ART Progress 2016

R.M. Gulick, MD, MPH Gladys and Roland Harriman Professor of Medicine

Chief, Division of Infectious Diseases Weill Cornell Medical College

New York City

Disclosures No financial interests or relationships to disclose. Co-Chair, U.S. DHHS Antiretroviral Guidelines Panel Member, Voluntary Board of Directors, International Antiviral Society (IAS)-USA

•

Life Expectancy: Kaiser Permanente • Kaiser Permanente California 1996-2011 • Individuals followed: 25,768 HIV+ and 257,600 HIV- • Deaths: 2229 (HIV+) and 4970 (HIV-) • Life expectancy (years) at age 20:

• 1996-2006: +36 (HIV+) vs. +62 (HIV-); ∆=26 • 2007-2011: +48 (HIV+); ∆=14

• lowest were among blacks (+45) and IDU (+43) • start ART CD4 >500 +54; ∆=9 • no history HBV, HCV, drug/ETOH/cigs ∆=6-7

Marcus CROI 2016 #54

ART: Questions

• When to start? • What to start? • When to change? • What to change to?

When to Start?

START (Strategic Timing of Antiretroviral Treatment Study): Design

HIV+, ART-naïve, CD4+ >500 cells/mm3

Immediate ART Group Initiate ART immediately

N=2,326

Deferred ART Group Defer ART until CD4+ <350 or AIDS

N=2,359

Primary composite endpoint, target = 213 Serious AIDS or death from AIDS Serious Non-AIDS Events and death not attributable to AIDS

– CVD, ESRD, decompensated liver disease, & non-AIDS defining cancers

Stopped early by DSMB; average f/u 3 years

INSIGHT, N Engl J Med 2015;373:795-807

START: Primary Endpoint

No. of Participants

Type of event Imm. ART Def. ART

Serious AIDS 14 50

Serious non-AIDS 29 47

Total* 42 (1.8%) 96 (4.1%)

* One participant in each group had both a Serious AIDS and a Serious Non-AIDS Event

HR 0.43 (0.30, 0.62; P<0.001)

Most common: AIDS events: TB, Lymphoma, Kaposi’s sarcoma, PCP, dissem VZV Non-AIDS events: Non-AIDS cancers, CV disease

INSIGHT, N Engl J Med 2015;373:795-807

START: Other Analyses

No difference (all groups benefit) by: age, sex, race, geography (low/middle vs. high income) cigarette smoking, Framingham risk baseline CD4, baseline VL

↑ risk of clinical events with ↑ age, ↓ CD4, ↑ Framingham score

Toxicity: no differences

Conclusion: ART benefits all

Implications (IAS 2015): Chile, Thailand, UK all changed to recommend ART for ALL WHO changed to recommend all in September 2015

INSIGHT, N Engl J Med 2015;373:795-807

When to Start?: Guidelines AIDS/

symptoms CD4 <200

CD4 200-350

CD4 350-500

CD4 >500

US DHHS 2016 www.aidsinfo.nih.gov

YES YES YES YES YES

IAS-USA 2014 JAMA 2014;312:390

YES YES YES YES YES

EACS 2015 www.europeanaidsclinicalsociety.org/

YES YES YES YES YES

UK 2015 www.bhiva.org

YES YES YES YES YES

WHO 2015 http://apps.who.int/iris/bitstream/10665/186275/1/9789241509565_eng.pdf

YES YES YES YES YES

What to Start?

Antiretroviral Drug Approval: 1987 - 2016

0

5

10

15

20

25

30

1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015

AZT ddI ddC d4T

3TC SQV

RTV IDV NVP

NFV DLV

EFV ABC

APV LPV/r

TDF

ENF ATV FTC FPV TPV

DRV

ETR RAL MVC RPV

EVG DTG TAF

Recommended ART Regimens (2 NRTI + 3rd drug)

• Protease Inhibitor-based – TDF/FTC + DRV/r

• Integrase Inhibitor-based

– ABC/3TC/DTG – TDF/FTC + DTG – TAF/FTC/EVG/c – TDF/FTC/EVG/c – TDF/FTC + RAL

U.S. DHHS Guidelines 1/28/16 www.aidsinfo.nih.gov

ART Overview: U.S. Center for AIDS Research (CFAR) Network of Integrated Clinical Systems (CNICS) Cohort • 29,467 participants at 8

U.S. HIV clinics 19972014

• After 2010, predictors of VS were: older, white, male, ↑ adherence, integrase inhibitor use

Simoni CROI 2016 #1034

Newer ART Rx-Naïve Studies Study (reference) N Regimen VL <50 (96 wks)

ACTG 5257 Lennox Ann Intern Med 2014;161:461

605 2 NRTI + ATV/r 88%

601 2 NRTI + DRV/r 89% 603 2 NRTI + RAL 94%*

SINGLE Walmsley NEJM 2013;369:1807 + JAIDS 2015;70:515

414 ABC/3TC + DTG 80%*

419 TDF/FTC/EFV 72% FLAMINGO Molina Lancet 2014;383:2222 + Lancet HIV 2015;2:e127

242 2 NRTI + DTG 80%*

242 2 NRTI + DRV/r 68% * = significant difference

When to Change? US DHHS 2016 www.aidsinfo.nih.gov

confirmed HIV RNA >200

IAS-USA 2014 JAMA 2014;312:390

HIV RNA >200

EACS 2015 www.europeanaidsclinicalsociety.org/

confirmed HIV RNA >50 after 6 months of ART

UK 2015 www.bhiva.org

confirmed HIV RNA >200

WHO 2014 http://www.who.int/hiv/pub/guidelines/arv2013/arvs2013upplement_march2014/en/

persistently detectable HIV RNA >1000

Virologic Failure Threshold • 332 randomly selected clinical trials pts + 61

additional pt with VL >50 • VL assayed with: (1) Monitor (Roche); (2) Real

Time (Abbott); (3) Roche TaqMan 2.0 • Results (% VL <50): 19% (Monitor), 25% (Real

Time), 22% (Taqman) • Despite concordance, Real Time was most likely to

detect VL >50 and Taqman was more likely than Monitor; confirmed VF >50 differed

• With threshold VL >200, no differences Lalama J Clin Micro 2015;53:2659

What to change to? US DHHS 2016 www.aidsinfo.nih.gov

2, preferably 3, fully active agents

IAS-USA 2014 JAMA 2014;312:390

PI/r + 1 fully active drug

EACS 2015 www.europeanaidsclinicalsociety.org/

At least 2, and preferably 3, active drugs (including one PI/r and one from a new class)

UK 2015 www.bhiva.org

At least 2, and preferably 3, fully active agents (including one PI/r and one with

novel mechanism – FI, II, CCR5)

WHO 2014 http://www.who.int/hiv/pub/guidelines/arv2013/arvs2013upplement_march2014/en/

(TDF + FTC ↔ AZT + 3TC) + ATV/r or LPV/r

Newer ART Agents (partial list) NRTI NNRTI PI Entry

Inh II MI

Phase 3 doravirine BMS-663068 cabotegravir

Phase 2 apricitabine dexelvucitabinefestinavir

BILR 355 cenicriviroc ibalizumab PF-232798

GS-9883

BMS-955176

Phase 1/2 elvucitabine TMC 310911

HGS004

Phase 1 EFdA (MK-8591) CMX157

RDEA 806 CTP-298 CTP-518 PPL-100 SPI-256

SCH532706VIR-576

BI 224436 INH-1001

GSK-2838232

NRTI

Need: • Less long-term toxicity • Longer acting

Tenofovir alafenamide (TAF) • TAF vs. TDF: Similar virologic efficacy

– 1733 pts on [TAF or TDF]/FTC/EVG/c Sax Lancet 2015;385:2606

• Switch TDFTAF improved renal/bone markers – 1443 pts on TDF with GFR >50 cc/min Mills Lancet ID 2016;16:43 – 663 pts on TDF with GFR >50 cc/min Gallant Lancet HIV 2016;3:e158 – 242 pts on TDF (65%) or not (35%) with eGFR 30-69

Pozniak JAIDS 2016;71:530

• Co-formulations – TAF/FTC/EVG/c (FDA approved 11/5/15) – TAF/FTC/RPV (FDA approved 3/1/16) – TAF/FTC (FDA approved 4/4/16) – TAF/FTC/DRV/c (in clinical trials)

MK-8591 (EFdA)

Grobler CROI 2016 #98 Friedman CROI 2016 #437LB

• 4’-ethynyl-2-fluoro-2’-deoxyadenosine; EFdA

• Non-obligate chain terminator

• Inhibits RT by preventing translocation (NRTTI)

• Potent antiviral activity (PBMC EC50 = 0.2 nM) with broad coverage (HIV-1, HIV-2, MDR strains)

Grobler CROI 2016 #98 Friedman CROI 2016 #437LB

MK-8591 (EFdA)

NNRTI needs: • Less toxic and better tolerated • Fewer drug interactions • Active against resistant viral strains

Doravirine (DOR; MK-1439) • Investigational NNRTI • Pre-clinical

–Potent at low milligram dose –Metabolized by CYP3A4; not a CYP450 inhibitor or inducer –Active in vitro against viral strains with:

• K103N • Y181C • G190A • E101K • E138K • K103N/Y181C

Lai AAC 2014;58:1652-1663

Doravirine (DOR): Phase Ib Double-blind, randomized, placebo-controlled

Study population: HIV+, treatment-naïve (N=18)

Schurmann AIDS 2016;30:57-63

Doravirine – Phase 2

Gatell CROI 2016 #470

Randomized, double-blind, 2-part study Study population: Rx-naïve participants, VL >1000, CD4 >100 (N=216) Study regimen: TDF/FTC + DOR or EFV

TDF/FTC+

• Phase 3 studies in progress

Doravirine – Phase 2

Gatell CROI 2016 #470

Integrase Inhibitors Needs: • long-acting

Cabotegravir (CAB) • Integrase inhibitor similar to DTG; similar resistance • Potent in HIV+ individuals (10, 30, 60 mg oral)

Margolis EACS 2013 • Nanotechology formulation; SC + IM injections • T½ 21-50 days! • Supports monthly

or quarterly dosing • Safety: ISR and

nodules with SC dosing

• Phase 2 study with CAB and RPV IM (LATTE-2)

Spreen JAIDS 2014;67:481

New Mechanisms of Action

HIV Entry Inhibitors

Virus-Cell Fusion

Adapted from Moore JP, PNAS 2003;100:10598-10602.

gp41 gp120

V3 loop

CD4 Binding

CD4

Cell Membrane

Coreceptor Binding

CCR5/CXCR4 (R5/X4)

CCR5 Inhibitors maraviroc

enfuvirtide BMS 663068

BMS-663068: Oral HIV Attachment Inhibitor

• Prodrug of BMS-626529 • Inhibits CD4 binding by

binding to gp120 • PK suggest QD or BID

dosing without boosting • ↓ baseline susceptibility in

12% of pts due to envelope polymorphisms; screened by baseline IC50

Nettles JID 2012;206:1002

Study pop: CD4 >200, VL >5000 off ART X >8 wks or ART-naive (N=50)

BMS-663068: Phase 2b

Lalezari Lancet HIV 2015;2:e427-37 and DeJesus CROI 2016 #472

Phase 2b, randomized, controlled, partially blinded (to ‘068 dose) Study pop: Rx-experienced (>1 wk on >1 ART); IC50 <100 nM for ‘529 (N=254) Study rx: TDF + RAL + [BMS-663068 or ATV/r]

80% 69% 76% 72% 75% VL<50

61% 53% VL<50

BMS-663068: Phase 2b Safety

DeJesus CROI 2016 #472 Given FDA “Breakthrough Status” 7/15; currently in phase 3 in rx-experienced pts.

HIV Maturation Inhibitors (MI)

Lataillade CROI 2015, #114LB

• No serious adverse events, grade 3/4 events, no d/c due to adverse events • Phase 2b studies in progress in treatment-experienced pts.

Study population: HIV+, VL >5K, CD4 >200, PI and MI naive

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TDF/FTC 300 mg/200 mg + ATV 300 mg + RTV 100 mg* BMS-955176 40 mg + ATV 300 mg + RTV 100 mg BMS-955176 40 mg + ATV 400 mg BMS-955176 80 mg + ATV 400 mg

Study day 10 15 20 25 30 35 40 45 50 5 0

Dosing period

BMS-955176 (Maturation Inhibitor)

Median change in HIV-1 RNA at Day 29: •-1.66 to -2.18 log10 c/mL (BMS-955176 arms) •-2.22 log10 c/mL (2 NRTI +ATV/r arm) Hwang IAS 2015 #TUAB0106LB

Study population: Rx-naïve, VL>5000, CD4>200 (N=28)

BMS-955176: PI-resistant viral strains

• 21 clinical isolates from 15 patients – median 6 years on PI therapy – all had major PI resistance-associated mutations in

protease – 17 of 21 had 2o changes in GAG associated with PI

resistance (at positions 128, 431, 436, 437, 449, 452, 453)

• 7 highly PI-resistant virus strains • BMS-955176 retained virologic activity

Ray CROI 2016 #464

ART Controversies: Conclusions • ART improves life expectancy. • When to start? At any CD4 and “when the patient

is ready.” • What to start? Many excellent options and new

comparative data; individualization is key. • When to change? Confirmed VL >200. • What to change to?: Drugs with new mechanisms

of action (CD4 attachment and maturation inhibitors) offer hope.

• Further research is necessary.

Acknowledgments • Cornell HIV Clinical Trials

Unit (CCTU) Division of Infectious Diseases

• Weill Medical College of Cornell University

• AIDS Clinical Trials Group (ACTG)

• Division of AIDS, NIAID, NIH

• The patient volunteers!

Cornell HIV Clinical Trials Unit

Kristie Marshall Trip

Tim

Joanne Valery Marisol

Glenn Luis

Todd

Yismilka

Mufida

Jaylyza Leah

Tiina Ashley

Eileen

Brian

Julia

Christina