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?”

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

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

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.

DHHS, 2014 1 TDF/FTC TDF/FTC TDF/FTC ABC/3TC CHOICE OF INITIAL 3 RD ART DRUG EFV ATV/r DRV/r DTG EVG/c RAL DTG ART guidelines EACS, 2014 2 TDF/FTC EFV RPV* IAS-USA, 2014 3 TDF/FTC EFV RPV* ABC/3TC TDF/FTC ABC/3TC EFV RPV ATV/r DRV/r ATV/r DRV/r ABC/3TC TDF/FTC ABC/3TC EFV ATV/r DRV/r ATV/r TDF/FTC RAL EVG/c TDF/FTC DTG EVG/c RAL ABC/3TC DTG WHO, 2013 4 TDF/FTC TDF/3TC EFV

NRTIs NNRTI PI/r INI *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 1. DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, May 2014 2. EACS Guidelines Version 7.02, June 2014 3. Günthard HF, et al. JAMA 2014;312:410-425 4. WHO guidelines for the use of antiretroviral drugs for treating and preventing HIV infection, June 2013

DESIRABLE ATTRIBUTES OF NEW AGENTS AS PART OF A FIRST-LINE TREATMENT REGIMEN

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

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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

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Dolutegravir Clinical Trials in Treatment Naive Pts

 Randomized, noninferiority phase III studies  Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 48 SPRING-2 [1] (placebo controlled) 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) SINGLE [2] (placebo controlled) 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) FLAMINGO (open label) [3] ART-naive pts VL ≥ 1000 c/mL (N = 484) DTG 50 mg QD + 2 NRTIs* (n = 242) 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].

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SINGLE: Dolutegravir + ABC/3TC vs Efavirenz/TDF/FTC in Tx-Naive Pts

DTG + ABC/3TC EFV/TDF/FTC 100 DTG: 80% 80   60 40 20 CD4 ∆ from BL EFV: 72% Wk 96 adjusted difference in response (95% CI): +8.0% (+2.3% to +13.8%);

P

= .006

Treatment

DTG + ABC/3TC QD (n = 414) EFV/TDF/FTC QD (n = 419)

Wk 96 ∆ From BL Adjusted Mean

325.3

281.4

SE

10.5

10.9

Difference in Response (95% CI)

44.0 (14.3, 73.6)

P

= .004

0 0 4 8 12 16 24 32 40 48 Wk 60 72 84 96 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 1. Walmsley S, et al. N Engl J Med. 2013;369:1807-1818. 2. Walmsley S, et al. CROI 2014. Abstract 543.

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Activity of Integrase-Based Therapies Maintained at High HIV-1 RNA

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

24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com

Increased Risk of Suicidality Associated With EFV

5% .05

.04

Efavirenz Efavirenz-free HR (95% CI) 2.28 (1.27-4.10),

P

= .006

.03

.02

47 events/5817 PY* (8.08/1000 PY) .01

15 events/4099 PY* (3.66/1000 PY) 0 As-treated HR 2.16 (1.16-4.00) 0 24 48 Wks to Suicidality *Person-years, sum of at-risk follow-up.

72 96 120 144 168 192 Mollan K, et al. IDWeek 2013. Abstract 40032.

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ACTG 5257: Open-Label ATV/RTV vs RAL vs DRV/RTV in First-line ART

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) 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.

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

ACTG 5257: Primary Endpoint Analyses at Wk 96

Virologic Failure Regimens equivalent in time to VF  Tolerability Failure Significantly greater incidence of treatment failure with ATV/RTV vs RAL or DRV/RTV – In part due to high proportion of pts with hyperbilirubinemia   Composite Endpoint Considering both efficacy and tolerability, RAL superior to either boosted PI DRV/RTV superior to ATV/RTV -10 0 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) 10 20 -10 0 Favors RAL ATV/RTV vs RAL 13% (9.4-16.0) DRV/RTV vs RAL 3.6% (1.4-5.8) Favors DRV/RTV ATV/RTV vs DRV/RTV 9.2% (5.5-13.0) 10 20 -10 0 Difference in 96-Wk Cumulative Incidence (97.5% CI) Favors RAL ATV/RTV vs RAL 15% (10-20) Favors RAL DRV/RTV vs RAL 7.5% (3.2-12.0) Favors DRV/RTV ATV/RTV vs DRV/RTV 7.5% (2.3-13.0) 10 20 Landovitz R, et al. CROI 2014. Abstract 85. Reproduced with permission.

Novel Strategies for Treatment

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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.

24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com

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 + 2 NRTIs* 744 10 mg + RPV 25 mg 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 30 mg + RPV 25 mg 744 60 mg + 2 NRTIs* 744 60 mg + RPV 25 mg EFV 600 mg + 2 NRTIs* D1 Wk 16 20 24 48 *ABC/3TC or TDF/FTC.

 Patients on 744 + NRTI: If Wk 20 VL < 50 c/mL, simplify to 744/RPV at Wk 24.

Margolis D, et al. EACS 2013. Abstract PS7/1. 72 96

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744 + RPV Regimen Maintained Suppression Comparable to EFV-Based Therapy

Induction Phase 744 OR Wk 24 87% Maintenance Phase 744 OR Wk 48 82% 100 80 60 40 20 0 BL 2 744 10 mg (N = 60) 4 8 12 16 Margolis D, et al. CROI 2014. Abstract 91LB.

EFV response Wk 24 74% EFV response Wk 48 71%

Median (IQR) Change From BL CD4+ Cell Count (Cells/mm 3 ) 744 overall EFV Wk 48

+219 (141,343) +227 (134,369) 744 30 mg (N = 60) 24 Wk 2628 32 36 744 60 mg (N = 61) 40 48 EFV 600 mg (N = 62)

Investigational Drugs

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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

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Doravirine vs EFV Phase II: 24-Wk Results

MK-1439 all doses combined: 76.4% 100 80.0

80 76.2

78.0

71.4

60 40 20 0 32/40 MK-1439 25 mg 64.3

32/42 MK-1439 50 mg 30/40 MK-1439 100 mg 32/41 MK-1439 200 mg 27/42 Efavirenz 600 mg Morales-Ramirez J, et al. CROI 2014. Abstract 92LB.

GSK744 LA Is Formulated as a 200 mg/mL Nanosuspension

GSK1265744 (GSK744)

F F O N H O N H O N OH O F F

Dolutegravir

O N H O N OH O H O N 1. Müller et al. Eur J Pharm Biopharm. 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.

Pharmacokinetic Evaluation of a Single Intramuscular GSK744 LA Injection in Human Volunteers

10 200 mg 400 mg 800 mg 1 4X PAIC 90 1X PAIC 90 0.10

0.01

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Time (weeks)

Adapted from Spreen et al. IAC 2012; Washington, DC. Abstract TUPE040.

Andrews et al. CROI 2014; Boston, MA. Abstract 39.

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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.

Adherence as a Driver for Treatment Success

MSD Satellite Symposium EACS Belgrade, Oct 12 2011

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….

24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com

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?

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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

