% 6% ABC/3TC 41% 4% Raffi F, et al, 19th IAC; Washington, DC; July 22-27, 212; Abst. THLB4.

44 SPRING-2: Virologic Success Over Time Proportion <5 c/ml (%) DTG 88% RAL 85% Median CD4 Change: Both arms +23 DTG 5 mg QD RAL 4 mg BID BL W4 W8 W12 W16 W24 W32 W4 W48 Raffi F, et al, 19th IAC; Washington, DC; July 22-27, 212; Abst. THLB4.

45 Spring-2: Select Summary of Adverse Events DTG 5 mg QD n=411 n (%) RAL 4 mg BID n=411 n (%) Grade 2-4 Drug-Related Events 24 (6) 27 (7) Grade Grade 4 2 Serious Adverse Events 29 (7) 31 (8) Drug related 3 Arrhythmia, hypersensitivity, hepatitis 5 Convulsion (2), Aphasia, hypersensitivity, diarrhea, CPK increased AEs Leading to Withdrawal 1 (2) 7 (2) Events with >1 subject Acute Hepatitis C 2 (<1) ALT increased 2 (<1) 1 (<1) AST increased 1 (<1) 1 (<1) Nausea 1 (<1) 1 (<1) Raffi F, et al, 19th IAC; Washington, DC; July 22-27, 212; Abst. THLB4.

46 Conclusions: Integrase Inhibitors Role in HIV Treatment Targets a constitutive step in viral replication High rates of virologic response ITT 8-85% <5 copies 1 year and beyond OT % <5 copies 1 year and beyond Results in rapid virologic suppression (<12wks) Improving adherence? Clinical relevance? Extremely well tolerated class Metabolically Friendly Little impact on Lipids and Glucose metabolism Unprecedented Efficacy, Safety and Convenience 46