Antiretroviral effect of MK0518, a novel HIV1 integrase inhibitor, in ARTnaive HIV1 infected patient

1
The Promise and Puzzles of More and More New
Antiretrovirals
David M. Margolis, MD, FACP Professor of
Medicine, Microbiology, Immunology,
EpidemiologyThe University of North Carolina at
Chapel Hill
The International AIDS SocietyUSA
DM Margolis, MD, FACP. Presented at IASUSA New
York Course, March 14, 2008.
2
Slide 2
Examples of Investigational Antiretroviral Agents
presented at CROI 2008
3
Slide 3
Potential targets for future therapy under study
DM Margolis, MD, FACP. Presented at IASUSA New
York Course, March 14, 2008.
4
Slide 4
Raltegraviron-label use
A HIV Integrase Strand Transfer
Inhibitor Indicated In Combination with Other
Antiretroviral Agents for the Treatment of HIV-1
Infection in Treatment-Experienced Adults Who
Have Evidence of Viral Replication and HIV-1
Strains Resistant to Multiple Antiretroviral
Agents Use has not yet been established
In treatment-naive adult patients or pediatric
patients
DM Margolis, MD, FACP. Presented at IASUSA New
York Course, March 14, 2008.
5
Confronting Treatment Failure by Using New Agents
Slide 5
the need to better define fully active to
achieve long-term success
1. Department of Health and Human Services Panel
on Antiretroviral Guidelines for Adults and
Adolescents. October 10, 2006. http//AIDSinfo.nih
.gov/contentfiles/AdultandAdolescentGL.pdf.
Accessed September 2007. 2. Gallant JE. Curr
HIV/AIDS Reports. 200528389.
DM Margolis, MD, FACP. Presented at IASUSA New
York Course, March 14, 2008.
6
BENCHMRK-1 -2 Study Design
Slide 6

• Randomized, double-blind, placebo-controlled with
  Data and Safety Monitoring Board
• Primary analysis at Week 16 secondary analysis
  at Week 48

Primary endpoints Week 16
Planned duration Week 156
HIV-1-infected Triple-class resistant HIV-1 RNA
gt1000 copies/mL No CD4 cell cut-off Protocol 018
(N352) (Europe, Asia/Pacific and Peru) Protocol
019 (N351) North and South America
Raltegravir 400 mg BID OBT P018 (n234) P019
(n232)
21
Placebo OBT P018 (n118) P019 (n119)

• OBT was selected by investigator based on
  baseline resistance testing
• and prior treatment history. Selected
  investigational ARTs, darunavir
• and tipranavir, were permitted.

DM Margolis, MD, FACP. Presented at IASUSA New
York Course, March 14, 2008.
7
Patient Characteristics (Benchmrk 2)
Slide 7
8
Percent of Patients Achieving HIV RNA lt50
Copies/mL (BENCHMRK-1, Non-CompleterFailure
Approach)
9
BENCHMRK-1 2 Combined EfficacyPercent of
Patients with HIV RNA lt50 copies/mLat Week 48 by
Baseline HIV RNA and CD4 Cell Count
Slide 9
Subgroup
Percent of Patients
N
64
443
Total
34
228
Baseline HIV RNA copies/mL
gt100,000
48
156
16
76
?100,000
73
287
43
152
Baseline CD4 cells/mm3
50
50
139
20
75
67
167
gt50 and ?200
39
82
76
136
gt200
44
71
0
20
40
60
80
100
Virological failures carried forward
Raltegravir OBT
Placebo OBT
DM Margolis, MD, FACP. Presented at IASUSA New
York Course, March 14, 2008.
m518p18p19bar50HIVRNACD4crioposter
10
BENCHMRK-1 2 Combined EfficacyPercent of
Patients With HIV RNAlt50 copies/mL at Week 48 by
Genotypic Sensitivity Score (GSS)
Slide 10
P
e
r
c
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n
t

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P
a
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t
s
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S
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T
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6
4
4
4
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4
2
2
8
G
S
S
4
5
1
1
2
0
3
6
5
6
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6
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2

o
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m
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9
6
8
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8
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R
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O
B
T
P
l
a
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O
B
T

• Virological failures carried forward
• For patients with GSS1, 4 ART agents represented
  at least 80 of the active agents in OBT
  darunavir (52, 52 in raltegravir and placebo
  groups, respectively), enfuvirtide (8, 16),
  tenofovir (12, 6), and tipranavir (11, 11).

DM Margolis, MD, FACP. Presented at IASUSA New
York Course, March 14, 2008.
11
BENCHMRK-1 2 Combined EfficacyPercent of
Patients With HIV RNAlt50 copies/mL at Week 48
Slide 11
P
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r
c
e
n
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o
f

P
a
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i
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n
t
s
N
S
u
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o
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p

6
4
4
4
3
T
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a
l
3
4
2
2
8
G
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S
4
5
1
1
2
0
3
6
5
6
7
1
6
6
1
3
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9
2
7
5
1
5
8
2

o
r

m
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r
e
5
9
6
8
P
S
S



0
5
1
6
5
PSS Based on lower cutoff Reported at study
initiation
2
4
4
6
1
1
3
7
P
S
S



1

2
9
6
9
7
1
2
2
1
P
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gt


2
4
8
1
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8
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O
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T
DM Margolis, MD, FACP. Presented at IASUSA New
York Course, March 14, 2008.
12
BENCHMRK-1 2 Combined EfficacyPercent of
Patients HIV RNAlt50 copies/mL at Week 48 by PSS
Based on Upper and Lower Cutoffs
Slide 12
P
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c
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n
t

o
f

P
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s
N
P
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5
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6
5
(
)
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)
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1

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P
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T
The analysis by PSS score has been reanalyzed
using the upper cutoff to better account for the
impact of partial ART activity. Isolates with
fold-change IC50 above the lower but below the
upper cutoff are now reported as "partially
sensitive". The upper cutoff was developed as the
lower cutoff may underestimate partial ART
activity in a regimen. At the time the BENCHMRK
studies were initiated, only the lower cutoff was
reported. The efficacy by PSS has been reanalyzed
using the upper cutoffs, where available, to
better account for the impact of partial ART
activity. Virological failures carried forward.
Conclusion At all levels of PSS, the results
using the upper and lower cutoffs are similar,
confirming the contribution of raltegravir in the
treatment regimen.
DM Margolis, MD, FACP. Presented at IASUSA New
York Course, March 14, 2008.
13
BENCHMRK-1 2 Combined Efficacy Percent of
Patients With HIV RNA lt50 copies/mL at Week 48 by
Selected ARTs in OBT
Slide 13


o
f

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s
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S
u
b
g
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p
6
4
4
4
3
3
4
2
2
8
New Enfuvirtide New Darunavir
8
9
4
4
6
8
2
2
8
0
4
5
N
e
w

E
n
f
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O
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5
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5
N
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D
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O
n
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y
4
7
4
7
No new Enfuvirtide or new Darunavir
6
0
1
9
1
2
0
9
0
0
2
0
4
0
6
0
8
0
1
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DM Margolis, MD, FACP. Presented at IASUSA New
York Course, March 14, 2008.
14
Number of Patients Treated with Raltegravir With
Virologic Failure by Week 48 With HIV Integrase
Mutations (BENCHMRK-2)
Slide 14
Virologic failure is generally associated with
mutations at one of two primary residues, Q148 or
N155, in combination with at least one other
mutation in integrase.
Virologic failure with integrase tests.
Includes only patients with virologic failure (as
defined in Table 1) for whom integrase genotypic
data were available. ? 3 patients with only
baseline sequence available Included 1 patient
with Y143C, L74M, S230R, and 1 patient with Y143R
Included 1 patient with G163R.
DM Margolis, MD, FACP. Presented at IASUSA New
York Course, March 14, 2008.
15
Cancer Events in the BENCHMRK Trials
Slide 15
Cooper D, et al. 15th CROI 2008 Poster 788.
Steigbigel R, et al. 15th CROI 2008 Poster 789.
DM Margolis, MD, FACP. Presented at IASUSA New
York Course, March 14, 2008.
16
Conclusions
Slide 16

• In ART-experienced patients failing therapy with
  3-class resistance
• Raltegravir 400 mg b.i.d. plus OBT has potent and
  superior to placebo through Week 48.
• Up to 89 achieved HIV RNA lt 50 copies /mL at
  Week 48.
• Virologic failure is generally associated with
  mutations Q148 or N155, in combination with at
  least one other mutation.
• Raltegravir is generally well tolerated.
• Few adverse experiences leading to
  discontinuation
• Risk of developing malignancy is comparable
  between raltegravir/OBT and placebo/OBT groups.

DM Margolis, MD, FACP. Presented at IASUSA New
York Course, March 14, 2008.
17
Slide 17
Raltegravir future uses?

• Place in the paradigm for drug resistance
• Recent studies have often selected advanced
  populations similar to those in the Benchmrk
  studies, and have not achieved the levels of
  success seen in this study.
• 89 of patients receiving 3 new drugs (RAL, DRV,
  ENF) were lt 50 copies at 48 weeks
• Nearly equal numbers of patients (ca. 65)
  receiving RAL (in some cases with recycled DRV
  /or ENF) as their only new drug and patients
  receiving new DRV ENF without RAL (placebo)
  were lt50 copies at 48 weeks

DM Margolis, MD, FACP. Presented at IASUSA New
York Course, March 14, 2008.
18
Slide 18
Raltegravir future uses?

• Place in the paradigm for drug resistance
• Decisions around the use of RAL in 2nd-line
  therapy in the absence of 3-class resistance must
  be made on an individual basis, taking into
  account clinical factors. The tolerability of
  RAL makes it attractive, but this attribute also
  makes it attractive in the setting of multidrug
  resistance.
• At the present time, RAL is reliably a fully
  active agent

DM Margolis, MD, FACP. Presented at IASUSA New
York Course, March 14, 2008.
19
Slide 19
Raltegravir future uses?

• Use in ART-naïve patients
• clinical trials ongoing
• The use of RAL in novel combinations (e.g. RAL
  and PI/r) is under study
• Effect on low-level replication (below 50 copies)
  or reservoirs (eg. ongoing replication in gut
  lymphoid tissue)
• research studies ongoing, but no evidence yet
  that this makes any clinical difference in the
  emergence of resistance, durability of ART, or
  possibilities for eradication of infection.

DM Margolis, MD, FACP. Presented at IASUSA New
York Course, March 14, 2008.
20
Dual tropic Virus
DM Margolis, MD, FACP. Presented at IASUSA New
York Course, March 14, 2008.
21
Slide 21
Maravirocon-label use

• Maraviroc, is indicated for combination therapy
  of treatment-experienced adult patients
• in patients in whom CXCR4-tropic or dual/mixed
  HIV-1 is not detectable
• who have evidence of viral replication with HIV-1
  strains resistant to multiple antiretroviral
  agents.

DM Margolis, MD, FACP. Presented at IASUSA New
York Course, March 14, 2008.
22
MOTIVATE 2 MVC in Treatment-Experienced Patients
With R5 Virus
Slide 22

• Randomized, double-blind, placebo-controlled,
  phase IIb/III study

• 221 randomization
• stratified by ENF use and HIV-1 RNA lt or ?
  100,000 c/mL

Week 24 planned endpoint analysis
Week 48
MVC 150 mg or 300 mg BID OBR (n 191)
Triple classresistant or triple
classexperienced patients with R5 virus and
HIV-1 RNA 5000 copies/mL Without detectable X4
or D/M (N 474)
MVC 150 mg or 300 mg QD OBR (n 182)
Placebo OBR (n 91)
Patients receiving PI (except TPV) or
delavirdine received 150 mg all others received
300 mg.
Fatkenheuer G, et al. EACS 2007. Abstract PS3.5.
DM Margolis, MD, FACP. Presented at IASUSA New
York Course, March 14, 2008.
23
Slide 23
MOTIVATE 2 Virologic and Immunologic Outcomes at
Week 48
Placebo OBR (n 91)
MVC BID OBR (n 235)
MVC QD OBR (n 182)
HIV-1 RNA lt 50 copies/mL
CD4 Cell Count Change
100
150
128
121
80
100
60
46
Mean Change From BL (cells/mm3)
69
45
Patients ()
40
45
50
41
20
18
21
185
n
180
90
0
0
0
4
8
12
16
20
24
28
32
36
40
44
48
Placebo OBR
MVC QD OBR
MVC BID OBR
Time (Weeks)
P lt .0001 vs placebo. P lt .0005 vs placebo.
Fatkenheuer G, et al. EACS 2007. Abstract PS3.5.
DM Margolis, MD, FACP. Presented at IASUSA New
York Course, March 14, 2008.
24
Patients with HIV-1 RNA lt 50 Copies/mL by
Screening Viral Loads and Baseline CD4 Cell
Count (Week 48)
Slide 24
Includes all patients who received at least one
dose of study medication
Patients were stratified at time of
randomization by screening HIV-1 RNA (lt or
100,000 copies/mL) Baseline CD4 cell count
calculated as the average of all pre-dose
measurements Includes all treated patients with
valid baseline and on-treatment measurements
Missing values imputed using last observation
carried forward
MOTIVATE 1 2 Week 48
DM Margolis, MD, FACP. Presented at IASUSA New
York Course, March 14, 2008.
25
Slide 25
MOTIVATE 1/2 Week 24 Outcomes Based on Tropism
Of 1042 pts with R5 virus at screening, 83 (8)
had D/M virus detected at study entry Detection
of D/M virus correlated with lower CD4 cell
count and slightly higher viral loads at
screening Patients with D/M virus at baseline had
inferior virologic outcomes at Week 24
100
90
80
Tropism result at baseline
70
D/M
R5
60
Patients () achieving HIV-1 RNA lt50 copies/mL
50
50
50
40
27
26
30
18
18
20
10
0
17
187
33
362
33
377
N
MVC QD OBR
MVC BID OBR
OBR alone
Van der Ryst, et al. ICAAC 2007 Abstract H-715.
DM Margolis, MD, FACP. Presented at IASUSA New
York Course, March 14, 2008.
26
Slide 26
MOTIVATE Time to Failure and Tropism Reversion

• Two thirds of patients failing MVC had detectable
  X4 virus at failure
• Time to MVC failure shorter (by 30 days) in
  patients failing with D/M or X4 virus vs those
  failing with R5 virus
• After MVC discontinuation, R5 virus typically
  re-emerged
• In the 44 MVC recipients with D/M or X4 virus at
  failure and follow-up data obtained off drug, 30
  (68) had R5 virus re-emerge
• In those with D/M or X4 virus at last visit,
  duration of follow-up off-drug was shorter than
  in those with reversion to R5 (median 16 vs 203
  days)
• 30 (97) of 31 MVC recipients with follow-up data
  obtained gt 1 month after failure reverted to R5
  virus

Van der Ryst E, et al. ICAAC 2007. Abstract H-715.
DM Margolis, MD, FACP. Presented at IASUSA New
York Course, March 14, 2008.
27
Slide 27
Maraviroc dose modifications

• 150 mg bid CYP3A inhibitors (even with a CYP3A
  inducer) protease inhibitors (except TPV/r),
  delavirdine, ketoconazole, itraconazole,
  clarithromycin,other strong CYP3A inhibitors
  (e.g., nefazadone, telithromycin)
• 300 mg bid Any other concomitant medications,
  including tipranavir/ritonavir, nevirapine, all
  NRTIs and enfuvirtide
• 600 bid CYP3A inducers (without a strong CYP3A
  inhibitor) efavirenz, rifampin, carbamazepine,
  phenobarbital, and phenytoin

DM Margolis, MD, FACP. Presented at IASUSA New
York Course, March 14, 2008.
28
Potential for emerging toxicities in newly
approved agents
Slide 28

• Short-term toxicities of raltegravir and
  maraviroc similar to placebo
• Some incidence of rash, liver abnormalities,
  postural hypotension with MVC
• Theoretical risk of selected infections with
  long-term R5 blockade (severe West Nile virus
  disease in ?32-CCR5 deletion homozygotes)

• Special immunological benefit of CCR5 receptor
  antagonists?

DM Margolis, MD, FACP. Presented at IASUSA New
York Course, March 14, 2008.
29
Unique effects of novel agents when used in
therapy?(eradication??)
Slide 29

• Residual viral expression (without failure of
  ART)
• a) Not enough drug gets to some part of the body
• b) Persistent expression in long-lived cells
• Persistence of proviral DNA
• a) latent infection of resting CD4 T cells

DM Margolis, MD, FACP. Presented at IASUSA New
York Course, March 14, 2008.
30
Low-level viremia persists for at least 7 years
in patients on suppressive antiretroviral
therapy. Palmer et al. PNAS March 2008