Resistance is Futile Without a Resistance Test: Case-Based Discussion

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Resistance is Futile Without a Resistance Test
Case-Based Discussion
Michael S. Saag, MDProfessor of MedicineThe
University of Alabama at Birmingham
The International AIDS SocietyUSA
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TPV RESIST T-20 in Optimized Background Regimen
(OBR)
TPV arm 27 on T-20 CPI arm 22 on T-20
70
70
70
58
60
60
50
50
35
37
Pts with VL reduction ?1 log10 copies/mL
Pts with VL reduction ?1 log10 cps/mL
40
40
31
29
26
30
30
18
18
17
20
20
8
9
10
10
0
0
TPV/r
CPI/r
TPV/r
CPI/r
T-20 Included in OBR
T-20 Not Included in OBR
T-20 Experienced
Overall
T-20 Naive
Cooper, CROI 2005, abst. 560
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RESIST-1Proportion with undetectable viral load
Intent-to-treat non-completer failure
lt400 copies/mL
lt50 copies/mL
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Resist Proportion of Patients with lt 50 c/ml
Based on Prior PI use
R. B. Pollard, S. Staszewski, R. LeBlanc, D.
Neubacher, H. Valdez. IAS 2006
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POWER 1 and 2 patients with VL lt50 copies/mL
over time to Week 48 (ITT-TLOVR)
100
TMC114/r 600/100mg bid CPI(s)
80
46 (n50/110)
45(n59/131)
60
Patients ()
40
12 (n15/124)
10 (n12/120)
20
0
0
4
8
12
16
20
24
28
32
36
40
44
48
1
2
Weeks
TMC114/r n 131 131
131 130
120 110CPI(s) n 124
124 124
124 121 120
plt0.001 vs CPI(s) ITT intent-to-treat, TLOVR
time to loss of virologic response Not all
patients had reached Week 48 at the time of
analysis patients who had not reached Week 48
were censored at their last available visit
Lazzarin A, et al. XVI IAC 2006. Abstract TUAB0104
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POWER 1 and 2 virologic response defined as VL
lt50 copies/mL by BL subgroups at Week 48
(ITT-TLOVR)
70
TMC114/r 600/100mg bid CPI(s)
6/9
60
50
39/70
40
Patients ()
20/46
24/55
30
10/29
20
3/16
5/30
10
4/74
11/76
0/10
0/16
0/24
0
TMC114 FC gt40
2 primary PI mutations
TMC114 FC ?10
TMC114 FC gt1040
?1 primary PI mutation
3 primary PI mutations
FC fold change in EC50 Based on IAS-USA
guidelines 2004 (Johnson VA, et al. Top HIV Med
20041211924)
Lazzarin A, et al. XVI IAC 2006. Abstract TUAB0104
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POWER 1 and 2 virologic response defined as VL
lt50 copies/mL by BL subgroups at Week 48
(ITT-TLOVR)
70
TMC114/r 600/100mg bid CPI(s)
60
21/36
50
44/82
40
27/61
Patients ()
30
20
11/100
5/25
7/70
1/15
10
2/13
4/35
0/18
0
0 sensitive ARV in OBR
1 sensitive ARV in OBR
ENF used (naïve)
ENF used (non-naïve)
ENF not used
ARV antiretroviral drug OBR optimized
background regimen ENF enfuvirtide. Use of ENF
was not randomized in POWER 1 and 2.
Lazzarin A, et al. XVI IAC 2006. Abstract TUAB0104
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POWER 1 and 2 mean change from BL in CD4 count
over time to Week 48 (LOCF)
TMC114/r 600/100mg bid CPI(s)
140
102
120
92
100
80
Mean change in CD4 count
(cells/mm3)
60
40
19
17
20
0
2
0
4
8
12
16
20
24
28
32
36
40
44
48
Weeks
TMC114/r n 131 131
131 130
120 110CPI(s) n 124
124 124 124
121 120
plt0.001 vs CPI(s)LOCF last observation
carried forward
Lazzarin A, et al. XVI IAC 2006. Abstract TUAB0104
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Summary of Principles

• Avoid Sequential Monotherapy Wait for new agents
  if possible.
• Substitute single drug for agent suspected of
  causing toxicity
• Hypersusceptability can occur with 3TC / FTC
  mutations
• Mutations can be harbored well after a drug has
  been used
• Phenotypes are often helpful in determining which
  drugs are active when complex genotypes are
  likely
• No evidence for double-boosted PIs

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Summary of Principles

• Likely some residual benefit of continued 3TC or
  FTC
• Goal of Therapy is lt 50 c/ml in any patient
  regardless of stage of disease or prior exposure
• Key to achievement of lt 50 c/ml is the
  availability of at least 2 potent drugs the
  more, the better
• Many new drugs in the pipeline Significant hope
  for the future