1. Paul E. Sax, MD Clinical Director Division of Infectious Diseases Brigham and Women’s Hospital Professor of Medicine Harvard Medical School Boston, Massachusetts Antiretroviral Therapy Update 2014 Supported by educational grants from multiple commercial supporters.

2. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium About These Slides  Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Antiretroviral Therapy Update  Where are we in mid-2014? –Prevention –Initial therapy –Novel strategies and switch –Investigational drugs  Focus on data presented, published, or released in past 12 mos  A look forward to the next 12 mos

4. Prevention

5. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium ART Prophylaxis for HIV Infection in Injection Drug Users in Bangkok, Thailand  Randomized, double-blind, placebo-controlled, phase 3 clinical trial of tenofovir vs placebo to prevent HIV  DOT option based on investigator discretion  N = 2413 –Median age, 31 yrs –80% men –< 10% injected daily; 18% shared needles Choopanya K, et al. 2013;381:2083-2090.

6. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium PrEP for IDUs: Results Kaplan-Meier Estimates of Time to HIV Infection in Modified ITT Population Incident infections: TDF: 17 Placebo: 33 48.9% reduction (95% CI: 9.6-72.2; P =.01) Choopanya K, et al. Lancet. 2013;381:2083-2090. Cumulative Probability of HIV Infection (%) Mos Since Randomization 10 8 6 4 2 0 0 12 24 36 48 60 72 84 Pts at Risk, n Tenofovir Placebo 1204 1207 1007 1029 933 948 857 844 736 722 521 500 241 234 Tenofovir Placebo

7. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Update to Interim Guidance for PrEP for Prevention of HIV Infection: PrEP for IDUs  Issued concurrently with publication of paper  Recommendations –Consider for those at “very high risk”: –Sharing of equipment –Injecting daily –Using cocaine or crystal meth –Critical to exclude HIV first –Use TDF/FTC (not tenofovir) MMWR. 2013;62:463-465.

8. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium US PrEP Demonstration Project: Implementation of PrEP (2012-2014)  STD clinics in San Francisco, Miami, Washington, DC (N = 831)  Offered up to 48 wks of open-label TDF/FTC –Accepted PrEP: 60.4%  Adherence rate higher than in previously reported studies ̶ 77% had TDF-DP levels consistent with taking > 4 doses/wk  PrEP acceptance associated with –Self-referral –Prior PrEP awareness –Higher-risk sexual behaviors Cohen SE, et al. CROI 2014. Abstract 954. Tenofovir-DP Levels (Wk 4) < 250 250-550> 550-950 BLD Samples (%) 18 43 14 5 2 > 950 2 11 27 4 4 52 43 40 35 Miami (n = 157) Washington, DC (n = 100) San Francisco (n = 300) Doses/Wk: 4 Tenofovir-DP (fmol/punch)* 0 *Measure of flux density. 60 50 40 30 20 10 0

9. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium PrEP Proof-of-Concept: Long-Acting Integrase Inhibitor in Nanosuspension for Injection  Macaque model of SHIV transmission  Study 1 (vaginal transmission) [1] –Low-dose SHIV (50 TCID 50 ) twice a wk –GSK744 LA (50 mg/kg) 3 injections at Wks 0, 4, 8 –6 of 6 pigtail macaques (lunar menstrual cycles) protected against SHIV infection  Study 2 (rectal transmission) [2,3] –Wkly SHIV (50 TCID 50 ) until systemic infection detected –One GSK744 LA (50 mg/kg) injection at Wk 0 –After 1 to 2 challenges, placebo macaques became infected –With a single GSK744 injection, infection was delayed by 5-10 challenges with SHIV 1. Radzlo J, et al. CROI 2014. Abstract 40LB. 2. Andrews CD, et al. CROI 2014. Abstract 39. 3. Andrews CD, et al. Science. 2014;343:1151-1154. P =.0005 Wk Aviremic (%) GSK744 LA (n = 6) Placebo (n = 6) Wk 0 2 4 6 8 10 12 14 16 30 Vaginal SHIV Exposure Aviremic (%) GSK744 LA (n = 12) Placebo (n = 4) Rectal SHIV Exposure 0 2 4 6 8 10 12 14 16 18 20 22 24 P <.0001 100 80 60 40 20 0 100 80 60 40 20 0

10. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium PARTNER: Risk of HIV Transmission With Condomless Sex on Suppressive ART  Observational study of rate of HIV transmission in heterosexual and MSM serodiscordant couples (N = 767 couples) –HIV+ partner on suppressive ART –Condoms not used  Analyses: Risk-behavior questionnaire every 6 mos, HIV-1 RNA (HIV+), HIV test (HIV)  Endpoint: Phylogenetically linked transmissions  No linked transmissions recorded in any couple during study period Rodger A, et al. CROI 2014. Abstract 153LB. Reproduced with permission. 0204060 80100 Risk Behaviors, % Vaginal sex with ejaculation Vaginal sex Receptive anal sex Receptive anal sex with ejaculation Only insertive anal sex MSM HT♀ HT♂ 0123 4 Rate of Within-Couple Transmission Events Per 100 CYFU, % (95% CI) HT♀ Vaginal sex with ejaculation (CYFU = 192) HT♂Vaginal sex (CYFU = 272) Receptive anal sex with ejaculation (CYFU = 93) Receptive anal sex without ejaculation (CYFU = 157) Insertive anal sex (CYFU = 262) MSM Estimated rate95% CI

11. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Management of Occupational Exposure to HIV and Recommendations for PrEP  First choice: TDF/FTC + raltegravir x 28 days [1] –Numerous alternatives, including TDF/FTC/EVG/COBI  No 2-drug options for low-risk exposures  No need to rule out window period in source patient  “Expert consultation” recommended for complex cases  Follow-up shortened to 4 mos if 4th-generation Ag/Ab combination test used –NY state guidelines: only 3 mos needed [2] 1. Kuhar DT, et al. Inf Cont Hosp Epi. 2013. 2. NYS Dept Health. HIV prophylaxis following occupational exposure. October 2012.

12. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Hammer SM, et al. 2013;369:2083-2092.

13. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium The HIV Vaccine Effort to Date  Billions of dollars (nearly $1 billion annually) invested in research effort—basic and clinical  6 efficacy studies –1 slightly effective –1 (and possibly 2) increased infection risk –3 did nothing  Lack of progress starkly contrasts with other HIV prevention efforts

14. Initial Therapy— Established Drugs

15. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Extensive New Data on Integrase-Based First-line Therapy  The following DTG studies all presented and/or published in past yr –SPRING-2 –SINGLE –FLAMINGO  TDF/FTC/EVG/COBI: no new cases of renal tubulopathy in long-term f/u  ACTG 5257: raltegravir vs boosted PIs

16. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Dolutegravir Clinical Trials in Treatment- Naive Pts  Randomized, noninferiority phase III studies  Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 48 ART-naive pts VL ≥ 1000 c/mL (N = 822) DTG 50 mg QD + 2 NRTIs* (n = 411) RAL 400 mg BID + 2 NRTIs* (n = 411) *Investigator-selected NRTI backbone: either TDF/FTC or ABC/3TC. ART-naive pts VL ≥ 1000 c/mL HLA-B*5701 neg CrCl > 50 mL/min (N = 833) DTG 50 mg QD + ABC/3TC QD (n = 414) EFV/TDF/FTC QD (n = 419) SPRING-2 [1] (placebo controlled) SINGLE [2] (placebo controlled) DTG 50 mg QD + 2 NRTIs* (n = 242) DRV/RTV 800/100 mg QD + 2 NRTIs* (n = 242) ART-naive pts VL ≥ 1000 c/mL (N = 484) FLAMINGO [3] (open label) 1. Raffi F, et al. Lancet. 2013;381:735-743. 2. Walmsley S, et al. N Engl J Med. 2013;369:1807-1818. 3. Clotet B, et al. Lancet. 2014;[Epub ahead of print].

17. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium 1. Walmsley S, et al. N Engl J Med. 2013;369:1807-1818. 2. Walmsley S, et al. CROI 2014. Abstract 543. 2432404860847296161284 Wk 96 adjusted difference in response (95% CI): +8.0% (+2.3% to +13.8%); P =.006 Treatment Wk 96 ∆ From BL Adjusted MeanSE Difference in Response (95% CI) DTG + ABC/3TC QD (n = 414)325.310.5 44.0 (14.3, 73.6) P =.004 EFV/TDF/FTC QD (n = 419)281.410.9 DTG: 80% EFV: 72% CD4 ∆ from BL SINGLE: Dolutegravir + ABC/3TC vs Efavirenz/TDF/FTC in Tx-Naive Pts  DTG superior to EFV at Wk 48 [1] and Wk 96 [2]  Treatment-related study d/c: 3% in DTG vs 11% in EFV arm at Wk 96; comparable rates of virologic failure (6% in each arm at Wk 96)  No resistance in DTG arm through Wk 9 Proportion of Patients (%) 100 80 60 40 20 0 0 Wk DTG + ABC/3TCEFV/TDF/FTC

18. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium 1. Lennox J, et al. Lancet. 2009;374:796-806. 2. Sax PE, et al. Lancet. 2012;379:2439-2448. 3. De Jesus E, et al. Lancet. 2012;379:2429-2438. 4. Brinson C, et al. CROI 2013. Abstract 554. 5. Feinberg J, et al. ICAAC 2013. Abstract 1464a. ≤ 100,000 c/mL > 100,000 c/mL SPRING-2 [4] 3020 10 0 -20 -10 Difference, % (DTG-RAL) and 95% CI In favor of RAL In favor of DTG ≤ 100,000 c/mL > 100,000 c/mL SINGLE [4] 3020 10 0 -20 -10 Difference, % (DTG-EFV) and 95% CI In favor of DTG In favor of EFV Study 102 [2] FLAMINGO [5] ≤ 100,000 c/mL > 100,000 c/mL 3020 10 0 -20 -10 Difference, % (DTG-DRV/RTV) and 95% CI In favor of DTGIn favor of DRV/RTV 40 ≤ 100,000 c/mL > 100,000 c/mL Difference, % (EVG/COBI-EFV) and 95% CI In favor of EFV In favor of EVG/COBI Study 103 [3] -15 -10 -5 5 10 15 0 ≤ 100,000 c/mL > 100,000 c/mL Difference, % (EVG/COBI-ATV/RTV) and 95% CI In favor of ATV/RTV In favor of EVG/COBI ≤ 100,000 c/mL > 100,000 c/mL STARTMRK [1] 3020 10 0 -20 -10 Difference, % (RAL-EFV) and 95% CI In favor of EFV In favor of RAL -15 -10 -5 5 10 15 0 Activity of Integrase-Based Therapies Maintained at High HIV-1 RNA

19. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium ACTG 5257: Open-Label ATV/RTV vs RAL vs DRV/RTV in First-line ART  Primary endpoints –Virologic failure: time to HIV-1 RNA > 1000 c/mL (at Wk 16 or before Wk 24) or > 200 c/mL (at or after Wk 24) –Tolerability failure: time to discontinuation of randomized component for toxicity –Composite endpoint: the earlier occurrence of either VF or TF in a given participant –Switch of regimens allowed for tolerability Landovitz R, et al. CROI 2014. Abstract 85. ART-naive patients with HIV-1 RNA ≥ 1000 c/mL (N = 1809) ATV/RTV 300/100 mg QD + TDF/FTC (n = 605) RAL 400 mg BID + TDF/FTC (n = 603) Stratified by HIV-1 RNA < or ≥ 100,000 c/mL, participation in metabolic substudy, CV risk DRV/RTV 800/100 mg QD + TDF/FTC (n = 601) Wk 96 after last patient enrolled

20. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium ACTG 5257: Primary Endpoint Analyses at Wk 96  Regimens equivalent in time to VF Landovitz R, et al. CROI 2014. Abstract 85. Reproduced with permission.  Significantly greater incidence of treatment failure with ATV/RTV vs RAL or DRV/RTV –In part due to high proportion of pts with hyperbilirubinemia  Considering both efficacy and tolerability, RAL superior to either boosted PI  DRV/RTV superior to ATV/RTV Virologic FailureTolerability FailureComposite Endpoint Difference in 96-Wk Cumulative Incidence (97.5% CI) 0-10 1020 ATV/RTV vs RAL 3.4% (-0.7 to 7.4) DRV/RTV vs RAL 5.6% (1.3 -9.9) ATV/RTV vs DRV/RTV -2.2% (-6.7 to 2.3) 0-10 1020 ATV/RTV vs RAL 15% (10-20) DRV/RTV vs RAL 7.5% (3.2-12.0) ATV/RTV vs DRV/RTV 7.5% (2.3-13.0) Favors RAL Favors DRV/RTV Favors RAL 0-10 1020 ATV/RTV vs RAL 13% (9.4-16.0) DRV/RTV vs RAL 3.6% (1.4-5.8) ATV/RTV vs DRV/RTV 9.2% (5.5-13.0) Favors RAL Favors DRV/RTV

21. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium 89% ACTG 5257: Virologic Efficacy  In ITT analysis with ART changes allowed (per protocol), regimens similar in virologic efficacy at Wk 96 and through Wk 144 [1]  In ITT analysis when change = failure (Snapshot), RAL superior to both boosted PIs at Wk 96 and DRV/RTV superior to ATV/RTV at Wks 96 and 144 [1]  Lipid, bone results also favored RAL over ATV/RTV and DRV/RTV [2,3] 1. Landovitz R, et al. CROI 2014. Abstract 85. 2. Ofotokun I, et al. CROI 2014. Abstract 746. 3. Brown T, et al. CROI 2014. Abstract 779LB. 1.0 Proportion With HIV-1 RNA ≤ 50 c/mL 0.8 0.6 0.4 0.2 0 ITT, Regardless of ART Change 0 24 48 64 80 96 120144 1.0 0.8 0.6 0.4 0.2 0 ITT, NC = Failure (Snapshot) RAL DRV/RTV ATV/RTV Study Wk 0 24 4864 80 96 120 144 88% 94% 63% 73% 80% RAL DRV/RTV ATV/RTV

22. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium DHHS May 2014: What to Start DHHS guidelines. May 2014. For All Pts, Regardless of BL VL or CD4+ Count Only for Pts With Pre-ART VL < 100,000 c/mL NNRTI  EFV/TDF/FTC  EFV + ABC/3TC*  RPV/TDF/FTC  Boosted PI  ATV/RTV + TDF/FTC  DRV/RTV + TDF/FTC  ATV/RTV + ABC/3TC* INSTI  RAL + TDF/FTC  EVG/COBI/TDF/FTC  DTG + ABC/3TC*  DTG + TDF/FTC *Only for pts who are HLA-B*5701 negative.  Only for those with CD4+ cell counts > 200 cells/mm 3.

23. Novel Strategies for Treatment

24. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium HIV Cure: The Score So Far  Still without HIV relapse –1 patient (“Berlin”) post–stem-cell transplant from CCR5 delta 32 negative donor –1 baby (“Mississippi”) treated at birth [1]  No consistently detectable virus in reservoir (important: both still on ART) –Another baby treated at birth (“Long Beach”) [1] –A recently infected patient in PrEP trial started on ART with HIV-1 RNA 220 c/mL [2]  Relapsed 12 wks and 4 mos after stopping ART [3] –2 patients (“Boston”) post–stem-cell transplant from wild-type donors 1. Persaud D, et al. CROI 2014. Abstract 75LB. 2. Hatano H, et al. CROI 2014. Abstract 397LB. 3. Heinrich TH, et al. CROI 2014. Abstract 144LB.

25. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium 3 Active Drugs—Not 2, Not 4—Have Been the Sweet Spot for Initial HIV Treatment Studies With 2-Drug Strategies  DMP-066  ACTG 5142  SPARTAN  ACTG 5162  RADAR  PROGRESS  A4001078 Studies With 4-Drug Strategies  ACTG 5095  ACTG 5173  COL40263 None to date offers compelling evidence to move from 3-drug approach.

26. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium GARDEL: Study Design  Randomized, international, controlled, open-label phase III study  Study included adult patients from Argentina, Chile, Mexico, Peru, Spain, US Cahn P et al. Lancet Infect Dis. 2014;[Epub ahead of print]. DT: LPV/RTV 400/100 mg BID + 3TC 150 mg BID (n = 217) TT: LPV/RTV 400/100 mg BID + (3TC or FTC) and a third investigator-selected NRTI in fixed-dose combination (n = 209) Stratified by screening HIV-1 RNA (≤ or > 100,000 copies/mL) Wk 48 primary endpoint *Defined as ≥ 1 major or ≥ 2 minor LPV/r mutations. LPV major mutations include the following mutations: V32I; I47V/A; L76V; V82A/F/T/S. Wk 24 interim analysis ARV-naive patients, ≥ 18 yrs HIV-1 RNA > 1000 copies/mL No IAS-USA defined NRTI or PI resistance at screening* (N = 426)

27. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium GARDEL: Dual Therapy Noninferior to Triple Therapy Percent of Patients (%) P =.171, difference +4.6% (Cl 95%: -2.2% to 11.8%) Wk 48 < 50 copies/mL Observed (n = 373) DT 95.5% TT 96.6% -1.1% (-5.6% to 3.4%) P =.777 Wk VL < 50 Copies/mL (ITTe) Cahn P, et al. Lancet Infect Dis. 2014;[Epub ahead of print]. DT TT 100 80 60 40 20 0 90 70 50 30 10 BL4 8 12 24 36 48 88.3 83.7

28. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium NEAT-001/ANRS 143: DRV/RTV + RAL vs DRV/RTV + TDF/FTC in Naive Pts  Randomized, open-label, phase III study  Primary endpoint –Virologic: Change of treatment before Wk 32 because of insufficient response or HIV-1 RNA ≥ 50 c/mL at Wk 32 or beyond –Clinical: Death, any new AIDS-defining event, any new non-AIDS event Raffi F, et al. CROI 2014. Abstract 84LB. ART-naive pts with HIV-1 RNA > 1000 c/mL CD4+ cell count ≤ 500 cells/mm 3 (N = 805)  DRV/RTV 800/100 mg QD + RAL 400 mg BID (n = 401) Wk 96 DRV/RTV 800/100 mg QD + TDF/FTC 300/200 mg QD (n = 404) Stratified by country of origin and participation in virology/immunology substudy

29. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium NEAT: RAL + DRV/RTV Noninferior to TDF/FTC + DRV/RTV at 96 Wks  Overall, regimens noninferior by % reaching composite primary endpoint of 6 virologic and clinical endpoints at Wk 96 –RAL: 17.4%; TDF/FTC: 13.7% –Inferior response in pts with BL CD4+ < 200 and a trend toward more primary endpoints in pts with BL VL ≥ 100K  Similar numbers of pts with PDVF (RAL: n = 66; TDF/FTC: n = 52)  No pts with resistance in TDF/FTC arm vs 5 with integrase mutations and 1 with K65R Raffi F, et al. CROI 2014. Abstract 84LB. Reproduced with permission. OverallN = 805 BL HIV-1 RNA < 100,000 c/mL ≥ 100,000 c/mL n = 530 n = 275 BL CD4+ cell count < 200/mm 3 ≥ 200/mm 3 n = 123 n = 682 Primary Endpoint at Wk 96: Adjusted Difference Estimate (95% CI) RAL – TDF/FTC -100102030 RALTDF/FTC 17.413.7 7 36 7 27 (P =.09) 39.0 13.6 21.3 12.2 (P =.02)  Significantly greater mean increases in fasting lipids in RAL arm Difference in Estimated Proportion (95% CI) RAL – TDF/FTC; Adjusted

30. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium MODERN Study: DRV/RTV Plus MVC vs DRV/RTV Plus FTC/TDF  Randomized, double-blind, double-dummy, active- controlled study ClinicalTrials.gov. NCT01345630. DRV/RTV + MVC QD FTC/TDF placebo QD DRV/RTV + FTC/TDF QD MVC placebo QD n = 393 n = 398 Wk 48 Wk 96 Primary Endpoint Secondary Endpoint Primary endpoint: Proportion of subjects with plasma HIV-1 RNA < 50 copies/mL at Wk 48 ART-naive subjects HIV-1 RNA > 1000 c/mL CD4 ≥ 100 cells/mm 3 Tropism-proven CCR5 virus only No resistance to DRV, TDF, FTC ART-naive subjects HIV-1 RNA > 1000 c/mL CD4 ≥ 100 cells/mm 3 Tropism-proven CCR5 virus only No resistance to DRV, TDF, FTC

31. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium MODERN Study Wk 48 Results: DRV/RTV + MVC Inferior to DRV/RTV + TDF/FTC MODERN Study (A4001095 Early Termination Investigator Letter). ClinicalTrials.gov. NCT01345630. Noninferiority Margin (95% CI) -10% (-17.7% to -6.1%) HIV-1 RNA <50 c/mL (%) Virologic Failures  DRV/RTV + MVC, 38  DRV/RTV + TDF/FTC, 13 Virologic Failures  DRV/RTV + MVC, 38  DRV/RTV + TDF/FTC, 13 Study terminated early due to inferior efficacy October 4, 2013, following Data Monitoring Committee recommendation Study terminated early due to inferior efficacy October 4, 2013, following Data Monitoring Committee recommendation 100 80 60 40 20 0 90 70 50 30 10 DRV/RTV + MVC (n = 393) DRV/RTV + TDF/FTC (n = 398) 72% 83%

32. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Summary of 2-Drug Studies  Results of 3 fully powered studies released in last yr –GARDEL: LPV/RTV + 3TC noninferior to LPV/RTV + 2 NRTIs –NEAT: DRV/RTV + RAL with more virologic failures at high HIV-1 RNA and/or low CD4+ cell count than DRV/RTV + TDF/FTC –MODERN: DRV/RTV + MVC inferior to DRV/RTV + TDF/FTC  Results underscore critical role of 3TC (or FTC) as part of initial therapy

33. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium STRATEGY Trials: Switch to EVG/COBI/TDF/FTC in Suppressed Pts  Randomized, open-label switch studies in pts virologically suppressed on an NNRTI- or boosted PI–based regimen (both with TDF/FTC) for ≥ 6 mos  Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48 HIV-1 RNA < 50 c/mL,  2 previous regimens, no resistance to FTC or TDF and CrCl ≥ 70 mL/min STRATEGY-NNRTI [1] (N = 434) STRATEGY-PI [2]* (N = 433) Switch to EVG/COBI/TDF/FTC QD (n = 291) Remain on NNRTI + TDF/FTC (n = 143) Switch to EVG/COBI/TDF/FTC QD (n = 293) Remain on Boosted PI + TDF/FTC (n = 140) 1. Pozniak A, et al. CROI 2014. Abstract 553LB. 2. Arribas J, et al. CROI 2014. Abstract 551LB. *Pts with previous VF ineligible.

34. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium STRATEGY-NNRTI: Change to EVG/COBI Noninferior to Stable NNRTIs at Wk 48  Regimens: EFV, 78%; NVP, 17%; RPV, 4%; ETR, < 1%; 74% on EFV/TDF/FTC; 91% on first regimen  Results similar across all baseline virologic and demographic subgroups  3 pts with VF in EVG/COBI arm and 1 in NNRTI arm –No pts with resistance in either arm  5 in the switch arm and 1 in the NNRTI arm discontinued due to AE Patients (%) 93 88 Δ +5.3% (95% CI: -0.5 to +12) EVG/COBI/TDF/FTC (n = 290) Stable NNRTIs (n = 143) 0 20 40 60 80 100 1313 < 1 1 6 11 Virologic Success* Virologic Nonresponse No Data  n = *HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm.  Discontinued for AE, death, or missing data. Pozniak A, et al. CROI 2014. Abstract 553LB. Reproduced with permission. 27112616

35. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium STRATEGY-PI: Change to EVG/COBI Better Than Maintaining bPIs at Wk 48  Regimens: ATV, 40%; DRV, 40%; LPV, 17%; FPV, 3%; SQV, < 1%; 79% on first regimen  Results similar across all baseline virologic and demographic subgroups  2 pts with VF in each arm but no pts with resistance in either arm  5 in the switch arm and 2 in the bPI arm discontinued due to AE  Lipids in switch pts –  TGs vs all bPIs –  TC, TG, HDL-C vs LPV/RTV –  HDL-C vs DRV/RTV Patients (%) 94 87 Δ +6.7% (95% CI: 0.4-13.7) EVG/COBI/TDF/FTC (n = 290) Stable bPIs (n = 139) 0 20 40 60 80 100 < 1 2 1212 6 12 Virologic Success* Virologic Nonresponse No Data  n = *HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm.  Discontinued for AE, death, or missing data. Arribas J, et al. CROI 2014. Abstract 551LB. 27212116

36. Investigational Drugs

37. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium 48-Wk Results of TAF vs Tenofovir DF in ART-Naive Pts  TAF (GS-7340), investigational prodrug of tenofovir with lower TFV plasma concentrations, increased delivery to hepatocytes, lymphoid cells  Randomized, placebo- controlled, phase II trial of TAF vs TDF, each coformulated with FTC/EVG/COBI, in ART-naive patients Zolopa A, et al. CROI 2013. Abstract 99LB. Sax P, et al. ICAAC 2013. Abstract H-1464d. Reproduced with permission. ART-naive patients, CD4+ cell count > 50 cells/mm 3, eGFR ≥ 70 mL/min (N = 170) TAF/FTC/EVG/COBI (n = 112) TDF/FTC/EVG/COBI (n = 58) Wk 48 Wk 24 Gut TFV TDF TAF Plasma TDF/TFV TAF Lymphoid Cells TAF TFV TFV-MP TFV-DP Cathepsin A

38. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium 6 TAF/FTC/EVG/COBI Noninferior to TDF/FTC/EVG/COBI Through Wk 48  Noninferiority at Wk 24 primary endpoint analysis [1] –89.7% vs 87.5 % with HIV-1 RNA < 50 c/mL, respectively  6 pts (3 per arm) eligible for resistance analysis at Wk 48 [2] –No pts with resistance in TAF arm –1 pt with NRTI and INSTI resistance in TDF arm (M184V, E92Q) Patients (%) 88.4 87.9 Δ 1.0% (95% CI: -12.1 to +10.0; P =.84) TAF/FTC/EVG/COBI TDF/FTC/EVG/COBI 9951 0 20 40 60 80 100 6.3 10.3 5.4 1.7 1 7 6 Virologic Success* Virologic Nonresponse No Data  1. Zolopa A, et al. CROI 2013. Abstract 99LB. 2. Sax P, et al. ICAAC 2013. Abstract H-1464d. n = *HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm.  Discontinued for AE, death, or missing data.

39. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium TAF vs TDF Phase II Study: Change in Estimated GFR Over Time -5.5 -10.0 P =.041 TAF/FTC/EVG/COBI also had significantly less effect on markers of renal tubular toxicity (retinol binding protein, B2 microglobulin) than TDF/FTC/EVG/COBI Sax P, et al. ICAAC 2013. Abstract H-1464d. TAF/FTC/EVG/COBI TDF/FTC/EVG/COBI Median (Q1, Q3) Change From Baseline eGFR Cockroft-Gault (mL/min) 20 10 0 -10 -20 0 12 24 3648 Time (Wks)

40. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium HIP SPINE Wk 48 Median Value of Bone Biomarkers as % of Baseline: TAF/FTC/EVG/COBI vs TDF/FTC/EVG/COBI Procollagen Type 1 N-terminal propeptide (P1NP):109% vs 169% (P <.001) C-terminal telopeptide (CTx):119% vs 178% (P <.001) -0.62 P <.001 -2.39 P <.001 -3.37 No decrease in hip BMD in 32% TAF/FTC/EVG/COBI pts vs 7% TDF/FTC/EVG/COBI pts (P <.001) Sax P, et al. ICAAC 2013. Abstract H-1464d. TDF/FTC/EVG/COBI TAF/FTC/EVG/COBI TAF vs TDF Phase II Study: % Change in Spine and Hip BMD (DEXA) 2 0 -2 -4 -6 Median (Q1, Q3) Change, % 012243648 Time (Wks) 2 0 -2 -4 -6 012243648 Time (Wks)

41. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Tenofovir Alafenamide: Summary and What’s Coming  Phase II and preclinical data suggest the following potential benefits –Reduced renal and bone toxicity –Lower dose allows smaller pill, novel coformulations –Possible activity vs some TDF-resistant strains  Phase III studies of “ECF-TAF” or “Quad-II” fully enrolled  Development of TAF/FTC and TAF/FTC/DRV/COBI planned

42. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Doravirine (MK-1439): Investigational NNRTI Morales-Ramirez J, et al. CROI 2014. Abstract 92LB. Efavirenz MK-1439 200 mg* Efavirenz* Wk 96 End of study treatment for part 1 Wk 96 End of study treatment for part 1 MK-1439 selected dose PART 1 Dose-ranging ~ 200 patients (~ 40/group) PART 1 Dose-ranging ~ 200 patients (~ 40/group) MK-1439 50 mg* MK-1439 100 mg* MK-1439 25 mg* Wk 24 Primary time point for dose selection Wk 24 Primary time point for dose selection *All with TDF/FTC

43. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium MK-1439 all doses combined: 76.4% 32/4032/4127/42 Doravirine vs EFV Phase II: 24-Wk Results Morales-Ramirez J, et al. CROI 2014. Abstract 92LB. HIV-1 RNA < 40 Copies/mL (%) 0 20 40 60 80 100 MK-1439 25 mg MK-1439 50 mg MK-1439 100 mg MK-1439 200 mg Efavirenz 600 mg 80.0 76.2 71.4 78.0 64.3 32/4230/40

44. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Increased Risk of Suicidality Associated With EFV Mollan K, et al. IDWeek 2013. Abstract 40032. *Person-years, sum of at-risk follow-up. As-treated HR 2.16 (1.16-4.00) HR (95% CI) 2.28 (1.27-4.10), P =.006 47 events/5817 PY* (8.08/1000 PY) 15 events/4099 PY* (3.66/1000 PY) 5% Efavirenz Efavirenz-free Probability.05.04.03.02.01 0 0 24 48 72 96 120 144 168 192 Wks to Suicidality

45. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium LATTE: Study Design  Phase IIb, randomized, multicenter, partially blind, dose-ranging study comparing S/GSK744 plus RPV to EFV plus NRTIs *ABC/3TC or TDF/FTC.  Patients on 744 + NRTI: If Wk 20 VL < 50 c/mL, simplify to 744/RPV at Wk 24. HIV-1 ART-naive HIV-1 RNA > 1000 c/mL 1:1:1:1 randomization Stratified by VL and NRTI HIV-1 ART-naive HIV-1 RNA > 1000 c/mL 1:1:1:1 randomization Stratified by VL and NRTI 744 30 mg + 2 NRTIs* 744 10 mg + 2 NRTIs* Oral Induction Phase 744 60 mg + 2 NRTIs* Oral Maintenance Phase  744 10 mg + RPV 25 mg 744 30 mg + RPV 25 mg 744 60 mg + RPV 25 mg 24 1620 489672 EFV 600 mg + 2 NRTIs* Wk D1 Margolis D, et al. EACS 2013. Abstract PS7/1.

46. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium 744 + RPV Regimen Maintained Suppression Comparable to EFV-Based Therapy Wk 744 OR Wk 48 82% EFV response Wk 48 71% 744 OR Wk 24 87% EFV response Wk 24 74% Median (IQR) Change From BL CD4+ Cell Count (Cells/mm 3 ) Wk 48 744 overall+219 (141,343) EFV+227 (134,369) 2424812164032483626 28 BL Induction Phase Maintenance Phase Margolis D, et al. CROI 2014. Abstract 91LB. Proportion, % 0 20 40 60 80 100 744 10 mg (N = 60)744 30 mg (N = 60)744 60 mg (N = 61) EFV 600 mg (N = 62)

47. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium PDVF and Resistance 744 Total n = 181 EFV n = 62 Subjects with PDVF during induction3* (2%)3 (5%) No NRTI, NNRTI, or INI treatment-emergent mutations PDVF: < 1.0 log 10 c/mL decrease in plasma HIV-1 RNA by Wk 4 or confirmed HIV-1 RNA ≥ 200 c/mL at or after Wk 16 or after prior suppression to < 200 c/mL 744 Total n = 160 EFV n = 47 Subjects with PDVF during maintenance2  (1%)1 (2%) IN genotypic results at BL and time of PDVF11 INI-r mutations10 PR/RT genotypic results at BL and time of PDVF21 NRTI-r mutations NNRTI-r mutations 0101 0000 *1 subject per 744 dose.  744 10 mg: treatment-emergent INI (Q148R) and NNRTI (E138Q) at Wk 48; 744 FC = 3; RPV FC = 2; 744 and RPV concentrations < 50% of expected; extreme calorie restricted diet Wk 40- Wk 48  744 30 mg: PDVF at W36; no treatment-emergent mutations Margolis D, et al. CROI 2014. Abstract 91LB.

48. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Drugs With Novel Mechanisms for Pan-Resistant HIV in Phase II or Later  BMS-663068 (attachment inhibitor)  … that’s it! It is therefore critical that patients with highly resistant virus preserve virologic suppression through excellent adherence! Lalezari J, et al. CROI 2014. Abstract 86. Discontinuation notice for vircoTYPE, November 2013

49. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Lalezari J, et al. CROI 2014. Abstract 86. AI438011: BMS-663068 Monotherapy: Mean Change in HIV-1 RNA From BL* Mean Change in HIV-1 RNA From Baseline (Log 10 C/mL) 0.5 0 -0.5 -1.5 -2 0 2 4 6 8 Day *Error bars represented standard error of the mean. 400 mg BID (n = 7) 800 mg BID (n = 5) 600 mg QD (n = 10) 1200 mg QD (n = 10) -0.69 -1.22 -1.37 -1.47

50. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Antiretroviral Therapy: What to Expect in the Next 12 Mos  Coformulated ABC/3TC/DTG  Coformulated DRV/COBI  Coformulated ATV/COBI  Phase III data of TAF/FTC/EVG/COBI  Other key data?

51. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Antiretroviral Therapy in 2014: Conclusions  Treatment has become the cornerstone of HIV prevention  Data on integrase inhibitor–based initial therapies are increasingly favorable  2-drug strategies should generally be avoided pending further data  Drugs in development may offer improvements in safety, tolerability, convenience