ART Progress 2016 R.M. Gulick, MD,...
Transcript of ART Progress 2016 R.M. Gulick, MD,...
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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
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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
•
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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
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ART: Questions
• When to start? • What to start? • When to change? • What to change to?
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When to Start?
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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
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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
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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
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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
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What to Start?
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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
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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
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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
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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
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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
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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
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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
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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
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NRTI
Need: • Less long-term toxicity • Longer acting
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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)
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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)
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Grobler CROI 2016 #98 Friedman CROI 2016 #437LB
MK-8591 (EFdA)
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NNRTI needs: • Less toxic and better tolerated • Fewer drug interactions • Active against resistant viral strains
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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
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Doravirine (DOR): Phase Ib Double-blind, randomized, placebo-controlled
Study population: HIV+, treatment-naïve (N=18)
Schurmann AIDS 2016;30:57-63
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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+
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• Phase 3 studies in progress
Doravirine – Phase 2
Gatell CROI 2016 #470
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Integrase Inhibitors Needs: • long-acting
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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
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New Mechanisms of Action
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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
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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)
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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
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BMS-663068: Phase 2b Safety
DeJesus CROI 2016 #472 Given FDA “Breakthrough Status” 7/15; currently in phase 3 in rx-experienced pts.
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HIV Maturation Inhibitors (MI)
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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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–2.5
–2
–1.5
–1
–0.5
0
0.5
1
Med
ian
chan
ge in
HIV
-1
RN
A (l
og10
c/m
L)
from
bas
elin
e
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)
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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
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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.
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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!
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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
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