19811986 19871995 19962005 20062011 2012 3 rd Gen HAART 19301980 THE FUTURE OF ANTIRETROVIRAL THERAPY 3 rd Generation Future HAART 2012 New drugs INSTI Elvitegravir ID: 785535
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Slide1
The Eras of the HIV Epidemic
1981-1986
1987-1995
1996-2005
2006-2011
2012+
3
rd
Gen.
HAART
1930-1980
Slide2THE FUTURE OF ANTIRETROVIRAL THERAPY
3
rd
Generation Future HAART: 2012 +
New drugs
INSTI:
Elvitegravir
,
Dolutegravir
NNRTI:
Lersivirine
NRTI: GS-7340 (TDF-
prodrug
)
New combinations
INSTI-NRTI: TDF-FTC-EVG-
Cobi
PI/
cobi
: DRV-Cobicistat
boosterPI/c-NRTI: DRV-
Cobi-TDFpro-FTC New strategiesNew classes
Future needs
Slide3EVR Non-Inferior to RAL at Week 48
Molina JM, et al. IAS 2011. Abstract WELBB05.
*TLOVR: Difference: 1.1% (95% CI: -6.0 to 8.2;
P = .001).Noninferiority: lower limit of 95% CI for difference between arms ≥ -10%.
New Drugs: INSTI Elvitegravir: once daily therapy
3
rd
Generation Future HAART: 2012 +
Slide4VIKING: Dolutegravir “Functional Monotherapy” in Pts With RAL Resistance
*HIV-1 RNA < 400 copies/mL or ≥ 0.7 log
10 copies/mL reduction from baseline at Day 11.
100
80
60
40
20
0
Primary Endpoint* (%)
Other
Mutations
All Patients
Q148 + ≥ 1
Other Mutation
at Baseline
Dolutegravir 50 mg QD
(n = 27)
Dolutegravir 50 mg BID
(n = 24)
78
96
33
100
100
92
Eron J. CROI 2011, Abstract 151LB.
New Drugs: INSTI Dolutegravir: active against resistance
3
rd
Generation Future HAART: 2012 +
Slide5Lersivirine vs Efavirenz with TDF/FTC in ART-Naive Pts
Vernazza P, et al. IAS 2011. Abstract TUAB0101.
LRV 500 mg
LRV 750 mg
EFV 600 mg
HIV-1RNA < 50 copies/mL
Through Wk 48 (%)
100
80
60
40
20
0
VL < 100,000
VL ≥ 100,000
n =
45
44
41
20
21
22
80
86
88
75
62
82
0
100
80
60
40
20
HIV-1 RNA < 50 copies/mL Through Wk 48 (%)
0
48
2
4
8
16
24
32
40
LRV 500 mg
LRV 750 mg
EFV 600 mg
54/63 (86%)
51/65 (79%)
51/65 (79%)
New Drugs: NNRTI Lersivirine:
once daily without psych or CNS
3
rd
Generation Future HAART: 2012 +
Slide60.5
0
-0.5
-1
-1.5
-2
14-day monotherapy in HIV+ patients:
Lower TDF plasma concentrations
Higher intracellular concentrations
Greater VL reduction
Markowitz M, et al. CROI 2011. Abstract 152LB. Graphic used with permission.
TDF 300 mg QD (n = 10)
GS-7340 50 mg QD (n = 10)
GS-7340 150 mg QD (n = 10)
Change in VL From Baseline
(log
10
c/mL)
Day
0
7
14
21
28
35
New Drugs: GS-7340 TDF Prodrug
3
rd
Generation Future HAART: 2012 +
Slide7TDF-FTC-EVR/Cobi -vs- TDF-FTC-EFV
Week 48 results in Tx-Naïve Patients
Cohen AIDS 2011; 25:F7-12
New Combinations: 3
rd
STR: The “Quad”: TDF-FTC-EVR-Cobi
3
rd
Generation Future HAART: 2012 +
Slide8THE FUTURE OF ANTIRETROVIRAL THERAPY
3
rd
Generation Future HAART: 2012 +
New drugs
New combinations
New strategies
NRTI-sparing regimens
2-drug potent regimens: INSTI-PI/r
New classes
Mono-clonal antibody
Zinc fingers
Future needs
HIV Vaccine
“Functional” cure
Slide9MVC vs TDF/FTC With ATV/RTV in ART-Naive Patients
Portsmouth S, et al. IAS 2011. Abstract TUAB0103.
0
Patients (%)
20
40
60
80
100
0
Wk
4
8
12
16
20
24
28
32
36
40
44
48
83.6
74.6
HIV-1 RNA < 50 copies/mL
MVC + ATV/RTV (n = 59)
TDF/FTC + ATV/RTV (n = 61)
HIV-1 RNA < 400 copies/mL
89.8
86.9
New strategies: NRTI-Sparing “2-Drug” CCR5-PI/r regimen
3
rd
Generation Future HAART: 2012 +
Slide10Taiwo
B. CROI
IAS 2011.
Abstract 551
New strategies: NRTI-Sparing “2-Drug” INSTI-PI/r regimen
3
rd
Generation Future HAART: 2012 +
ACTG A5262: DRV/r + RAL in
Tx
-Naïve: Faster failure at higher VL
Slide11Median Maximum Change in HIV-1 RNA
From Baseline With Monotherapy in HIV-infected Patients
-1.64
-1.59
-1.78
-1.63
-1.22
-1.64
Median Change in HIV-1 RNA From Baseline (log
10
copies/mL)
0
-0.5
-1.0
-1.5
-2.0
-2.5
600 mg
q12h +
100 mg
RTV q12h
(n = 9)
1200 mg
QHS +
100 mg
RTV QHS
(n = 9)
1200 mg
q12h +
100 mg
RTV q12h
(n = 10)
1200 mg
q12h +
100 mg
RTV
QAM
(n = 10)
1200 mg
q12h
(n = 10)
Overall
(N = 48)
Nettles R, et al. CROI 2011. Abstract 49.
Envelope polymorphisms may reduce baseline susceptibility
New Classes: BMS-663068: Oral Attachment Inhibitor
3
rd
Generation Future HAART: 2012 +
Slide12gp41
gp120
V3 loop
CD4
Ibalizumab
Khanlou H, et al. ICAAC 2011. Abstract H2-794b.
Wk
0
4
8
12
16
20
24
HIV-1 RNA <50 (%)
0
80
60
40
20
< 400 c/mL
< 50 c/mL
800 mg q2w
2000 mg q4w
100
Monoclonal antibody to non-HIV binding epitope of CD4
Blocks HIV-1 entry into cell
IV infusion
Ibalizumab + OBR in Treatment-Experienced Patients
New Classes: Ibalizumab: IV Entry Inhibitor
3
rd
Generation Future HAART: 2012 +
Slide13Mechanism:T: ZFN cleavage results in double-stranded DNA break with
nonhomologous end repair leading to permanent CCR5 gene modification
Treated CD4+ cells anticipated to be resistant to HIV infectionMitsuyasu R. ICAAC 2011. Abstract H1-375; Lalezari J. CROI 2011. Abstract 46.
Early HIV-infected patient studies :
Engraftment with rapid clonal expansion and persistence of ZFN-modified cells in circulation and rectal mucosaMedian ~100 cells/mm3 increase in CD4+ count after 1 year
Most AEs mild; no SAEs by median 337 d
DNA
ZFPZFP
∆32 mutation
CCR5
ZFN modification
Site 165
Fokl
Fokl
New Classes: Zinc Finger Nuclease (ZFN)
Disruption of CCR5 Gene in Autologous CD4+ Cells
3
rd
Generation Future HAART: 2012 +
Slide14Desimmie CROI 2011 #526; Urano CROI 2011 #525; Wilen CROI 2011 #47; Titolo CROI 2010 #50.
New Classes: Investigational Targets
3
rd
Generation Future HAART: 2012 +
LEDGF/p75 Inhibitors
Cellular tethering factor for integration
In-vitro identification of inhibitory peptides
Gag Inhibitors
Viral factor for particle assembly at cell membrane
In-vitro identification of inhibitory molecules
CXCR4 Zinc Finger Nucleases
Cell culture-mouse model proof of concept tested
Capsid Assembly Inhibitors
Formation of viral core
In-vitro identification of inhibitory molecules
Slide15Concept proven: Thai RV144 study: 31% protection Human studies on-going to determine correlates of immunity from elite controllers:
Broadly reacting neutralizing antibodiesSpecific neutralizing envelope epitopes
Precise B-cell clonal expansionAnimal studies on-going to elucidate immune response Comments, A. Fauci, NIH, 2011
Future Needs: Potential for HIV Vaccine
3
rd
Generation Future HAART: 2012 +
Slide16Early Treatment:Smaller latent reservoirSubsequent therapeutic vaccination boosting of immune control
Future Needs: Functional Cure -vs- Microbial Eradication
3
rd
Generation Future HAART: 2012 +
Novel Therapies:
Therapies to eliminate latent reservoir
Gene therapy to inactivate or excise incorporated virus
Comments, A. Fauci, NIH, 2011
Slide17Expanded Prevention Efforts
Challenges Facing the Global AIDS Pandemic: 2012 +
Uganda mobile male circumcision clinic
Slide18Efficacy of HIV Prevention Strategies From Randomized Clinical Trials
Abdool Karim SS, et al. Lancet. 2011;[Epub ahead of print].
100
0
20
40
60
80
Efficacy (%)
Study
Effect Size, % (95% CI)
ART for prevention
; HPTN 052, Africa,
Asia, Americas
PrEP for discordant couples
;
Partners PrEP, Uganda, Kenya
PrEP for heterosexual
men and
women; TDF2, Botswana
Medical male circumcision
;
Orange Farm, Rakai, Kisumu
PrEP for MSMs
; iPrEX, Americas,
Thailand, South Africa
Sexually transmitted diseases
treatment
; Mwanza, Tanzania
Microbicide
;
CAPRISA 004, South Africa
HIV vaccine
;
RV144, Thailand
96 (73-99)
73 (49-85)
63 (21-84)
54 (38-66)
44 (15-63)
42 (21-58)
39 (6-60)
31 (1-51)
Multi-Pronged Prevention Approach
Challenges Facing the Global AIDS Pandemic: 2012 +
Slide19Gender Inequality
Challenges Facing the Global AIDS Pandemic: 2012 +
Slide20Maternal Child Health
Challenges Facing the Global AIDS Pandemic: 2012 +
Slide21http://www.unaids.org/en/media/unaids/contentassets/documents/unaidspublication/2011/20110607_JC2069_30Outlook_en.pdf
Comprehensive Reduction Of Women’s Vulnerability
Challenges Facing the Global AIDS Pandemic: 2012 +
Slide22http://www.unaids.org/en/media/unaids/contentassets/documents/unaidspublication/2011/20110607_JC2069_30Outlook_en.pdf
Stigma and Discrimination
Challenges Facing the Global AIDS Pandemic: 2012 +
Slide23Country Policies That Impede Access To HIV Services
Challenges Facing the Global AIDS Pandemic: 2012 +
http://www.unaids.org/en/media/unaids/contentassets/documents/unaidspublication/2011/20110607_JC2069_30Outlook_en.pdf
Slide24Health Infrastructure
Challenges Facing the Global AIDS Pandemic: 2012 +
Slide25De Cock; Jaffe; Curran. Emerging Infectious Diseases. 2011;17(6) (CDC)
Competing health problems
Global financial downturn
Donor fatigue and shifting priorities
External Factors:
Challenges Facing the Global AIDS Pandemic: 2012 +
Slide26Patient Engagement in HIV Care
Challenges Facing the Global AIDS Pandemic: 2012 +
Adapted from Gardner Clin Inf Dis 2011;52:181
Not in
HIV Care
Engaged
in HIV Care
Unaware
of HIV
infection
Source of
infection
spread
Increased
testing
Fully
engaged
in HIV care
Potential
eventual
epidemic
containment
Intermittent
user of
HIV care
Risk of
ARV
resistance
Outreach
to patients
Aware of HIV
infection
not in care
Risk of
infection
spread
“Test and
Treat”
Receiving
medical care
not HIV care
Risk of
disease
progression
Outreach
to medical
providers
Entered HIV
care but lost
to follow-up
Risk of
disease
progression
Outreach
to patients
Slide27Slide28The Eras of the HIV Epidemic
1981-1986
1987-1995
1996-2005
2006-2011
1930-1980
2012+