Medical Perspective on HIV/AIDS and the Importance of Treatment

1. Medical Perspective on HIV/AIDS and the Importance of Treatment Corklin R. Steinhart, MD, PhD Global Medical Lead, “TRII” Executive Director Medical Strategy, North America ViiV Healthcare August 4, 2014

2. Thanks to Clinical Care Options (Dr. Paul Sax) and to Dr. Andrew Carr for the use of some slides

6. Take Home Messages • The HIV virus “sets up shop” in the human body within hours of infection • HIV is a chronic viral infection • Question: why would you want a viral infection to cause relentless damage to your body before beginning effective cART? • All guidelines are changing to begin therapy regardless of CD4 count: it’s about time! • HIV therapy is needed for life at this time • Is there a place for newer and better ARVs and strategies? • Yes, because currently there are no perfect ARVs or strategies! • If you take the medicines, they work: ADHERENCE is the key to success!

7. “OK. I’m done! Any questions?”

8. Major reduction in AIDS-mortality inequalities after HAART: Fig. 1 Age and sex-adjusted (European population was used as standard) AIDS mortality rates (per 100,000 person-years) in population aged 20–49 years. Region of Madrid (Spain), 1990–2003. Social Science & Medicine, Volume 68, Issue 3, 2009, 419 - 426 http://dx.doi.org/10.1016/j.socscimed.2008.10.039

10. JAMA. 2014; 312 (4): 410-425

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

13. Choice of initial 3rd ART drug ART guidelines 1. DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, May 20142. EACS Guidelines Version 7.02, June 20143. Günthard HF, et al. JAMA 2014;312:410-4254. WHO guidelines for the use of antiretroviral drugs for treating and preventing HIV infection, June 2013 *For patients with HIV-1 RNA <100,000 c/mLDHHS, Department of Health and Human Services; EACS, European AIDS Clinical Society; IAS-USA, International Antiviral Society USA Panel; WHO, World Health Organization; TDF/FTC tenofovir/emtricitabine; EFV, efavirenz; ABC/3TC abacavir/lamivudine; RPV, rilpivirine; ATV/r, atazanavir/ritonavir; DRV/r, darunavir/ritonavir; DTG, dolutegravir; EVG/c, elvitegravir/cobicistat; RAL, raltegravir; NRTIs, nucleoside reverse transcriptase inhibitors; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI/r, boosted protease inhibitor; INI, integrase inhibitor NRTIs NNRTI PI/r INI

14. Once-daily administration without a PK enhancer Desirable Attributes of new agents as part of A first-line treatment regimen Low PK variability and predictable exposure-response relationship Highly potent antiviral activity Safe and generally well tolerated Favourable resistance profile ARV Simple regimen No food requirements DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, May 2014 ARV, antiretroviral; PK, pharmacokinetic

15. 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. Dolutegravir Clinical Trials in Treatment-Naive Pts • Randomized, noninferiority phase III studies • Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 48 DTG 50 mg QD + 2 NRTIs*(n = 411) ART-naive pts VL ≥ 1000 c/mL(N = 822) SPRING-2[1] (placebo controlled) RAL 400 mg BID + 2 NRTIs*(n = 411) DTG 50 mg QD + ABC/3TC QD(n = 414) ART-naive pts VL ≥ 1000 c/mLHLA-B*5701 neg CrCl > 50 mL/min(N = 833) SINGLE[2] (placebo controlled) EFV/TDF/FTC QD (n = 419) DTG 50 mg QD + 2 NRTIs*(n = 242) ART-naive pts VL ≥ 1000 c/mL(N = 484) FLAMINGO[3] (open label) DRV/RTV 800/100 mg QD + 2 NRTIs*(n = 242) *Investigator-selected NRTI backbone: either TDF/FTC or ABC/3TC. 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. 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 DTG + ABC/3TC EFV/TDF/FTC 100 DTG: 80% 80 60 EFV: 72% Proportion of Patients (%) Wk 96 adjusted difference in response (95% CI): +8.0% (+2.3% to +13.8%); P = .006 40 CD4 ∆ from BL 20 0 0 4 8 12 16 24 32 40 48 60 72 84 96 Wk 1. Walmsley S, et al. N Engl J Med. 2013;369:1807-1818. 2. Walmsley S, et al. CROI 2014. Abstract 543.

18. Activity of Integrase-Based Therapies Maintained at High HIV-1 RNA STARTMRK[1] SPRING-2[4] Difference, % (RAL-EFV) and 95% CI Difference, % (DTG-RAL) and 95% CI In favor of DTG In favor of EFV In favor of RAL In favor of RAL ≤ 100,000 c/mL ≤ 100,000 c/mL > 100,000 c/mL > 100,000 c/mL -20 -10 -20 0 20 30 -10 0 20 30 10 10 SINGLE[4] Study 102[2] Difference, % (DTG-EFV) and 95% CI Difference, % (EVG/COBI-EFV) and 95% CI In favor of DTG In favor of EFV In favor of EFV In favor of EVG/COBI ≤ 100,000 c/mL ≤ 100,000 c/mL > 100,000 c/mL > 100,000 c/mL -20 -10 5 15 -10 -15 -5 0 10 0 20 30 10 Study 103[3] FLAMINGO[5] Difference , % (DTG-DRV/RTV) and 95% CI Difference, % (EVG/COBI-ATV/RTV) and 95% CI In favor of DRV/RTV In favor of DTG In favor of EVG/COBI In favor of ATV/RTV ≤ 100,000 c/mL ≤ 100,000 c/mL > 100,000 c/mL > 100,000 c/mL -20 -10 5 15 -15 -5 0 10 -10 0 20 30 40 10 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.

19. Mollan K, et al. IDWeek 2013. Abstract 40032. Increased Risk of Suicidality Associated With EFV 5% .05 EfavirenzEfavirenz-free .04 HR (95% CI) 2.28 (1.27-4.10), P = .006 .03 Probability 47 events/5817 PY* (8.08/1000 PY) .02 .01 15 events/4099 PY* (3.66/1000 PY) 0 192 96 48 144 72 24 168 120 0 As-treated HR 2.16 (1.16-4.00) Wks to Suicidality *Person-years, sum of at-risk follow-up.

20. 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 Stratified by HIV-1 RNA < or ≥ 100,000 c/mL, participation in metabolic substudy, CV risk Wk 96 after last patient enrolled ATV/RTV 300/100 mg QD + TDF/FTC(n = 605) ART-naive patients with HIV-1 RNA ≥ 1000 c/mL (N = 1809) RAL 400 mg BID + TDF/FTC(n = 603) DRV/RTV 800/100 mg QD + TDF/FTC(n = 601) Landovitz R, et al. CROI 2014. Abstract 85.

21. Regimens equivalent in time to VF ACTG 5257: Primary Endpoint Analyses at Wk 96 Virologic Failure Tolerability Failure Composite Endpoint • 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 Favors RAL Favors RAL ATV/RTV vs RAL3.4% (-0.7 to 7.4) ATV/RTV vs RAL13% (9.4-16.0) ATV/RTV vs RAL15% (10-20) Favors RAL DRV/RTV vs RAL3.6% (1.4-5.8) DRV/RTV vs RAL5.6% (1.3 -9.9) DRV/RTV vs RAL7.5% (3.2-12.0) Favors DRV/RTV Favors DRV/RTV ATV/RTV vs DRV/RTV-2.2% (-6.7 to 2.3) ATV/RTV vs DRV/RTV9.2% (5.5-13.0) ATV/RTV vs DRV/RTV7.5% (2.3-13.0) -10 0 10 20 -10 0 10 20 -10 0 10 20 Difference in 96-Wk Cumulative Incidence (97.5% CI) Landovitz R, et al. CROI 2014. Abstract 85. Reproduced with permission.

22. Novel Strategies for Treatment

23. 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.

24. *ABC/3TC or TDF/FTC. Patients on 744 + NRTI: If Wk 20 VL < 50 c/mL, simplify to 744/RPV at Wk 24. LATTE: Study Design • Phase IIb, randomized, multicenter, partially blind, dose-ranging study comparing S/GSK744 plus RPV to EFV plus NRTIs Oral Induction Phase Oral Maintenance Phase 744 10 mg + RPV 25 mg 744 10 mg + 2 NRTIs* HIV-1 ART-naive HIV-1 RNA > 1000 c/mL 1:1:1:1 randomization Stratified by VL and NRTI 744 30 mg + RPV 25 mg 744 30 mg + 2 NRTIs* 744 60 mg + RPV 25 mg 744 60 mg + 2 NRTIs* EFV 600 mg + 2 NRTIs* 24 48 72 96 Wk 16 20 D1 Margolis D, et al. EACS 2013. Abstract PS7/1.

25. 744 + RPV Regimen Maintained Suppression Comparable to EFV-Based Therapy 744 OR Wk 24 87% 744 OR Wk 48 82% Induction Phase Maintenance Phase 100 80 60 Proportion, % EFV response Wk 48 71% EFV response Wk 24 74% 40 20 0 BL 2 4 8 12 16 24 26 32 36 40 48 28 Wk 744 10 mg (N = 60) 744 30 mg (N = 60) 744 60 mg (N = 61) EFV 600 mg (N = 62) Margolis D, et al. CROI 2014. Abstract 91LB.

26. Investigational Drugs

27. 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

28. Doravirine vs EFV Phase II: 24-Wk Results MK-1439 all doses combined: 76.4% 100 80.0 78.0 76.2 80 71.4 64.3 60 HIV-1 RNA < 40 Copies/mL (%) 40 20 32/40 32/42 30/40 32/41 27/42 0 MK-143925 mg MK-143950 mg MK-1439100 mg MK-1439200 mg Efavirenz600 mg Morales-Ramirez J, et al. CROI 2014. Abstract 92LB.

29. GSK744 LA Is Formulated as a 200 mg/mL Nanosuspension GSK1265744 (GSK744) Dolutegravir 1.Müller et al. Eur J PharmBiopharm. 2011;78:1-9. 2. Spreen et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract WEAB0103.3. Min et al. ICAAC 2009; San Francisco, CA. Abstract H-1228. 4.Taoda et al. International Congress on Drug Therapy in HIV Infection 2012; Glasgow, Scotland. Abstract P206. Andrews et al. CROI 2014; Boston, MA. Abstract 39.

30. Pharmacokinetic Evaluation of a Single Intramuscular GSK744 LA Injection in Human Volunteers 4X PAIC90 1X PAIC90 Adapted from Spreen et al. IAC 2012; Washington, DC. Abstract TUPE040. Andrews et al. CROI 2014; Boston, MA. Abstract 39.

31. Drugs With Novel Mechanisms for Pan-Resistant HIV in Phase II or Later • BMS-663068 (attachment inhibitor) It is therefore critical that patients with highly resistant virus preserve virologic suppression through excellent adherence! Lalezari J, et al. CROI 2014. Abstract 86.

32. Adherence as a Driver for Treatment Success MSD Satellite Symposium EACS Belgrade, Oct 12 2011

33. cART 4 life – the patient marathon • Long-term adherence is difficult: Toxicities, side effects, co-morbidities, mental health • Non-adherenceis dangerous: Resistance risk • Individual adherence barriers: Drug or alcohol use, Problems at work or in relationships, readiness relapse • System related barriers: Insurance coverage, stock-outs, stigmatisation

35. ADHERENCE “The bottom line is this: if patients take their meds they will do well!”

36. Assuming they are all available….

37. 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 • Additional data on long acting parenteral formulations • Other key data?

38. 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

39. Take Home Messages • The HIV virus “sets up shop” in the human body within hours of infection • HIV is a Chronic Viral Infection • Question: why would you want a viral infection to cause relentless damage to your body before beginning effective cART? • All guidelines are changing to begin therapy regardless of CD4 count: it’s about time! • HIV therapy is needed for life at this time • Is there a place for newer and better ARVs and strategies? • Yes, because currently there are no perfect ARVs or strategies! • If you take the medicines, they work: ADHERENCE is the key to success!

40. Thanks very much 