Yesterday

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Yesterdays Failure is Todays Success!! Initial
Therapy and Antiretroviral FailureCase-based
Discussion
Michael S. Saag, MDProfessor of MedicineThe
University of Alabama at Birmingham
The International AIDS SocietyUSA
2
Case 1

• 47 yo man newly diagnosed
• Asymptomatic
• PMH significant for HTN, diet controlled
• Baseline laboratory tests are unremarkable
• CD4 count 203 cells/ul
• HIV RNA 45,300 c/ml
• He is willing to start therapy if you recommend
  he should

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You recommend that he starts

• 2 nRTIs and an NNRTI
• 2 nRTIs and a boosted PI
• 3 nRTIs
• 4 nRTIs
• Boosted PI monotherapy
• Some other kind of regimen
• Making frequent international telephone calls on
  his cell phone to keep the NSA busy!

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Case 1B

• 49 yo man newly diagnosed
• Asymptomatic
• PMH significant for HTN, diet controlled
• Baseline laboratory tests are unremarkable
• CD4 count 23 cells/ul
• HIV RNA 445,300 c/ml
• He is willing to start therapy if you recommend
  he should

5
Which regimen would you choose for this patient?

• 2 nRTIs and an NNRTI
• 2 nRTIs and a boosted PI
• 3 nRTIs
• 4 nRTIs
• Boosted PI monotherapy
• Something else

6
Which nucleoside/tide backbone would you use?

• ZDV / 3TC (fdc)
• ABC / 3TC (fdc)
• ddI / D4T
• ddI / 3TC (or FTC)
• ZDV / D4T

• D4T / 3TC (or FTC)
• TDF / ZDV
• TDF / FTC (fdc)
• TDF/ ddI
• Some other choice

Fdc indicates fixed-dose combination.
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Which third drug would you use?

• ABC
• NFV
• ATZ
• ATZ / rit
• LPV / rit

• F-AMP / rit
• SQV / rit
• EFV
• NVP
• Some other choice

8
Which regimen is associated with more virologic
success?

• 2 NRTIs plus EFV
• 2 NRTIs plus LPV/rit
• EFV plus LPV/rit

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Bartlett, JA, et al Abst 586 CROI 2005
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Case 2

• 26 yo man diagnosed with HIV 16 months ago
• No OI
• Initial lab values
• CD4 140 cells/uL
• VL 156,000 c/mL
• Started on ZDV / 3TC (fdc) plus ATZ (unboosted)
• Never went below 50 c/mL

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Returned 4 weeks ago

• VL 123,000 CD4 155 cells/uL
• Resistance Test Ordered
• M184V
• No NNRTI mutations
• K20K/T, M36I, L63P, A71V, V77I, N88S

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In addition to an NNRTI, which nRTI drugs would
you include?

• ZDV / 3TC
• TDF / FTC
• ZDV / TDF
• D4T / 3TC
• ddI / TDF
• ABC / 3TC
• ZDV / 3TC / ABC
• Another choice

M184V
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(No Transcript)
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Principles

• Hypersusceptability can occur with 3TC / FTC
  mutations

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Case 3

• 34 yo woman diagnosed with HIV 6 years ago
• Initially presented with PCP
• Initial Lab Values
• CD4 82 cells/ul
• VL 106,000 c/ml
• Started on ZDV / 3TC (FDC) plus EFV
• Did well for a while, then the regimen failed
• Then treated with
• ABC, ddI, Fos-AMP/r

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Now on ZDV / 3TC / LPV/r

• VL 78,000 c/mL CD4 125 cells/uL
• Resistance Test Ordered
• M41L, D67N, V118I, M184V, L210W, T215Y
• No NNRTI mutations
• L10I, I13L, L33F, E34Q, M46L, I54K, L63P, A71V,
  V77I, V82A

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(No Transcript)
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Would you include an NNRTI in the next regimen?

• Yes
• No
• Not sure

19
Principles

• Hypersusceptability can occur with 3TC / FTC
  mutations
• Mutations can be harbored well after a drug has
  been used

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(No Transcript)
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Which nRTI drugs would you include?

• ZDV / 3TC
• TDF / FTC
• ZDV / TDF
• D4T / 3TC
• ddI / TDF
• ddI / 3TC
• ABC / 3TC
• ZDV / 3TC / ABC
• Another choice

M41L D67N V118I M184V L210W T215Y
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Which other ritonavir boosted PI drugs would you
include?
L10I I13L L33F E34Q M46L I54K L63P A71V V77I V82A

• Lop / r
• SQV / r
• F-AMP / r
• ATZ / r
• IND / r
• TPR / r
• DRV (TMC-114) / r
• I would not use a PI here

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Slide 23
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Which ritonavir-boosted PI would you include?

• LPV / r
• SQV / r
• F-AMP / r
• ATZ / r
• IND / r
• TPR / r
• DRV (TMC-114) / r
• I would not use a PI here

L10I I13L L33F E34Q M46L I54K L63P A71V V77I V82A
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Principles

• 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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Which EAP drug would you include?

• Raltegravir (MK 0518 integrase inhibitor)
• Maraviroc (CCR5 inhibitor)
• Etravirine (TMC125)
• All of the above
• I dont have enough information to decide

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Quasispecies Tropism
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Co-receptor tropism assay
CD4 CCR5
CD4 CXCR4
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R5 tropism
CD4 CCR5
CD4 CXCR4
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X4 tropism
CD4 CCR5
CD4 CXCR4
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Dual co-receptor tropism
CD4 CCR5
CD4 CXCR4
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R5/X4 (mixed) co-receptor tropism
CD4 CCR5
CD4 CXCR4
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Co-receptor tropism assay
CD4/CXCR4 cells
() co-receptor inhibitor
() co-receptor inhibitor
CD4/CCR5 cells
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Case 4

• 42 year old man diagnosed with HIV in 1991
  multiple opportunistic infections
• Has taken all existing antiretroviral drugs
  available except DRV, ENF, and EAP drugs
• Currently on TDF / FTC / TPV / r
• CD4 count 33 / uL (nadir CD4 6)
• CD4 count 3 months ago was 76 cells/uL
• HIV RNA 98,000 c/mL (max VL 167,000)

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(No Transcript)
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Would you change his ARV regimen now?

• Yes
• No
• It depends

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Principles

• 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

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Model for VL lt400 copies/mL at week 24 on the
TORO studies
Montaner, IAS 2003, abst 116
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TORO 2 Secondary Analysis Time to Virological
Failure
1
0.75
Plt0.0001
Prob Virological Success
0.5
ENFOB
0.25
OB
Time to protocol definedVF starts at week 6
0
0
4
8
12
16
20
24
Study Week
XIV International AIDS Conference 2002 Abstract
LbOr19A Clotet, B et al.
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POWER 1 of patients with lt 50 copies/mL
24 weeks
63 n19
ENF (naive use)
22 n18
56 n34
ENF not used
19 n36
³3 primaryPI mutations
59 n29
9 n35
46 n28
TMC114 FC gt4
16 n25
TMC114/r 600/100 mg bid Control
No sensitiveARV in OBR
17 n12
0 n9
0 20 40 60 80
Patients with lt50 copies/mL ()
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MOTIVATE 1 and 2 Percentage of Patients with
HIV-1 RNA lt 50 copies/mL by Number of Active
Drugs in OBT
Includes all patients who received at least one
dose of study medication
Placebo OBT
MVC QD OBT
100
MVC BID OBT
90
80
70
61
58
60
55
53
52
Patients ()
50
43
43
40
29
30
19
18
20
9
10
3
0
N
35
51
56
44
130
134
59
104
64
132
121
88
Number of active drugs in OBT
Based on overall susceptibility score LOCF
MOTIVATE 1 2-Week 24
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Combined Efficacy (2) Patients with HIV RNA
lt 400 copies/mL at Week 16 by PSS/GSS of OBT
Virological failures carried forward
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Would you use 3TC or FTC?

• Yes
• No
• It depends

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Residual Benefit of 3TC (FTC) post-M184VMonothera
py with 3TC
300 -
200 -
CD4
100 -
2 wks
4 wks
6 wks
8 wks
24 wks
0
- 1.0 -
Viral Load
- 2.0 -
0.5 log
- 3.0 -
M184V
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Principles

• Likely some residual benefit of continued 3TC or
  FTC
• No consensus / clarity on how to count
  partially active drugs in a new regimen

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Which nRTI would you include?

• ZDV
• TDF
• D4T
• ddI
• ABC
• I wouldnt use any other nRTI agents

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(No Transcript)
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Which ritonavir boosted PI would you include?

• LPV / r
• SQV / r
• F-AMP / r
• ATZ / r
• IND / r
• TPR / r
• DRV (TMC-114) / r
• I would not use a PI here

L10I M36I M46L I54V Q58Q/E L63P A71V I84V L89V
L90M
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If he has R5 tropic virus, would you use
maraviroc?

• Yes
• No
• It depends

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If he has R5/X4 (D/M) tropic virus, would you use
maraviroc?

• Yes
• No
• It depends

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Would you use raltegravir?

• Yes
• No
• It depends

52
Change from Baseline in HIV RNA With GS-9137 125
mg Influence of Activity of OBT
Data from GS-9137 125 mg patients after addition
of a PI were excluded
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Would you recommend enfuvirtide?

• Yes
• No
• I want a COFFEE BREAK!

54
If he had used enfuvirtide in the past and
experienced treatment failure while on
enfuvirtide, would you recommend enfuvirtide?

• Yes
• No
• Not sure

55
Mean Change in HIV-1 RNA from Baseline at Week 24
According to Previous Enfuvirtide Use
Includes all patients who received at least one
dose of study medication
Placebo OBT
MVC QD OBT
MVC BID OBT
ENF Experienced
ENF Naive
ENF - Yes
ENF - No
ENF - Yes
ENF - No
176
74
67

• 83

• 34

• 32

58
91
109
N
170
71
69
0
-0.5
-0.46
-0.50
-1.0
-1.5
-1.41
-1.45
-1.52
-1.67
-1.70
-1.80
-2.0
-2.28
-2.31
-2.5
-2.51
-2.49
LOCF
MOTIVATE 1 2 -Week 24
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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

57
Summary of Principles

• 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
• Likely some residual benefit of continued 3TC or
  FTC
• No consensus / clarity on how to count
  partially active drugs in a new regimen
• Many new drugs in the pipeline Significant hope
  for the future