1. Fall 2015 HIV Update CCO Independent Conference Coverage of the 55th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 17-21, 2015, San Diego, California; IDWeek 2015, October 7-11, 2015, San Diego, California; and 15th European AIDS Conference, October 21-24, 2015, Barcelona, Spain* *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. This program is supported by educational grants from Bristol-Myers Squibb and ViiV. Jointly provided by Annenberg Center for Health Sciences at Eisenhower and Clinical Care Options, LLC

2. clinicaloptions.com/hiv Fall 2015 HIV Update 2015 Update: EACS Guidelines for Treatment of HIV-Infected Pts in Europe  ART initiation now recommended for all pts, regardless of CD4+ cell count 1. EACS HIV Guidelines. V 8.0. October 2015. 2. DHHS Guidelines. April 2015. 3. Günthard H, et al. JAMA. 2014;312:410-425. 4. WHO When to Start Guidelines. September 2015. Guideline AIDS or HIV-Related Symptoms CD4+ Cell Count, cells/mm 3 < 350350-500> 500 EACS [1] Yes DHHS [2] Yes IAS-USA [3] Yes WHO [4] Yes

3. clinicaloptions.com/hiv Fall 2015 HIV Update 2015 Update: EACS Guidelines for Treatment of HIV-Infected Pts in Europe  Changes in initial regimen recommendations in 2015 EACS guidelines: –Number of recommended regimens decreased from 13 to 6 –EFV- and ATV-based regimens no longer recommended EACS HIV Guidelines. V 8.0. October 2015. Recommended First-line Regimens INSTI + 2 NRTIs  DTG/ABC/3TC  DTG + TDF/FTC  EVG/COBI/TDF/FTC  RAL + TDF/FTC NNRTI + 2 NRTIs  RPV/TDF/FTC Boosted PI + 2 NRTIs  DRV/RTV + TDF/FTC

4. clinicaloptions.com/hiv Fall 2015 HIV Update Comparison of Current International Guidelines for Treatment-Naive Pts RegimenDHHS [1] EACS [2] BHIVA [3] IAS-USA [4] GeSIDA [5] EFV/TDF/FTC RPV/TDF/FTC ATV/RTV + TDF/FTC DRV/RTV + TDF/FTC DTG/ABC/3TC DTG + TDF/FTC EVG/COBI/TDF/FTC RAL + TDF/FTC 1. DHHS Guidelines. April 2015. 2. EACS HIV Guidelines. V 8.0. October 2015. 3. BHIVA Guidelines. 2015. 4. Günthard H, et al. JAMA. 2014;312:410-425. 5. GeSIDA. Enferm Infecc Microbiol Clin. 2013;31:602.e1-e602. Preferred/recommendedAlternative

5. clinicaloptions.com/hiv Fall 2015 HIV Update Subanalyses of Studies 104/111: TAF vs TDF in Treatment-Naive Pts  Studies 104/111: parallel, randomized, double-blind, active-controlled phase III trials –Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48 EVG/COBI/FTC/TAF* single-tablet regimen (n = 866) EVG/COBI/FTC/TDF † single-tablet regimen (n = 867) Treatment-naive HIV-infected pts with HIV-1 RNA ≥ 1000 copies/mL, eGFR ≥ 50 mL/min (N = 1733) Stratified by HIV-1 RNA, CD4+ cell count, geographic region Wk 48 Primary endpoint Wk 144 *10/200/150/150 mg once daily. † 300/200/150/150 mg once daily. Sax PE, et al. Lancet. 2015;385:2606-2615.

6. clinicaloptions.com/hiv Fall 2015 HIV Update Studies 104/111: Wk 48 Efficacy of TAF and TDF in Black vs Nonblack Pts  Race not significant predictor of virologic efficacy in multivariate analysis Wohl D, et al. IDWeek 2015. Abstract 1073. Reproduced with permission. HIV-1 RNA < 50 c/mL (%) Black Pts 100 80 60 40 20 0 Virologic Success Virologic Failure No Data E/C/F/TAF (n = 223) E/C/F/TDF (n = 213) 88 83 5 8 7 9 Nonblack Pts -14-10-6-2261014 -1.8 5.2 12.2 Treatment Difference (95% CI) E/C/F/TAFE/C/F/TDF 100 80 60 40 20 0 Virologic Success Virologic Failure No Data E/C/F/TAF (n = 643) E/C/F/TDF (n = 654) 94 93 3 3 3 4 -12-8-404812 -1.5 1.3 4.1 Treatment Difference (95% CI) E/C/F/TAFE/C/F/TDF

7. clinicaloptions.com/hiv Fall 2015 HIV Update Studies 104/111: Renal Outcomes With TAF vs TDF in Black vs Nonblack Pts  In black pts, decrease in median eGFR significantly smaller with TAF vs TDF –Median proteinuria decrease numerically greater with TAF vs TDF  Better bone safety with TAF vs TDF in both black and nonblack pts Wohl D, et al. IDWeek 2015. Abstract 1073. Reproduced with permission. 15 10 5 0 -5 -10 Mean eGFR Change (mL/min) Black Pts -15 -20 -25 -30 E/C/F/TAF E/C/F/TDF 15 10 5 0 -5 -10 Nonblack Pts -15 -20 -25 -30 E/C/F/TAF E/C/F/TDF 02481216243648 Wk 02481216243648 Wk

8. clinicaloptions.com/hiv Fall 2015 HIV Update Studies 104/111: High Virologic Efficacy of TAF at Wk 48 in Pts 50 Age Yrs or Older Daar ES, et al. IDWeek 2015. Abstract 1074. Reproduced with permission. 100 80 60 40 20 0 HIV-1 RNA < 50 c/mL (%) Virologic Success Virologic Failure No Data E/C/F/TAF (n = 89) E/C/F/TDF (n = 114) 94 91 3 4 2 4 -14-10-6-2261014 -5.2 3.5 12.2 Treatment Difference (95% CI) Favors E/C/F/TAF Favors E/C/F/TDF

9. clinicaloptions.com/hiv Fall 2015 HIV Update Studies 104/111: Renal and Bone Safety of TAF vs TDF in Pts Aged 50 Yrs or Older  Mean % BMD decrease from baseline to Wk 48 significantly lower with TAF vs TDF (spine: P =.01; hip: P <.001) Daar ES, et al. IDWeek 2015. Abstract 1074. Reproduced with permission. Mean (SD) eGFR Change (mL/min) E/C/F/TAF E/C/F/TDF Wk -5.8 15 10 5 0 -5 -10 -15 -20 -25 -30 02481216243648 -11.7 P =.01 80 60 40 20 0 Median Proteinuria (mg/g) UPCR UACR E/C/F/TAF 56 6.3 8 72 49 55 6 6.2 E/C/F/TDF Wk 48 Baseline

10. clinicaloptions.com/hiv Fall 2015 HIV Update 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 ART-naive pats with HIV-1 RNA > 1000 copies/mL; no NRTI/PI resistance; HBsAg negative (N = 426) 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) Wk 48 primary analysis Stratified by HIV-1 RNA (≤ vs > 100,000 c/mL) Wk 24 interim analysis Cahn P, et al. EACS 2015. Abstract 961. *ZDV/3TC: 54%; TDF/FTC: 37%; ABC/3TC: 9% Wk 96 extension analysis

11. clinicaloptions.com/hiv Fall 2015 HIV Update GARDEL: Dual ART Noninferior to Triple ART at Wk 48 and Wk 96  Safety and tolerability also similar between treatment arms Virologic Success Virologic Nonresponse D/C due to AE or Death D/C for Other Reasons Cahn P, et al. EACS 2015. Abstract 961. Cahn P, et al. Lancet Infect Dis. 2014;14:572-580. 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) 100 80 60 40 20 0 Pts (%) Dual ART Triple ART 4.7 5.9 1.4 5.4 6.1 7.9 2.4 2.1 0.6 2.8 6.6 10.6 88.3 83.7 90.3 84.4 Wk:9648964896489648

12. clinicaloptions.com/hiv Fall 2015 HIV Update  Open-label, single-arm phase IV exploratory trial –Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48 (ITT-e, FDA snapshot analysis) PADDLE: Dolutegravir + Lamivudine in Treatment-Naive Pts Figueroa MI, et al. EACS 2015. Abstract 1066. Treatment-naive pts with HIV-1 RNA 5000-100,000 copies/mL; CD4+ cell count ≥ 200 cells/mm 3 ; HBsAg negative (N = 20) Second Cohort Dolutegravir 50 mg QD + Lamivudine 300 mg QD (n = 10) Dolutegravir 50 mg QD + Lamivudine 300 mg QD (n = 10) First Cohort Second cohort to be enrolled following confirmation of first cohort success at Wk 8

13. clinicaloptions.com/hiv Fall 2015 HIV Update PADDLE: All Pts Virologically Suppressed by Wk 8 of Dolutegravir + Lamivudine  Included 4 pts with HIV-1 RNA > 100,000 copies/mL at BL Figueroa MI, et al. EACS 2015. Abstract 1066. Reproduced with permission. Pt # HIV-1 RNA, copies/mL ScreenBLDay 2Day 4Day 7Day 10Wk 2Wk 3Wk 4Wk 6Wk 8Wk 12Wk 24 1 558410,909370138310171< 50 2 888710,2335671318< 50 3 67,335151,56937,604156511782669753< 50 4 99,291148,37011,797330343217917855< 50 5 34,36220,54446801292570168107< 50 6 16,02414,49937541634162< 50 7 37,60418,597294881961< 50 8 25,07124,36862641377Not done268105< 50 9 14,70710,832Not done516202< 50 10 10,67979785671318< 50 11 50,089273,676160,97468,12938802247784290288147< 50 12 13,50864,10334963296135351 8467< 50 13 28,09333,82937,35026,34353926861< 50 14 15,34815,151399479119898< 506164< 50 15 23,18523,50015,830421719269< 50 Not done< 50 16 11,377391037097143< 50 17 39,10025,82811,879197046014752< 50 18 60,77173,06931,1702174692358156< 50 19 82,803106,32035,517290289735216876< 50 20 51907368343314756< 50

14. clinicaloptions.com/hiv Fall 2015 HIV Update STRIIVING: Switch From Suppressive ART to Fixed-Dose DTG/ABC/3TC  Ongoing randomized, open-label phase IIIB study –Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 24 HIV-1 RNA < 50 copies/mL on stable ART ≥ 6 mos; no previous virologic failure; HLA-B*5701 negative (N = 551) DTG/ABC/3TC (n = 274) Wk 48Wk 24 Trottier B, et al. ICAAC 2015. *Containing 2 NRTIs plus NNRTI, PI, or INSTI. Baseline ART* (n = 277) DTG/ABC/3TC (n = 277) PINNRTIINSTITDF/FTC BL ART use, %42312677

15. clinicaloptions.com/hiv Fall 2015 HIV Update STRIIVING: Study Disposition at Wk 24 Trottier B, et al. ICAAC 2015. Reproduced with permission. 13% of subjects withdrawn (n = 35) Adverse event10 (4%) Lack of efficacy (virologic failure)0 Protocol deviation15 (5%) Stopping criteria met0 Lost to follow-up3 (1%) Investigator discretion3 (1%) Withdrew consent4 (1%) 87% completed (n = 239) Screened (N = 841) 12% of subjects withdrawn (n = 32) Adverse event0 Lack of efficacy (virologic failure)0 Protocol deviation17 (6%) Stopping criteria met0 Lost to follow-up3 (1%) Investigator discretion3 (1%) Withdrew consent9 (3%) Randomized and treated Baseline ART (n = 277) 88% completed (n = 244) 1 with missing information Randomized and treated DTG/ABC/3TC (n = 274)

16. clinicaloptions.com/hiv Fall 2015 HIV Update 5 2 STRIIVING: Virologic Outcomes at Wk 24  Switch to DTG/ABC/3TC noninferior to maintaining baseline ART  No cases of protocol-defined virologic failure –3 pts in DTG/ABC/3TC arm (1%) and 4 pts in BL ART arm (1%) had HIV-1 RNA > 50 but < 100 copies/mL through Wk 24 Trottier B, et al. ICAAC 2015. Reproduced with permission. Primary Efficacy Analysis: ITT-Exposed and Per Protocol Populations 100 80 60 40 20 0 Virologic Success Virologic Nonresponse No Virologic Data HIV-1 RNA < 50 c/mL (%) DTG/ABC/3TC (ITT-E, n = 274) Baseline ART (ITT-E, n = 277) DTG/ABC/3TC (PP, n = 220) Baseline ART (PP, n = 215) 85 88 93 14 10 6 11 < 1 12-12-8-4048 12-12-8-4048 -4.9 -0.3 4.4 2.3-9.1 ITT-E Population PP Population -3.4 DTG/ABC/3TCBaseline ART

17. clinicaloptions.com/hiv Fall 2015 HIV Update STRIIVING: Adverse Events and Treatment Satisfaction  10 pts discontinued for AEs in DTG/ABC/3TC arm vs 0 in baseline ART arm  However, significantly greater increase in treatment satisfaction score from baseline to Wk 24 in DTG/ABC/3TC arm vs baseline ART arm –Adjusted mean difference: 2.4 (P <.001) Trottier B, et al. ICAAC 2015. Reproduced with permission. AEs in 10 Pts Who Withdrew*Grade Insomnia2 Diarrhea, flatulence, rash Abdominal pain, anxiety, nausea, body ache 1212 Euphoric mood Headache 1212 Abdominal cramps, chills, diarrhea, dizziness, headache 2 Pruritus2 Abdominal pain, diarrhea, flulike syndrome, profuse sweating, change in body odor Fatigue, † malaise, depression 1212 Nasal congestion Worsening fatigue Nausea 123123 Alopecia1 Fatigue † 1 Homicide † N/A *None serious AEs except homicide. † Not drug related.

18. clinicaloptions.com/hiv Fall 2015 HIV Update  Randomized, active-controlled, open-label study –Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 48  Current analysis focused on pts receiving EVG/COBI/FTC/TDF at baseline Study 109: Switch From E/C/F/TDF to E/C/F/TAF in Suppressed Pts Thompson M, et al. IDWeek 2015. Abstract 725. Pts with HIV-1 RNA < 50 copies/mL (≥ 48 wks) on stable TDF-based regimen and eGFR ≥ 50 mL/min (N = 1436) Switch to EVG/COBI/FTC/TAF QD (n = 959) Continue Previous TDF-Based Regimen* (n = 477) Primary Endpoint Wk 48 *Previous TDF-based regimens: EVG/COBI/FTC/TDF (n = 459), EFV/TDF/FTC (n = 376), ATV/COBI or ATV/RTV + TDF/FTC (n = 601). Continue through Wk 96

19. clinicaloptions.com/hiv Fall 2015 HIV Update Study 109: Wk 48 Efficacy Thompson M, et al. IDWeek 2015. Abstract 725. Reproduced with permission. 100 80 60 40 20 0 P =.48 98 97 0.7 1 2 E/C/F/TAF (n = 306) E/C/F/TDF (n = 153) HIV-1 RNA < 50 c/mL (%) Virologic Success Virologic Failure No Data -1.93.9 1 E/C/F/TDF E/C/F/TAF -12012 Treatment Difference (95% CI)

20. clinicaloptions.com/hiv Fall 2015 HIV Update Study 109: Renal Outcomes Thompson M, et al. IDWeek 2015. Abstract 725. Reproduced with permission. E/C/F/TAF E/C/F/TDF Median % Change UPCRUACRRBP:Crβ2-M:Cr Tubular Proteinuria 14 -16 -18 -29 -43 8 27 21 0.1 0.08 0.06 0.04 0.02 0 -0.02 -0.04 -.0.06 -0.08 -0.1 Median Change in Serum Creatinine (mg/dL) BL Wk 24812243648 P <.001 E/C/F/TAF (n = 306) E/C/F/TDF (n = 153) 40 30 20 10 0 -10 -20 -30 -40 -50

21. clinicaloptions.com/hiv Fall 2015 HIV Update NormalOsteopeniaOsteoporosis Study 109: Bone Outcomes Thompson M, et al. IDWeek 2015. Abstract 725. Reproduced with permission. Spine 100 80 60 40 20 0 Pts (%) BLWk 48BLWk 48 P =.017 E/C/F/TAF n = 291 E/C/F/TDF n = 146 4.14.3 7.5 7.7 36.2 59.7 31.6 34.9 35.2 64.257.557.0 Hip 100 80 60 40 20 0 Pts (%) BLWk 48BLWk 48 P =.012 E/C/F/TAF n = 291 E/C/F/TDF n = 146 0.7 1.7 0.9 28.9 70.4 25.2 28.1 29.6 74.071.269.0 Spine Hip 3 2 1 0 -2 -3 3 2 1 0 -2 -3 BLWk 48Wk 24 BLWk 48Wk 24 1.33 (3.6) -0.50 (3.4) 1.15 (2.7) -0.24 (2.7) E/C/F/TAF E/C/F/TDF Mean % Change in BMD (SD) P <.001

22. clinicaloptions.com/hiv Fall 2015 HIV Update  Multicenter, open-label phase III trial –Primary endpoint: change in eGFR from BL to Wk 24 GS-112: Switching to a TAF-Based Regimen in Pts With Renal Impairment Gupta S, et al. ICAAC 2015. Abstract. Virologically suppressed pts with mild to moderate renal impairment (stable eGFR CG [30-69 mL/min]) (N = 242) eGFR < 50 mL/min (n = 80) eGFR ≥ 50 mL/min (n = 162) EVG/COBI/FTC/TAF (N = 242) Wk 96 PINNRTIINSTI CCR5 Antag. TDFABC Other NRTI No NRTI BL ART use, %4442243652275 Wk 48Wk 24

23. clinicaloptions.com/hiv Fall 2015 HIV Update GS-112: Renal Outcomes  In pts with lowest 5% eGFR at BL, median eGFR increased by 6.4 mL/min from BL to Wk 48 (P =.03)  2 pts discontinued for decreased eGFR, neither had evidence of tubulopathy  Rates of SAEs and potential FTC-related AEs similar between BL eGFR subgroups Clinically Relevant Proteinuria Measured GFR by Iohexal Clearance Gupta S, et al. ICAAC 2015. Abstract. 100 80 60 40 20 0 eGFR (mL/min/1.73 m 2 ) BL < 50 mL/minBL ≥ 50 mL/min BLWk 2/4/8 Wk 24 47 43 44 65 67 BLWk 2/4/8 Wk 24 100 80 60 40 20 0 Pts (%) Proteinuria (UPCR) ≤ 200 mg/g BLWk 48 BL Wk 48 > 200 mg/g 56 75 65 91 44 25 35 9 BL < 50 mL/minBL ≥ 50 mL/min

24. clinicaloptions.com/hiv Fall 2015 HIV Update  Multicenter, open-label randomized trial –Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 24 by FDA snapshot –37% pts receiving ≥ 6 pills/day at baseline Study 119: Switch to EVG/COBI/FTC/TAF + DRV in Treatment-Experienced Pts Huhn GD, et al. IDWeek 2015. Abstract 726. Treatment-experienced pts, HIV-1 RNA 50 mL/min (N = 135) Switch to EVG/COBI/FTC/TAF + DRV 800 mg QD (n = 89) Wk 144Wk 48 Baseline ART (n = 46) EVG/COBI/FTC/TAF + DRV 800 mg QD (n = 46) Wk 24Randomized 2:1 *Resistance to ≥ 2 ARV classes, including ≤ 3 thymidine analogue mutations and K65R, but not integrase inhibitors, unless currently receiving raltegravir, and no DRV resistance.

25. clinicaloptions.com/hiv Fall 2015 HIV Update Virologic Failure Study 119: Virologic Suppression After Switch to EVG/COBI/FTC/TAF + DRV  Similar rates of maintained virologic suppression at Wk 24, but significantly higher rates with switch vs baseline ART at Wk 48 Huhn GD, et al. IDWeek 2015. Abstract 726. Reproduced with permission. Wk 24 HIV-1 RNA < 50 c/mL No Data EVG/COBI/FTC/TAF + DRV Baseline ART 100 80 60 40 20 0 Pts (%) 97 91 2 0 1 9 Wk 48 HIV-1 RNA < 50 c/mL Virologic Failure No Data 94 76 2 11 3 13 Treatment difference: 5.3% (95% CI: -3.4% to 17.4%; P =.23) Treatment difference: 18.3% (95% CI: 3.5% to 33.0%; P =.004)

26. clinicaloptions.com/hiv Fall 2015 HIV Update Study 119: Safety and Tx Satisfaction After Switch to EVG/COBI/FTC/TAF + DRV  AEs more frequent in switch arm, yet no pts discontinued  As in other TAF switch studies, proteinuria decreased with switch  Increases in eGFR at Wk 48 similar with switch vs continuing BL ART (+7.4 vs +3.9 mL/min; P =.18)  Significantly greater improvement in mean treatment satisfaction score with switch vs continuing BL ART –Wk 24: +28 vs +21 (P <.001) –Wk 48: +27 vs +20 (P <.001) Huhn GD, et al. IDWeek 2015. Abstract 726. Reproduced with permission. EVG/COBI/FTC/TAF + DRV Baseline ART Median % Change at Wk 48 20 10 0 -10 -20 -30 P =.005 P =.038P =.002 UPCRRBP:Crβ2-M:Cr Tubular Proteinuria -27 -17 -29 5 14 13

27. clinicaloptions.com/hiv Fall 2015 HIV Update 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 200 cells/mm 3 (≥ 6 mos), and no previous virologic failure (N = 266) 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 48 primary endpoint Wk 24 interim analysis Wk 96 planned follow-up Di Giambenedetto S, et al. EACS 2015. Abstract 867.

28. clinicaloptions.com/hiv Fall 2015 HIV Update 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  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 2015. Abstract 867. Reproduced with permission. 1.2 18.4 9.8 ATV/RTV + 2 NRTIs ATV/RTV + 3TC -12012 Treatment Difference (95% CI) 100 80 60 40 20 0 Pts Free of Treatment Failure (%) BLW4W12W24W36W48 ATV/RTV + 3TCATV/RTV + 2NRTIs 99.2 100 97.7 94 94.7 91 91.7 85.7 89.5 83.5 89.5 79.7

29. clinicaloptions.com/hiv Fall 2015 HIV Update Switch From Suppressive ART to Dolutegravir Monotherapy  Single-arm, 24-wk pilot study –Primary endpoint: HIV-1 RNA < 37 c/mL at Wk 24 (ITT, NC=F)  Eligibility: HIV-1 RNA < 50 c/mL on ART for ≥ 12 mos –Switched to DTG 50 mg QD monotherapy if ≥ 2 of the following: ART or ART- comorbidity toxicity, avoidance of DDIs, or potential loss of virologic control due to archived resistance  Baseline ART: PI (67%), NNRTI (27%), INSTI (6%) Rojas J, et al. EACS 2015. Abstract 1108. Reproduced with permission. Reasons for Switch, % Pts (N = 33) Underlying cause  Comorbidities97  DDIs85  ART-related AEs76  Resistance48 Immediate cause  DDIs39  GI symptoms33  Dyslipidemia27  Osteoporosis18  High CVD risk12  CKD progression3

30. clinicaloptions.com/hiv Fall 2015 HIV Update Switch From Suppressive ART to Dolutegravir Monotherapy  97% of pts maintained virologic suppression at Wk 24 [1]  Reasons for switch improved in most pts from BL to 24 wks [1] –T-scores unchanged in 2 pts with osteoporosis –In single pt with renal disease, eGFR ↓ from 59 mL/min at BL to 52 mL/min at Wk 24; urine protein:creatinine ratio ↓ from 330 to 146 mg/mg  In separate study of switch from suppressive ART to DTG monotherapy, 89% of pts maintained virologic suppression 24 wks after switch [2] 1. Rojas J, et al. EACS 2015. Abstract 1108. 2. Katlama C, et al. EACS 2015. Abstract 714. Reason for SwitchPts at Risk, nOutcome Improved/Avoided, n DDIs 13 GI symptoms 119 Dyslipidemia 99 High Framingham score 33

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

32. clinicaloptions.com/hiv Fall 2015 HIV Update MARCH: Switch to Maraviroc-Based ART in Pts With Virologic Suppression  Randomized, multicenter, open-label trial –Primary endpoint: HIV-1 RNA < 200 copies/mL 48 wks Pts with HIV-1 RNA 24 wks) on PI/RTV + 2 NRTIs, no known resistance, and R5-tropic virus by proviral DNA (N = 395) Switch to PI/RTV + MVC (n = 157) Continue current PI/RTV + 2 NRTIs (n = 82) Switch to MVC + 2 NRTIs (n = 156) Pett SL, et al. EACS 2015. Abstract 252. HIV-1 RNA < 200 c/mL at Wk 48, % Continue PI/RTV + 2 NRTIs (Control) Switch to MVC + 2 NRTIs Switch to PI/RTV + MVC Difference for Switch to MVC + 2 NRTIs vs Control (95% CI) Difference for Switch to PI/RTV + MVC vs Control (95% CI) ITT 97.693.684.1-4.0 (-9.0 to 2.2)-13.5 (-19.8 to -5.8) NC=F 96.388.580.3-7.9 (-14.1 to -0.4)-16.1 (-23.1 to -7.6) PP 98.898.690.0-0.2 (-3.8 to 4.4)-8.8 (-14.2 to -2.1)

33. clinicaloptions.com/hiv Fall 2015 HIV Update BMS-663068 600 mg QD + RAL + TDF (n = 51) AI438011: Efficacy of BMS-663068 + RAL + TDF in Treatment-Experienced Pts  Randomized, active-controlled, phase IIb study, blinded to dose –BMS-663068: HIV-1 attachment inhibitor prodrug, metabolized to BMS- 626529 attachment inhibitor; proposed MOA is by binding gp120 to prevent viral attachment and host CD4+ cell entry; active against R5, X4, and dual tropic HIV-1 Feinberg J, et al. IDWeek 2015. Abstract 1075. HIV-infected pts with exposure to ≥ 1 ARV for ≥ 1 wk, HIV-1 RNA ≥ 1000 c/mL, CD4+ ≥ 50 cells/mm 3, virus susceptible to RAL, TDF, ATV, and BMS-626529 IC 50 < 100 nM (N = 251) Wk 48 Wk 24: 1 ̊ endpoint ATV/RTV 300/100 mg QD + RAL + TDF (n = 51) BMS-663068 1200 mg QD + RAL + TDF (n = 50) BMS-663068 400 mg BID + RAL + TDF (n = 50) BMS-663068 800 mg BID + RAL + TDF (n = 49) Wk 96

34. clinicaloptions.com/hiv Fall 2015 HIV Update AI438011 : Virologic Suppression With BMS-663068 + RAL + TDF at Wk 48  No significant differences in virologic efficacy through Wk 48 regardless of race, sex, age, baseline HIV-1 RNA, or baseline CD4+ cell count in subgroup analyses Feinberg J, et al. IDWeek 2015. Abstract 1075. Reproduced with permission. 100 80 60 40 20 0 HIV-1 RNA < 50 c/mL, % (95% CI) 04812162024324048 Wk 400 mg BID91 800 mg BID73 600 mg QD69 1200 mg QD79 ATV/RTV88 Wk 48 HIV-1 RNA < 50 c/mL (%)

35. clinicaloptions.com/hiv Fall 2015 HIV Update Longitudinal Assessment of Comorbidities in HIV-Infected Pts During 11-Yr Period  Retrospective analysis to characterize age and comorbidity trends from 2003-2013 across payer types –Also assessed 5-yr comorbidity trends from 2009-2014  Data obtained from administrative claims in 3 settings –Commercial database: > 41 million enrollees in 2014 –Medicaid database: ~ 8 million enrollees –Employer-sponsored Medicare supplemental database: ~ 4 million enrollees  Included pts with ≥ 1 inpatient or outpatient HIV claim during analysis period and ≥ 6 mos continuous medical and prescription coverage before and after earliest diagnosis of HIV Meyer N, et al. ICAAC 2015. Abstract.

36. clinicaloptions.com/hiv Fall 2015 HIV Update Comorbidity Prevalence Increased 2003- 2013 in Commercial and Public Settings Meyer N, et al. ICAAC 2015. Abstract. Reproduced with permission. *P <.05 Commercial 2003: n = 4501 2013: n = 14,638 Medicaid 2003: n = 14,203 2013: n = 4869 Medicare 2003: n = 240 2013: n = 848 100 80 60 40 20 0 CV Renal Bone HTN DM Obesity HL 2.3 2.8 5.1 2.5 3.0 11.6 25.0 6.4 9.4 0.6 5.1 9.5 21.9 100 80 60 40 20 0 3.0 6.9 4.8 10.5 4.3 6.1 16.6 48.2 8.7 19.4 1.7 13.5 7.1 27.3 100 80 60 40 20 0 9.6 16.0 9.2 20.1 6.7 11.2 34.2 65.1 20.4 31.1 0.0 6.3 12.1 47.5 2003 2013  In 5-yr trend analysis, HTN, DM, hyperlipidemia, and renal dysfunction rates increased for all 3 payer groups CV Renal Bone HTN DM Obesity HL CV Renal Bone HTN DM Obesity HL * * * * * * * * * * * * * * * * * * Pts With Event (%) *

37. clinicaloptions.com/hiv Fall 2015 HIV Update High Prevalence of Asymptomatic Chlamydia and Gonorrhea in HIV+ MSM  Asymptomatic MSM with HIV infection at single center screened by NAAT for chlamydia and gonorrhea in urethral, pharyngeal, and rectal samples –149 samples from 151 participants  Participants with positive CT or NG results more likely to have: –Had receptive anal sex in previous yr (P =.02) –Reported use of cocaine (P =.05) or methamphetamine (P =.004) during previous 6 mos –Test positive for syphilis, but association not statistically significant (P =.2) Sandkovsky U, et al. IDWeek 2015. Abstract 120. Reproduced with permission. Race/Ethnicity NG and/or CT Positive (%) n/N = 8/90 5/32 5/27 WhiteBlack Latino 20 15 10 5 0 8.9 15.6 18.5

38. clinicaloptions.com/hiv Fall 2015 HIV Update Urine-Only Testing HIV+ MSM for CT and NG Misses Majority of Infections  CT and NG incidence rate 3% for urine-only testing vs 11% when extragenital sites tested –IRR: 3.67 (95% CI: 1.26-10.7) –Urine-only testing missed all NG infections and 75% of CT infections Sandkovsky U, et al. IDWeek 2015. Abstract 120. Reproduced with permission. Anatomical Site of Detection NG and/or CT Positive (%) Extragenital onlyUrine onlyUrine + extragenital 15 10 5 0 11.02 3.03

39. clinicaloptions.com/hiv Fall 2015 HIV Update No Relevant DDIs Between LDV/SOF and E/C/F/TAF or R/F/TAF  2 phase I, multiple-dose DDI studies in healthy volunteers Custodio JM, et al. IDWeek 2015. Abstract 727. GMR for AUC (90% CI) E/C/F/TAF + LDV/SOF vs E/C/F/TAF R/F/TAF + LDV/SOF vs R/F/TAF E/C/F/TAF + LDV/SOF vs LDV/SOF R/F/TAF + LDV/SOF vs LDV/SOF TAF 0.86 (0.78-0.95)1.32 (1.25-1.40)NA TDF 1.27 (1.23-1.31)1.75 (1.69-1.81)NA E 1.1 (1.0-1.2)NA C 1.5 (1.5-1.6)NA RPV NA0.95 (0.91-0.98)NA F 0.97 (0.93-1.00)1.00 (0.98-1.02)NA LDV NA 1.79 (1.63-1.96)1.02 (0.97-1.06) SOF NA 1.47 (1.35-1.59)1.05 (1.01-1.09) GS-331007 NA 1.48 (1.44-1.53)1.08 (1.06-1.10)

40. clinicaloptions.com/hiv Fall 2015 HIV Update Summary of DDIs Between HCV DAAs and Selected HIV ARVs ARVSimeprevir [1] Sofosbuvir [2] Ledipasvir [3-6] Daclatasvir [7-9] OBV/PTV/RTV + DSV [10-13] ATV/rNo data LDV ↑; ATV ↑*DCV ↑ † PTV ↑; ATV ↑ DRV/rSIM ↑; DRV ↔SOF ↔; DRV ↔LDV ↑, DRV ↔*DCV ↑PTV ↓/↑; DRV ↓ LPV/rNo data No data*DCV ↑PTV ↑; LPV ↔ EFVSIM ↓; EFV ↔SOF ↔; EFV ↔LDV ↓; EFV ↓*DCV ↓ † No PK data ‡ RPVSIM ↔; RPV ↔SOF ↔; RPV ↔LDV ↔; RPV ↔No dataPTV ↑; RPV ↑ RALSIM ↔; RAL ↔SOF ↔; RAL ↔LDV ↔; RAL ↔No dataO/P/R + D ↔; RAL ↑ EVG/cNo dataSOF ↑; COBI ↑*LDV ↑; COBI ↑*No data DTGNo data LDV ↔; DTG ↔*DCV ↔; DTG ↑ PTV ↓ ; DTG ↑ TDFSIM ↔; TFV ↔SOF ↔; TFV ↔LDV ↔; TFV ↑DCV ↔; TFV ↔O/P/R + D ↔; TFV ↔ *When administered with TDF, TFV levels increased. † Decrease DCV dose to 30 mg QD with ATV, increase DCV dose to 90 mg QD with EFV. ‡ OBV/PTV/RTV + DSV + EFV led to premature study d/c due to toxicities. Slide courtesy of J Kiser. Revised 11/2/15. 1. Ouwerkerk-Mahadeven S, et al. IDWeek 2012. Abstract 1618. 2. Kirby B, et al. AASLD 2012. Abstract 1877. 3. LDV/SOF package insert. 4. German P, et al. Pharmacology Workshop 2014. Abstract O_06. 5. German P, et al. CROI 2015. Abstract 82. 6. Garrison K. Pharmacology Workshop 2015. Abstract 71. 7. Bifano M, et al. Antivir Ther. 2013;18:931-940. 8. Eley T, et al. HIV DART 2014. Abstract 63. 9. Song I, et al. Pharmacology Workshop 2015. Abstract 79. 10. Khatri A, et al. ICAAC 2014. Abstract V-483. 11. Khatri A, et al. ICAAC 2014. Abstract V-484. 12. OBV/PTV/RTV + DSV package insert. 13. Khatri Pharmacology Workshop 2015.

41. clinicaloptions.com/hiv Fall 2015 HIV Update BMD Subanalysis of START: Immediate vs Deferred ART  SMART: International, randomized phase IV study involving 215 sites in 35 countries  Study stopped by DSMB following results of interim analysis –Overall HR: 0.43 (P <.001) –HR for serious AIDS-related events: 0.28 (P <.001) HR for non-AIDS–related events: 0.61 (P =.04) Serious AIDS and Non-AIDS Events, n 42 96 Lundgren JD, et al. N Engl J Med. 2015;373:795-807. Immediate ART Delayed ART (until CD4+ ≤ 350 cells/mm³) Treatment-naive pts with CD4+ count > 500 cells/mm³ (N = 4685)

42. clinicaloptions.com/hiv Fall 2015 HIV Update START Substudy: BMD Changes With Immediate vs Deferred ART Over 3 Yrs  Substudy included 193 pts in early ART arm and 204 pts in deferred ART arm with f/u  Greater BMD loss in hip and spine with immediate vs deferred ART –Estimated mean difference for hip: -1.5% (95% CI: -2.3% to -0.8%; P <.001) –Estimated mean difference for spine: -1.6% (95% CI: -2.2% to -1.0%; P <.001)  Osteoporosis incidence similar between arms (P =.27) Hoy JF, et al. EACS 2015. Abstract ADRLH-62. Reproduced with permission. Change From BL (%) Total Hip BMD 0 -2 -3 -4 -5 0 1224 36 Immediate ART Deferred ART Total Spine BMD 0 -2 -3 -4 -5 0 1224 36 Mos From Randomization

43. clinicaloptions.com/hiv Fall 2015 HIV Update Drug Resistance by HIV-1 DNA vs HIV-1 RNA Profile (Historical) in Suppressed Pts  Archived drug resistance in latent viral reservoir assessed using HIV-1 DNA from PBMCs of 48 pts in SCOPE cohort –Resistance detected in DNA compared with variants previously detected in plasma HIV-1 RNA  Pts eligible for study if currently virologically suppressed but with documented history of drug resistant variants  Features of HIV-1 DNA assay assessed –Sensitivity: ability to detect drug resistance and RAMs –NPV: ability to correctly identify drug susceptibility and/or wild-type status of resistance variant position Toma J, et al. ICAAC 2015. Abstract.

44. clinicaloptions.com/hiv Fall 2015 HIV Update High Concordance of HIV-1 DNA Assay With Historical Resistance Profile Toma J, et al. ICAAC 2015. Abstract. *Frequency that resistance variant detected by HIV-1 RNA (in historical profile) is identified as WT by HIV-1 DNA assay. HIV-1 DNA Assay % (95% CI) OverallNRTINNRTIPI Sensitivity for drug resistance 89 (86-91)93 (89-95)91 (83-96)83 (78-88) NPV for drug susceptibility 85 (81-88)76 (65-84)93 (86-97)84 (79-88) Sensitivity for major RAMs 85 (80-89)89 (83-94)82 (67-91)77 (66-85) NPV for absence of RAMs 97 (95-97)96 (93-97)98 (96-99)96 (94-98) Major variant false omission rate* 3 (3-5)4 (3-7)2 (1-4)4 (2-6)

45. clinicaloptions.com/hiv Fall 2015 HIV Update No Transmission of INSTI Resistance in CA AIDS Healthcare Foundation Network  Analysis of 339 genotypic resistance test results determined to be from treatment-naive HIV-infected pts (from among 1060 total pts) March 2013 to June 2015 at 13 AIDS Healthcare Foundation sites  Overall TDR rate: 24.9% –2013: 24.2%; 2014: 30.2%; 2015: 15.9%  No cases of transmitted INSTI resistance detected –TDR rates: NNRTI 16.9%; NRTI 6.5%; PI 4.2%; INSTI 0%  Most frequent mutations: K103N/S 13.0%; L90M 2.7%; Y181C/I/V, M41L, M184V/I 2.1%  TDR prevalence increased with increasing pt age Volpe JM, et al. ICAAC 2015. Abstract.