Download - The Eras of the HIV Epidemic
The Eras of the HIV Epidemic1981-1986 1987-1995 1996-2005 2006-2011 2012+
3rd Gen.
HAART
1930-1980
THE FUTURE OF ANTIRETROVIRAL THERAPY
3rd 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 booster PI/c-NRTI: DRV-Cobi-TDFpro-FTC
New strategies New classes Future needs
EVR 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
3rd Generation Future HAART: 2012 +
VIKING: Dolutegravir “Functional Monotherapy” in Pts With RAL Resistance
*HIV-1 RNA < 400 copies/mL or ≥ 0.7 log10 copies/mL reduction from baseline at Day 11.
100
80
60
40
20
0
Prim
ary
Endp
oint
* (%
)
OtherMutations
All Patients Q148 + ≥ 1Other Mutation
at Baseline
Dolutegravir 50 mg QD (n = 27)
Dolutegravir 50 mg BID (n = 24)
78
96
33
100 10092
Eron J. CROI 2011, Abstract 151LB.
New Drugs: INSTI Dolutegravir: active against resistance
3rd Generation Future HAART: 2012 +
Lersivirine vs Efavirenz with TDF/FTC in ART-Naive Pts
Vernazza P, et al. IAS 2011. Abstract TUAB0101.
LRV 500 mgLRV 750 mgEFV 600 mg
HIV
-1R
NA
< 50
cop
ies/
mL
Thro
ugh
Wk
48 (%
)
100
80
60
40
20
0
VL < 100,000 VL ≥ 100,000n = 45 44 41 20 21 22
80 86 8875
62
82
0
100
80
60
40
20
HIV
-1 R
NA
< 50
cop
ies/
mL
Thro
ugh
Wk
48 (%
)
0 482 4 8 16 24 32 40
LRV 500 mgLRV 750 mgEFV 600 mg
54/63 (86%)
51/65 (79%)51/65 (79%)
New Drugs: NNRTI Lersivirine: once daily without psych or CNS
3rd Generation Future HAART: 2012 +
0.5
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)
Cha
nge
in V
L Fr
om B
asel
ine
(log 1
0 c/m
L)
Day0 7 14 21 28 35
New Drugs: GS-7340 TDF Prodrug
3rd Generation Future HAART: 2012 +
TDF-FTC-EVR/Cobi -vs- TDF-FTC-EFVWeek 48 results in Tx-Naïve Patients
Cohen AIDS 2011; 25:F7-12
New Combinations: 3rd STR: The “Quad”: TDF-FTC-EVR-Cobi
3rd Generation Future HAART: 2012 +
THE FUTURE OF ANTIRETROVIRAL THERAPY
3rd 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
MVC vs TDF/FTC With ATV/RTV in ART-Naive Patients
Portsmouth S, et al. IAS 2011. Abstract TUAB0103.
0
Patie
nts
(%)
20
40
60
80
100
0Wk
4 8 12 16 20 24 28 32 36 40 44 48
83.674.6
HIV-1 RNA < 50 copies/mL
MVC + ATV/RTV (n = 59)TDF/FTC + ATV/RTV (n = 61)
HIV-1 RNA < 400 copies/mL
89.886.9
New strategies: NRTI-Sparing “2-Drug” CCR5-PI/r regimen
3rd Generation Future HAART: 2012 +
Taiwo B. CROI IAS 2011. Abstract 551
New strategies: NRTI-Sparing “2-Drug” INSTI-PI/r regimen
3rd Generation Future HAART: 2012 +
ACTG A5262: DRV/r + RAL in Tx-Naïve: Faster failure at higher VL
Median 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
Med
ian
Cha
nge
in H
IV-1
RN
A Fr
om B
asel
ine
(log 1
0 co
pies
/mL)
0
-0.5
-1.0
-1.5
-2.0
-2.5
600 mgq12h +100 mg
RTV q12h (n = 9)
1200 mgQHS +100 mg
RTV QHS(n = 9)
1200 mg q12h +100 mg
RTV q12h (n = 10)
1200 mg q12h +100 mgRTV 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
3rd Generation Future HAART: 2012 +
gp41
gp120
V3 loopCD4
Ibalizumab
Khanlou H, et al. ICAAC 2011. Abstract H2-794b. Wk0 4 8 12 16 20 24
HIV
-1 R
NA
<50
(%)
0
80
60
40
20
< 400 c/mL
< 50 c/mL
800 mg q2w2000 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
3rd Generation Future HAART: 2012 +
Mechanism: 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 infection
Mitsuyasu 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 mucosa
Median ~100 cells/mm3 increase in CD4+ count after 1 year
Most AEs mild; no SAEs by median 337 d
DNA
ZFP
ZFP ∆32 mutation
CCR5ZFN modification
Site 165
Fokl
Fokl
New Classes: Zinc Finger Nuclease (ZFN) Disruption of CCR5 Gene in Autologous CD4+ Cells
3rd Generation Future HAART: 2012 +
Desimmie CROI 2011 #526; Urano CROI 2011 #525; Wilen CROI 2011 #47; Titolo CROI 2010 #50.
New Classes: Investigational Targets
3rd 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
Concept proven: Thai RV144 study: 31% protection Human studies on-going to determine
correlates of immunity from elite controllers: Broadly reacting neutralizing antibodies Specific neutralizing envelope epitopes Precise B-cell clonal expansion
Animal studies on-going to elucidate immune response
Comments, A. Fauci, NIH, 2011
Future Needs: Potential for HIV Vaccine
3rd Generation Future HAART: 2012 +
Early Treatment: Smaller latent
reservoir Subsequent
therapeutic vaccination boosting of immune control
Future Needs: Functional Cure -vs- Microbial Eradication
3rd Generation Future HAART: 2012 +
Novel Therapies:Therapies to eliminate latent reservoirGene therapy to inactivate or excise incorporated virus
Comments, A. Fauci, NIH, 2011
Expanded Prevention Efforts
Challenges Facing the Global AIDS Pandemic: 2012 +
Uganda mobile male circumcision clinic
Efficacy of HIV Prevention Strategies From Randomized Clinical Trials
Abdool Karim SS, et al. Lancet. 2011;[Epub ahead of print].
1000 20 40 60 80Efficacy (%)
Study Effect Size, % (95% CI)
ART for prevention; HPTN 052, Africa, Asia, AmericasPrEP for discordant couples;Partners PrEP, Uganda, KenyaPrEP for heterosexual men and women; TDF2, BotswanaMedical male circumcision; Orange Farm, Rakai, KisumuPrEP for MSMs; iPrEX, Americas, Thailand, South AfricaSexually transmitted diseases treatment; Mwanza, TanzaniaMicrobicide;CAPRISA 004, South AfricaHIV 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 +
Gender Inequality
Challenges Facing the Global AIDS Pandemic: 2012 +
Maternal Child Health
Challenges Facing the Global AIDS Pandemic: 2012 +
http://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 +
http://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 +
Country 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
Health Infrastructure
Challenges Facing the Global AIDS Pandemic: 2012 +
De 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 +
Patient Engagement in HIV Care
Challenges Facing the Global AIDS Pandemic: 2012 +
Adapted from Gardner Clin Inf Dis 2011;52:181
Not inHIV Care
Engaged in HIV Care
Unawareof HIV
infection
•Source of infectionspread
•Increasedtesting
Fullyengaged
in HIV care
• Potentialeventualepidemic
containment
Intermittentuser of
HIV care
• Risk of ARV
resistance• Outreach to patients
Aware of HIVinfection
not in care
• Risk of infectionspread
• “Test andTreat”
Receivingmedical carenot HIV care
• Risk of disease
progression• Outreach to medicalproviders
Entered HIVcare but lostto follow-up
• Risk of disease
progression• Outreach to patients
The Eras of the HIV Epidemic1981-1986 1987-1995 1996-2005 2006-20111930-1980 2012+