Transcript Multidrug Resistance - The University of North Carolina at Chapel Hill

Multidrug Resistance
New Options and
Advanced Approaches to Management
Program Presenter
David Alain Wohl, MD
Associate Professor, Division of Infectious DIseases
The University of North Carolina
Chapel Hill, NC
2
Virologic Failure, Multidrug Resistance,
and General Principles of Management
Long-Term Risk of Developing Drug
Resistance on HAART: UK CHIC Study
Time to Multi-Class Resistance
30
Patients (%)
25
3-class resistance
2-class resistance
1-class resistance
27%
20
20%
19%
14%
15
10
9%
6%
5
2.7%
1%
0
2
3.1%
4
Years Since Starting HAART
n=4306
Overall risk of treatment failure: 38% over 6 years.
Phillips AN, et al. AIDS. 2005;19:487-494.
5
6
Increased Disease Progression
With Class-Wide Drug Resistance
Cumulative Survival or Remaining Free of AIDS Events
Stratified by Class-Wide Drug Resistance (CWDR)
Cumulative Survival
1
0.9
0 CWDR
1 CWDR
0.8
2 CWDR
0.7
3 CWDR
0.6
0
10
20
30
40
50
60
Time After Genotypic Resistance Test (months)
n=623 patients who failed HAART and underwent genotypic testing, then were followed for a median of 19 months (IQR 12-29).
Multivariate Cox's model: increased risk of death was significantly associated with higher HIV RNA, prior AIDS,
and detection of 3 CWRD (hazard ratio 5.34 [95% CI 1.76-16.24]).
Zaccarelli M, et al. AIDS. 2005;19:1081-1089.
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Assessment of Treatment Failure
 Adherence
 Medication intolerance
 Pharmacokinetic issues
 Suspected drug resistance
Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision January 29, 2008.
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General Approaches to the
Management of Virologic Failure
 Goal is to achieve plasma HIV RNA <50 copies/mL
 Identify fully active agents
– Add at least two and preferably three fully active agents
– Drug potency and susceptibility more important than
number of drugs
– Adding a single active drug is not recommended
• Risk rapid development of resistance
 Discontinuing or briefly interrupting therapy is not
recommended
– Increases risk of clinical progression
Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision January 29, 2008.
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Multidrug Resistance:
Recent Clinical Trials of Interest
Multidrug Resistance:
Recent Clinical Trials of Interest
 Boosted PIs
– RESIST, POWER, and TITAN
 Second-generation NNRTI
– DUET
 CCR5 antagonist
– MOTIVATE
 Integrase inhibitor
– BENCHMRK
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RESIST Studies: Tipranavir + Ritonavir
in Patients With PI Failure
 Two, phase 3, multicenter, open-label trials
 Patients with >3-class antiretroviral experience
– >2 previous PI-based regimens for at least 3 months
– >1 primary PI mutation
• 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V, or 90M
– <3 mutations
• Codons 33, 82, 84, and 90
– HIV RNA >1000 copies/mL
– Any CD4 cell count
 Treatment arms
– Control: ritonavir-boosted comparator PI regimen
– Tipranavir + ritonavir
– All patients received an optimized background regimen
• >2 NRTIs + enfuvirtide
Hicks CB, et al. Lancet. 2006;368:466-475.
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RESIST Studies:
Combined 48-Week Analysis
HIV RNA <50 Copies/mL
CD4 Cell Gain
100
Tipranavir + RTV
CPI + RTV
Patients (%)
75
50
28.4%*
25
22.8%*
14.1%
10.2%
0
All Patients
Enfuvirtide Use
(n=746/737)
(n=124/97)
*P<0.0001 versus CPI + RTV.
ITT: non-completer=failure.
Hicks CB, et al. Lancet. 2006;368:466-475.
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Change (cells/mm3)
150
125
100
75
50
45*
21
25
0
Tipranavir + RTV
CPI + RTV
(n=740)
(n=727)
POWER Studies: Darunavir + Ritonavir
in Patients With 3-Class Experience
 Two, phase 2b, multicenter, open-label trials
 Patients with >3-class antiretroviral experience
– Currently receiving a PI-containing regimen
– >1 primary PI mutation (any combination, IAS-USA March 2003)
• Proportion with >2 primary PI mutations limited to 30% of patients
– HIV RNA >1000 copies/mL and any CD4 cell count
 Treatment arms
– Control: investigator chosen PI
– Darunavir/r 600/100 mg bid
• Other doses included 400/100 and 800/100 mg qd and 400/100 mg bid
– All patients received an optimized background regimen
• >2 NRTIs + enfuvirtide
Clotet B, et al. Lancet. 2007;369:1169-1178.
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POWER Studies:
Combined 48-Week Analysis
HIV RNA <50 Copies/mL
CD4 Cell Gain
100
Darunavir + RTV (600/100 mg bid)
Control PI
Patients (%)
75
58%*
50
45%*
25
11%
10%
0
All
Patients
Enfuvirtide
Use (naïve)
(n=131/124)
(n=36/35)
*P<0.0001 versus control PI.
ITT: non-completer=failure.
Clotet B, et al. Lancet. 2006;369:1169-1178.
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Change (cells/mm3)
150
125
100
102*
75
50
25
0
19
Darunavir + RTV
600/100 mg bid
(n=131)
Control PI
(n=124)
TITAN Study: Darunavir + Ritonavir
Versus Lopinavir/Ritonavir Regimen
 Phase 3, 96-week study
 Treatment-experienced, lopinavir/ritonavir-naïve patients (n=595)
– HIV RNA: 4.30 log10 copies/mL
– CD4: 232 cells/mm3
– PI-naïve: 31%
– Susceptible to >4 PIs: 82%
 Baseline susceptibility
– Lopinavir fold-change >10: 10%
– Darunavir fold-change >10: 2%
 Randomized arms
– Darunavir + ritonavir (600/100 mg bid)
– Lopinavir/ritonavir (400/100 mg bid; soft-gel capsules)
– Both arms received investigator-selected optimized background regimen
Madruga JV, et al. Lancet. 2007;370:49-58.
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TITAN Study:
48-Week Analysis
CD4 Cell Gain
HIV RNA <50 Copies/mL
Patients (%)
75
150
71%*
60%
50
25
0 Darunavir + RTV
(n=298)
Lopinavir/r
(n=297)
*P=0.005 versus lopinavir/r.
ITT: non-completer=failure.
Madruga JV, et al. Lancet. 2007;370:49-58.
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CD4 Cell Gain (cells/mm3)
100
125
100
88
81
75
50
25
0
Darunavir + RTV
Lopinavir/r
(n=298)
(n=297)
DUET Studies: Etravirine in
Treatment-Experienced Patients
 Two, phase 3, 96-week studies
– Treatment-experienced patients
with evidence of resistance to
current NNRTIs
Placebo
Etravirine
(n=604)
(n=599)
109
99
4.8
4.8
Enfuvirtide
47
46
– Etravirine 200 mg bid or placebo
0 active drugs
16
17
– All patients received optimized
background therapy
1 active drug
39
37
– Stratified by baseline enfuvirtide
use, previous darunavir use, and
HIV RNA (<30K, >30K
copies/mL)
 Treatment arms
• Darunavir + RTV plus optimized
NRTIs and optional enfuvirtide
Haubrich R, et al. 15th CROI. Boston, 2008. Abstract 790.
Johnson M, et al. 15th CROI. Boston, 2008. Abstract 791.
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Baseline Values
Median CD4
(cells/mm3)
Mean HIV RNA
(log10 copies/mL)
OBT (%)
DUET Studies:
Combined 48-Week Analysis
CD4 Cell Gain
HIV RNA <50 Copies/mL
150
Patients (%)
75
61%
50
P<0.0001
40%
25
0
Etravirine
Placebo
(n=599)
(n=604)
Haubrich R, et al. 15th CROI. Boston, 2008. Abstract 790.
Johnson M, et al. 15th CROI. Boston, 2008. Abstract 791.
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CD4 Cell Gain (cells/mm3)
100
125
100
98
73
75
P=0.0006
50
25
0
Etravirine
Placebo
(n=599)
(n=604)
MOTIVATE Studies: Maraviroc in TreatmentExperienced Patients With R5-Only HIV
 Combined analysis of two 48-week
phase 2b/3 trials
Baseline Values
Maraviroc
– Triple-class experienced (+ triple-class
resistance)
– R5-only virus
– Stratified by baseline HIV RNA
(<100K, >100K copies/mL) and
enfuvirtide use in optimized
background therapy (OBT)
 Treatment arms
– Maraviroc 150 mg once daily
Median CD4
Placebo
Once
Daily
Twice
Daily
(n=209)
(n=414)
(n=426)
187
196
189
4.86
4.86
4.85
66
66
69.7
(cells/mm3)
Mean HIV RNA
(log10 copies/mL)
OBT (%)
– Maraviroc 150 mg twice daily
<2 active
drugs
– Placebo
Enfuvirtide
43.5
40.6
42.7
– All patients received OBT (darunavir
not included in OBT)
Tipranavir
13.9
15.9
14.8
Patients receiving a PI (except tipranavir) and/or delavirdine in their OBT received maraviroc 150 mg;
all others received 300 mg.
Hardy D, et al. 15th CROI. Boston, 2008. Abstract 792.
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MOTIVATE Studies:
Combined 48-Week Analysis
CD4 Cell Gain
HIV RNA <50 Copies/mL
100
Patients (%)
75
50
43.2%*
45.5%*
25
0
16.7%
Once-Daily Twice-Daily
(n=414)
(n=426)
OBT Alone
(n=209)
Maraviroc
All maraviroc patients received optimized background therapy.
*P<0.0001 versus OBT alone.
Hardy D, et al. 15th CROI. Boston, 2008. Abstract 792.
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CD4 Cell Gain (cells/mm3)
150
125
124
116
100
75
61
50
25
0
Once-Daily Twice-Daily
(n=414)
(n=426)
Maraviroc
OBT Alone
(n=209)
BENCHMRK Studies: Raltegravir in
Patients With Triple-Class Resistance
 Two phase 3, 156-week studies
BENCHMRK 1/2
– Treatment-experienced patients
with triple-class resistance
– Stratified by baseline HIV RNA,
enfuvirtide and darunavir use in
optimized background therapy
(OBT)
 Treatment arms
– Raltegravir 400 mg twice-daily +
OBT
– Placebo + OBT
Cooper D, et al. 15th CROI. Boston, 2008. Abstract 788.
Steigbigel R, et al. 15th CROI. Boston, 2008. Abstract 789.
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Placebo
Raltegravir
(n=118/119)
(n=232/230)
105/132
140/102
4.5/4.7
4.6/4.7
89/91
94/91
New enfuvirtide
20/20
21/19
New darunavir
25/50
27/45
Mean CD4
(cells/mm3)
Mean HIV RNA
(log10 copies/mL)
AIDS (%)
OBT (%)
BENCHMRK Studies:
48-Week Analysis
CD4 Cell Gain
HIV RNA <50 Copies/mL
150
BENCHMRK-1
BENCHMRK-2
Patients (%)
80
65%*
60
60%*
40
31%
34%
20
0
Raltegravir
Placebo
*P<0.001 versus placebo.
Cooper DA, et al. 15th CROI. Boston, 2008. Abstract 788.
Steigbigel R, et al. 15th CROI. Boston, 2008. Abstract 789.
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CD4 Cell Gain (cells/mm3)
100
125
100
BENCHMRK-1
BENCHMRK-2
120*
98*
75
49
50
40
25
0
Raltegravir
Placebo
Multidrug Resistance:
Advanced Approaches to Management
Case 1: 37-Year-Old Female With
Viremia and Stable CD4 Cell Count
 At time of HIV diagnosis in 1994
– Cryptococcal meningitis
– CD4: 32 cells/uL
 Antiretroviral history
– 1994 to 1996: dual NRTIs
– 1996 to 1998: dual NRTIs + indinavir with undetectable HIV RNA
– 1998: viral rebound
– 1998 through January 2008: multiple changes in therapy
• Sequential regimens included all available NRTIs except stavudine, all PIs
except darunavir, and efavirenz (in 2002)
– No history of using CCR5 antagonists or any entry or integrase
inhibitors
24
Current Presentation
 Current presentation
– HIV RNA: 37,000 copies/mL
– CD4: 210 cells/µL
(stable over last 12 months)
 Regimen for past 6 months
– Zidovudine/lamivudine/abacavir +
tenofovir DF + tipranavir + ritonavir
– States good tolerance and adherence
 No diabetes mellitus, dyslipidemia,
HCV or HBV infection
– Not abusing drugs or alcohol
25
Genotype
NRTI
NNRTI
PI
D67N
T69D
K70R
V118I
M184V
T215V
K219Q
K103N
I13V
L33F
F53L
I54V
L63P
A71V
G73S
I84V
L90M
Resistance Test
DRUG
SUSCEPTIBILITY
Susceptibility
PT
26
GT
ASSESSMENT
Would You Use NRTIs in the
Next Regimen?
DRUG
27
SUSCEPTIBILITY
Susceptibility
ASSESSMENT
Would You Consider NRTIs as One of the
Fully Active Drugs in the Next Regimen?
DRUG
28
SUSCEPTIBILITY
Susceptibility
ASSESSMENT
Would You Consider Etravirine as a Potentially
Fully Active Drug in the Next Regimen?
DRUG
29
SUSCEPTIBILITY
Susceptibility
ASSESSMENT
DUET Studies: Baseline Etravirine
Mutations and Virologic Response
– V90I, A98G, L100I, K101E/P,
V106I, V179D/F, Y181C/I/V,
G190A/S
 Presence of >3 etravirine
resistance mutations was
associated with response
similar to placebo + OBR
– Etravirine resistance
mutations at baseline
• 0 or 1: 70% of patients
• >3: 15%
Picchio G, et al. 15th CROI. Boston, 2008. Abstract 866.
30
100
80
Patients (%)
 13 mutations associated
with etravirine resistance
Week 24
HIV RNA <50 Copies/mL
75%
60%
60
58%
40
33%
20
0
0
1
2
>3
(n=161)
(n=121)
(n=64)
(n=60)
Number of Baseline
Etravirine Mutations
31
Prevalence of Etravirine Resistance in
Clinical Populations
Number of
Samples
>3 Etravirine Mutations
at Baseline (%)*
DUET 1 and 21
1203
15
Thailand2
158
25
Nigeria3
214
11
Spain4
4981
9.3
Virco5
226,491
2.9
*V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, G190A/S
1Cahn
P, et al. 47th ICAAC. Chicago, 2007. Abstract H-717.
S, et al. 15th Boston, 2008. Abstract 865.
3Taiwo B, et al. 15th CROI. Boston, 2008. Abstract 867.
4Llibre JM, et al. 15th CROI. Boston, 2008. Abstract 868.
5Picchio G, et al. 15th CROI. Boston, 2008. Abstract 866.
2Sungkanuparpha
32
Which Boosted PI Would You Use?
 Darunavir + ritonavir
 Other
 Indinavir + ritonavir
 None
 Tipranavir + ritonavir
DRUG
33
SUSCEPTIBILITY
Susceptibility
ASSESSMENT
Results of the Tropism Assay
34
Prevalence of Co-Receptor Tropism
Co-Receptor Usage (%)
R5
R5/X4
X4
Treatment-experienced patients
Chelsea and Westminster cohort (n=141)1
Demarest (n=117)2
MOTIVATE 1 and 2 (n=2560)3
TORO 1 and 2 (n=724)4
ACTG 5211 (n=391)5
Treatment-naïve patients
Coakley 2006 (n=1428)3
Homer cohort (n=979)6
Chelsea and Westminster cohort (n=402)1
Demarest (n=325)2
1Moyle
GJ, et al. J Infect Dis. 2005;191:866-872.
J, et al. 44th ICAAC. Washington, DC, 2004. Abstract H-1136.
3Coakley E, et a. 2nd IWTHIVE. Boston, 2006. Abstract 8.
4Melby T, et al. J Infect Dis. 2006;194:238-246.
5Wilkin T, et al. Clin Infect Dis. 2007;44:591-595.
6Brumme ZL, et al. J Infect Dis. 2005;192:466-474.
2Demarest
35
78
67
56
50
50
22
28
41.4
48
46
<1
5
2.6
2
4
85
82
81
88
14.7
18
19
12
0.3
<1
<1
0
Case Summary
 Current regimen and status
– Zidovudine/lamivudine/abacavir + tenofovir DF + tipranavir + ritonavir
– CD4: 210 cells/uL
– HIV RNA: 37,000 copies/mL
 Phenotypic susceptibility
– NRTIs
• Tenofovir DF, abacavir, stavudine
• Intermediate: didanosine
– PIs
• Indinavir + ritonavir, darunavir + ritonavir
• Intermediate: fosamprenavir + ritonavir, tipranavir + ritonavir, lopinavir/ritonavir
– NNRTIs
• Predicted susceptibility to etravirine
– Tropism assay: “R5” only
– Integrase inhibitor and enfuvirtide naïve
36
What Would You Recommend Be
Included in the Next Regimen?
 PI plus ritonavir + NRTIs
 PI plus ritonavir + 1 new drug* + NRTIs
 PI plus ritonavir + 2 new drugs* + NRTIs
 PI plus ritonavir + 3 new drugs* + NRTIs
 PI plus ritonavir + 4 new drugs* + NRTIs
 Something else
*New drugs for this patient would include enfuvirtide, etravirine, maraviroc, or raltegravir.
37
MOTIVATE 1 and 2:
Combined 24-Week Analysis
HIV RNA <50 Copies/mL
70
Patients (%)
60
50
OBT alone
Maraviroc qd
Maraviroc bid
61%
52% 53%
44%* 45%*
55%
58%
43%
40
29%
30
23%
20
19%
18%
9%
10
3%
0
All Patients
None
1
2
>3
(n=118/232/235)
(n=35/51/56)
(n=44/130/134)
(n=59/88/104)
(n=64/132/121)
Number of Active Agents (OSS) in OBT
*P<0.0001 versus placebo.
All maraviroc patients received OBT.
OSS=overall susceptibility score based on phenotypic and genotypic susceptibility at baseline.
Gulick RM, et al. 4th IAS Conference. Sydney, 2007. Abstract WePEB116LB.
38
BENCHMRK Studies:
Combined 48-Week Analysis
HIV RNA <50 Copies/mL
100
OBT
Raltegravir
Patients (%)
80
70%
67%
59%
60
45%
40
OBT
Raltegravir
80
75%
37%
20
Patients (%)
100
HIV RNA <50 Copies/mL
60
52%
48%
43%
40
20
8%
13%
3%
0
0
1
>2
(n=65/112)
(n=92/166)
(n=68/158)
Genotypic Sensitivity Score
Cooper DA, et al. 15th CROI. Boston, 2008. Abstract 788.
Steigbigel R, et al. 15th CROI. Boston, 2008. Abstract 789.
39
0
0
1
>2
(n=12/33)
(n=54/71)
(n=153/313)
Phenotypic Sensitivity Score
(upper cut-off)
Discussion
 If you do not feel there is a need to include more
than two of the new drugs,* what information would
guide the decision as to which one(s) to use?
*New drugs for this patient would include enfuvirtide, etravirine, maraviroc, or raltegravir.
40
Case 2: 48-Year-Old Male With
Advanced AIDS
 At time of HIV diagnosis in 1990
– CD4: 118 cells/mm3
– Pneumocystis pneumonia, CMV retinitis, thrush
 Antiretroviral history (never achieved HIV RNA <500 copies/mL)
– 1990 to 1993: NRTI monotherapy (zidovudine, didanosine, stavudine)
– 1993 to 1995: zidovudine/lamivudine
– 1995 to 1996: Saquinavir + ritonavir
– 1996: zidovudine/lamivudine + ritonavir
– 1996 to 1999: zidovudine/lamivudine + abacavir + amprenavir
– 1999 to 2001: stavudine + lamivudine + efavirenz
– 2001 to 2003: off treatment
– 2003 to 2007: tenofovir DF + lamivudine + efavirenz + lopinavir/ritonavir
– 2007 to present: zidovudine/lamivudine + tenofovir DF + darunavir +
ritonavir + enfuvirtide
41
Current Presentation
 Current presentation
– HIV RNA: 975,000 copies/mL
– CD4: 9 cells/mm3
 Current regimen
– Zidovudine/lamivudine + tenofovir DF +
darunavir + ritonavir + enfuvirtide
• Injection site reactions and moderate diarrhea
 Comorbid conditions
– Lipodystrophy, wasting, hyperlipidemia
 Other medications
– Trimethoprim-sulfamethoxazole, fluconazole,
azithromycin, valganciclovir, atorvastatin
42
Genotype
NRTI
NNRTI
PI
M41L
T69AKG
V75S
V118I
M184V
L210W
T215Y
K219E
K103N
V108V/I
Y181C
L10V
K20R
V32I
L33F
E34Q
M36I
K43T
M46I
F53L
I54L
L63P
A71V
G73G/C
T74P
V77I
I84V
L90M
Resistance Test
DRUG
SUSCEPTIBILITY
Susceptibility
PT
43
GT
ASSESSMENT
Which NRTIs Might Be of Benefit?
DRUG
44
SUSCEPTIBILITY
Susceptibility
ASSESSMENT
NRTI Resistance:
Everything One Needs To Know*
M184V
Selected by
Effects on other NRTIs
Lamivudine,
Emtricitabine
Loss of susceptibility to lamivudine, emtricitabine
Decreased susceptibility to abacavir, didanosine (clinically insignificant)
Delayed TAMs and increased susceptibility to zidovudine,
stavudine, tenofovir DF
TAMs
Zidovudine, stavudine
Decreased susceptibility to all NRTIs based on number of TAMs
Greatest loss of susceptibility with 41/210/215 pathway
Q151M
T69ins
Zidovudine/didanosine,
didanosine/stavudine
Resistance to all NRTIs
T69ins: tenofovir DF resistance
K65R
Tenofovir DF, abacavir,
didanosine
Variable decreased susceptibility to tenofovir DF, abacavir,
didanosine (and lamivudine, emtricitabine)
Increased susceptibility to zidovudine
L74V
Abacavir, didanosine
Decreased susceptibility to abacavir, didanosine
Increased susceptibility to zidovudine, tenofovir DF
44, 118
Zidovudine, stavudine
Increased NRTI resistance with 41/210/215 pathway
*According to Joel Gallant, MD
45
Continuing NRTIs in the Presence of
Resistance Has Virologic Benefit
 Selective single-class interruption
in the presence of resistance
– Viral rebound during NRTI
interruption precedes genotypic
switch1
– PI interruption led to little change
in HIV RNA levels or genotype2
– Enfuvirtide resistance waned
rapidly following enfuvirtide
interruption (background regimen
continued)2
1Deeks
2Deeks
46
SG, et al. J Infect Dis. 2005;192;1537-1544.
SG, et al. J Infect Dis. 2007;195:387-391.
Change (log10 copies/mL)
 Nonrandomized studies in adults
with multidrug-resistant HIV1,2
Change in HIV RNA
1.5
Interrupt NRTI (n=6)
(continue PI)1
1
0.5
Interrupt enfuvirtide (n=16)2
0
-0.5
Interrupt PI (n=18)
(continue NRTI)1
0
4
8
12
16
20
Week of Interruption
24
Is There a Role for NNRTIs?
DRUG
47
SUSCEPTIBILITY
Susceptibility
ASSESSMENT
DUET Studies: Baseline Etravirine
Mutations and Virologic Response
– V90I, A98G, L100I, K101E/P,
V106I, V179D/F, Y181C/I/V,
G190A/S
 Presence of >3 etravirine
resistance mutations was
associated with response
similar to placebo + OBR
– Etravirine resistance
mutations at baseline
• 0 or 1: 70% of patients
• >3: 15%
Picchio G, et al. 15th CROI. Boston, 2008. Abstract 866.
48
100
80
Patients (%)
 13 mutations associated
with etravirine resistance
Week 24
HIV RNA <50 Copies/mL
75%
60%
60
58%
40
33%
20
0
0
1
2
>3
(n=161)
(n=121)
(n=64)
(n=60)
Number of Baseline
Etravirine Mutations
Which PIs Are Options?
DRUG
49
SUSCEPTIBILITY
Susceptibility
ASSESSMENT
Discussion
 Other options
– Enfuvirtide
– Maraviroc
– Raltegravir
 Do you include PIs if all are resistant?
 What is the likelihood of this patient being
enfuvirtide resistant?
50
TORO 1 and 2:
Enfuvirtide Susceptibility
Biological Cutoff
ENF Naïve
0.001
0.01
0.1
1.0
10.0
ENF Failure
0.001
0.01
0.1
Normalized IC50 (mg/mL)
Melby T, et al. AIDS Res Hum Retroviruses. 2006;22:375-385.
51
1.0
10.0
HIV RNA Patterns in 25 Subjects on
Enfuvirtide Salvage Therapy
 Enfuvirtide resistance
can emerge rapidly
HIV RNA (log10 copies/mL)
– Dependent on quality
of the optimized
background regimen
HIV RNA Values
6
5
4
3
2
1
0
SCOPE cohort.
Personal communication. Deeks SG, 2005.
52
8
16
24
32
Week of Enfuvirtide Therapy
40
Clinical Case 2
 Enfuvirtide resistance testing was performed
– Fold-change value was several hundred, at the upper limit
of detection and well above susceptible range
 What is the likelihood this patient has no detectable
CXCR4-utilizing virus?
53
Prevalence of Co-Receptor Tropism
Co-Receptor Usage (%)
R5
R5/X4
X4
Treatment-experienced patients
Chelsea and Westminster cohort (n=141)1
Demarest (n=117)2
MOTIVATE 1 and 2 (n=2560)3
TORO 1 and 2 (n=724)4
ACTG 5211 (n=391)5
Treatment-naïve patients
Coakley 2006 (n=1428)3
Homer cohort (n=979)6
Chelsea and Westminster cohort (n=402)1
Demarest (n=325)2
1Moyle
GJ, et al. J Infect Dis. 2005;191:866-872.
J, et al. 44th ICAAC. Washington, DC, 2004. Abstract H-1136.
3Coakley E, et a. 2nd IWTHIVE. Boston, 2006. Abstract 8.
4Melby T, et al. J Infect Dis. 2006;194:238-246.
5Wilkin T, et al. Clin Infect Dis. 2007;44:591-595.
6Brumme ZL, et al. J Infect Dis. 2005;192:466-474.
2Demarest
54
78
67
56
50
50
22
28
41.4
48
46
<1
5
2.6
2
4
85
82
81
88
14.7
18
19
12
0.3
<1
<1
0
Prevalence of D/M or X4 HIV by
Treatment Status and CD4 Count
Prevalence of D/M or X4 Tropism
100
Patients (%)
80
Treatment-naïve patients
Treatment-experienced patients
P<0.001
60
P=0.04
40
P<0.001
P=0.02
20
0
<134
135 to 257
258 to 365
CD4 Cell Count (cells/mm3)
Hunt P, et al. J Infect Dis. 2006;194:926-930.
55
>365
Results of the Tropism Assay
56
Discussion
 Is there a benefit to using maraviroc in a patient with
D/M virus?
57
Study 1029: Maraviroc in Treatment-Experienced
Patients With D/M or X4 Virus (Week 48 Results)
CD4 Cell Gain
HIV RNA <50 Copies/mL
100
Patients (%)
75
50
25
0
27%
18%
Once-Daily Twice-Daily
(n=57)
(n=52)
22%
OBT Alone
(n=54)
Maraviroc
All maraviroc patients received optimized background therapy.
Goodrich JM, et al. 45th IDSA. San Diego, 2007. Abstract LB-2.
58
CD4 Cell Gain (cells/mm3)
150
125
Difference from
placebo + OBT (97.5% CI)
+15
+28
(-18, +47)
(-5, +61)
100
75
78
65
51
50
25
0
Once-Daily Twice-Daily
(n=57)
(n=52)
Maraviroc
OBT Alone
(n=54)
Discussion
 If raltegravir were the only fully active drug in the
regimen, what are the chances of integrase
resistance?
59
BENCHMRK Studies:
Combined 48-Week Analysis
HIV RNA <50 Copies/mL
100
OBT
Raltegravir
Patients (%)
80
70%
67%
59%
60
45%
40
OBT
Raltegravir
80
75%
37%
20
Patients (%)
100
HIV RNA <50 Copies/mL
60
52%
48%
43%
40
20
8%
13%
3%
0
0
1
>2
(n=65/112)
(n=92/166)
(n=68/158)
Genotypic Sensitivity Score
Cooper D,A et al. 15th CROI. Boston, 2008. Abstract 788.
Steigbigel R, et al. 15th CROI. Boston, 2008. Abstract 789.
60
0
0
1
>2
(n=12/33)
(n=54/71)
(n=153/313)
Phenotypic Sensitivity Score
(upper cut-off)
Discussion
 Even with a PSS=0 (upper cutoff), >50% of subjects
on raltegravir had HIV RNA <50 copies/mL at week
48
 However, do not use raltegravir as monotherapy
when other agents are available
61
Considerations for Choosing a NonSuppressive “Holding Regimen”
 Never use an NNRTI
– NNRTI mutations have no beneficial impact on viral fitness
– Accumulation of additional mutations may result in cross-resistance to
second-generation NNRTIs
 Always use lamivudine or emtricitabine
– Simple and well-tolerated drugs
– M184V decreases viral fitness
– Persistent viral load reduction in presence of M184V
– Increased activity of zidovudine, stavudine, tenofovir DF
 Choose PIs and/or NRTIs based on resistance and
tolerability/toxicity considerations
 If possible, continue therapy until availability of at least 2 new
active drugs
62
Principles for Using New Drugs
 Have a clear understanding of treatment goals
– Virologic suppression is possible in most patients
– Immunologic preservation
– Prevention of HIV disease progression
– Quality of life, minimize side effects and toxicities
 Incorporate as much information as possible
– Use input from patient on dosing, side effects
– Treatment history
– Resistance testing: past and present
 Use new agents wisely
– Include 2, and preferably 3, fully active agents when possible
– Preferably at least one from a new class
63
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