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Rectal Microbicides Ian McGowan MD PhD FRCP Center for HIV Prevention Research David Geffen School of Medicine at UCLA
Rectal Microbicides
Ian McGowan MD PhD FRCP
Center for HIV Prevention ResearchDavid Geffen School of Medicine at
UCLA
OverviewEpidemiology of anal intercourseRectal transmission of HIV infectionPhase 1 rectal safety studies of vaginal microbicidesDevelopment of rectal-specific microbicidesUpdate on rectal microbicide advocacy
Epidemiology
Population N Prevalence of AI
Reference
High risk women
1268 32% Gross M et al. 2000
College students
210 20% Civic D 2000
US Survey15 – 44 yearsNSFG
12,571 35-40% Mosher WD et al. 2005
Californian residents
3545 6-8% Erickson PI et al. 1995
Heterosexual Anal Intercourse is Common in the US
Lifetime Experience of RAI in Women
Brazil
Peru
Sout
h Afri
ca
Kenya
0
10
20
30
40
50%
Brazil: Guimares MD et al. 1995, South Africa: Karim SS and Ramjee G 1998Peru: Caceres C et al. 1997, Kenya: Schwandt M et al. 2006
Rectal Transmission
Rectosigmoid Anatomy
Mucosal Targets for HIV Infection
McGowan, Biologicals 2006
The Anal Canal as a Target for HIV Infection
Cranston et al. WEPEA040
Anal Tissue Infection in Vivo
0
1
2
3
4
5
6
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Subject Number
VL L
og10 PVL
AVLRVL
PVL > 10,000PVL < 50
T Cell Phenotype in Anal TissueRectal Tissue Anal Tissue
CCR5CXCR4
Ex Vivo / In Vitro Infection of Anal Explants
Rectal Bal
0 5 10 150
5000
10000
15000
20000840101110128411020102110321026
Day
HIV
-1 p
24 p
g/m
L
Anal Lav
0 5 10 150
2000
4000
6000
8000840101110128411020102110321036
Day
HIV
-1 p
24 p
g/m
L
Anal Bal
0 5 10 150
5000
10000
15000
20000840101110128411020102110321026
Day
HIV
-1 p
24 p
g/m
L
Rectal Lav
0 5 10 150
200
400
600
800840101110128411020102110321026
Day
HIV
-1 p
24 p
g/m
L
Rectal Tissue
Anal Tissue
HIV-1 R5 HIV-1 X4
Preclinical Studies
Preclinical Rectal Safety DataCandidate Murine Primate Explant Human
N-9 +++ +++ +++ +++
Buffergel ? (±) ? ?
PRO 2000 ? ? (±) Pending
Carraguard Neg ? ? ?
VivaGel ? Neg (±) Pending
PMPA ? ? Neg ?
UC-781 Neg Neg Neg Ongoing
Rectal Cytotoxicity is a ProblemCompound Cellular
toxicityEnhanced
HSV-2 Infection
Rectal Sloughing
KY-Plus ++++ ++++ ++++Delube ++++ ++++ ++++Astroglide ++ ++ ++Vagisil ++ ++ ++Viamor + ++ ++Carraguard - - -Methylcellulose - - -PBS - - -
Sudol and Phillips. 2004
N-9 Effect on Rectal Epithelium
Phillips et al. Contraception 2004
Baseline
+ 15 minutes
+ 15 minutes
+ 2 hours
+ 2 hours + 8 hours
Lubricants Vary in OsmolalityProduct Osmolality
(Median mOsm/Kg)
Tap water 3
Femglide 42Semen 340Gynol II 1182
Fleet enema 2127KY Jelly 2424
Astroglide 3126Prepair 4026
Fuchs et al J Infect Dis 2007
Effect of Osmolality on Mucosal Integrity
Iso-osmolar Hyperosmolar
Fuchs et al J Infect Dis 2007
IRMWG Lubricant Survey
http://www.irmwg.org/
Phase 1 Rectal Safety Studies
HPTN 056 Study Design
Screening
Week - 2 0 + 2 + 4
Baseline Week 2 Week 4
ConsentPhysicalAnoscopyRectal GC/CHHIV AbCD4 / Viral load
SigmoidoscopyIntestinal biopsy at 10cm and 30cmCell isolation and flow cytometryTissue cytokinesRectal immunoglobulinsTissue / rectal secretion viral load
Key Findings from HPTN-056
High adherence rates are possible in studies with mucosal samplingStability of safety assays variable
Good: T cell phenotype, cytokine mRNAPoor: Quantitative histology
Modest differences between samples collected at 10 and 30 cm
McGowan I JAIDS 2007 (In Press)
Rectal Safety StudiesProducts N Safety Assessment Reference
N-9 (3.5%) 35 AnoscopyRectal biopsy & qualitative histology (+12 hrs)
Tabet et al. 1999
N-9 (1% &2%), Carraguard, methycelluloseN-9 (2%)
4 Qualitative lavageElectron microscopy
Phillips et al. 2000
18 Histology (BL, +2hrs, +8hrs)Lavage (+15min, +>8hrs)
Phillips et al. 2004
UC-781 Phase 1 Rectal Safety Study
Primary objective:To evaluate the safety and acceptability of 0.1% and 0.25% UC-781 vaginal microbicide gel versus placebo when applied rectally
Endpoints:Frequency of ≥Grade 2 adverse eventsAcceptability
Design of UC-781 Phase 1 Rectal Safety Study
Three arms (Men and women with history of RAI)
0.1% UC-781 (N = 12)0.25% UC-781(N = 12)Placebo (N = 12)
Single dose followed by 7 days of study drug
UC-781 Phase 1 Rectal Safety Study
Secondary Objective:To determine whether use of study product is associated with rectal mucosal damage
Endpoints:Epithelial sloughingHistopathologyMucosal mononuclear cell phenotypeMucosal cytokine mRNAMucosal immunoglobulinsFecal calprotectinExplants- Mucosal cytokine mRNA and susceptibility to HIV infection
UC-781 Trial Design
Screening Enrollment Randomization
0.1%
0.25%
Placebo
Baseline Endoscopy
Single dose 2nd
Endoscopy7 singleDoses
3rd
Endoscopy
Phase 1RM Safety StudiesProduct Status Timeline Sponsor
UC-781 Ongoing NIAID/DAIDS
Polyanion Planned Q3 2007 NIAID/DMID
PRO-2000 Planned Q1 2008 MDP MRC-UK
UC-781(Rectal formulation)
Possible Q4 2010 TBD
Development of Rectal-Specific Microbicides
Is There a Need?High prevalence of unprotected RAI among heterosexual and MSM populationMSM still most affected demographic in Western Europe and the Americas88% of MSM use lubricants for RAI*26% are still using N-9 products*
*Carballo-Dieguez et al. AIDS Behav 2007
Rectal Macaque PMPA Data
PMPA 2 hours after virus challengeD15, D18, D293E
PMPA 2 hours prior to virus challengeD14, D56, D693D
No treatmentD77, D83, E73, E81
4C
Placebo 15 minutes prior to virus challengeC57, D26, D9, D68
4B
PMPA 15 min prior to virus challengeD3, D30, D37, D39, D43, D79
6A
TreatmentAnimal No.No.Group
PMPA 2 hours after virus challengeD15, D18, D293E
PMPA 2 hours prior to virus challengeD14, D56, D693D
No treatmentD77, D83, E73, E81
4C
Placebo 15 minutes prior to virus challengeC57, D26, D9, D68
4B
PMPA 15 min prior to virus challengeD3, D30, D37, D39, D43, D79
6A
TreatmentAnimal No.No.Group
-2 0 1 2 6 12 16 20week-2 0 1 2 6 12 16 20week
+/- Tx: SIVmac32H 20 MID50 i.r.
PBMC (VI & PCR); Plasma (vRNA); Serum (anti-SIV antibodies)
necropsy
PK
Cranage et al. CROI 2007
Rectal Macaque PMPA Data
---------------------D79
+--+--+--+++-++------D43
---------------------D39
---------------------D37
---------------------D30
+++++++++++++++------D3
PFVPFVPFVPFVPFVPFVPFV
Week 20
Week 16
Week 12
Week 6
Week 2
Week 1
Week 0
---------------------D79
+--+--+--+++-++------D43
---------------------D39
---------------------D37
---------------------D30
+++++++++++++++------D3
PFVPFVPFVPFVPFVPFVPFV
Week 20
Week 16
Week 12
Week 6
Week 2
Week 1
Week 0
Rectal Macaque PMPA Data
C57
Tim e (w eeks)
0 5 10 15 20
vRN
A e
quiv
alen
ts /
ml p
lasm
a
102
103
104
105
106
107
108
100
101
102
103
104
105
D26
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
100
101
102
103
104
105
D9
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
100
101
102
103
104
105
D68
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
prov
iral D
NA
copi
es /
105
PBM
C
100
101
102
103
104
105
D3
Tim e (w eeks)
0 5 10 15 20
vRN
A eq
uiva
lent
s / m
l pla
sma
102
103
104
105
106
107
108
100
101
102
103
104
105
D30
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
100
101
102
103
104
105
D37
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
100
101
102
103
104
105
D39
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
100
101
102
103
104
105
D43
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
100
101
102
103
104
105
D79
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
prov
iral D
NA
copi
es /
105
PBM
C
100
101
102
103
104
105
D15
Tim e (w eeks)
0 5 10 15 20
vRN
A eq
uiva
lent
s / m
l pla
sma
102
103
104
105
106
107
108
100
101
102
103
104
105
D29
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
prov
iral D
NA
copi
es /
105 P
BM
C
100
101
102
103
104
105
D18
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
100
101
102
103
104
105
D14
Tim e (w eeks)
0 5 10 15 20
vRN
A e
quiv
alen
ts /
ml p
lasm
a
102
103
104
105
106
107
108
100
101
102
103
104
105
D69
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
prov
iral D
NA
cop
ies
/ 105 P
BM
C
100
101
102
103
104
105
D56
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
100
101
102
103
104
105
D77
Tim e (w eeks)
0 5 10 15 20
vRN
A eq
uiva
lent
s / m
l pla
sma
102
103
104
105
106
107
108
100
101
102
103
104
105
E73
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
100
101
102
103
104
105
D83
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
100
101
102
103
104
105
E81
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
prov
iral D
NA
copi
es /
105 P
BM
C
100
101
102
103
104
105
C57
Tim e (w eeks)
0 5 10 15 20
vRN
A e
quiv
alen
ts /
ml p
lasm
a
102
103
104
105
106
107
108
100
101
102
103
104
105
D26
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
100
101
102
103
104
105
D9
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
100
101
102
103
104
105
D68
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
prov
iral D
NA
copi
es /
105
PBM
C
100
101
102
103
104
105
D3
Tim e (w eeks)
0 5 10 15 20
vRN
A eq
uiva
lent
s / m
l pla
sma
102
103
104
105
106
107
108
100
101
102
103
104
105
D 30
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
10 8
100
101
102
103
104
105
D37
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
100
101
102
103
104
105
D 39
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
100
101
102
103
1 04
105
D43
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
100
101
102
103
104
105
D 79
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
prov
iral D
NA
copi
es /
105
PBM
C
100
101
102
103
104
105
D15
Tim e (w eeks)
0 5 10 15 20
vRN
A eq
uiva
lent
s / m
l pla
sma
102
103
104
105
106
107
108
100
101
102
103
104
105
D29
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
prov
iral D
NA
copi
es /
105 P
BM
C
100
101
102
103
104
105
D18
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
100
101
102
103
104
105
D14
Tim e (w eeks)
0 5 10 15 20
vRN
A e
quiv
alen
ts /
ml p
lasm
a
102
103
104
105
106
107
108
100
101
102
103
104
105
D69
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
prov
iral D
NA
cop
ies
/ 105 P
BM
C
100
101
102
103
104
105
D56
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
100
101
102
103
104
105
D77
Tim e (w eeks)
0 5 10 15 20
vRN
A eq
uiva
lent
s / m
l pla
sma
102
103
104
105
106
107
108
100
101
102
103
104
105
E73
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
100
101
102
103
104
105
D83
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
100
101
102
103
104
105
E81
Tim e (w eeks)
0 5 10 15 20
102
103
104
105
106
107
108
prov
iral D
NA
copi
es /
105 P
BM
C
100
101
102
103
104
105
No Rx
Placebo-15 m in
PMPA-15 m in
PMPA-2 hrs
PMPA+ 2 Hrs
• Proviral DNA• Viral RNA
Where to Protect and What to Measure?
Hendrix et al., 2004
Colonic Distribution of Microbicides
0.00
0.01
0.02
0.03
0.04
0.05
0.06
05
10
15
20-15 -10 -5 0 5 10 15 20
AUC
adj
uste
d "C
once
ntra
tion"
Hours
after
Dosing
Centimeters from Point Source
Tc-SC (HIV Surrogate)
0.00
0.01
0.02
0.03
0.04
0.05
0.06
05
10
15
20-20 -15 -10 -5 0 5 10 15 20
AUC
adj
uste
d "C
once
ntra
tion"
Hour
s af
ter D
osin
g
Centimeters from Point Source
In-DTPA (Microbicide ARV Surrogate)Tc-SC (HIV Surrogate) In-DTPA Microbicide ARV Surrogate
Hendrix et al. Microbicides 2006
Direct Endoscopic Sampling
99mTc-DTPA Concentration / Initial Concentration
0.00 0.05 0.10 0.15 0.20 0.25
Dis
tanc
e fro
m A
nus
(cm
)
0
10
20
30
40
50
60
70
S004 BrushS003 Brush
Cytology brush (20 ml) @ 4 HRSPECT/CT S004 @ 4 HR
Hendrix et al. Microbicides 2006
Applicator Design
Courtesy of Dr. Alex Carballo-Dieguez/amfAR
Update on Rectal Microbicide Advocacy
International Rectal Microbicide Working Group (IRMWG)
Founded in Spring 2005Current membership 360 advocates from 35 countries on 5 continents
http://www.irmwg.org/
http://www.irmwg.org/
Conclusions
ConclusionsVaginal microbicides being considered for effectiveness studies should be evaluated for rectal safetyPhase 1 rectal safety studies have begun and will increase in numberDesign methodology is still in evolution but moving towards simplified studiesRectal microbicide advocacy is increasing and will include demands for rectal safety and effectiveness
Bargello Museum, Florence, Italy
Acknowledgements
NIH/NIAID/DAIDS IPCP ProgramNIH/NIAID/DMIDamfARGilead SciencesCONRADInternational Partnership for MicrobicidesUCLA CPR
