Viewing from a different angle:

1
Viewing from a different angle
FUZEON a new approach to NRTI-sparing regimens
in treatment-experienced patients
David A Cooper MD, DSc Professor of Medicine and
Director of the National Centre in HIV
Epidemiology and Clinical Research, University
of New South Wales, Australia
2
Toxicity is a key driver of treatment switches
Reasons for treatment switch / discontinuation
of a first HAART regimen
Virologicalfailure 14.1
Toxicity58.3
Non-adherence19.6
Other 8.0
Sub-study n 312
Monforte et al. AIDS 2000 14499507
3
Kaplan-Meier time to modification of HAART
Reasons for stopping
40
35
30
25
20
Percentage modification
15
10
5
0
0
3
6
12
9
15
18
Months after starting HAART
Diamonds toxicities, patient choice/poor
compliance Squares immunological/virological
failure
Mocroft A et al. AIDS 2001, 15185194
Sub-study n 231
4
When might we consider an NRTI-sparing regimen?

• Extensive NRTI experience
• Multiple NRTI resistance-associated mutations
  (NAMs) and multidrug resistance
• Serious NRTI-associated toxicity
• Avoiding NRTI-associated lipoatrophy
• Compact regimen to promote adherence

5
NRTI-associated mitochondrial toxicities
Carr A, et al. Nat Rev Drug Disc 2003 2624634
online
6
MITOX Study Limb fat increase is greater
switching to ABC than maintaining AZT or d4T
1.8
1.6
ABC
1.4
AZT or d4T
1.2
1.0
Mean (SEM) change in limb fat from baseline (kg)
0.8
0.6
0.4
0.2
0
0
24
48
72
104
Weeks
ABC n 50 48 41
40 35 AZT/d4T n 56 54
46 42 36
Martin A, et al. AIDS 2004 1810291036
ITT
7
Possible disadvantages of NRTI-sparing

• Most clinical trial experience and
  evidence-based medicine is for NRTI backbones
• Potential for more NNRTI/PI drug interactions
  through CYP450
• Fitness/residual activity considerations
• Limits options/chances of constructing an
  optimized treatment regimen
• Uncertain coverage of sanctuary sites (CNS)

8
SQV/r EFV PK crossover study Steady-state PK
of SQV not affected by EFV in healthy volunteers
3500
SQV/r (1600/200 mg qd)
3000
SQV/r/EFV (1600/200/600 mg qd)
2500

Mean Cmin (ng/mL)
Mean SQV concentration (ng/mL)
2000
SQV/r
124.8
1500
P 0.85
SQV/r/EFV
129.1
1000
500
0
0
4
8
12
16
20
24
Time (hours)
n 24
Kurowski M et al. 8th ECCATH, Athens, 2001
abstract LB/P9
9
Examples of NRTI-sparing strategies
1Boyd MA et al. 15th IAC Bangkok, 2004, abstract
MoOrB1084 2Gisolf EH et al. AIDS 2000
14405413 3Stephan C et al. AIDS 2004
18503508 4Hellinger J et al. 9th CROI Seattle,
2002 abstract 451W 5Workman C et al. 16th ASHM
Canberra, 2004
10
Examples of NRTI-sparing strategies
1Boyd MA et al. 15th IAC Bangkok, 2004, abstract
MoOrB1084 2Gisolf EH et al. AIDS 2000
14405413 3Stephan C et al. AIDS 2004
18503508 4Hellinger J et al. 9th CROI Seattle,
2002 abstract 451W 5Workman C et al. 16th ASHM
Canberra, 2004
11
NNRTI/PI HIVNAT 009

• 96-week, single-arm, open-label, prospective
  study
• IDV/r 800/100 mg bid EFV 600 mg qd
• Patients who have failed multiple NRTI
  combination regimens
• Substudies
• PK and mitochondrial toxicity (PBMC and fat
  biopsies)

Boyd MA, et al. 15th IAC Bangkok, 2004, abstract
MoOrB1084
12
HIVNAT 009 Response over 96 weeks
100
69
75
Patients () with HIV RNA lt50 copies/mL
50
25
0
-25
Week
0 4 8 12 24 36
48 60 72
84 96
on study 61 60 60 60 60
59 58 57 52
52 51
CD4 ITT, LOCF VL ITT, M F
Boyd MA, et al. 15th IAC Bangkok, 2004, abstract
MoOrB1084
13
HIVNAT 009 Response over 96 weeks
100
300
69
75
200
Patients () with HIV RNA lt50 copies/mL
Median CD4 count (cells/mm3)
50
100
25
146 67232
0
-25
Week
0 4 8 12 24 36
48 60 72
84 96
on study 61 60 60 60 60
59 58 57 52
52 51
CD4 ITT, LOCF VL ITT, M F
Boyd MA, et al. 15th IAC Bangkok, 2004, abstract
MoOrB1084
14
HIVNAT 009 Changes in adipose tissue on CT scan
25
Week 048
20
15
10
8.6
7.9
5
P 0.05
P 0.04
3.5
P lt 0.001
0
L4 VAT
L4 SAT
Mid thigh SAT
VAT, visceral adipose tissue SAT, subcutaneous
adipose tissue
Boyd MA, et al. 15th IAC Bangkok, 2004, abstract
WePeB5867
15
HIVNAT 009 Changes in adipose tissue on CT scan
25
Week 048
Week 4896
20
12.2
15
P lt 0.001
3.5
10
P 0.23
8.6
7.9
5
P 0.05
P 0.04
1.9
P 0.018
3.5
P lt 0.001
0
L4 VAT
L4 SAT
Mid thigh SAT
VAT, visceral adipose tissue SAT, subcutaneous
adipose tissue
Boyd MA, et al. 15th IAC Bangkok, 2004, abstract
WePeB5867
16
HIVNAT 009 Changes in fasted lipids and glucose
were significant
All P lt 0.01
Baseline
10
7.9
Week 96
8
6.0
5.4
4.7
4.8
4.3
6
5.0
4.0
Median lipids and glucose (mmol/L)
4
2.7
1.4
1.2
2
0.9
0
Total cholesterol
HDL- cholesterol
LDL- cholesterol
Total cholesterol HDL ratio
Triglycerides
Glucose
Boyd MA, et al. 15th IAC Bangkok, 2004, abstract
MoOrB1084
17
Double PI Prometheus

• 48-week multicentre, open-label, controlled trial
• 208 patients were randomized 11 to receive
  treatment with
• SQV 400 mg/RTV 400 mg bid or
• SQV 400 mg/RTV 400 mg/d4T 40 mg bid

Gisolf GH, et al. AIDS 2000 14405413
18
Prometheus Patients were initially more likely
to achieve undetectable HIV RNA with d4T, but
this benefit diminished by 48 weeks
100
SQV/RTV/d4T
80
P 0.38
60
SQV/RTV
Patients () with HIV RNA lt400 copies/mL
40
20
0
0
4
8
12
16
20
24
28
32
36
40
44
48
Time (weeks)
Gisolf GH, et al. AIDS 2000 14405413
n 104 each arm, ITT
19
Prometheus Lipodystrophy-free survival was
higher without d4T
1.00
SQV/RTV
P 0.003
0.75
SQV/RTV/d4T
0.50
Lipodystrophy-free survival
0.25
0.00
48
36
96
84
72
60
24
12
0
Time (weeks)
82
85
n 87
75
88
n 88
van der Valk M, et al. AIDS 2001 15847855
No. of patients not reported at 96 weeks
20
Enfuvirtide Expanding treatment options for RTI-
or PI-sparing regimens

• With enfuvirtide there are now four classes of
  ARV
• Enfuvirtide provides a potent new option with
  which to construct treatment regimens sparing one
  or more ARV classes
• Works in patients with resistant virus
• Does not exacerbate most of the known toxicities
  associated with other ARVs
• Safety profile confirmed over 96 weeks

21
TORO Most frequent 48-week exposure-adjusted AEs
Katlama C, et al. 2nd IAS Conference, Paris,
2003 abstract LB02
22
TORO Most frequent 48-week exposure-adjusted AEs
Katlama C, et al. 2nd IAS Conference, Paris,
2003 abstract LB02
23
Enfuvirtide does not adversely affect body
composition and glycaemic parameters
Cooper DA, et al. 11th CROI, San Francisco, 2004
abstract 715
24
FI/PI ALLIANCE

• National Centre in HIV Epidemiology and Clinical
  Research (NCHECR)
• Open-label, multicentre 48-week study plus
  48-week extension
• Aim
• To assess the safety and efficacy of switching
  patients with current or historical
  treatment-limiting NRTI-associated toxicities to
  a new NRTI-sparing combination regimen containing
  enfuvirtide

25
FI/PI ALLIANCE

• 59 triple-class-experienced (NRTI, NNRTI, PI)
  patients with documented current or prior
  treatment-limiting NRTI-associated toxicity
• Primary endpoint change in HIV RNA over 48 weeks
• Secondary endpoints include CD4, adherence,
  lipoatrophy, quality of life and resolution of
  toxicity (if applicable)
• Study fully enrolled in lt6 weeks

26
FI/PI ALLIANCE
27
FI/PI ALLIANCE

• At week 48
• Total body lean and fat mass increased by 1.25 kg
  (P 0.01) and 1.6 kg (P 0.001), respectively
• Peripheral fat increased by 0.32 kg (P 0.03)
• Fasting lipids and glycaemics were unchanged
• NRTI toxicities resolved in 20 of patients
• 52 (88) patients were still taking enfuvirtide
  at week 48

28
NRTI-sparing summary

• NRTI-sparing regimens offer therapeutic options
  for patients with
• Failed NRTI regimens and/or NAMs
• Serious NRTI toxicities
• NRTI-sparing may be appropriate for simple yet
  potent maintenance therapy

29
Enfuvirtide a new approach to NRTI-sparing
regimens

• Four classes allow more opportunities to spare
  classes and construct regimens that are
• Efficacious
• Durable
• Well-tolerated
• The favourable toxicity profile of enfuvirtide
  and its activity against MDR HIV makes it a
  particularly strong candidate for use in class
  sparing