The clinical significance of detectable viremia

1
The clinical significance of detectable viremia
Calvin Cohen USA
2
When a patient on treatment is viremic, a choice
must be made
Choice
Delay a treatment switch
Switch
3
When a patient on treatment is viremic,a choice
must be made
Choice
Delay a treatment switch
Switch
What is the risk of keeping a patient on a
failing regimen?
What are the risks of a premature switch?
4
Why have we delayed switching?
5
Complete viral suppression leads to a strong
immunologic response
200
Change in CD4 count(cells/mm3)
100
6
12
24
36
48
72
96
0
0
Weeks
Change in HIV-1 RNA(log10 copies/mL)
1.5
2.5
171
100
73
131
118
122
123
Complete
133
Deeks et al. J Infect Dis 2000 18194653
6
Incomplete viral suppression also improves
immunologic response
200
Change in CD4 count(cells/mm3)
100
6
12
24
36
48
72
96
0
0
Weeks
Change in HIV-1 RNA(log10 copies/mL)
1.5
2.5
49
45
59
67
59
60
50
Transient
86
171
100
73
131
118
122
123
Complete
133
Deeks et al. J Infect Dis 2000 18194653
7
risks of incomplete suppression
Resistance mutations
Increasing viral load
Decreasing CD4
Clinical progression
Time (years)
8
Risks of non-suppressive treatment Cumulative
resistance mutationse.g. ZDV/3TC/ABC
M184V only or wild-type
M184V any TAM(s)
100
90
80
60
of patients with mutation
40
20
10
0
08 n 39
Number of weeks on therapy after viral rebound
Melby et al. 8th CROI 2001 Poster 448
9
Risks of non-suppressive treatment Cumulative
resistance mutationse.g. ZDV/3TC/ABC
M184V only or wild-type
M184V any TAM(s)
100
90
76
75
80
67
60
56
60
44
of patients with mutation
40
33
40
25
24
20
10
0
08 n 39
1724 n 28
2532 n 24
3340 n 20
4148 n 16
916 n 34
Number of weeks on therapy after viral rebound
Melby et al. 8th CROI 2001 Poster 448
10
The risk of some TAMsM41L, L210W, T215Y/F
M184V (n 108)
Lanier et al. 10th CROI 2003 Poster 586
11
NNRTI mutations and virologic response to TMC125
(800 mg bid) at week 24
Baseline NNRTI mutations in TMC125 arm
Active control
TMC125
0
1
2
3
0
n 40
n 79
n 15
n 18
n 17
n 29
0.19
0.5
0.66
Mean change in viral load (log10 copies/mL)
1.0
1.00
1.18
1.5
Relevant NNRTI mutations K101P, V179E, V179F,
Y181I, Y181V, G190S, M230L
1.65
1.82
2.0
All subjects had NNRTI mutations from prior
genotyping
Vingerhoets et al. 13th CROI 2006 Oral 154
12
Treatment response by TPV resistance
Change in viral load was the change in HIV RNA
from baseline through week 2 (OT) or week 24
(LOCF) in log10 copies/mL
Valdez et al. Antivir Ther. (2005) 10 Suppl 1S29
13
Treatment response by TPV resistance
Change in viral load was the change in HIV RNA
from baseline through week 2 (OT) or week 24
(LOCF) in log10 copies/mL
Valdez et al. Antivir Ther. (2005) 10 Suppl 1S29
14
Treatment response by TPV resistance
Change in viral load was the change in HIV RNA
from baseline through week 2 (OT) or week 24
(LOCF) in log10 copies/mL
Valdez et al. Antivir Ther. (2005) 10 Suppl 1S29
15
Accumulation of resistance mutations

1.00

• SCOPE cohort Treatment-experienced patients (n
  106)
• Stable ART for 120 days
• HIV RNA gt 1000 copies/mL
• 1 resistance mutation
• Resistance testing every 4 months until ART
  modification

0.75
Without new mutation
0.50
1 new major PI mutation 1 new NRTI mutation Any
new mutation
0.25
Data are for PI-treated subjects (n 71)
0
0
4
8
12
16
20

24

Time (months)
Hatano et al. 13th CROI 2006 Poster 615
16
compromises treatment options

1.00

• SCOPE cohort Treatment-experienced patients (n
  106)
• Stable ART for 120 days
• HIV RNA gt 1000 copies/mL
• 1 resistance mutation
• Resistance testing every 4 months until ART
  modification
• New mutations at 1 year
• Any 44 (95 CI 3356)
• NAM 23 (95 CI 1534)
• PI 18 (95 CI 934)

0.75
Without new mutation
0.50
1 new major PI mutation 1 new NRTI mutation Any
new mutation
0.25
Data are for PI-treated subjects (n 71)
0
0
4
8
12
16
20

24

Time (months)
1.00

0.75
Without loss of 1 drug equivalent
0.50
0.25
0
0
4
8
12
16
20
24
Time (months)
Number of available ARVs from the following ZDV,
3TC, ddI, ABC, TDF, EFV, IDV, NFV, SQV, RTV, APV,
LPV
Hatano et al. 13th CROI 2006 Poster 615
17
compromises treatment options

1.00

• SCOPE cohort Treatment-experienced patients (n
  106)
• Stable ART for 120 days
• HIV RNA gt 1000 copies/mL
• 1 resistance mutation
• Resistance testing every 4 months until ART
  modification
• New mutations at 1 year
• Any 44 (95 CI 3356)
• NAM 23 (95 CI 1534)
• PI 18 (95 CI 934)

0.75
Without new mutation
0.50
1 new major PI mutation 1 new NRTI mutation Any
new mutation
0.25
Data are for PI-treated subjects (n 71)
0
0
4
8
12
16
20

24

Time (months)
1.00

0.75
Without loss of 1 drug equivalent
0.50
0.25
0
0
4
8
12
16
20
24
Time (months)
Number of available ARVs from the following ZDV,
3TC, ddI, ABC, TDF, EFV, IDV, NFV, SQV, RTV, APV,
LPV
Hatano et al. 13th CROI 2006 Poster 615
18
Time to immunologic failure after virologic
failure
1.0
0.8
0.6
Proportion not inimmunologic failure
0.4
0.2
0.0
0
6
12
18
24
30
36
42
Months since onset of virologic failure

• Immunologic failure was defined as return of CD4
  count to pre-therapy levels
• Virologic failure was defined as persistent
  plasma HIV RNA level gt 500 copies/mL

Deeks et al. AIDS 2002 162017
19
Time to immunologic failure after virologic
failure
1.0
0.8
0.6
Proportion not inimmunologic failure
0.4
0.2
0.0
0
6
12
18
24
30
36
42
Months since onset of virologic failure

• Immunologic failure was defined as return of CD4
  count to pre-therapy levels
• Virologic failure was defined as persistent
  plasma HIV RNA level gt 500 copies/mL

Deeks et al. AIDS 2002 162017
20
When is waiting to switch therapy appropriate?

• When the chance of resuppression is low
• One or no active drugs for a regimen
• Newer drugs anticipated soon enough
• Patient clinically stable

21
Waiting is appropriate when a patient has one or
no active drugs for a regimen
TORO Median viral load decline over the first 28
days of therapy, OB GSS 0
Day
7
14
21
28
0
OB
-0.04
-0.06
-0.07
-0.5
HIV-1 RNA change from baseline (log10 copies/mL)
-1
-1.5
-2
51
52
51
53
OB
Bartlett et al. XV IAC 2004 Poster TuPeB4484
22
Waiting is appropriate when a patient has one or
no active drugs for a regimen
TORO Median viral load decline over the first 28
days of therapy, OB GSS 0
Day
7
14
21
28
0
OB
-0.04
-0.06
-0.07
-0.5
HIV-1 RNA change from baseline (log10 copies/mL)
ENF OB
-1
-0.92
-1.19
-1.5
-1.42
-2
108
106
104
112
ENF OB
51
52
51
53
OB
Bartlett et al. XV IAC 2004 Poster TuPeB4484
23
More patients reach lt 400 copies/mL when at least
2 active drugs are available
100
ENF OB (n 541)
OB (n 286)
75
p lt 0.05
52


46
Patients with lt 400 copies/mL at week 48 ()
44

50
32

20
19
19
25

9
8
0
0
0
1
2
3
4
Baseline GSS (non-STI, not including ENF)
ENF OB 98 179
152 83
27 OB 49
88 84 46
16
Miralles et al. HIV7 2004 Poster P17
DCSwitchFailure
24
When a patient on treatment is viremic,a choice
must be made
Choice
Delay a treatment switch
Switch
25
Approaches to consider when waiting to switch
therapy
Choice
Delay a treatment switch
Switch
Partial treatment interruption

• Completetreatmentinterruption

26
Complete treatment interruptionSMART study
Log rank 31.1
p lt 0.0001
20
DC Group
15
Patients with event () (HIV disease progression
or death)
10
VS Group
5
0
0
4
8
12
16
20
24
28
32
36
40
44
Months from randomization
DC 2720
589
322
1170
VS 2752
625
334
1167
VS viral suppression DC discontinue according
to CD4
Wafaa El-Sadr et al. 13th CROI 2006 Oral LB106
27
Approaches to consider when waiting to switch
therapy
Choice
Delay a treatment switch
Switch
Partial treatment interruption

• Completetreatmentinterruption

28
Partial treatment interruption 3TC monotherapy
vs. treatment interruption

• Prospective, open-label randomized study (n 29
  in both groups) on 3TC-containing regimen

• HIV RNA gt 1000 copies/mL
• CD4 gt 500 cells/mm3
• Have M184V mutation

Mean change in CD4 count (cells/mm3)
Mean change in HIV RNA (log10 copies/mL)
0
2.00
1.75
50
1.50
100
1.25
150
1.00
0.75
200
0.50
250
p 0.122
p 0.0015
0.25
300
0
0
4
8
12
16
20
24
48
36
0
4
8
12
16
20
24
36
48
Weeks
Weeks
Treatment interruption
3TC
Castagna et al. AIDS 2006 20(6)795-803
29
Partial treatment interruption 3TC monotherapy
vs. treatment interruption

• Prospective, open-label randomized study (n 29
  in both groups) on 3TC-containing regimen

• HIV RNA gt 1000 copies/mL
• CD4 gt 500 cells/mm3
• Have M184V mutation

Mean change in CD4 count (cells/mm3)
Mean change in HIV RNA (log10 copies/mL)
0
2.00
1.75
50
1.50
100
1.25
150
1.00
0.75
200
0.50
250
p 0.122
p 0.0015
0.25
300
0
0
4
8
12
16
20
24
48
36
0
4
8
12
16
20
24
36
48
Weeks
Weeks
Treatment interruption
3TC
Castagna et al. AIDS 2006 20(6)795-803
30
Activity of ARVs after viremiaPartial treatment
interruption studies
Week 2 viral load increase after drugs in one
class interrupted other ARVs maintained
1.5
1.0
Change in HIV RNA levels (log10 copies/mL)
0.5
0.0
-0.5
NRTI
PI
NNRTI
ENF
Discontinued treatment class
Deeks et al. 12th CROI 2005 Poster 680.
31
Conclusions

• There are clinical consequences when a patient is
  maintained on a failing regimen
• Accumulation of resistance mutations leading to
  the loss of current and future treatment options
• Immunologic failure resulting in clinical
  deterioration
• When the chance for resuppression is low it may
  be appropriate to delay a switch in therapy
• Newer therapeutic options improve the odds of
  resuppression when a switch is made by increasing
  the number of active drugs utilized