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Antiretrovirals
2010
Roy M. Gulick, MD, MPHProfessor of Medicine
Chief, Division of Infectious Diseases
Weill Medical College of Cornell University
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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.
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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
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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
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Life Cycle of HIV
DS dna COMPLEX
fusion
inhibitors
reverse
transcriptase
inhibitors
protease
inhibitors
integrase
inhibitors
chemokine
receptor
inhibitorsHIV entry
inhibitors
nucleosides non-nucleosides
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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)
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zidovudine (3’-azido-2’,3’-dideoxythmidine, AZT)
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Reverse Transcriptase Mechanism (1)
Yarchoan NEJM 1987;316:557
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Reverse Transcriptase Mechanism (2)
Yarchoan NEJM 1987;316:557
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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)
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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
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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
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Structures of NNRTI
nevirapine (NVP) efavirenz (EFV)
delavirdine (DLV) etravirine (ETR)
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Reverse Transcriptase Enzyme
NNRTI
binding
site
Reverse Transcriptase
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Initial ART
NNRTI-based regimens:
DHHS Guidelines, 12/1/09
Preferred EFV
Alternative NVP
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HIV Protease Inhibitors (2)
amprenavir (APV) lopinavir (LPV)
atazanavir (ATV) fosamprenavir (FPV)
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tipranavir (TPV)
HIV Protease Inhibitors (3)
darunavir (DRV)
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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%
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Initial ART
PI-based regimens:
DHHS Guidelines, 12/1/09
Preferred ATV/r
DRV/r
Alternative FPV/r
LPV/r
SQV/r
Acceptable ATV
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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
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Study 903E:
TDF+3TC+EFV
Cassetti
HIV Clin Trials
2007;8:164-72;
IAS 2008 abstract
#TuPE0057
81%
+469
Durability of ART: 7 years
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3-Drug Combination ART:
2006
TDF/FTC/EFV
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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
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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
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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
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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
S
L
I
L
P
I
V
T
I
L
F
YV
W
L
M
F
Y
I
P
L
F
I
I
V
N
A
L
L
MV
I
F
Y
P
V
G
L
G
L
S
L
F
N
V
F
I
L
L
I
LI
N
I
N
F
C
TV
M
A
P
Y
C
V
TL
M
T
I
A
I
G
E
G
Q
H
EI
D
L
KR M
T
K S
Y
T
M
CQ
N
F G
RY
L
A
VV
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
R
DQ
L
C
K
K
F
FR N
YL L
V
HIAKRF
F
QK
ACC S I
FQ Q
SVYTRS
TG
E
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
I S V G L
R
PL
D
K
R
277-
DW
Q
LSD
TF
F
LR
A
PI
A
L
HY
V
LV
W
L
FI
L
S
TV
L
A
LI
V
IV
V
Y
AS
L
YN
H
S
YVP
IF
L
A
GV
I
DT
F
L
VV
W
PL
I
A
ICI
IV
G
H
YI
L
GL
I
I
CI
S
LP
M
V
IL
T
F
YG
W
I
IV
F
IP
S
C
LT
A
YL
I
AGV
I
T
YP
I
I
GL
G
L
TS
F
F
NV
I
V
II
L
L
MG
Y
LN
F
C
AI
F
W
PY
C
L
TL
I
F
IA
L
G
GA
S
H
AKD
L
KK M
T
R S
D
FLCK
N
Y FG
DR
YLAI
V
N S R PRKLL
A
KE
HT Q
VS
EAD
DRYI
CD
N D L WVV
VFQF
Q
F
PY
R
SK
LS
KLAKR
KQHGKS
H
DSFILLE
II K QG
CEFEN
T
HK
V
LK
K
LF
K TS
A QH
VSRGSS
A
TS
GI
L SK
G KR
TESESSS
F
G
HS
SVSHS S
VA
AN
W
KN
FNAN
EE R F C
PE
KMSDY
DG
SGMEE
TY
ND
S T Y I S I G E M- NH 2
*
*
*
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)
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Tropism Test
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HIV Integrase Mechanism
Strand Transfer
Inhibitors
X
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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
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Survival: CASCADE Cohort23 cohorts from Australia, Europe and Canada
Bhaskaran, JAMA 2008; 300: 51-59
HIV+ pre-1996
HIV+ 2004-06
HIV- 2004-06
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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.
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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!