THIS IS THE HEADLINE STYLE - ADAP Advocacy Association

Report
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.
CHOICE OF INITIAL 3RD ART DRUG
ART guidelines
DHHS, 20141
TDF/FTC
EFV
EACS, 20142
EFV
RPV*
EFV
RPV
ATV/r
DRV/r
TDF/FTC
EFV
RPV*
ABC/3TC
EFV
TDF/FTC
ATV/r
DRV/r
ABC/3TC
ATV/r
DRV/r
ABC/3TC
ATV/r
TDF/FTC
RAL
EVG/c
TDF/FTC
ABC/3TC
TDF/FTC
TDF/FTC
ABC/3TC
NRTIs
ATV/r
DRV/r
DTG
EVG/c
RAL
DTG
NNRTI
IAS-USA, 20143
TDF/FTC
TDF/FTC
ABC/3TC
PI/r
INI
WHO, 20134
TDF/FTC
TDF/3TC
EFV
DTG
EVG/c
RAL
DTG
1. DHHS Guidelines for the Use of Antiretroviral Agents in
*For patients with HIV-1 RNA <100,000 c/mL
HIV-1-Infected Adults and Adolescents, May 2014
DHHS, Department of Health and Human Services; EACS, European AIDS Clinical Society; IAS-USA,
2. EACS Guidelines Version 7.02, June 2014
International Antiviral Society USA Panel; WHO, World Health Organization;
TDF/FTC tenofovir/emtricitabine; EFV, efavirenz; ABC/3TC abacavir/lamivudine; RPV, rilpivirine;
3. Günthard HF, et al. JAMA 2014;312:410-425
ATV/r, atazanavir/ritonavir; DRV/r, darunavir/ritonavir; DTG, dolutegravir; EVG/c, elvitegravir/cobicistat;
4. WHO guidelines for the use of antiretroviral drugs
RAL, raltegravir; NRTIs, nucleoside reverse transcriptase inhibitors; NNRTI, non-nucleoside reverse
for treating and preventing HIV infection, June 2013
transcriptase inhibitor; PI/r, boosted protease inhibitor; INI, integrase inhibitor
DESIRABLE ATTRIBUTES OF NEW AGENTS AS
PART OF A FIRST-LINE TREATMENT REGIMEN
Highly potent
antiviral activity
Favourable resistance
profile
No food requirements
ARV
Simple regimen
Low PK variability and
predictable exposureresponse relationship
ARV, antiretroviral; PK, pharmacokinetic
Safe and generally
well tolerated
Once-daily
administration without
a PK enhancer
DHHS Guidelines for the Use of Antiretroviral Agents in
HIV-1-Infected Adults and Adolescents, May 2014
24th Annual CCO HIV and Hepatitis C Symposium
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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
24th Annual CCO HIV and Hepatitis C Symposium
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Dolutegravir Clinical Trials in TreatmentNaive 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)
SINGLE[2]
(placebo controlled)
ART-naive pts
VL ≥ 1000 c/mL
HLA-B*5701 neg
CrCl > 50 mL/min
(N = 833)
FLAMINGO[3]
(open label)
ART-naive pts
VL ≥ 1000 c/mL
(N = 484)
DTG 50 mg QD + 2 NRTIs*
(n = 411)
RAL 400 mg BID + 2 NRTIs*
(n = 411)
DTG 50 mg QD + ABC/3TC QD
(n = 414)
EFV/TDF/FTC QD
(n = 419)
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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Proportion of Patients (%)
SINGLE: Dolutegravir + ABC/3TC vs
Efavirenz/TDF/FTC in Tx-Naive Pts
DTG + ABC/3TC
100
EFV/TDF/FTC
DTG: 80%
80
60
EFV: 72%
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
Wk 96 ∆ From BL
Adjusted Mean
SE
DTG + ABC/3TC QD (n = 414)
325.3
10.5
EFV/TDF/FTC QD (n = 419)
281.4
10.9
Treatment
24
32
40
48
Wk
60
72
Difference in
Response (95% CI)
44.0 (14.3, 73.6)
P = .004
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.
24th Annual CCO HIV and Hepatitis C Symposium
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Activity of Integrase-Based Therapies
Maintained at High HIV-1 RNA
STARTMRK[1]
SPRING-2[4]
Difference, % (RAL-EFV) and 95% CI
In favor of EFV
≤ 100,000 c/mL
> 100,000 c/mL
-20
-10
Difference, % (DTG-RAL) and 95% CI
0
10
20
30
-20
-10
In favor of EVG/COBI
0
5
10 15
In favor of EVG/COBI
0
5
30
-20
-10
0
10
20
30
FLAMINGO[5]
Difference, % (EVG/COBI-ATV/RTV) and 95% CI
-15 -10 -5
20
In favor of DTG
In favor of EFV
≤ 100,000 c/mL
> 100,000 c/mL
Study 103[3]
In favor of ATV/RTV
≤ 100,000 c/mL
> 100,000 c/mL
10
Difference, % (DTG-EFV) and 95% CI
Difference, % (EVG/COBI-EFV) and 95% CI
-15 -10 -5
0
SINGLE[4]
Study 102[2]
In favor of EFV
≤ 100,000 c/mL
> 100,000 c/mL
In favor of DTG
In favor of RAL
≤ 100,000 c/mL
> 100,000 c/mL
In favor of RAL
10 15
Difference , % (DTG-DRV/RTV) and 95% CI
In favor of DRV/RTV
≤ 100,000 c/mL
> 100,000 c/mL
-20
-10
In favor of DTG
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
40
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Increased Risk of Suicidality
Associated With EFV
5%
.05
Efavirenz
Efavirenz-free
Probability
.04
HR (95% CI)
2.28 (1.27-4.10), P = .006
.03
47 events/5817 PY*
(8.08/1000 PY)
.02
.01
15 events/4099 PY*
(3.66/1000 PY)
0
As-treated HR
2.16 (1.16-4.00)
0
24
48
72
96
120 144
Wks to Suicidality
*Person-years, sum of at-risk follow-up.
Mollan K, et al. IDWeek 2013. Abstract 40032.
168 192
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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)

Primary endpoints
–
–
RAL 400 mg BID +
TDF/FTC
(n = 603)
DRV/RTV 800/100 mg QD +
TDF/FTC
(n = 601)
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

Tolerability Failure
Regimens equivalent
in time to VF

ATV/RTV vs RAL
3.4% (-0.7 to 7.4)
DRV/RTV vs RAL
5.6% (1.3 -9.9)
DRV/RTV vs RAL
3.6% (1.4-5.8)
10 20

In part due to high
proportion of pts with
hyperbilirubinemia
Favors RAL
ATV/RTV vs RAL
13% (9.4-16.0)
Considering both
efficacy and tolerability,
RAL superior to either
boosted PI
DRV/RTV superior to
ATV/RTV
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)
Favors DRV/RTV
ATV/RTV vs DRV/RTV
9.2% (5.5-13.0)
ATV/RTV vs DRV/RTV
-2.2% (-6.7 to 2.3)
0

Significantly greater
incidence of treatment
failure with ATV/RTV vs
RAL or DRV/RTV
–
-10
Composite Endpoint
-10
0
10 20
-10
0
Difference in 96-Wk Cumulative Incidence (97.5% CI)
Landovitz R, et al. CROI 2014. Abstract 85. Reproduced with permission.
10 20
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
Studies With 4-Drug
Strategies
 DMP-066
 ACTG 5095
 ACTG 5142
 ACTG 5173
 SPARTAN
 COL40263
 ACTG 5162
 RADAR
 PROGRESS
 A4001078
None to date offers compelling evidence to move from 3-drug approach.
24th Annual CCO HIV and Hepatitis C Symposium
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LATTE: Study Design
 Phase IIb, randomized, multicenter, partially blind, dose-ranging study
comparing S/GSK744 plus RPV to EFV plus NRTIs
HIV-1 ART-naive
HIV-1 RNA > 1000 c/mL
1:1:1:1 randomization
Stratified by
VL and NRTI
Oral Induction Phase
Oral Maintenance Phase
744 10 mg + 2 NRTIs*
744 10 mg + RPV 25 mg
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
100
744 OR Wk 24
87%
744 OR Wk 48
82%
Maintenance Phase
Proportion, %
80
60
EFV response Wk 48
71%
EFV response Wk 24
74%
40
Median (IQR) Change From BL
CD4+ Cell Count (Cells/mm3)
Wk 48
744 overall
+219 (141,343)
EFV
+227 (134,369)
20
0
BL
2 4
744 10 mg (N = 60)
8
12
16
744 30 mg (N = 60)
Margolis D, et al. CROI 2014. Abstract 91LB.
24 26 28 32
36
Wk
744 60 mg (N = 61)
40
48
EFV 600 mg (N = 62)
Investigational Drugs
24th Annual CCO HIV and Hepatitis C Symposium
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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
24th Annual CCO HIV and Hepatitis C Symposium
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HIV-1 RNA < 40 Copies/mL (%)
Doravirine vs EFV Phase II:
24-Wk Results
100
80
MK-1439 all doses combined: 76.4%
80.0
76.2
71.4
78.0
64.3
60
40
20
32/40
32/42
30/40
32/41
27/42
MK-1439
50 mg
MK-1439
100 mg
MK-1439
200 mg
Efavirenz
600 mg
0
MK-1439
25 mg
Morales-Ramirez J, et al. CROI 2014. Abstract 92LB.
GSK744 LA Is Formulated as a
200 mg/mL Nanosuspension
GSK1265744
(GSK744)
F
O
N
H
F
H
N
O
N
O
OH O
Dolutegravir
F
O
N
H
F
H
N
O
N
O
OH O
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
Plasma GSK744 (µg/mL)
10
200 mg
400 mg
800 mg
1
4X PAIC90
1X PAIC90
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.
24th Annual CCO HIV and Hepatitis C Symposium
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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, stockouts, 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
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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?
24th Annual CCO HIV and Hepatitis C Symposium
clinicaloptions.com
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 

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