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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
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)
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!
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