The Eras of the HIV Epidemic - PowerPoint Presentation

The Eras of the HIV Epidemic
The Eras of the HIV Epidemic

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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 Download

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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

Slide2

THE 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

Slide3

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

3

rd

Generation Future HAART: 2012 +

Slide4

VIKING: 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 +

Slide5

Lersivirine 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 +

Slide6

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)

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 +

Slide7

TDF-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 +

Slide8

THE 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

Slide9

MVC 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 +

Slide10

Taiwo

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

Slide11

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

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 +

Slide12

gp41

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 +

Slide13

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 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 +

Slide14

Desimmie 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

Slide15

Concept 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 +

Slide16

Early 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

Slide17

Expanded Prevention Efforts

Challenges Facing the Global AIDS Pandemic: 2012 +

Uganda mobile male circumcision clinic

Slide18

Efficacy 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 +

Slide19

Gender Inequality

Challenges Facing the Global AIDS Pandemic: 2012 +

Slide20

Maternal Child Health

Challenges Facing the Global AIDS Pandemic: 2012 +

Slide21

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 +

Slide22

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 +

Slide23

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

Slide24

Health Infrastructure

Challenges Facing the Global AIDS Pandemic: 2012 +

Slide25

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 +

Slide26

Patient 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

Slide27

Slide28

The Eras of the HIV Epidemic

1981-1986

1987-1995

1996-2005

2006-2011

1930-1980

2012+

Shom More....
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