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


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


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


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


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


THE FUTURE OF ANTIRETROVIRAL THERAPY


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


Taiwo B. CROI IAS 2011. Abstract 551

New strategies: NRTI-Sparing “2-Drug” INSTI-PI/r regimen


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


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


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


Desimmie CROI 2011 #526; Urano CROI 2011 #525; Wilen CROI 2011 #47; Titolo CROI 2010 #50.

New Classes: Investigational Targets


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


Early Treatment: Smaller latent

reservoir Subsequent

therapeutic vaccination boosting of immune control

Future Needs: Functional Cure -vs- Microbial Eradication


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


Gender Inequality


Maternal Child Health


http://www.unaids.org/en/media/unaids/contentassets/documents/unaidspublication/2011/20110607_JC2069_30Outlook_en.pdf

Comprehensive Reduction Of Women’s Vulnerability




Stigma and Discrimination



Country Policies That Impede Access To HIV Services





Health Infrastructure


De Cock; Jaffe; Curran. Emerging Infectious Diseases. 2011;17(6) (CDC)

Competing health problems Global financial downturn

Donor fatigue and shifting priorities

External Factors:


Patient Engagement in HIV Care


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+

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The Eras of the HIV Epidemic