Gerald Pierone Jr' M'D'

1
Retrovirus and Investigational Agent Update

• Gerald Pierone Jr. M.D.
• AIDS Research Treatment Center of the Treasure
  Coast
• Ft. Pierce, FL

2
Disclosure of Financial RelationshipsThis
speaker has the following significant financial
relationships with commercial entities to
disclose

• Pfizer
• Roche
• Therea-Techonologies
• Tibotec
• NIH

• Abbott
• Boerhinger Ingelheim
• BMS
• Gilead
• GSK
• Merck

This slide set has been peer-reviewed to ensure
that there areno conflicts of interest
represented in the presentation.
3
Lecture Outline

• Trials in Treatment-naïve Patients
• Trials in Treatment-experienced Patients
• Medication-related Toxicities and
• Metabolic Effects
• Management Issues in HIV infection
• Investigational Agents and Strategies

4
The 15th Conference on Retroviruses and
Opportunistic Infections

• Boston, Massachusetts
• February 3-6, 2008

5
The HIV-1 Replication Cycle
6
Recommended Regimens forTreatment-Naïve
Patients DHHS 2008
1Efavirenz is not recommended for use in the 1st
trimester of pregnancy or in sexually active
women with child-bearing potential who are not
using effective contraception 2The pivotal study
that led to the recommendation of
lopinavir/ritonavir as a preferred PI component
was based on twice-daily dosing NEJM 2002. A
smaller study has shown similar efficacy with
once-daily dosing but also showed a higher
incidence of moderate to severe diarrhea with the
once-daily regimen (16 vs. 5) JAIDS 2006
3Emtricitabine may be used in place of lamivudine
and vice versa 4Nevirapine should not be
initiated in women with CD4 T cell count gt250
cells/mm3 or in men with CD4 T cell count gt400
cells/mm3 because of increased risk of
symptomatic hepatic events in these patients
5Atazanavir must be boosted with ritonavir if
used in combination with tenofovir 6HLA-B5701
testing is recommended prior to ABC use with
positive patients not being given ABC.
Available at http//aidsinfo.nih.gov/Default.aspx
. Revision January 29, 2008.
7
HEAT ABC/3TC vs TDF/FTC Each With LPV/RTV QD in
Tx-Naive Patients
Primary efficacy analysisWeek 48
Stratification by HIV-1 RNA lt or 100,000
copies/mL
Week 96
ABC/3TC 600/300 mg QD LPV/RTV 800/200 mg
QD (n 343)
HIV-infected patients with HIV-1 RNA 1000
copies/mL and any CD4 cell count (N 688)
TDF/FTC 300/200 mg QD LPV/RTV 800/200 mg QD (n
345)
No HLA-B5701 screening at baseline. LPV/RTV
switched from soft-gel capsules to tablets at
Week 48.
Smith K, et al. CROI 2008. Abstract 774.
8
HEAT Virologic and Immunologic Outcomes at Week
48
100
ABC/3TC
87
84
TDF/FTC
80
68
67
64
63
62
61
60
Patients With HIV-1 RNA lt 50 c/mL at Week 48 ()
40
20
0
M F
TLOVR
Obs
MD F
NRTI switches allowed. NRTI switches counted
as failure.LPV/RTV could be switched to FPV
RTV.

• Numerically greater median CD4 cell count
  increases with ABC/3TC vs TDF/FTC
• 201 vs 173 cells/mm3 at Week 48, respectively

Smith K, et al. CROI 2008. Abstract 774.
9
HEAT Treatment-Emergent Mutations at Virologic
Failure
Smith K, et al. CROI 2008. Abstract 774.
10
HEAT ABC/3TC Noninferior to TDF/FTC Each Safe,
Well Tolerated

• ABC/3TC noninferior to TDF/FTC in combination
  with LPV/RTV QD in treatment-naive patients
• Relatively low efficacy rate largely accounted
  for by high rate of premature withdrawal ABC/3TC
  (20) and TDF/FTC (24)
• Potentially associated with QD use of LPV/RTV SGC
• Similar rate of adverse events, lipid elevations,
  treatment discontinuations, and switches in both
  arms
• Suspected ABC HSR ABC/3TC (4) and TDF/FTC (1)
• Renal function improved in both arms with no
  significant difference between arms
• Proximal renal tubular dysfunction ABC/3TC (0)
  and TDF/FTC (1)

Smith K, et al. CROI 2008. Abstract 774.
11
CASTLE ATV/RTV vs LPV/RTV in Treatment-Naive
Patients
Primary endpointWeek 48
Stratification by HIV-1 RNA lt or 100,000
copies/mL and by geographic region
Week 96
Atazanavir Ritonavir 300/100 mg QD
Tenofovir/Emtricitabine 300/200 mg QD (n 440)
Antiretroviral-naive HIV-infected patients with
HIV-1 RNA 5000 copies/mL and no CD4 cell
count restriction (N 883)
Lopinavir/Ritonavir 400/100 mg BID
Tenofovir/Emtricitabine 300/200 mg QD (n 443)
Lopinavir/ritonavir administered as soft-gel
capsules through Week 48 tablet formulation
administered after Week 48 where available.
Molina JM, et al. CROI 2008. Abstract 37.
12
Baseline Characteristics
CASTLE
Molina JM, et al. 15th CROI Boston, MA (2008)
Abst. 37.
13
CASTLE Patients With VL lt 50 c/mL at Week 48
(ITT-CVR, NC F)

• ATV RTV QD met virologic efficacy criteria for
  noninferiority to LPV/RTV BID
• Mean increase in CD4 cell count lower with use
  of ATV RTV vs LPV/RTV
• 203 cells/mm3 vs 219 cells/mm3 difference -16.4
  (95 CI -35.9 to 3.1)

ATV RTV
LPV/RTV
100
100
Patients ()
82
90
80
74
78
80
80
72
76
70
60
60
Patients ()
50
40
40
30
20
20
Estimated difference 1.7 (95 CI, -3.8, 7.1)
10
n
223
225
217
218
0
0
4
BL
12
24
36
48
HIV-1 RNA lt 100,000 c/mL
HIV-1 RNA 100,000 c/mL
Weeks
Molina JM, et al. CROI 2008. Abstract 37.
14
CASTLE Response Rate by Baseline CD4 Cell Count
Post Hoc Analysis
Jean-Michel Molina et al. CROI 2008 abstract 37.
15
CASTLE Adverse Events at Week 48
Excluding laboratory abnormalities reported as
adverse events.
Molina JM, et al. CROI 2008. Abstract 37.
16
CASTLE Mean Change in Fasting Lipids at Week 48
(LOCF)
ATV RTV
60
LPV/RTV

50
Change From BL ()
40
P lt .0001
30


20
10
0
TC
LDL
HDL
NonHDL
TG
Difference estimates ()
-9.5
-2.9
-3.8
-11.6
-25.2

• 2 of ATV RTV vs 7 of LPV/RTV subjects
  initiated lipid-lowering therapy during study

Molina JM, et al. CROI 2008. Abstract 37.
17
ACTG 5142 Sex and Race Associated With Time to
Virologic Failure

• ACTG 5142 BL factors associated with virologic
  failure younger age, female sex, lower CD4 cell
  count, black race

Baseline Factor
0.81
.005
Age, per 10-yr increase
Male sex
0.73
.046
CD4 cell count, per category increase
0.88
.03
Nonblack race
0.64
.002
1.0
2.0
0.1
Multivariate hazard ratio stratified by
screening HIV-1 RNA level, presence of hepatitis,
NRTI used.
Riddler S, et al. CROI 2008. Abstract 776.
18
MERIT Comparison of Efavirenz and Maraviroc in
ARV-Naïve Patients

• Patient eligibility criteria
• Treatment naive
• R5 HIV-1 infection
• Patients stratified by
• HIV-1 RNA lt and 100,000 copies/mL at screening
• Geographic location No. and So. Hemispheres

N721 Randomization 11
MVC (300 mg BID) ZDV/3TC (n360)
EFV (600 mg QD) ZDV/3TC (n361)
Week 48 Primary Analysis
Saag M, et al. 4th IAS Conference Sydney,
Australia (2007) Abst. WESS104 Heera J, et
al. 15th CROI Boston, MA (2008) Abst. 40LB.
19
New Subanalyses of MERIT Maraviroc vs Efavirenz
in Treatment-Naive Pts

• Phase III trial in treatment-naive patients with
  HIV-1 RNA 2000 copies/mL and R5 virus
• MVC 300 mg BID ZDV/3TC (n 360)
• EFV ZDV/3TC (n 361)
• MVC failed to meet primary endpoint of
  noninferiority in HIV-1 RNA lt 50 copies/mL at
  Week 48 (lower 97.5 CI -10.9)
• MVC noninferior in HIV-1 RNA lt 400 copies/mL
• MVC associated with higher CD4 cell count
  increases
• Superior safety profile for MVC vs EFV
• Current analyses examined viral factors
  associated with lack of response in MVC-treated
  patients and 48-week lipid changes in patients
  receiving study drugs

20
MERIT Substudy Viral Suppression at Week 48 by
Baseline Tropism

• Change in detected HIV-1 tropism from R5 at
  screening to D/M at BL and potentially adherence
  may explain some treatment failures on MVC
• 3.5 of patients experienced change in detected
  tropism between screening and BL
• 50.0 of patients with R5 virus at BL and without
  confirmed X4 at failure had plasma MVC
  concentrations below limit of detection
• Tropism changes more common in patients with
  lower mean CD4 cell count at screening as well
  as with clade B or other/undetermined HIV-1
  subtype vs clade C

100
EFV
90
MVC
80
69.3
69.3
68.0
70
65.3
60
54.6
50
Patients With VL lt 50 c/mL at Week 48 ()
40
30
20
7.1
10
n
11
14
339
331
361
360
0
Tropism at Screening (Overall)
Tropism at Baseline(R5)
Tropism at Baseline(D/M)
Heera J, et al. CROI 2008. Abstract 40LB.
21
Virologic Efficacy by by Tropism Result at
Baseline
MERIT




Heera J, et al. 15th CROI Boston, MA (2008)
Abst. 40LB.
22
Tropism Summary
MERIT

• No significant differences in response rates of
  EFV and MVC inR5-tropic only patients at
  baseline
• 31.3 of MVC failures with R5-only at baseline
  by tropism assay had detectable CXCR4
• 13 patients (3.8) were found to have D/M virus
  at baseline after having R5-only at screening
• MVC response significantly reduced in this
  subgroup
• Tropism changes were 50 less frequent with clade
  C than other clades
• Patients failing MVC had higher CD4 cell counts
  at failure than EFV, regardless of tropism
  result at failure

Heera J, et al. 15th CROI Boston, MA (2008)
Abst. 40LB.
23
Median Maximum Change From Baseline in Lipid
Parameters
MERIT
TriglyceridesP0.0002
N 318 322 319 323 320 324 318 322Median 35.9 2.
0 13.5 6.9 20.7 -9.0 20.8 -9.0
DeJesus E, et al. 15th CROI Boston, MA (2008)
Abst. 929.
24
Studies in Treatment Experienced Patients




25
Darunavir/r 600/100 mg b.i.d.Pooled
AnalysisPOWER 1 and 2
26
Pooled Analysis Viral Load (lt50 copies/mL) at
Week 24
63.0
Plt.001 vs CPI(s) arm.
45.0
19.0
12.1
OBR consisted of ?2 NRTIs /- ENF. Approximately
47 of all subjects used ENF, and 35 of the use
was in subjects who were ENF-naïve. 61 of
patients in the CPI(s)/r arm were resistant to
all available PIs. Data on file. Tibotec, Inc
2006.
27
Pooled Analysis 3 Times as Many Patients
Achieved ?1.0 log10 Reduction With Darunavir/r
OBR at Week 24
100
90
80
69.5
70
60
Patients () with ?1.0 log10 reduction in HIV-1
RNA from baseline (ITT-TLOVR)
50
40
30
21.0
20
10
0
1
2
4
8
12
16
20
24
Time (weeks)
Plt.001 vs CPI(s) arm.
OBR consisted of ?2 NRTIs /- ENF. Approximately
47 of all subjects used ENF, and 35 of the use
was in subjects who were ENF-naïve. 61 of
patients in the CPI(s)/r arm were resistant to
all available PIs, excluding tipranavir.
ITT-TLOVRintent-to-treat, time to loss of
virologic response. Data on file. Tibotec, Inc
2006.
28
Pooled Analysis 4 Times Greater Mean Increase in
CD4 Cell Count With Darunavir/r OBR at Week 24
110
100
92
90
80
70
Mean (SE) change in CD4 count cells/mm3
(ITT-LOCF)
60
50
40
30
20
17
10
0
2
4
8
12
16
20
24
Plt.001 vs CPI(s) arm.
Time (weeks)
OBR consisted of ?2 NRTIs /- ENF. Approximately
47 of all subjects used ENF, and 35
of the use was in subjects who were ENF-naïve.
61 of patients in the CPI(s)/r arm were
resistant to all available PIs. Patients were
treatment experienced with prior exposure to a
median of 6 NRTIs, 1 NNRTI, and 5 PIs LOCFlast
observation carried forward. Data on file.
Tibotec, Inc 2006.
29
Virologic Response by Number of Darunavir
Resistance-associated Mutations at Baseline
50
Patients () with HIV-1 RNA lt50 copies/mL at week
24
22
10

• For patients in POWER 1, 2, or 3 experiencing
  virologic failure on Darunavir/r 600/100 mg
  b.i.d., the amino acid substitutions V32I and
  substitutions at I54 developed in gt30 and gt20
  of virologic failure isolates, respectively. The
  following amino acid substitutions occurred in
  10-20 of virologic failure isolates I15, L33,
  I47, G73, and L89. More than half of these
  patients remained susceptible to tipranavir lt5
  were susceptible to other PIs (amprenavir,
  atazanavir, indinavir, lopinavir, nelfinavir,
  ritonavir, or saquinavir)

Based on supportive analyses of POWER 1, 2, and 3
examining patients achieving viral load lt50
copies/mL at week 24.
30
BENCHMRK-1 and -2 Study Design
Raltegravir 400 mg twice daily OBTa (n462)
Treatment-experienced subjects
Documented resistance to at least 1 drug in each
of the 3 classes (NRTIs, NNRTIs,
PIs)
Placebo OBTa (n237)
Enrollment
Randomizationb
Ongoing Investigation
aOptimized background therapy (OBT) selected by
investigator based on genotypic/phenotypic
resistance testing and ART history.
bRandomization was stratified by the degree of
resistance to PI (1 PI vs gt1 PI) and use of
enfuvirtide in the OBT. NRTInucleoside reverse
transcriptase inhibitor NNRTInonnucleoside
reverse transcriptase inhibitor PIprotease
inhibitor
31
BENCHMRK-1 and -2 Mean Change in Viral Load and
CD4 Cell Count at 24 Weeks
Mean Change From Baseline in Viral Load
Mean Change From Baseline in CD4 Cell Count
Log10 copies/mL
Cells/mm3
Raltegravir 400 mg twice daily OBT (n462)
Placebo OBT(n237)
32
BENCHMRK-1 2 Combined EfficacyPercent of
Patients With HIV RNA lt 50 Copies/mL at Week 48
by Genotypic Sensitivity Score (GSS)
For patients with GSS 1, 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).
David Cooper et al. CROI 2008 abstract 788.
Key Research From CRO 2008
33
BENCHMRK-1 Summary of Clinical Adverse Events
(AEs)
David Cooper et al. CROI 2008 abstract 788.
34
DUET-1 and -2 Phase III Trials of ETR Plus DRV
RTV-Containing OBR
Week 48
HIV-infected patients with VF on current HAART
regimen, history of 1 NNRTI resistance
mutations, 3 primary PI mutations, HIV-1 RNA gt
5000 copies/mL (DUET-1 N 612 DUET-2 N
591)
ETR 200 mg BID DRV/RTV-containing OBR (n 599)
Placebo DRV RTV-containing OBR (n 604)
Investigator-selected OBR consisting of DRV
RTV (600/100 mg/mL BID) 2 NRTIs ENF.
Haubrich R, et al. CROI 2008. Abstract 790.
Johnson M, et al. CROI 2008. Abstract 791.
35
DUET-1 and -2 VL lt 50 c/mL at Wk 48,Overall and
by Active Agents in OBR

• Mean changes in CD4 cell count response at Week
  48 significantly greater in etravirine arm 98
  cells/mm3 vs 73 cells/mm3 in placebo1,2
• VircoType assay clinical cutoffs for ETR
  susceptibility defined lower clinical cutoff
  (1.6), upper clinical cutoff (27.6)3

100
ETR (n 599)
100
Placebo (n 604)
ITT-TLOVR
90
76
80
80
61
70
61
60
60
60
Patients with VL lt 50 c/mL ( 95 CI)
Patients with VL lt 50 c/mL ()
50
40
33
40
26
30
40
0
20
20
121/203
229/300
187/305
51/196
12/36
10
P lt .0001
0/35
0
0
0
1
³ 2
0
20
48
40
32
24
2
4
8
12
16
of Active Agents in OBR by PSS(DRV considered
active if FC lt 40)
Time (Weeks)
Haubrich R, et al. CROI 2008. Abstract 790. 2.
Johnson M, et al. CROI 2008. Abstract
791. Winters B, et al. CROI 2008. Abstract 873.
36
DUET-1 Response (lt 50 Copies/mL) By PSS (DRV FC
lt 10) at Week 48
Richard Haubrich et al. CROI 2008 abstract 790.
37
Adverse Events at Week 48
DUET 1 2

• No consistent or clinically relevant trends in
  lab, vital signs or ECGs observed
• Lab abnormalities, including hepatic and lipid
  parameters similar between arms

All deaths in the ETR group were considered
unlikely to be related to trial medication. One
death in the pooled placebo group was considered
possibly related to the background regimen (BR)
Haubrich R and Johnson M, et al. 15th CROI
Boston, MA (2008) Absts. 790 and 791.
38
Motivate 1 and 2 Week 48 Data
Percentage of patients with HIV-RNA lt50 copies/mL
at week 48
Hardy D, et al. 15th CROI Boston, MA (2008)
Abst. 792.
39
Toxicities and Metabolism




40
DAD Study Assessing Risk of Myocardial
Infarction withCertain NRTIs
N 33,347 212 clinics (EU, Australia USA)
157,912 patient-years of prospective
follow-up 517 patients developed MI
10 year predictive CHD risk Framingham equation
Poisson regression assessed impact of cumulative,
recent past use of 5 NRTIS
Adjusted for
Demographic factors (age, sex, ethnicity)
Calendar year cohort
Non-HAART CHD risk factors (smoking, family
history, previous CV event, BMI)
Cumulative exposure to other ARVs (TDF, main PIs
NNRTIs)
Sabin C, et al. 15th CROI Boston, MA (2008)
Abst. 957c.
41
Rates of MI for Recent Use of ddI or ABC by
Predicted 10 Year CHD risk
DAD Study
Stratified by recent didanosine use
Stratified by recent Abacavir use
no recent ddI
recent ddI
no recent ABC
recent ABC
32
24
20
Per 1000 patient years
16
9
9
7
7
7
5
5
5
3
3
3
2.5
2
2
2
1
Over All
Low
Moderate
High
Not known
Over All
Low
Moderate
High
Not known
Test of interaction between moderate/high CHD
risk and recent ddI use p0.36
Test of interaction between moderate/high CHD
risk and recent ABC use p0.04
recent still using or stopped within last 6
months
Sabin C, et al. 15th CROI Boston, MA (2008)
Abst. 957c.
42
Adjusted MI Risk with RecentddI and ABC Use
DAD Study
Recent still using or stopped within last 6
months All data also adjusted for demographic
factors, calendar year, cohort, CV risk factors
that are unlikely to be modified strongly by cART
use and cumulative exposure to other ARVs.
Sabin C, et al. 15th CROI Boston, MA (2008)
Abst. 957c.
43
Relationship with Recent use of NRTIs and Risk of
CHD and Stroke
DAD Study
CHD (MI, CV deaths, invasive procedures
n693) Stroke (possible/definitive n195)
AZT
RR 1.40 (p0.005)
ddI
d4T
3TC
RR 1.63 (p0.0001)
ABC
1
0.5
0.75
1.25
1.5
1.75
2
2.25
Adjusted relative rate (95 CI)
Sabin C, et al. 15th CROI Boston, MA (2008)
Abst. 957c.
44
Effect of Ritonavir onLipid Profiles
Boffito M, et al. 15th CROI Boston, MA (2008)
Abst. 930.
45
SWEET Study DesignSWEET Simplification With
Easier Emtricitabine and Tenofovir
48 wks
N250 Randomized 11
DEXA sub-study (N 100)
HIV RNA lt50 c/mL on ZDV/3TC FDC EFV 6
months
48 wks
48 wks
Other Entry Criteria CrCl 60 ml/min, AST/ALT
5 x ULN, HBsAg negative, No resistance to Study
Drugs
Moyle G, et al. 15th CROI Boston, MA (2008)
Abst. 938.
46
Limb and Body Fat Changes from Baseline to Week 48
SWEET
Total Limb Fat
0
.
6
0
.
4
p

0
.
0
7
3
0
.
2
Median Change (Kg)
4
.
7
8

0
p0.039
4
.
6
7

-0
.
2
p

0
.
2
4
-0
.
4
-0
.
6
Median baseline total limb fat or whole body
fat
Moyle G, et al. 15th CROI Boston, MA (2008)
Abst. 938.
47
Effect of ZDV and Baseline Limb Fat on Limb Fat
Change
SWEET
Week 48 change in Limb Fat by Baseline Total
Limb Fat
Median Baseline Limb Fat, Median Baseline
Limb Fat ranges
Moyle G, et al. 15th CROI Boston, MA (2008)
Abst. 938.
48
Effect of Continued Tesamorelin in HIV Persons
with Increased Abdominal Girth
Tesamorelin (2mg/day) for 52 Weeks
Tesamorelin (2mg/day) for 26weeks Placebo for
26 weeks
plt0.05 vs. baseline plt0.001 vs. baseline.
No increase in glucose, TGs significantly reduced
Falutz J, et al. 15th CROI Boston, MA (2008)
Abst. 943.
49
Effects of Growth Hormone on Glucose Tolerance
2-Hour Glucose (mg/dL)
Note No effects on fasting glucose, insulin or
hemoglobin A1c were observed.
Adapted from Janet Lo et al. CROI 2008 abstract
146LB.
50
Chromium Supplementation and Body Composition
P 0.004
P 0.003
P 0.013
Baseline Wk 16
Aghdassi et al. CROI 2008 abstract 936.
51
Chromium Supplementation and Blood Biochemistry
P 0.009
P 0.025
Baseline
Week 16
Ellie Aghdassi et al. CROI 2008 abstract 936.
52
Management




53
ACTG 5164 Early vs. Deferred ART with Acute OIs

• Assessment of optimal timing of ART
• Should ART be started during the treatment of an
  acute OI?
• -or-
• Should ART be deferred until after treatment of
  an acute OI is completed?
• N 282 85 men 92 treatment-naive
• Median CD4 count 29 cells/mm3, HIV RNA 5.07
  log10 c/ml
• OIs with effective antimicrobial therapy only
• PCP (63), bacterial infections, cryptococcal
  disease, MAC, toxoplasmosis
• TB excluded
• Any antiretroviral regimen allowable d4T XR,
  TDF/FTC, LPV/r provided

Zolopa A, et al. 15th CROI Boston, MA (2008)
Abst. 142.
54
ACTG 5164 Study Design
A5164
Opportunistic InfectionTreatmentStarts
ImmediateArmStart ART
48wks
48wks
Deferred ArmStart ART
RecommendedStart window
-14
0
2
28
42
84
224
Study day
Enrollment
Zolopa A, et al. 15th CROI Boston, MA (2008)
Abst. 142.
55
ACTG 5164 Results Through 48 Weeks
A5164

• No difference in composite primary endpoint of
  death, progression, and virologic suppression
• No difference in IRIS (10 immediate, 13 deferred)
  or need for ART changes
• Less risk of death/disease progression in
  immediate treatment group

Zolopa A, et al. 15th CROI Boston, MA (2008)
Abst. 142.
56
Treatment During PrimaryHIV-1 Infection (PHI)

• ACTG 3711
• ARVs in acute (Ab- within 14 days, n 28) and
  recent (detuned EIA negative, n 45) infection
• Primary endpoint HIV-1 RNA lt 5000 copies/mL 24
  weeks after treatment interruption
• Acute arm 43 (95 CI 24 to 63) recent arm
  38 (95 CI 24 to 53 P .8)
• ANRS Primo Cohort2
• Patients enrolled within 3 months of HIV
  infection ARVs (HAART 15 days after enrollment
  for 6-24 months, n 73) vs no ARVs (untreated
  for gt 3 months, n 149)
• Primary endpoint time to CD4 cell count lt 350
  cells/mm3
• More rapid CD4 decline during first 10 months in
  no-ARV group benefit not sustained

1. Volberding P, et al. CROI 2008. Abstract 693.
2. Desquilbet L, et al. CROI 2008. Abstract 694.
57
Reproductive Options For HIV Women

• Retrospective review from a French center of
  assisted reproductive treatment in
  sero-discordant couples with infertility desiring
  pregnancy (2002-2006)
• To be eligible, HIV women needed to have a CD4
  count gt 200 cells/mm3 and an undetectable HIV RNA
• 52 HIV-infected women compared to 82
  HIV-uninfected.
• All women underwent in vitro fertilization
• HIV- HIV
• Oocytes recovered 95 95
• Pregnancy rate 12.9 15.8
  
• Live birth 15.9 26.9 pns
• Pregnancy success rate comparable in HIV and
  HIV- women

Tubiana R, et al. 15th CROI Boston, MA (2008)
Abst. 670.
58
Cervicovaginal Fluid Exposure
Dumond et al. CROI 2008 abstract 135LB
59
Male-to-Female Transmission by Timing of Wound
Healing and Resumption of Sex
Excludes uncircumcised men (8) and couples who
did not resume sex (3)
Wawer et al. CROI 2008 abstract 33LB.
60
DHHS Guidelines When To Start 2008
Available at http//aidsinfo.nih.gov/Default.aspx
. Revision January 29, 2008.
61
Risks of Ongoing Virus Replication

• Increased fibrosis in patients with HIV-HCV
  Coinfection1
• Hepatic stellate cells (HSC) mediate fibrosis in
  patients with HCV
• HIV infects HSC in vitro by CD4-independent
  pathways
• Result inflammation of HSC and increased
  collagen gene expression
• May help explain increased level of fibrosis in
  HIV-HCV coinfection
• Increased HIV-Associated Neuocognitive
  dysfunction (HNCI)2
• In patients with neurocognitive dysfunction
  starting or changing ARV, 60 fail to normalize
  neuropsychiatric function after 24 weeks
• Factors associated with incomplete recovery
  Nadir CD4 count, pre-ART HIV RNA in CSF, lower
  pre-ART HIV RNA levels in blood, and greater
  expansion of CD8 lymphocyte cells

1. Tuyama A, et al. 15th CROI Boston, MA
(2008) Abst. 57 2. Letendre A, Ibid. Abst. 68.
62
Incidence of Second Virologic Failure Declining
Over Time
RR 1.46113.6
120
REF70.7
90
RR 0.8241.5
60
Incidence per 100 PY
RR 0.5117.9
RR 0.5415.1
30
0
1998-99
2004-05
1996-97
2000-01
2002-03
Adjusted for time from HAART initiation, sex,
age, AIDS, CD4 cell count, HIV-1 RNA level at
HAART initiation and switch, and type of HAART.
Deeks S, et al. CROI 2008. Abstract 41.
63
HCV Treatment Does NRTI Choice Influence
Response?

• Multicenter review of HIV/HCV pts treated with
  PEG-IF RBV and on ABC/3TC (n70) or TDF/FTC (or
  3TC) (n186)
• SVR significantly better with TDF
• OR 2.6 (85 CI 1.05-6.9, p.03)
• No significant difference with HCV GT 2,3 HCV
  RNA lt 600K and RBV dose gt 13.2 mg/kg/d

Mira J, et al. 15th CROI Boston, MA (2008)
Abst. 1074.
64
HCV Treatment Does NRTI Choice Influence
Response?

• 35 site review of HIV/HCV therapy from 2003-2005
  (n719)1
• Treatment with TDF associated with increased SVR
  (OR1.70 95 CI 1.05-2.77)
• ZDV reduced likelihood of SVR (OR0.60 95 CI
  .37-.99)
• Review of HIV/HCV patients treated in a Madrid
  hospital from2001-2006 (n174)2
• Weight-based dosing of RBV
• No apparent effect of NRTI choice on SVR rates

1. Gonzalez-Garcia J, et al. 15th CROI Boston,
MA (2008) Abst. 1076 2. Moreno A, et al.
Ibid. Abst. 1075.
65
SLAM-C Continued Peg-IFN for Early HCV
Non-Responders

• Inclusion Criteria
• HIV RNA lt 50,000 c/mL
• CD4 gt 200
• metavir stage 1 on liver bx within 104 weeks
• No previous HCV Rx

Sherman K, et al. 15th CROI Boston, MA (2008)
Abst. 59.
66
Results EVR andPrevention of Fibrosis
SLAM C

• Early Virologic Response
• 329 Subjects Dosed, 295 completed 12 weeks, EVR
  in 183 (56)
• EVR higher in
• HCV Genotype 2,3 vs 1, 4 (90.3 vs 53.4,
  plt0.0001)
• White vs Black vs Hispanic (64.8 vs 42.3 vs
  56, p0.001)
• Male vs Female (58.4 vs 42.8, p0.02)
• Prevention of Liver Fibrosis in Early
  Non-Responders
• 86 subjects enrolled 44 maintenance Rx, 42
  observation
• Similar with respect to age, gender, race, HIV
  RNA lt50 c/mL, HCV RNA, HCV genotype 1, cirrhosis
• No improvement in Metavir fibrosis score for
  those on Peg-IFN study stopped early

Sherman K, et al. 15th CROI Boston, MA (2008)
Abst. 59.
67
Investigational NRTIs and NNRTIs in Early
Clinical Development

• Apricitabine
• AVX-201 phase IIb study1 NRTI apricitabine 600
  mg or 800 mg BID OBR (added 21 days after
  functional monotherapy) safe, well tolerated, and
  active over 24 weeks in pts failing 3TC-based
  therapy
• VL lt 50 c/mL at Week 24 Apricitabine 600 mg
  (71.4) or 800 mg (73.3) vs 3TC (58.3)
• Amdoxovir (DAPD)
• 10-day amdoxovir NRTI monotherapy or amdoxovir
  ZDV safe, generally well tolerated, and potent in
  pts not currently on treatment2
• DAPD ZDV 2 log10 c/mL VL reduction after 10
  days
• Substantially greater VL reduction than either
  drug alone
• IDX899
• NNRTI IDX899 800 mg QD median VL decrease 2.11
  log10 c/mL after 7 days in treatment-naive
  patients
• Higher in vitro barrier to resistance compared
  with EFV3

1. Cahn P, et al. CROI 2008. Abstract 793. 2.
Murphy R, et al. CROI 2008. Abstract 794. 3.
Richman DD, et al. CROI 2008. Abstract 729.
68
IM Formulation of TMC 278

• TMC 278 is a second generation NNRTI entering
  phase III trials at dose of 25mg daily
• Investigational formulation of crystalline TMC
  278 has been shown to result in plasma levels
  well above the IC of virus for greater than one
  month
• Future studies are planned

69
Long-Acting ARV Formulations a New Paradigm?

• Uses of such formulations could include
• Once monthly injectable HAART
• Maintenance of undetectable viral load
• Prophylaxis
• Infrequent parenteral dosing offers potential
  advantages over daily (oral) treatment
• Sustained concentrations of drugs in plasma
• May improve adherence to therapy/prophylaxis
• May avoid gastro-intestinal adverse events

vant Klooster, et al. 15th CROI 2008. Abstract
134
70
Single-dose TMC278 LA Provided Sustained Plasma
Levels for up to 12 Weeks in Humans

• Dose proportionality and similar PK profiles
  after single SC and IM injections

SC, subcutaneous IM, intramuscular
vant Klooster, et al. 15th CROI 2008. Abstract
134
71
Therapeutic Concentrations Achievable With
Monthly Intramuscular Injections

• Steady-state simulations TMC278 LA, 600mg/month,
  and oral TMC278 25mg qd

300
Oral TMC278, 25 mg QD
TMC278LA, 600 mg/month
250
200
150
Cpl TMC278 (ng/ml)
100
TMC278 LA
TMC278 LA
50
0
-1
0
1
2
3
4
5
Time (weeks)

• Once monthly 600mg of TMC278 LA is predicted to
  achieve similar troughs as oral TMC278 25mg qd

SC, subcutaneous IM, intramuscular
vant Klooster, et al. 15th CROI 2008. Abstract
134
72
Conclusions and Next Steps

• Injectable long-acting formulations may provide a
  new paradigm in ARV use
• TMC278 LA was demonstrated to be a promising
  depot formulation
• Single doses gave prolonged TMC278 exposure
• In humans, PK profiles and exposures were similar
  after IM and SC administration
• Injections were well tolerated, particularly when
  administered IM
• A novel formulation will contain 300mg/mL TMC278
• Evaluation in a single and repeated dose study in
  healthy volunteers

vant Klooster, et al. 15th CROI 2008. Abstract
134
73
Prevention and Therapeutic Vaccine Trials

• STEP Trial1,2
• MRKAd5 (HIV-1 gag/pol/nef) vs placebo
• 3000 high-risk men and women stratified by Ad5 Ab
  200 or gt200
• Trial stopped by DSMB
• Increased risk of infection in vaccine recipients
  with previous Ad5 exposure and uncircumcised men
• Similar CD4 and CD8 immune responses and levels
  of immune activation in blood in infected vs
  uninfected subjects
• ACTG 519733
• Ad5 HIV-1 gag
• 3 injections in HIV patients with VL lt50 c/mL,
  CD4 count gt500 cells/mm3
• All subjects discontinue ARVs to measure VL set
  point
• Virologic endpoints
• TA-AUC 0.26 log10 c/mL lower in vaccine arm
  (pNS)
• Set point 0.27 log10 c/mL lower in vaccine arm
  (pNS)

1. Robertson M, et al. 15th CROI Boston, MA
(2008) Abst. 88LB 2. Robertson M, et al.
Ibid. Abst. 89LB 3. Schooley R, et al. Ibid.
Abst. 87.