Transcript Slide 1

The Body PRO Presents:
Primary Drug Resistance and
Strategies for First-Line HIV
Treatment
Faculty: Ian Frank, M.D.
Associate Professor of Medicine at the
Hospital of the University of Pennsylvania
This activity is supported by an educational grant from
This activity is jointly sponsored by Postgraduate
Institute for Medicine and The Body PRO.
Copyright © 2008 Body Health Resources Corporation. All rights reserved.
Ian Frank, M.D.
1
Faculty for This Activity
The Body PRO
Ian Frank, M.D.
Ian Frank, M.D., has worked for the past 10 years in the Infectious Diseases Division of
the Hospital of the University of Pennsylvania where he serves as an Attending
Physician; Director, Antiretroviral Clinical Research; and Associate Professor,
Department of Medicine. Formerly he was Director, Immunodeficiency Program Clinic,
and Director, Outpatient Infectious Diseases Program also at the Hospital of the
University of Pennsylvania.
Dr. Frank is on numerous hospital and medical school committees, and national
committees, such as the Undergraduate Medical Education Committee; the Institutional
Review Board; the Medical Center AIDS Committee; and the Medical School HIV
Curriculum Committee. He has also worked on the HIV Research Agenda Committee,
Protease Inhibitor Focus Group, Adult AIDS Clinical Trials Group; and the Combination
Therapy Working Group of Primary Therapy Committee, Adult AIDS Clinical Trials Group.
Dr. Frank received his M.D. from Dartmouth Medical School and is a member of many
professional and scientific societies, including the American Association for the
Advancement of Science, the Infectious Diseases Society of America, and the
International AIDS Society.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
2
Agenda
The Body PRO
• Review DHHS guidelines for the initiation of antiretroviral therapy
• Review DHHS guidelines with respect to the recommended
agents and recent data influencing initial treatment decisions
• Discuss data on transmitted drug resistance and its
impact on treatment response and the selection of an
antiretroviral combination
• Discuss the selection of an initial antiretroviral combination
based upon specific patterns of resistance and sequencing
• Discuss the selection of an initial combination when resistance
testing isn’t available
Primary Drug Resistance and Strategies for First-Line HIV Treatment
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DHHS Guidelines: Recommendations for
When to Initiate Antiretroviral Therapy
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Clinical Condition and/or CD4+ Cell Count
Recommendations
History of AIDS-defining illness
CD4+ cell count < 350 cells/mm3
Other (regardless of CD4+ cell count)
– Pregnant women
– Persons with HIV-associated nephropathy
– Patients coinfected with HBV when
treatment for HBV infection is indicated
CD4+ cell count > 350 cells/mm3 in the absence of
any of the above conditions
Antiretroviral therapy
should be initiated
Antiretroviral therapy
should be considered,
based on the benefits and
risks, co-morbidities,
patient readiness, and
adherence
Adapted from Panel on Antiretroviral Guidelines for Adults and Adolescents. US Dept of Health and Human Services; 2008 Jan 29.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
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DHHS Guidelines: Recommendations for
Treatment-Naive Patients
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Select One Component From Column A + One From Column B
Column A (NNRTI or PI—in
alphabetical order)
Preferred Components
Alternative to
Preferred Components
Column B (Dual-NRTIs)
NNRTI
EFV1
or
PI
ATV/r
FPV/r (BID)
LPV/r2 (BID)
(in alphabetical order)
ABC/3TC3 (coformulated) for
HLA-B*5701 negative patients
or
TDF/FTC3 (coformulated)
NNRTI
NVP4
or
PI
ATV5
FPV
FPV/r (QD)
LPV/r (QD)
SQV/r
(in order of preference)
AZT/3TC3 (coformulated)
or
ddI + (FTC or 3TC)
1EFV
is not recommended for use in the first trimester of pregnancy or in sexually active women with childbearing potential who are not using
effective contraception.
2The pivotal study that led to the recommendation of LPV/r as a preferred PI component was based on twice-daily dosing [NEJM 2002]. A
smaller study has shown similar efficacy with once-daily dosing but also showed a higher incidence of moderate to severe diarrhea with
the once-daily regimen (16% vs. 5%) [JAIDS 2006]. In addition, once-daily dosing may be insufficient for those with VLs > 100,000
copies/mL [AIDS 2002].
3FTC may be used in place of 3TC and vice versa.
4NVP should not be initiated in women with CD4+ cell count > 250 cells/mm 3 or in men with CD4+ cell count > 400 cells/mm 3 because of
increased risk of symptomatic hepatic events in these patients.
5ATV must be boosted with RTV if used in combination with EFV or TDF.
Adapted from Panel on Antiretroviral Guidelines for Adults and Adolescents. US Dept of Health and Human Services; 2008 Jan 29.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
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ACTG 5142: Study Design
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Randomized, Multicenter, Open-Label Trial
Study Duration: 96 Weeks
N = 753
ARV-Naive
≥ 13 Years of Age
HIV-1 RNA ≥ 2,000 Copies/mL
Stratified at randomization
HIV-1 RNA < 100,000 vs. ≥ 100,000 Copies/mL
Chronic Hepatitis B/C Infection*
NRTI Selection
EFV 600 mg at bedtime + 2 NRTIs
N = 250
LPV/r 400/100 mg twice daily
+ 2 NRTIs
N = 253
EFV 600 mg at bedtime
+ LPV/r 533/133 mg twice daily
N = 250
LPV/r given as soft gel capsules
2 NRTIs included 3TC (150 mg twice daily or 300 mg once daily) + investigator selection of:
‡
ZDV 300 mg twice daily or d4T XR† 100 mg once daily or TDF 300 mg once daily
*Based on the presence of hepatitis C antibody or hepatitis B surface antigen, or both
†d4T XR was an investigational formulation of stavudine that is not commercially available
‡75
mg if subject weighed < 60 kg
Adapted from Sharon Riddler et al. N Engl J Med. 2008;358:2095-2106.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
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ACTG 5142: Virologic Response
Through 96 Weeks
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ITT: Missing Values Ignored
Percent with HIV-1 RNA
< 50 copies/mL
100
Percent at 96 Weeks
90
EFV + 2 NRTIs
LPV/r + 2 NRTIs
EFV + LPV/r
80
70
60
50
40
30
EFV + 2 NRTIs
LPV/r + 2 NRTIs
EFV + LPV/r
20
10
0
0 4 8
16
24
Number of Patients
32 40 48 56 64 72
Weeks After Randomization
80
88
96
EFV + 2 NRTIs
250
236
224
212
201
178
LPV/r + 2 NRTIs
253
235
226
217
201
177
EFV + LPV/r
250
242
228
217
206
180
Reprinted with permission from Ian Frank, M.D. Adapted from Sharon Riddler et al. N Engl J Med. 2008;358:2095-2106.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
89%
77%
83%
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ACTG 5202: Study Design
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96-Week, Phase 3B, Randomized, Partially Blinded Study
Comparing efficacy, safety and tolerability of regimens shown
below as initial therapy for HIV-1 infection
TDF/FTC QD
HIV-1 RNA ≥ 1,000 Copies/mL
Any CD4+ Cell Count
≥ 16 Years of Age
ABC/3TC Placebo QD
ABC/3TC QD
ART-Naive
ART-naïve
NN=1858
= 1,858
Randomized1:1:1:1
1:1:1:1
Randomized
TDF/FTC Placebo QD
TDF/FTC QD
Stratified by HIV-1 RNA
(< or ≥ 100,000 Copies/mL)
ABC/3TC Placebo QD
ABC/3TC QD
TDF/FTC Placebo QD
EFV
QD
EFV
QD
ATV/r
QD
ATV/r
QD
Adapted from Paul Sax et al. AIDS 2008; abstract THAB0303.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
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ACTG 5202: DSMB Efficacy Findings
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• Virologic failure rates were significantly higher among those
randomized to ABC/3TC than to TDF/FTC within the high viral
load stratum*
• No difference by use of EFV versus ATV + RTV
Cumulative Virologic Failure Data, Screening HIV-1 RNA ≥ 100,000
Comparison
Log-rank test
P-Value
Estimated
Hazard Ratio
95% CI
ABC/3TC vs. TDF/FTC
.0003
2.33
(1.46, 3.72)
*Subjects with HIV RNA > 100,000 copies/mL at screening.
Adapted from ACTG news and announcements page. A5202 study. Available at: http://aactg.org/news_results.asp. Accessed March 4, 2008.
Adapted from NIAID press release. NIAID modifies HIV antiretroviral treatment study combination therapy that includes ABC/3TC found less effective in
subgroup of antiretroviral-naive individuals. Available at: http://www3.niaid.nih.gov/news/newsreleases/2008/actg5202bulletin.htm. Accessed February 28, 2008.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
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When to Use Resistance Testing
The Body PRO
DHHS1
European2
IAS-USA3
Primary/Acute
Recommend‡
Recommend
Recommend
Post-Exposure Prophylaxis
—
Recommend
—
Chronic,
Treatment Naive
Recommend‡
Strongly Consider*
Consider*
Failure
Recommend
Recommend
Recommend
Pediatric
—
Recommend†
—
Pregnancy
Recommend
Recommend†
Recommend†
*Especially if exposure to someone receiving ARVs is likely or if prevalence of drug resistance in untreated patients ≥ 5% (European: ≥ 10%)
†When viral load is detectable
‡December 1, 2007: The Panel recommends performing genotypic drug resistance testing for all treatment-naive patients entering into
clinical care, regardless of whether antiretroviral therapy is to be initiated. This recommendation is based on the fact that transmitted
resistance mutation may be detected at a time point more proximal to the time of infection than later. Repeat testing may be considered at
the time when therapy is to be initiated
1 US
Dept of Health and Human Services. Antiretroviral Guidelines for Adults and Adolescents. 2008 Jan 29.
2Anne-Mieke
Vandamme et al. Antivir Ther. 2004;9:829-848. 3Martin Hirsch et al. Clin Infect Dis. 2003;37:113-128.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
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Ordering Resistance Testing Prior to
Initiation of Antiretroviral Therapy
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• A genotypic resistance test is adequate to determine the
pattern of resistance and select an initial combination
• Obtain a genotype as part of the initial evaluation of a
patient
– Don’t delay ordering a resistance test in patients with
high CD4+ cell counts
Primary Drug Resistance and Strategies for First-Line HIV Treatment
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Patterns of Resistance Among Newly
Diagnosed Patients–CDC Data
The Body PRO
Patients With Transmitted
Resistance (%)
12
10.7
10
10.4
8.8
8
7.7
7.1
6.9
6
5.5
5.1
4
3.6
3.0
2
0
0
0.4
1.3
0
1
1.3
0.8
N = 239
N = 257
MDR
NNRTI
NRTI
1.9
1.7
1
1
1999
1998
1Hillard
2.4
2.1
PI
2000
2003-2006
N = 299
N = 3,130
2
Any Resistance
Weinstock et al. J Infect Dis. 2004;189:2174-2180. 2William Wheeler et al. CROI 2007; abstract 648.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
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PREPARE Study: Transmitted Drug
Resistance
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Percentage of ART-Naïve Subjects With Resistance Mutations to Any Drug or by Drug Class
From 2000-2005 Using the IAS-USA Defined Primary Resistance Mutations.
Bars Shown in Purple Use the Stanford Resistance Mutation Definitions.
Summary from Ian Frank, M.D.: Cohort (N = 2,035) from clinical trials (2000-2005) sponsored by one pharmaceutical company.
Increase in primary resistance in 2005 primarily due to increased incidence of NNRTI mutations (10% to 11%).
Lisa Ross et al. ICAAC 2006; abstract H-993. Reprinted with permission.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
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Transmission of Drug-Resistant HIV in
New York City
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Acute or recent infection from
primary infection cohort in
New York City
112 ART-naive individuals
(January 2003 to December 2004)
Prevalence of Transmitted ART
Resistance Mutations, 1995 - 2004
1995-1998
1999-2000
> 25% with resistance
NNRTI resistance increased from
1995 thru 1998 (2.6%) to
2003 thru 2004 (13.4%); P = .04
11 (9.8%) with MDR: increase in
MDR resistance from previous
dates; P =.03
2001-2002
2003-2004
0
4
8
12
16
20
24
Percentage of Newly Infected Individuals
MDR
NNRTI
NRTI
PI
All Resistance
Adapted from Anita Shet et al. CROI 2005; abstract 289.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
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14
Declines in Transmitted Drug Resistance
In the UK
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Analysis of results of genotypic resistance tests reported to the UK HIV Drug Resistance
Database in patients who were antiretroviral treatment-naive at the time of sampling
Rate of Transmitted Drug
Resistance by Drug Class
Rate of Transmitted Drug Resistance
by Chronicity of Infection
All Patients
14
Rate of TDR (%)
12
10
8
NRTI
10
6
Acutely Infected
Patients
8
NNRTI
4
6
PI
4
2
2
0
1997
0
1999
2001
2003
Year of Sample
2005
1997
1999
2001
2003
Year of Sample
Adapted from UK Collaborative Group on HIV Drug Resistance et al. AIDS. 2007;21:1035.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
2005
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15
Acquired Resistance Persists After
Acute Infection in the Absence of
Any Selective Pressure
Resistance
Follow-up (Weeks)
Reversions
n=101
NNRTI (n=9)
NRTI (n=3)
PI
(n=3)
n=1 MDR2
n=4 MDR3
n=2 MDR4
9-145
156
36-260
26-156
1 of 10
None
None
None
MDR = multiple drug resistance
1Susan
Little et al. N Engl J Med. 2002;347(6):385-394. 2Phillippe Colson et al. AIDS. 2002;16(3):507-509.
3Bluma Brenner et al. J Virology. 2002;766:1753. 4Keith Chan et al. AIDS. 2003;17:1256.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
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Genotype Predicts Virologic Failure
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Prospective, international study of 571 ARV-naive patients (FTC 301).
95% (546/571) had baseline resistance testing.
16% (90/546) showed baseline NRTI and/or NNRTI resistance.
Genotype Results and Virologic Failure Rates
Virologic Failure (%)
90
75
60
Any (N = 90)
45
K103N (N = 14)
NRTI (N = 34)
30
Other NNRTI (N = 34)
WT (N = 456)
15
0
d4T + ddI + EFV
FTC + ddI + EFV
Adapted from Katyna Borroto-Esoda et al. AIDS Res Hum Retroviruses. 2007;23:988-995.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
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Resistance Testing Can Improve
Outcomes in ARV-Naive Patients
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Baseline Resistance
All had baseline resistance testing to
select initial HAART.
Primary drug resistance [mostly NRTI]
in 11.2% of patients.
Week 48: No difference in virologic
outcomes if HAART selected based
on resistance testing.
100
90
< 50 copies/mL (%)
Prospective, multicenter study
N = 269
ARV-naive, chronically infected
patients between January 2001 and
December 2003
No Resistance
83
85
80
74
67
70
60
50
40
30
20
10
0
On Treatment
Intent-to-Treat
Adapted from Mark Oette et al. JAIDS. 2006;41:573-581.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
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Cost Effectiveness of Genotype
Resistance Testing
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• Simulation model of HIV disease
– Life expectancy, lifetime
costs, and cost-effectiveness
projected
• Assumed baseline prevalence of
drug resistance
– All: 8.3%
• NRTI: 4.7%
• PI: 1.9%
• NNRTI: 1.7%
• Genotypic resistance testing
– Improves clinical outcomes
– Cost effective
Resistance Testing
Newly Diagnosed
$23,900
HAART
$25,900
Resistance Testing PostTreatment Failure
$20,200
Cost ($)/Quality Adjusted Life-Year
Adapted from Paul Sax et al. Clin Infect Dis. 2005;41:1316-1323.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
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ACTG 5095: AZT+3TC+EFV vs. AZT+3TC+ABC+EFV
Impact of Minority Variants
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N=
219
183
183
183
Preexisting minority Y181C mutants associated with > 3-fold increased risk of virologic failure of first-line
EFV-based HAART, even among adherent patients.
Adapted from Roger Paredes et al. CROI 2008; abstract 83.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
20
Mutations Associated With
Resistance to NRTIs
The Body PRO
Reprinted with permission from Ian Frank, M.D. Adapted from Victoria Johnson et al. Top HIV Med. 2006;14:125-130.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
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NRTI Mutations, NRTI Resistance and
NRTI Options
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Mutation(s)
Resistant NRTIs
NRTI Options
184V
3TC, FTC
ABC, ddI, d4T, TDF, AZT
74V
ABC, ddI
3TC, FTC, d4T, TDF, AZT
65R
ABC, ddI, 3TC, FTC, TDF
d4T, AZT (do not use together)
Single TAM:
41, 67, 70, 210, 215, 219
AZT, d4T
3TC, FTC, TDF, ddI, ABC
41L + 210W
AZT, d4T, ABC (if 184V),
TDF (if 215Y)
ddI (?), 3TC (?), FTC (?)
67N + 70R
AZT, d4T, ABC (if 184V)
ddI, 3TC, FTC, TDF
Primary Drug Resistance and Strategies for First-Line HIV Treatment
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ACTG 5142: Virologic Response
Through 96 Weeks
The Body PRO
ITT: Missing Values Ignored
Percent with HIV-1 RNA
< 50 copies/mL
100
Percent at 96 Weeks
90
EFV + 2 NRTIs
89
LPV/r + 2 NRTIs
77%
EFV + LPV/r
83%
Nucleoside-Sparing Arm
80
70
60
50
40
30
EFV + 2 NRTIs
LPV/r + 2 NRTIs
EFV + LPV/r
20
10
0
0 4 8
16
24
Number of Patients
32 40 48 56 64 72
Weeks After Randomization
80
88
96
EFV + 2 NRTIs
250
236
224
212
201
178
LPV/r + 2 NRTIs
253
235
226
217
201
177
EFV + LPV/r
250
242
228
217
206
180
Reprinted with permission from Ian Frank, M.D. Adapted from Sharon Riddler et al. N Engl J Med. 2008;358:2095-2106.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
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Mutations Associated With
Resistance to NNRTIs
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Delavirdine
Efavirenz
K
V
Y
Y
P
103
106
181
188
236
N
M
C
L
L
K
V
V
Y
Y
G
P
103
106
108
181
188
190
225
N
M
I
C
L
S
A
H
I
Nevirapine
V
Etravirine*
A
L
K
V
V
Y
Y
G
100
103
106
108
181
188
190
I
N
A
M
V
I
C
I
Y
C
L
H
A
L
K
90 98 100 101
I
G
I
E
P
106
I
V
179 181
G
190
D
C
S
F
I
A
V
*No single mutation confers full resistance; efficacy decreases as number of mutations increases.
Reprinted with permission from Ian Frank, M.D. Adapted from Victoria Johnson et al. Top HIV Med. 2006;14:125-130.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
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In Second-Line Therapy After NNRTI Resistance,
the Boosted PI Contributes
Most of the Activity
MONARK Study: LPV/r Monotherapy vs. LPV/r + AZT/3TC in ARV-Naive Patients
P-value
Patients Randomized
LPV/r
AZT/3TC + LPV/r
83
53
Intent-to-Treat, M = F
Viral Load < 50 Copies/mL
at Week 48
0.69
58/82
(71%)
40/53
(75%)
As Treated, available VL
Viral Load < 50 Copies/mL
at Week 48
0.03
56/67
(84%)
40/41
(98%)
Good response rates to LPV/r alone, though outcomes better when used with NRTIs.
Adapted from Jean-Francois Delfraissy et al. AIDS 2006; abstract THLB0202.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
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25
Boosted PIs in ARV-Naive Patients:
Virological Suppression
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ARTEMIS1
CASTLE2
GEMINI3
KLEAN4
(ITT)
48 wk
(ITT)
48 wk
(ITT)
48 wk
(ITT-E, TLOVR)
48 wk
Noninferiority
Noninferiority
Noninferiority
Noninferiority
64 65
66 65
100
84*
90
80
81
78
76
71*
70
60
50
40
30
20
10
0
N=343 N=346 N=346
N=440 N=443
N=170 N=167
N=434 N=444
DRV/r LPV/r† LPV/r†
800/100 400/100 800/200
QD
BID
QD
ATV/r LPV/r
300/100 400/100
QD
BID
LPV/r
SQV/r
400/100 1000/100
BID +
BID +
TDF/FTC TDF/FTC
FPV/r LPV/r
700/100 400/100
BID
BID
*P <.05 between LPV/r QD and DRV/r QD; no other significant differences in any of the comparisons above
†Use of LPV/r BID or QD was not randomized and was dependent on site and patient preference
1Edwin
De Jesus et al. ICAAC 2007; abstract H-718b. 2Jean-Michel Molina et al. CROI 2008; abstract 37.
Walmsley et al. EACS 2007; abstract PS1/4. 4Joseph Eron et al. Lancet. 2006;368:476-482.
3Sharon
Primary Drug Resistance and Strategies for First-Line HIV Treatment
26
PI Potency: The Impact of Baseline Viral Load
The Body PRO
ARTEMIS2
ACTG 50731
N = 402
80
70
72
89*
76*
60
50
40
30
20
10
Patients with VL < 50 copies/mL (%)
Patients with VL < 200 copies/mL (%)
90
80
(ITT-E, TLOVR)
100
100
90
80
70
86
86
79
79*
71
60
56*
50
40
30
20
10
0
0
< 100,000
≥ 100,000
< 100,000
≥ 100,000
Patients with VL < 50 copies/mL (%)
(ITT)
100
KLEAN3
(ITT-E, TLOVR)
90
80
70
60
67
64
65
66
50
40
30
20
10
0
< 100,000 ≥ 100,000
Baseline HIV RNA (copies/mL)
LPV/r 800/200 mg QD
LPV/r 400/100 mg BID
DRV/r 800/100 mg QD
LPV/r† 800/200 mg QD
LPV/r† 400/100 mg BID
FPV/r 700/100 mg BID
LPV/r 400/100 mg BID
*P < .05 comparing LPV/r BID and QD in ACTG 5073 and comparing DRV/r QD and LPV/r QD in ARTEMIS
†Use of LPV/r BID or QD was not randomized and was dependent on site and patient preference
1Donna Mildvan et al. CROI 2007; abstract 138. 2Nathan Clumeck et al. EACS 2007; abstract LBPS7/5.
3Joseph Eron et al. Lancet. 2006;368:476-482.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
27
DUET 1 and 2: Etravirine vs. Placebo
Virologic Response by Baseline Mutations
The Body PRO
13 Baseline Resistance-Associated
Mutations (RAMs) Associated With a
Decreased Response to Etravirine:
A98G
L100I
V90I
G190A/S
V106I
K101E/P
V179D/F
Y181C/I/V
If three or more mutations are present,
response similar to placebo.
Note: 14% had > 3 etravirine RAMs.
HIV RNA < 50 Copies/mL (%)
80
60
40
20
0
0
1
2
3
4
5
% = 40
30
16
8
5
0.9
Number of Etravirine RAMs
Adapted from Christine Katlama et al. IAS 2007; abstract WESS204-2.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
28
Etravirine + Two NRTIs After Viremia on First
NNRTI-Based Regimen
The Body PRO
• Pilot study to evaluate
activity of etravirine plus
NRTIs in patients viremic
on an NNRTI / NRTI
first regimen
– PI naive
– Randomized to two
NRTIs plus either:
• Etravirine
• PI (95% boosted)
• Study stopped
prematurely due to
superiority of PI arm
• Predictors of response:
– # NNRTI mutations
– # NRTI mutations
Brian Woodfall et al. Glasgow 2006; abstract PL5.6. Reprinted with permission.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
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Activity of 2 NRTIs + Etravirine by Number of
NRTI (TAMS / 184V) Mutations
The Body PRO
Summary From Ian
Frank, M.D.
Use of etravirine with
“compromised”
NRTIs not as
durable as
PI-based regimen
Activity of etravirine
preserved with a
more active
background regimen
Brian Woodfall et al. Glasgow 2006; abstract PL5.6. Reprinted with permission.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
30
Mutations Associated With
Resistance to PIs
The Body PRO
L
G
K
L
V L E
32 33 34
I
I Q
F
V
Atazanavir
10 16 20 24
+/- Ritonavir
Fosamprenavir/r
Darunavir/r
I E R
F
M
V
I
L
T
C
10
F
I
R
V V
11
I
I
L G
L
K
M
36
I
L
V
M
46
I
L
V
32
I
M I
46 47
I V
L
V L
32 33
I F
L
V
G
48
V
L
M
M
M
I
F
50 53
L L
Y
I
I
D
54 60
L
E
V
M
T
I,A
54
L
V
M
I
50
54
V
M
I
I
I
50
V
I
47
V
E
I
G
I
Tipranavir/r 10 16 20 24 24 32 33 34 36 36 46 47 48 50
F E
L G
R I
K L
I
L
I
V
I Q
L E
I
M
I
M
I
M
V
I
V
G
L
I
Saquinavir/r 10 16 20 24 24 32 33 34 36 36 46 47 48 50
F
L
Lopinavir/r 10
F
I
R
V
E
R I
K L
20 24
M I
R
I
I
V
I Q
L
32 33
I
F
I
I
I
M
V
I
46 47
I V
L
V
F
D
I I A
62 64 71
V L V
M I
V T
L
G
73
C
S
T
A
G
73
S
V
I
I
82 84 85
A
V
V
T
F
I
V
I
82 84
A
V
F
T
L S
I
G
73 76
S V
I
I
A
G
V
84
V
V
I
N
88
S
L
I
90 93
M L
M
L
90
M
L
89
V
I
N
L
I
53 54 60
62 64 71 73 77 82 84
85
88
90 93
L
F
V
I
V
I
S
N
M
L
L
I
E
D
L
I
V
A
C
G
I
V
A
V
V
I
L
I
53 54 60
62 64 71 73 77 82 84
85 88
90 93
L
I
L
F
V
L
V
M
L
50
V
53 54
L V
L,A
M,T
S
L
I
E
63
P
L
V
A
C
G
71 73
V S
T
I
A
V
V
I
82 84
A
F
T
S
V
Reprinted with permission from Ian Frank, M.D. Adapted from Victoria Johnson et al. Top HIV Med. 2006;14:125-130.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
S
90
M
L
31
TITAN: LPV/r vs. DRV + RTV in
PI-Experienced—Study Design
The Body PRO
LPV/r-Naive
VL > 1,000 Copies/mL
Stable HAART for > 12 Weeks
OR Treatment Interruption
for > 4 Weeks
(N = 595)
DRV/r 600/100 mg BID
+ OBRa
1:1
Primary Endpoint
HIV RNA
< 400 Copies/mL
at 48 Weeks
LPV/rb 400/100 mg BID
+ OBR
Treatment Phase (96 Weeks)
Median VL, log10 copies/mL
Median CD4+ cell count, cells/mm3
Previous antiretroviral experience, %
≥ 4 NRTIs
0 PI
1 PI
2-class experienced, %
NRTI + NNRTI
NRTI + PI
3-class experienced, %
DRV/r (N = 298)
LPV/r (N = 297)
4.35
235
4.30
230
52
32
36
51
31
39
29
22
46
29
21
48
= ≥ 2 ARVs from approved NRTI/NNRTIs, enfuvirtide and tipranavir use excluded
of tablet formulation of LPV/r allowed if approved within country
aOBR
bUse
Adapted from Jose Valdez Madruga et al. Lancet. 2007;370:49-58.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
32
TITAN: LPV/r vs. DRV + RTV in PI-Experienced—
Impact of Baseline PI Mutations
All Patients With LPV FC ≤ 10a
90
DRV/r (N = 263)
78
80
LPV/r (N = 261)
69
70
68
66
65
59
60
50
50
43
40
30
20
10
0
0
N=
195 197
1
32 32
≥3
2
19 18
17 14
HIV RNA < 50 Copies/mL (ITT-TLOVR, %)
HIV RNA < 50 Copies/mL (ITT-TLOVR, %)
The Body PRO
Patients With Prior PI Experience
and LPV FC ≤ 10a
90
DRV/r (N = 172)
80
70
60
77
LPV/r (N = 174)
69
68
63
61
55
50
47
43
40
30
20
10
0
0
106 114
1
31 29
2
19
17
≥3
16 14
Number of IAS-USA Primary PI Mutations†
aExcludes
patients with missing LPV FC at baseline; †D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50V/L, I54L/M, L76V,
V82A/F/L/S/T, I84V, N88S or L90M. [Johnson VA, et al. Top HIV Med. 14:22-30.]
Adapted from Daniel Berger et al. EACS 2007; abstract P7.3/27.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
33
Trial 004: Raltegravir vs. Efavirenz in
ART-Naive Patients
The Body PRO
Percent of Patients With
HIV RNA < 50 Copies/mL
In ART-naive patients with viral load ≥ 5,000 copies/mL and CD4 ≥ 100 cells/mm3,
RAL studied for 48 weeks at all doses
100
80
60
Raltegravir 100 mg BID (N = 39)
Raltegravir 200 mg BID (N = 40)
Raltegravir 400 mg BID (N = 41)
Raltegravir 600 mg BID (N = 40)
Efavirenz 600 mg QD (N = 38)
40
20
0
0 2 4
8
12
16
24
Week
32
40
48
• Had potent antiretroviral activity: 83% - 88% with viral load < 50 copies/mL
Achieved viral suppression faster than EFV
• Was well tolerated, with no effect on lipids
Adapted from Martin Markowitz et al. IAS 2007; abstract TUAB104.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
m518p4 r50 7
July 10, 2007
The Body PRO
MERIT: Percentage of Patients With
Undetectable HIV-1 RNA at Week 48
(Primary Endpoint)
Michael Saag et al. IAS 2007; abstract WESS104. Reprinted with permission.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
34
The Body PRO
MERIT: Percentage of Patients With HIV-1 RNA
< 50 Copies/mL at Week 48 by Tropism
Result at Baseline
Jayvant Heera et al. CROI 2008; abstract 40LB. Reprinted with permission.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
35
36
Use of the Trofile Assay
The Body PRO
• Obtain a Trofile Assay to determine the tropism of virus
before prescribing maraviroc
– R5 virus uses CCR5 for entry
– X4 virus uses CXCR4 for entry
– Dual-tropic virus uses CCR5 or CXCR4
• Maraviroc is not active against X4 or dual-tropic virus
• An enhanced sensitivity Trofile assay is available
– Able to detect the presence of dual-tropic or X4 viruses
present in mixtures with a sensitivity of <1%
Primary Drug Resistance and Strategies for First-Line HIV Treatment
The Body PRO
Choosing an Initial Combination in a
Patient With Reverse Transcriptase
Inhibitor Resistance
• If NRTI resistance is present alone
– Use an NNRTI + boosted PI
– Use a boosted PI with the best NRTI combination available
– Do not use an NNRTI and partially active NRTIs
• If NNRTI resistance is present alone
– Use a boosted PI with two active NRTIs
Primary Drug Resistance and Strategies for First-Line HIV Treatment
37
38
Choosing an Initial Combination in a Patient
With PI Resistance Alone
The Body PRO
• Use two NRTIs + one NNRTI
• Virus with primary PI resistance does not usually contain
multiple PI-associated mutations
– If there is a PI with full or partial activity that agent can be
included in a regimen with two other fully active drugs
Primary Drug Resistance and Strategies for First-Line HIV Treatment
39
Choosing an Initial Combination in a Patient
With Multi-Drug Resistance
The Body PRO
• If the virus is fully susceptible to a protease inhibitor
– Use a boosted protease inhibitor and one or two new agents
• Etravirine is an option if K103N is present alone
• Maraviroc is an option if the virus is pure R5
• Raltegravir should be fully active
• If the virus is resistance to protease inhibitors
– Use the boosted PI with the most activity against the virus
– Add two fully active drugs among the newer agents
– Use enfuvirtide in the setting of broadly resistant virus
Primary Drug Resistance and Strategies for First-Line HIV Treatment
40
ACTG A5164: Immediate vs. Delayed ARVs in
Setting of Acute Opportunistic Infections
The Body PRO
P-value
Time of ARV initiation
Immediate ARV
Deferred ARV
Days to ARV
N/A
0
35
Days from OI to
ARV (95% CI)
< .001
12 (11–12)
45 (43–48)
• 282 patients with treatable opportunistic infection or AIDS-associated bacterial infection
within 14 days of study entry; no ARV within eight weeks
• Randomized to starting ARV within 48 hours (immediate) or after 42 days (deferred)
• Baseline: Median CD4+ = 29 cells/mm3, with 70% CD4+ < 50; > 90% of patients ARV naive
• All received 3TC or FTC; 80% received LPV/r
• Primary endpoint was composite endpoint consisting of:
– Death/AIDS progression
– No disease progression/HIV RNA ≥ 50 copies/mL
– No disease progression/HIV RNA < 50 copies/mL
Adapted from Andrew Zolopa et al. CROI 2008; abstract 142.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
41
ACTG A5164: Immediate vs. Delayed ARVs in
Setting of Acute Opportunistic Infections (2)
The Body PRO
Immediate
Probability of Surviving Without
Death/New AIDS-Defining Illness
• Immediate treatment group
had reduced rate of AIDS
progression or death (14.2%)
versus deferred treatment
group (24.1%).
– Most common OIs: PCP
(63%), Cryptococcus
(12%), bacterial infection
(12%); TB excluded.
• More rapid increase in CD4+
cell counts to > 50 and > 100
cells/mm3 for immediate group
versus deferred group.
• No differences in IRIS (10
immediate versus 13 deferred).
– However, 70% of patients
with PCP received
corticosteroids.
Deferred
1
116
0.8
94
0.6
0.4
0.2
0
4
12
20
28
36
44
Time to Death/New AIDS-Defining Illness
(Weeks)
HR = 0.53
99% CI (0.25, 1.09)
P = .023
Adapted from Andrew Zolopa et al. CROI 2008; abstract 142.
Primary Drug Resistance and Strategies for First-Line HIV Treatment
42
Starting Therapy in the Absence of Resistance
Test Results
The Body PRO
• Obtain a resistance test
• Begin a boosted PI-based regimen
– PI resistance is less common than NRTI and NNRTI
resistance
– Consider a PI with a greater threshold for resistance
• Simplify therapy when the resistance test results are available
Primary Drug Resistance and Strategies for First-Line HIV Treatment
43
Conclusions
The Body PRO
• Genotypic resistance testing should be obtained before
prescribing an antiretroviral combination in a treatment-naive
patient.
• In the presence of mutations, the antiviral combination
prescribed should contain three fully active drugs, or a boosted
protease inhibitor and one or two additional fully active drugs.
• If an antiretroviral combination must be prescribed in the
absence of resistance test results, start with a boosted PI-based
combination and modify therapy when results are available.
Primary Drug Resistance and Strategies for First-Line HIV Treatment