Second Regimens: Issues in Improving Success

1
Second RegimensIssues in Improving Success

• Calvin Cohen, MD, MS
• Clinical Instructor
• Harvard Medical School
• Research Director
• Community Research Initiative
• of New England
• Boston, MA

2
Treatment-Experienced Patients

• What is failure?
• Why did first regimen fail?

3
Success

• Ample data on how to create a successful regimen

4
Multiple RegimensMultiple Paths to Success
With HIV RNA ?50 at 48 Weeks ITT Analysis
Regimen (Trial)
Bartlett. 7th CROI 2001 San Francisco. Poster
519.
5
Success

• Ample data on how to create a successful regimen
• Active given any preexisting resistance

6
Prevalence of HIV Drug Resistance in Recently
Infected Cohorts

• Site n NRTI NNRTI PI
• Madrid1 30 23 3 7
• Boston2 45 11 2 2
• Spain3 112 3 0 2

1. Briones C, et al. 40th ICAAC, Toronto, 2000.
Abstract 1245 2. Balaguera HU, et al. 40th
ICAAC, Toronto, 2000. Abstract 1247 3.
Guerrero A, et al. 40th ICAAC, Toronto, 2000.
Abstract 1250 4. Routy JP, et al. 40th ICAAC,
Toronto, 2000. Abstract 1244
7
Success

• Ample data on how to create a successful regimen
• Active given any preexisting resistance
• Adequate adherence

8
Success

• Ample data on how to create a successful regimen
• Active given any preexisting resistance
• Adequate adherence
• Ample potency
• intrinsic vs. boosted

9
Who Has Drug Failure? Impact of High Baseline
HIV RNA
Patients With HIV RNA lt50 at wk 48
On Treatment
ITTNCF
EFV AZT 3TC

100
EFV IDV

IDV AZT 3TC
97
90
87
80
83
83
79



74
68
60
66
65
64
Patients lt50 ()
55
54
48
47
40
43
35
34
20
0
All
lt100,000
gt100,000
All
lt100,000
gt100,000
Baseline Plasma HIV RNA
Statistically significant difference from IDV
AZT 3TC, Plt.05. Tashima. 6th CROI 1999
Chicago. Abstract LB16.
10
DMP 006 Impact of Low vs High CD4 in HIV RNA
Response

• HIV RNA lt50
• CD4 lt100 CD4 gt100
• EFV AZT 3TC 58.1 66.6
• (25/43) (223/335)
• EFV IDV 23.8 56.1,
• (10/42) (189/337)
• IDV AZT 3TC 40.9 47.2
• (18/44) (161/341)

P .05 EFV AZT 3TC vs IDV AZT 3TC. P
.05 EFV IDU vs IDV AZT 3TC. P .05
comparing CD4 lt100 to CD4 gt100 within each
treatment group.
11
Drug Class Issues in Managing Resistance

• NRTIs
• NNRTIs
• PIs

12
Drug Class Issues in Managing Resistance

• NRTIs
• NNRTIs
• PIs

13
Differential Development of
Mutations Following ART Failure
RTI Resistance Without PI Resistance
100
14/16
14/17
17/23
10/14
75
Isolates WithResistance ()
M184V
M184V
M184V
50
AZTnotreported
AZTnotreported
4/16
3/14
25
2/16
0/26 IDV
3TC
IDV
EFV
AZT
3TC
APV
3TC
0
AZT 3TC IDV1 or AZT 3TC IDV2 IDV
EFV2 AZT 3TC APV3 IDV Monotherapy
1Havlir. JAMA 2000 283229. 2Holder. 6th
CROI 1999 Chicago. Abstract 492. 3De
Pasquale. Antivir Ther 19983(suppl 1)50.
14
HIV-1 RNA Response in Subjects With M184V (M184V
present by Week 12)
(n14)
Kuritzkes D, et al. AIDS 199610975-81.
15
CNA3005 Detection of Mutationson Therapy, ABC
CBV
Patients With Given Genotype
M184V any TAM(s)
100
90
M184V only or WT
76
75
80
67
60
56
Patients ()
60
44
40
40
33
25
24
20
10
0
0-8
17-24
25-32
33-40
41-48
9-16
(n 39)
(n 34)
(n 28)
(n 24)
(n 20)
(n 16)
Number of Weeks on Therapy After First Genotype
16
Effect of RT Mutationson Response to ABC
ART-Experienced Adults
lt400
100
gt0.5 log or lt400
84
Nonresponders
79
80
66
57
60
52
53
48
43
37
40
22
21
16
20
0
WT(n 19)
184V only (n 50)
1-2 muts (n 35)
?3 muts(n 50)
17
ddI Use in Second Regimens HUas Booster in
Experienced Patients?
Treatment Naive
Treatment Experienced
100
100
80
80
60
60
Proportion of Patients With HIV RNA lt400
copies/mL ()
40
40
3D HU
3D HU
3D placebo
3D placebo
20
20
HU/Placebo added
HU/Placebo added
0
0
0
4
8
12
16
20
24
28
32
36
40
44
48
0
4
8
12
16
20
24
28
32
36
40
44
48
Week
Week
1Murphy. 13th IAC 2000 Durban. Abstract 603.
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Regimen Sequencing NRTIs
ACTG 364 Objective

• Determine impact of baseline NRTI mutations on
  virologic response among heavily NRTI-treated
  patients receiving 2 new NRTIs EFV, NFV, or
  both
• Previous NRTIs New NRTIs
• AZT 3TC (n 40) d4T ddI
• vs vs
• AZT ddI or ddC (n 43) d4T 3TC

Katzenstein. Antivir Ther 19994(suppl 1)47.
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Regimen Sequencing NRTIs

• Virologic success (HIV RNA lt2000)by week 16
• AZT 3TC ? d4T ddI 22/40 (55)
• AZT ddI or ddC ? d4T 3TC 35/43 (82)
• Initiating ART with ddI (or ddC) may enhance
  second-line virologic response
• d4T ? 55-82 success rate after AZT-containing
  first-line regimen

Katzenstein. Antivir Ther 19994(suppl 1)47.
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Drug Class Issues in Managing Resistance

• NRTIs
• NNRTIs
• PIs

21
Drug Class Issues in Managing Resistance

• NRTIs
• NNRTIs
• PIs

22
ACTG 359Suppression After IDV
Prospective, Randomized, Partially Blind Study
50 40 30 20 10 0
47
38
33
31
Patients with HIV RNA lt500 ()
20
16
RTV SQV DLV
RTV SQV DLV ADV
RTV SQV ADV
NFV SQV DLV
NFV SQV DLV ADV
NFV SQV ADV
Acosta. 6th CROI 1999 Chicago. Abstract 365.
23
Distribution of Susceptibility to PIs if gt4-fold
Resistance to IDV or NFV
100
80
IDV
60
NFV
Susceptible ()
APV
SQV
40
RTV
20
0
IDV (n 70)
NFV (n 155)
24
Suppression After Resistance to IDV vs NFV
Impact of Phenotype ResistanceTesting on lt400
wk 16
100
PRT
80
SOC
63
55
60
50
Patients ()
40
28
20
0
IDV
NFV
n
30/48 23/46
30/62 23/55
25
Probability of Maintaining HIV RNA lt500 Based on
HIV RNA at Time of Switch
100 80 60 40 20 0
Patients lt500 ()
HIV RNA at Switch
lt30 000 (n 12) gt30 000 (n 12)
44
0
4
8
12
16
20
24
28
32
36
40
Week
bDNA. Tebas. AIDS 199913F23.
26
Impact of PK PIs Usually Dosed Near the EC90
for WT Virus
10
1
Drug Concentration (µg/mL)
4 x EC50 WT
0.1
EC50 WT
EC50 range of wild-type viral isolates
0.01
700
Adjusted for 50 serum. Sun. Antivir Ther
20005(suppl 3)70.
27
Impact of PK Can We Increase Drug
Concentration to Overcome Resistance?
10
EC50 range of resistant viral isolates
1
Drug concentration (µg/mL)
4 x EC50 WT
0.1
EC50 WT
0.01
700
Adjusted for 50 serum. Sun. Antivir Ther
20005(suppl 3)70.
28
Impact of PK Can We Increase Drug
Concentration to Overcome Resistance?
10
EC50 range of resistant viral isolates
1
Drug Concentration (µg/mL)
4 x EC50 WT
0.1
EC50 WT
0.01
Adjusted for 50 serum. Sun. Antivir Ther
20005(suppl 3)70.
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RTV intensification of IDV

• Detectable HIV RNA on IDV regimen
• Inclusion
• On 2 NRTIs IDV
• HIV RNA gt50-50,000
• Dose 400/400 RTV IDV (dose escalation used)
• NRTI changes allowed after 3 weeks

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IDV Cmin Following Change From IDV 800 TID ? RTV
IDV 400/400 BID
Plt.001
1
0.1
IDV Concentration, (?g/mL)
Wild Type EC50
0.01
0.001
Baseline C0
Week 3 C0
Crixivan package insert, Merck and Co., Inc.
C0 is predose concentration. Study is ongoing
results subject to change. Shulman. 7th CROI
2000 San Francisco. Abstract 534.
31
Virologic Response Stratified by Increase in
IDV Cmin at Week 3 of RTV Intensification
?Median
gtMedian
100
RTV AdditionWithout NRTI Change
NRTI Change Allowed
100
100
100
88
80
86
80
60
63
38
Patients ()
57
56
40
40
38
36
38
20
0
0
3
6
9
12
16
24
Week
14
14
n
16
16
12
15
19
The median IDV C0 at 800 mg q8h was 0.106 mcg/mL
increased to 0.792 mcg/mL at week 3 with RTV/IDV
400/400 mg BID. Study is ongoing results subject
to change.
32
IDV RTV BID PK Study
10,000
IDV RTV q12h 800/200 High-fat Meal
800/100 High-fat Meal 400/400 High-fat
Meal IDV q8h 800 mg Fasted
3000 nM
Highly Resistant Virus
IDV PlasmaConcentration (nM)
1000
800 nM
IC95 of wild strain HIV-1 susceptible to IDV (100
nM)
100
0
2
4
6
8
10
12
Time Postdose (hours)
Saaha. 6th CROI 1999 Chicago. Abstract 362..
33
Actual and Predicted Cmin forDifferent Doses of
SQV/rtv
SQV dosage with mini dose of ritonavir PK
trough at 12 hrs
Hill. Antivir Ther 20005(suppl 3)50.
34
APV 20001 Median Steady-State Plasma Amprenavir
Levels
APV 1200 mg BID (n 61)
7
APV 1200/rtv 200 mg QD (n 15)
APV 600/rtv 100 mg BID (n 12)
6
5
4
Total Plasma APV Concentration (?g/mL)
3
2
1
0
0
2
4
6
8
10
12
14
16
18
20
22
24
Hour
Wood. 8th CROI 2001 Chicago. Abstract 332.
35
Multiple PI Experience LPV/rtv EFV at 24 Weeks
OT 92 80
ITT 82 69

• M97-957 Design
• n 57, multiple PI exp, NNRTI naive
• LPV/rtv (400/100 mg BIDor 533/133 mg BID) EFV
  600 mg QD
• 3 D/C for virologic failure
• No significant changes inlipids from baseline
• CD4 cell increase 45

100
80
60
Patients ()
40
400/100 mg BID
533/133 mg BID
20
0
0
4
8
12
16
20
24
400/100 mg n 29 26 26 25 533/133 mg n
28 26 24 25
Clumeck. 13th IAC 2000 Durban. Abstract 3196
36
Boosted PI Optionsfor Second Regimens

• APV 600/100 BID
• IDV 800/100 BID
• SQV 1000/100 BID
• LPV/rtv 400/100 BID
• Note NFV not usually boosted

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Virologic Response to LPV/rtv in Multiple
PI-Experienced Patients at Week 24

• No difference in susceptibility with0-5 PI
  mutations
• Moderate decreasein susceptibility with6-7 PI
  mutations
• Significant decrease with gt8 PI mutations

Percent Response
ABT-378 Mutation Score

Kempf. Antivir Ther 2000 5(suppl 3)29.
38
ACTG 2 PIs Are Better Than 1
With HIV RNA lt200 at Week 24 (ITT)

• NNRTI Naive NNRTI Experienced Overall
• SQVsgc 47 15 34(n 116)
• IDV 50 19 36(n 69)
• NFV 46 21 34(n 139)
• Placebo 33 8 23(n 157)

OVERALL 2 PIs better than 1 (P .002) Hammer.
7th CROI, San Francisco, 2000. Abstract LB7
39
TNV in ARV-Experienced Patients HIV RNA Changes
Placebo
75 mg
150 mg
300 mg
0.2
Placebo roll-overto 300 mg TDF
0.1
0.0
0.1
0.2
0.3
Mean ? Log From Baseline
0.4
0.5
0.6
0.7
0.8
0.9
0
8
16
24
32
40
48
Weeks
28 53 51 54
23 48 43 48
19 42 39 41
Placebo75 mg150 mg300 mg
Schooley. 40th ICAAC 2000 Toronto. Abstract
692.
40
T20-205 48-WeekResponder Analysis
60
50
17
gt400 and gt1 log change from baseline
40
30
17
Patients Responding ()
10
gt50 and lt400
20
10
lt50
10
22
13
0
Intent-to-Treat (n 70)
All patients who completed 48 weeks (n 41)
Intent-to-treat (ITT) analysis non-completer
failure.
41
Therapeutic Drug Monitoring
HIV RNA Decreases in PI-Treated Patients
Month 0 3 6
0.05 0.15 0.35 0.55 0.75 0.95 1.05 1.35 1.
55
? Log HIV RNA, Log Decrease
Control suboptimal concentration Genotypic
suboptimal concentration Control optimal
concentration Genotypic optimal concentration
Control Standard of care. Source Garraffo.
Antiviral Ther 19994(1)75.
42
Resistance Testing

• Does it help?
• Several studies suggest it does
• Especially when there still are treatment options
  to choose from
• Both phenotype and genotype have favorable data
• Need to know what the test results mean

Cohen. 13th IAC 2000 Durban. Abstract 1433.
43
HAVANNA ITT Analysis
NoGenotype
n 317
Genotype
49
36
59
No Expert
46
69
Expert
41
42
58
P .02
Meynard. 40th ICAAC 2000 Toronto. Abstract 698.
44
Summary

• Not all rebound is failure
• If rebound occurs, why?
• What did we lose to viral resistance?
• What works against that resistance virus?
• New agents more than 1!
• Boosted drug levels
• Dont just guesstest
• Progress continues ...

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