hiv therapy 2004 - acthiv

Antiretrovirals

2010

Roy M. Gulick, MD, MPHProfessor of Medicine

Chief, Division of Infectious Diseases

Weill Medical College of Cornell University

Disclosures

Learning Objectives:

• At the conclusion of this presentation, you will be able to:

– Explain the 6 mechanistic classes of antiretroviral drugs to your

patients.

– Select the optimal number of antiretroviral drugs for an effective

HIV treatment regimen for your patients.

Off-Label Disclosure

• I intend to discuss investigational antiretroviral agents in

this presentation.

Goal of Antiretroviral Therapy

• To suppress HIV RNA (viral load level)

as low as possible, for as long as possible

• To preserve or enhance immune function

• To delay clinical progression of HIV

disease and prolong healthy survival

Antiretroviral Drug Approval:

1987 - 2010

0

5

10

15

20

25

30

1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007

AZT ddIddC d4T

3TC

SQV

RTV

IDV

NVP

NFV

DLV

EFV

ABCAPV

LPV/rTDF

ENF

ATV

FTC

FPV TPVDRV

ETRRAL

MVC

Number of

approved drugs

Life Cycle of HIV

DS dna COMPLEX

fusion

inhibitors

reverse

transcriptase

inhibitors

protease

inhibitors

integrase

inhibitors

chemokine

receptor

inhibitorsHIV entry

inhibitors

nucleosides non-nucleosides

Antiretroviral Drugs: 2010nucleoside/tide RTIs

(NRTIs)

• zidovudine (ZDV, AZT)

• didanosine (ddI)

• stavudine (d4T)

• lamivudine (3TC)

• abacavir (ABC)

• emtricitabine (FTC)

• tenofovir (TDF)

NNRTIs

• nevirapine (NVP)

• delavirdine (DLV)

• efavirenz (EFV)

• etravirine (ETR)

protease inhibitors (PIs)

• saquinavir (SQV)

• ritonavir (RTV)

• indinavir (IDV)

• nelfinavir (NFV)

• lopinavir/r (LPV/r)

• atazanavir (ATV)

• fosamprenavir (FPV)

• tipranavir (TPV)

• darunavir (DRV)

entry inhibitors (EIs)

• enfuvirtide (T-20, fusion inh)

• maraviroc (MVC, CCR5 ant)

integrase inhibitors (IIs)

• raltegravir (RAL)

zidovudine (3’-azido-2’,3’-dideoxythmidine, AZT)

Reverse Transcriptase Mechanism (1)

Yarchoan NEJM 1987;316:557

Reverse Transcriptase Mechanism (2)

Yarchoan NEJM 1987;316:557

N

NN

NH

NH2

O

HO

N

N

NNH

O

N

NN

N

NH2

O

P

OO

O

O

O

O CH3

CH3O

O

OH3C

CH3

N

HNN

NH

O

H2N

HO

N

N

NN

NH2

HN

N

NH

O

NH2

S

O

HO

N

NO

NH2

S

O

HO

N

NO

NH2

F

O

HO

N

NO

NH2

HN

NH

O

O

CH3

O

HO

N

HN

O

O

H3N

CH3

O

HO

N

HN

O

O

CH3CH3

O

O

HO

N

N

NN

NH2

NH2

adenosine

didanosine (ddI)

tenofovir (TDF)

cytosine

zalcitabine (ddC)

lamivudine (3TC)

emtricitabine

(FTC)

guanine

abacavir (ABC)

amdoxovir

(DAPD)

thymidine

zidovudine (AZT)

stavudine (d4T)

Combination Therapy: 2 vs 1

no differenceAZT, AZT/ddI,

AZT/ddC

92CPCRA 007

(N=1113)

Saravolatz, NEJM 1996

combos clinical

benefit

AZT, AZT/ddI,

AZT/ddC

210Delta 1 & 2

(N=3308)

Delta Coord.

Committee, Lancet,

1996

ddI, combos

clinical benefit

AZT, ddI,

AZT/ddI,

AZT/ddC

352ACTG 175

(N=2467)

Hammer, NEJM 1996

Results

(2-3 yrs f/u)

RegimensAvg

CD4

Study

Choice of Dual NRTIsCombo DHHS Dosing Toxicities Considerations

TDF/FTC preferred 1 tab qd renal (rare) TDF/FTC/EFV

available

ABC/3TC alternate 1 tab qd HSR (5-

8%)

B5701 testing;

?↑MI

ddI +

(FTC or

3TC)

alternate 2 tab qd

fasting

PN,

pancreatitis

least clinical

experience;

?↑MI

ZDV/3TC alternate 1 tab

bid

GI, anemia longest clinical

experience

d4T + 3TC inferior

to above

3

tab/bid

PN, pancr.,

lipoatrophy

toxicity

Structures of NNRTI

nevirapine (NVP) efavirenz (EFV)

delavirdine (DLV) etravirine (ETR)

Reverse Transcriptase Enzyme

NNRTI

binding

site

Reverse Transcriptase

Initial ART

NNRTI-based regimens:

DHHS Guidelines, 12/1/09

Preferred EFV

Alternative NVP

HIV Protease Inhibitors (2)

amprenavir (APV) lopinavir (LPV)

atazanavir (ATV) fosamprenavir (FPV)

tipranavir (TPV)

HIV Protease Inhibitors (3)

darunavir (DRV)

Combination Therapy: 3 vs. 2

3-drugs: ~75%

HIV RNA <400 cps/ml

(compared to 37%)

AZT/3TC vs.

AZT/3TC/NFV

AG 511

(N=297)

Saag, AIDS 2001

AZT/3TC vs.

AZT/3TC/IDV

ACTG 320

(N=1156)

Hammer, NEJM 1997

3-drugs: ~80%

HIV RNA <500 cps/ml

(compared to 30-45%)

AZT/3TC vs. IDV

AZT/3TC/IDV

Results (1 yr f/u)RegimensStudy

MRK 035

(N=97)

Gulick, NEJM 1997

3-drugs reduced

AIDS/death by

~50%

Initial ART

PI-based regimens:

DHHS Guidelines, 12/1/09

Preferred ATV/r

DRV/r

Alternative FPV/r

LPV/r

SQV/r

Acceptable ATV

Antiretroviral Activity: 1987-1997H

IV R

NA

ch

an

ge

(lo

g1

0c/

mL

)

1994:2-drug ART

1997: 3-drug ART

1987:AZT monotherapy

6 month responses

0

-0.5

-1

-1.5

-2

-2.5

-3

0

-0.5

-1

-1.5

-2

-2.5

-3

0

-0.5

-1

-1.5

-2

-2.5

-3

Fischl NEJM 1987 Eron NEJM 1995 Gulick NEJM 1997

Montaner JAMA 1998Hammer NEJM 1996

Study 903E:

TDF+3TC+EFV

Cassetti

HIV Clin Trials

2007;8:164-72;

IAS 2008 abstract

#TuPE0057

81%

+469

Durability of ART: 7 years

3-Drug Combination ART:

2006

TDF/FTC/EFV

ART Response: Clinical Cohorts

ART Cohort collaborationMay, AIDS 2007;21:1185

12 HIV clinical cohort studies in Europe and North America16167 individuals starting >3 drug ART76% had HIV RNA <500 cps/ml at 6 months

Antiretrovirals in Lower Income Countries (ART-LINC)

Braitstein, Lancet 2006;367:81718 ART programs in Africa, Asia, South America4810 individuals starting >3 drug ART 76% had HIV RNA <500 cps/ml at 6 months

Antiretroviral Drug Approval:

1987 - 2010

0

5

10

15

20

25

30

1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009

AZT ddIddC d4T

3TC

SQV

RTV

IDV

NVP

NFV

DLV

EFV

ABCAPV

LPV/rTDF

ENF

ATV

FTC

FPV TPVDRV

ETRMVC

RAL

Number of

approved drugs

HIV Entry Mechanism

3c. Fusion

Complete

1. CD4

Attachment

3b. coil-coil

interaction

CXCR4

CCR5

gp120

3a. Anchorage

CD4

2. Co-receptorinteraction

Cell

HIV

HIV

HIV

gp41

gp41

HIV

Chemokine

Receptor

Inhibitors

Fusion

Inhibitors

CCR5 or

CXCR4

CCR5

352

C

L

A

D

TF

F

H

L

L

S

P

L

A

F

N

Y

I

V

L

W

L

L

F

I

G

FG

F

L

I

L

I

L

I

L

F

I

T

F

Y

G

T

S

S

TV

LI

F

T

I

T

V

G

S

F

V

V

V

W

P

A

I

A

G

C

M

V

L

L

I

Y

I

V

G

L

V

L

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L

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P

I

V

T

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F

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L

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F

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L

F

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N

A

L

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MV

I

F

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G

L

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N

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N

F G

RY

L

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A F A K AR

T

V

T

F

VG

HV L

S

QK

EGL

H

YT

C

S

YS Q Y Q F

WKN

FQ

H

PF

S

KT

L

L

V

HR

KKENRC

R

NT

F

QE

FF

GL N N

CS

SS

N

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DQ

L

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FR N

YL L

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HIAKRF

F

QK

ACC S I

FQ Q

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TG

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P

ERAS

EQ

E

A

A

A

Q

AAI

QK

VN

I K Q CPE

STYYNIDYI

PS

S V Q Y D M- NH2

- COOH

R31-

-57 67-

-89 102-

-125 146-

-168 -197

219- -235

-258

303-

TL

R

A

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PL

D

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277-

DW

Q

LSD

TF

F

LR

A

PI

A

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HY

V

LV

W

L

FI

L

S

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L

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IV

V

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AS

L

YN

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IF

L

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F

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IV

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LP

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II

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MG

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LN

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GA

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FLCK

N

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A

KE

HT Q

VS

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CD

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LS

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II K QG

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*

*

*

N39-

-65 75-

-97 110-

-133 154-

-176 -202

224- -239

-262-282

308-

-352

F

A

CXCR4

R5 viruses

• a.k.a. M-tropic, NSI

• Transmitted variants

• Prevalent in early disease

X4 viruses

• a.k.a. T-tropic, SI

• Can emerge in late disease

• Associated with rapid CD4+

decline and progression

Dual-tropic viruses use CCR5 or CXCR4 (in vitro)

Tropism Test

HIV Integrase Mechanism

Strand Transfer

Inhibitors

X

DRV/r + ETR + RAL

Study Population Results

ETR exp. accessTowner

JAIDS 2010;53:614

206 treatment-

experienced pts.

HIV RNA <75 in

132/206 (64%)

48 weeks

Spain cohortImaz

JAIDS 2009;52:382

32 treatment-

experienced pts.,

no prior DRV/r

HIV RNA <50 in

30/32 (94%)

24 weeks

TRIO

(ANRS 139)Yazdanpanah

CID 2009;49:1441

103 pts with

NNRTI + PI

resistance, no prior

DRV/r, ETR, RAL;

could use NRTI or

ENF

HIV RNA <50 in

93/103 (90%)

24 weeks;

89/103 (86%)

48 weeks

Survival: CASCADE Cohort23 cohorts from Australia, Europe and Canada

Bhaskaran, JAMA 2008; 300: 51-59

HIV+ pre-1996

HIV+ 2004-06

HIV- 2004-06

ART 2010: Conclusions

• ART suppresses HIV RNA, improves

immune function, decreases disease

progression and prolongs survival.

• There are 25 approved antiretroviral drugs

in 6 mechanistic classes.

• A majority of patients achieve durable

suppression of HIV RNA, increased CD4,

decreased clinical progression, and

prolonged survival.

• Further research is needed.

Acknowledgments

• Cornell HIV Clinical Trials Unit

(CCTU)

• Division of Infectious Diseases

• Weill Medical College of Cornell

University

• AIDS Clinical Trials Group

(ACTG)

• Division of AIDS, NIAID, NIH

• The patient volunteers!