Management of Treatment Failure

1

New Antiretroviral Drugs and Drug Classes
Constance A. Benson, MDProfessor of
MedicineUniversity of California San Diego
The International AIDS SocietyUSA
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Why Do We Need New Drugs?

• Limitations of current drugs
• Toxicity
• Potency new drugs with greater activity against
  wild type and drug resistant virus
• Penetration of reservoirs
• Acquired and transmitted drug resistance
• Cross resistance
• Convenience/tolerability (particularly for second
  or third line regimens)

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ETV-C223 Study ART-Experienced
VL 48K, CD4 100, resistance to EFV (41-fold),
NVP (68-fold), ETV (1.6-fold), extensive PI
resistance (N199)
0.5
Active control (OBT, N 40)
0.0
0.2
-0.5
400 mg bid (N 80)
Mean change in log10 viral load ( SE)
-1.0
1.0, P lt 0.05
1.2, P lt 0.05
-1.5
800 mg bid (N 79)
ETV arms OBT NRTIs LPV/r ENF
P values versus active control
-2.0
0
2
4
8
12
16
20
24
Time (weeks)
EDTA samples and Roche viral load test version
1.5 used for HIV RNA analyses
TMC125-C223 Writing Group, AIDS 2007 21F1-10
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Rilpivirine (TMC278)
Study population ART-naïve VL gt5K (N268)
TMC278 25mg qd (n93)
TMC278 75mg qd (n95)
TMC278 150mg qd (n91)
EFV 600mg qd (n89)
81
81
80
77
Proportion with HIV RNA lt50 cps/ml (, 95 CI)
Time (Weeks)
CI confidence interval
ITT, NCF
Pozniak, CROI 2007, 144LB
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Vicriviroc in ART-Naïve Patients

• Patient population
• ART-naive R5 tropic, VL gt 5K, CD4 gt150, no BL
  resistance mutations
• Baseline VL 60K, CD4 290 (N92)
• Regimens
• Vicriviroc along x 14d then ZDV/3TC added vs.
  ZDV/3TC EFV (SOC) at day 14
• Study stopped by DSMB for VL rebound

Greaves CROI 2006, abst. 161LB Landovitz Sitges
2006, abst. 18
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ACTG A5211 Vicriviroc in ART-Experienced Patients
Pts 3-class exp., R5-tropic VL gt5K on
RTV-boosted ART (N118)
Placebo
VCV 5 mg VCV 15 mg VCV 10 mg
Gulick, JID 2007 (in press)
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Maraviroc Motivate I
Study population 3-class experienced, VL gt5K,
R5 virus (N585)
MVC BID OBT (n 235)
MVC QD OBT (n 232)
100
100
Placebo OBT (n 118)
90
90
lt 400 copies/mL
lt 50 copies/mL
80
80
p lt 0.0001 vs PBO
70
70
60
60
60
p lt 0.0001 vs PBO
55
p lt 0.0001 vs PBO
50
50
48
Patients ()
42
40
40
p 0.0006 vs PBO
31
30
30
25
20
20
10
10
0
0
0
4
8
12
16
20
24
2
16
20
24
0
4
8
12
2
Time (weeks)
Time (weeks)
Mayer, CROI 2007, 104aLB
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Slide 8
Raltegravir vs EFV 2NRTIs in ART-Naïve
Individuals
Percent lt50 c/ml (95 CI NCF)
P lt 0.001 for MK-0518 vs. EFV
Markowitz M, et al. JAIDS 2006 43509
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RAL Phase III in ART-Experienced PtsStudy
population 3-class experienced VL gt1K (N699)
BENCHMRK-1
BENCHMRK-2
Cooper Steigbigel CROI 2007 105a/bLB
OBT Plt0.001 at Week 16 for both parameters
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Elvitegravir (GS-9137) Study population gt1 PI
mutation, VL gt1K (N278)
Changed to 125 mg dose
37 switched to GS-9137
Zolopa, CROI 2007 143LB
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How to Use New Drugs and New Drug Classes

• ART-experienced failing current ART
• Raltegravir OBT (at least 2 active drugs)
• Pts with predominant CCR5 virus Maraviroc OBT
  (at least 2 active drugs)
• Pts with limited NNRTI resistance Etravirine
• ART-experienced suppressed on current ART
• Substitution for convenience, tolerability
• ART-naïve
• Raltegravir potent and well-tolerated limited
  data
• Maraviroc potent and well-tolerated limited
  data