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

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

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!

“OK. I’m done! Any questions?”

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, Major reduction in AIDS-mortality inequalities after HAART:

JAMA. 2014; 312 (4):

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.

CHOICE OF INITIAL 3 RD ART DRUG ART guidelines 1. DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, May EACS Guidelines Version 7.02, June Günthard HF, et al. JAMA 2014;312: WHO guidelines for the use of antiretroviral drugs for treating and preventing HIV infection, June 2013 DHHS, EACS, IAS-USA, WHO, TDF/FTCEFVTDF/FTC EFV RPV* TDF/FTC EFV RPV* TDF/FTC TDF/3TC EFV ABC/3TC EFV RPV ABC/3TCEFV TDF/FTC ATV/r DRV/r TDF/FTC ATV/r DRV/r TDF/FTC ATV/r DRV/r ABC/3TC ATV/r DRV/r ABC/3TCATV/r TDF/FTC DTG EVG/c RAL TDF/FTC RAL EVG/c TDF/FTC DTG EVG/c RAL ABC/3TCDTGABC/3TCDTG NRTIsNNRTIPI/rINI *For patients with HIV-1 RNA <100,000 c/mL DHHS, 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

DESIRABLE ATTRIBUTES OF NEW AGENTS AS PART OF A FIRST-LINE TREATMENT REGIMEN ARV Highly potent antiviral activity No food requirements Favourable resistance profile Once-daily administration without a PK enhancer Low PK variability and predictable exposure- response relationship Simple regimen Safe and generally well tolerated DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, May 2014 ARV, antiretroviral; PK, pharmacokinetic

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

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: Walmsley S, et al. N Engl J Med. 2013;369: Clotet B, et al. Lancet. 2014;[Epub ahead of print].

clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium 1. Walmsley S, et al. N Engl J Med. 2013;369: Walmsley S, et al. CROI Abstract 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) (14.3, 73.6) P =.004 EFV/TDF/FTC QD (n = 419) 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 (%) Wk DTG + ABC/3TCEFV/TDF/FTC

clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium 1. Lennox J, et al. Lancet. 2009;374: Sax PE, et al. Lancet. 2012;379: De Jesus E, et al. Lancet. 2012;379: Brinson C, et al. CROI Abstract Feinberg J, et al. ICAAC Abstract 1464a. ≤ 100,000 c/mL > 100,000 c/mL SPRING-2 [4] Difference, % (DTG-RAL) and 95% CI In favor of RAL In favor of DTG ≤ 100,000 c/mL > 100,000 c/mL SINGLE [4] 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 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] ≤ 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] Difference, % (RAL-EFV) and 95% CI In favor of EFV In favor of RAL Activity of Integrase-Based Therapies Maintained at High HIV-1 RNA

clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Increased Risk of Suicidality Associated With EFV Mollan K, et al. IDWeek Abstract *Person-years, sum of at-risk follow-up. As-treated HR 2.16 ( ) HR (95% CI) 2.28 ( ), P = events/5817 PY* (8.08/1000 PY) 15 events/4099 PY* (3.66/1000 PY) 5% Efavirenz Efavirenz-free Probability Wks to Suicidality

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 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

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 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) ATV/RTV vs RAL 3.4% (-0.7 to 7.4) DRV/RTV vs RAL 5.6% ( ) ATV/RTV vs DRV/RTV -2.2% (-6.7 to 2.3) ATV/RTV vs RAL 15% (10-20) DRV/RTV vs RAL 7.5% ( ) ATV/RTV vs DRV/RTV 7.5% ( ) Favors RAL Favors DRV/RTV Favors RAL ATV/RTV vs RAL 13% ( ) DRV/RTV vs RAL 3.6% ( ) ATV/RTV vs DRV/RTV 9.2% ( ) Favors RAL Favors DRV/RTV

Novel Strategies for Treatment

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  A Studies With 4-Drug Strategies  ACTG 5095  ACTG 5173  COL40263 None to date offers compelling evidence to move from 3-drug approach.

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 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 mg + 2 NRTIs* mg + 2 NRTIs* Oral Induction Phase mg + 2 NRTIs* Oral Maintenance Phase  mg + RPV 25 mg mg + RPV 25 mg mg + RPV 25 mg EFV 600 mg + 2 NRTIs* Wk D1 Margolis D, et al. EACS Abstract PS7/1.

clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium 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 overall+219 (141,343) EFV+227 (134,369) BL Induction Phase Maintenance Phase Margolis D, et al. CROI Abstract 91LB. Proportion, % mg (N = 60) mg (N = 60) mg (N = 61) EFV 600 mg (N = 62)

Investigational Drugs

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

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 Abstract 92LB. HIV-1 RNA < 40 Copies/mL (%) MK mg MK mg MK mg MK mg Efavirenz 600 mg /4230/40

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

Adapted from Spreen et al. IAC 2012; Washington, DC. Abstract TUPE040. Pharmacokinetic Evaluation of a Single Intramuscular GSK744 LA Injection in Human Volunteers Andrews et al. CROI 2014; Boston, MA. Abstract 39. 4X PAIC 90 1X PAIC 90

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

Adherence as a Driver for Treatment Success MSD Satellite Symposium EACS Belgrade, Oct

cART 4 life – the patient marathon Long-term adherence is difficult: Toxicities, side effects, co-morbidities, mental health Non-adherence is 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

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

Assuming they are all available….

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  Additional data on long acting parenteral formulations  Other key data?

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

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!

Thanks very much