Transcript Document

Drug Penetration into the Genital Tract:
Implications for Sexual Transmission
Dr Steve Taylor, FRCP, PhD
Consultant Physician
Sexual Health HIV Medicine
Lead Consultant HIV Service
Directorate of Infection
Disclaimer: Dr Taylor has received educational and/or travel
grants, speaker engagements and/or advisory meetings with
the following pharmaceutical companies: Abbott,
Boehringer, BMS, GSK, Gilead, Jansen, Merck, Roche, ViiV,
ww.sexualhealthbirmingham.co.uk
Presentations
Personalised Clinic Posters Available
Advocates required please
Genital Drug penetrations ,
does it matterrs... or what ?
Yea , but no , but yea but, no but...
Definitely ..Maybe ...
• Does it matter on a population
level
• Probably not
• Does it matter on an individual
level ?
• Maybe it does...
• What do we know re the
pharmacology of ARV’s in the
male and female genital tract?
• Explore some implications :
• MICROBICIDES
• PEPSE
• PREP
Variable Genital Tract penetration of ART:
Implications
STI’s and Local Immune
Activation/ Response
Biological / anatomical / physiological barriers
TRAFFIC
Cell associated DNA
Cell Free RNA
Drug 1
R
Genital compartment
S Taylor EACS Warsaw
Target Cells
Drug 1
Drug 2 Drug 3
Blood Compartment
Genital Tract penetration of ART
• Best case scenario
• Worst case scenario
• Differential drug penetration
does not matter
• No compartmental effect
• Undetectable in plasma =
undetectable in genital tract
• Under ART STI’s have no
effect on viral shedding
• Differential penetration & activity
• of ART in different body
compartments
• Under ART the Sexual
Transmission of HIV does
not occur
• STI’s enhance genital tract
replication & facilitate transmission
S. Taylor EACS Warsaw
• Marked compartmental effect
• Ongoing GT replication despite
undetectable plasma viral load
• +/- Selection of drug resistant HIV
• Under ART Sexual Transmission
can still occur
There are a lot of parallels
with the brain and genital
tract and the questions raised
regarding drug penetration
Lipid Solubility
(partition cœfficient)
Protein
Binding
Dissociation
constant (pKa)
Membrane
Penetration
Free Drug
Diffusion gradient
Weak acids
become ionised
 pH
Trapping in alkaline
compartments
Trapping in acidic
compartments
Weak bases
become
ionised pH
Journal of Sexually Transmitted Infections 2001; 77:4-11 + AAC 1999
Size
A
C
T
I
V
E
Prostate pH 6.6
,
Genital tract drug level monitoring:
an evolution in compartmental
pharmacokinetics
•
•
•
•
•
•
•
•
•
•
•
Does the drug get there?
The time matched measurements
The GT/ BP ratio
Time specific GT/BP ratio
The GT/ BP AUC !
Ratios vs Absolute concentrations
Seminal Protein Binding
The split ejaculate !
Endocervical sampling
Cervicovaginal fluid sampling
Vaginal and Rectal Tissue sampling !
Recognition that different
patterns of penetration existed
• The men came first !
• Different patterns of drug distribution
between classes of ART
• Also differences within classes
• Differences between the same drugs
between men and women!
Pattern 1: NNRTIs 10% -70%
Plasma
Genital tract
Taylor et al, AIDS 00,01, Reddy et al JID 02
Nevirapine (NVP) concentration in blood plasma
and semen plasma in 12 patients
10
9
8
7
6
NVP
concentration5
in ug/ml
4
MEC 3000 ng/ml
3
2
1
Pc EC50 40 ng/ml
0
0
2
4
6
n=12
8
AIDS 2000, 14:1979-1984 Time post drugs (h)
10
12
Nevirapine (NVP) drug concentration time curve
for BP and SP in a single patient allows construction
of a SP/BP AUC ratio
6
5
4
NVP
concentration3
in ug/ml
2
MEC 3400 ng/ml
1
Pc EC50 40 ng/ml
0
0
2
4
6
8
Time post drugs (h)
AIDS 2000, 14:1979-1984
10
12
Efavirenz concentrations in blood plasma and
seminal plasma at specific times post drug ingestion
100 000
BP
SP
10 000
MEC 1000 ng/ml
EFV
1 000
concentration
in ng/ml
(log scale)
100
92.8 ng/ml plasma
protein corrected EC90
10
4.42 ng/ml
1
0
AIDS 2001;15:2051-2053
5
10
15
20
Time post drug ingestion (h)
25
30
n=19
The Masturbatorium at Birmingham Heartlands
Pattern 2: NRTIs 100%-500%
Plasma
Genital tract
Henry et al 88, Pereira et al 99 , Taylor et al 00, Anderson et al, 00, van Praag
et al , Luizzi et al 00, Gatti et al 01, Kashuba 02
Lamivudine (3TC) concentration in blood plasma
and semen plasma in 8 patients
9000
3TC concentration ng/ml
8000
7000
6000
5000
4000
3000
2000
1000
0
0
2
AIDS 2000, 14:1979-1984
4
6
8
Time post drugs (h)
10
12
Protease Inhibitors
Pattern 4:
Pattern 3:
PI’s 20%-200%
PI’s <5%
NFV=SQV< RTV<LPV
IDV +RTV > IDV >> APV
Lafeuillade et al 02, Sankatsing 02, Taylor 99,01, Solas 03, Van Praag 00, 01, Pereira 02
Poor penetration of HIV-1 protease inhibitors into
the semen of HIV 1 positive men
10
IDV
SP:BP Ratio
(log scale)
1
0.1
SQV
RTV
0.01
0.001
0
2
4
6
8
Time post drug ingestion
Taylor et al AIDS 1999: JAC 2001; 48, 351-354
10
12
Semen (SP) vs Blood (BP) Darunavir Concentrations in 18 HIV +ve
Men & SP AUC0-24h vs BP AUC0-24h
10000
Time post Drug
Ingestion
1-3h
4-6h
22-24h
Median BP
5579
3734
2445
DRV concentrations (ng/ml)
[DRV]
(4639-7505) (2935-4586) (1365-3167)
IQR
ng/ml
1000
588
490
217
(509-778)
(479-640)
(172-261)
Median
0.11
0.13
0.11
SP:BP ratio
(0.09-0.15)
(0.07-0.18)
(0.09-0.15)
IQR
n=8
n=13
n=14
Median multiple
above
11 fold
9 fold
4 fold
(6-45)
(3-21)
(2-16)
Median SP
RES PC EC50 550 ng/ml
[DRV]
100
IQR
WT PC EC50 55g/ml
10
0
5
10
15
20
TIME POST DOSE (h)
25
30
n=18
PC EC 50 for WT
virus 55ng/ml
SP:BP DRV AUC
Jayasuryia , Taylor, Dufty et al AIDS 2010
0-24h
ratio = 0.17 (0.07-0.19)
Men
Women
600%
500%
Higher
Genital
Tract
Exposures
Semen:BP
Single time point
Ratios
SP /BP
AUC
RATIOS
400%
CVF:BP
CVF :BP
300%
AUC
RATIOS
Single time point
Ratios
200%
Equivalent
Blood and
Genital
Tract
Exposures
Lower
Genital
Tract
Exposures
100%
80%
60%
40%
20%
0%
Figure adapted from Taylor and Davies 2010 Current Opinion in HIV &AIDS and Cohen and Kashuba
TVFdp >1000%h
3TC 667% g
RAL 642%
600%
ABC 560% d
Semen/BP ratios
paired samples
Higher
Genital
Tract
Exposures
TVF 510% h
Semen/BP AUC
ratios
400%
d4T 350% v
Men
RAL 160%
Equivalent
Blood and
Genital
Tract
Exposures
IDV 140% p
RAL 142% m
TVF 330% i
500%
ZDV 330% g
ZDV 228% y
300%
200%
ABC 150% z
IDV 100% z
3TCtp 100% g
100%
80%
MVC 72%
MVC 71%
NVP 61% v
Lower
Genital
Tract
Exposures
60%
40%
ZDVtp 33% g
APV 20% cc
ENF ND s
MVC 62%
*DRV 12%
DLV 16% x
*DRV 9%
ATV 10% k
LPV 6% q
NFV 7% r
RTV 7% j
LPV 5 % j
SQV 3% p
RTV 3% q
LPV 2-3% t
d4T 2% v
RTV ND p
SQV ND d
LPV ND u
EFV ND i
*DRV 17%
20%
EFV 9% w
Figure adapted from Taylor and Davies 2010 Current Opinion in HIV &AIDS
EFV 3.3% s
0%
ddI 992% b
Women
ZDV 590% b
600%
500%
400%
GT/BP AUC
ratios
3TC 411% c
300%
GT/BP ratios
paired samples
IDV/r 380% aa
3TC 319% b
RAL 230 %
ZDV 235% c
ZDV 190% o
MVC 190% a*
ETR 130% n
100%
3TC 460% o
FTC 395% c
MVC 273% a
200%
TVF 515% b
DRV 150% n
TVF* 110% c
RAL 93% f
FTC 150% b
IDV/r 132% aa
IDV 145% bb
ddI 114% b*
NVP 130% bb
RTV 81% b
NVP 80% bb
TVF 90% o
80%
TVF 75% c
IDV 70% bb*
60%
ABC 58% b
NFV 54% o
APV 50% bb
RTV 54% o
40%
LPV 30% b
RTV 26% c
20%
ddI 21% c
ABC 8% c
d4T 5% c
0%
DLV 20% bb
RTV 19 b
LPV 3% b
LPV 5% bb
DLV 5% bb
SQV bb
EFV 1% b
RTV 3% b
ATV 18% c
LPV 8% c
EFV 0.4% c
LPV 12% b
Figure adapted from Taylor and Davies 2010 Current Opinion in HIV &AIDS
ddI 992% b
TVFdp >1000%h
MVC 2800 %Rectal
*
Tissue
RAL 642%
Semen/BP
ratios
paired
samples
Semen/
BP AUC
ratios
TVF 330% i
Tissue
ZDV 330% g
ZDV 228% y
GT/BP AUC
ratios
500%
400%
d4T 350% v
Men
MVC 200% *Vaginal
Equivalent
Blood and
Genital
Tract
Exposures
TVF 510% h
ZDV 590% b
600%
ABC 560% d
Higher
Genital
Tract
Exposures
Women
3TC 667% g
3TCtp 100% g
RAL 230 %
ZDV 235% c
MVC 190% a*
ZDV 190% o
FTC 150% b
ETR 130% n
DRV 150% n
IDV
IDV/r 132%
aa145% bb
TVF* 110% c
ddI 114%NVP
b* 130% bb
RAL 160%
IDV 100% z
100%
3TC 319% b
MVC 273% a
200%
RAL 93% f
TVF 90% o
80%
MVC 72%
RTV 81% b NVP 80% bb
TVF 75% c
MVC 71%
NVP 61% v
Lower
Genital
Tract
Exposures
MVC 62%
IDV 70% bb*
60%
ABC 58% b
NFV 54% o
RTV 54% o
APV 50% bb
40%
ZDVtp 33% g
LPV 30% b
RTV 26% c
APV 20% cc
ENF ND s
TVF 515% b
3TC 460% o
IDV/r 380% aa
3TC 411% c FTC 395% c
300%
ABC 150% z
RAL 142% m
IDV 140% p
GT/BP ratios
paired
samples
*DRV 12%
DLV 16% x
*DRV 9%
ATV 10% k
LPV 6% q
NFV 7% r
SQV 3% p
RTV 3% q LPV 2-3% t d4T 2% v
RTV ND p
SQV ND d
RTV 7% j
LPV ND u
*DRV 17%
20%
ddI 21% c
DLV 20% bb RTV 19 b
ATV 18% c
EFV 9% w
LPV 5 % j
EFV ND i
ABC 8% c
EFV 3.3% s
d4T 5% c
0%
Figure adapted from Taylor and Davies 2010 Current Opinion in HIV &AIDS
LPV 8% c
LPV 12% b
LPV 3% b
EFV 0.4% c
SQV bb
LPV 5% bb DLV 5% bb
EFV 1% b
RTV 3% b
HIV-1 Prevention Opportunities
UNEXPOSED
EXPOSED
EXPOSED
(precoital/coital)
(postcoital)
INFECTED
Vaccines
ART PrEP
Behavioral,
Structural
Microbicides
RX STIs
RX STIs
Vaccines
ART
PEPSE
Treatment of HIV
Reduced Infectivity
RX STIs
Circumcision/ Condoms
YEARS
HOURS
72 HRS
Slide courtesy of Myron Cohen et al. JCI 2008; Cohen. IAS Journal online 2008
YEARS
HIV-1 Prevention Opportunities
and Genital Tract Penetration…
UNEXPOSED
EXPOSED
EXPOSED
(precoital/coital)
(postcoital)
Vaccines
Vaccines
INFECTED
Microbicides
Behavioral,
Structural
RX STIs
ART PrEP
PEPSE
Treatment of HIV
Reduced Infectivity
RX STIs
RX STIs
Circumcision/ Condoms
YEARS
HOURS
Cohen et al. JCI 2008; Cohen. IAS Journal online 2008
72 HRS
YEARS
Does Drug
penetration
matter
?
Single use microbicides
Vaginal/Rectal Microbicides
Slide courtesy of Charles Lacey and Jonathon Weber
MRI scan with gadollinium-labelled D2S
Slide courtesy of Charles Lacey and Jonathon Weber
30 mins
MICROBICIDES
1st generation
VIRUS
Disable the
2nd generation
Block
Cellular
Entry
•Pro 2000
•N-9
•Dextrin Sulphate
•CAP
•Carageenin
•SAVVY
•Cellulose sulphate
•Buffergel
Post-entry
3rd generation
Block
Cellular
Entry
(with ARVs)
•PMPA
•UC 781
•TMC 120
•TDF 1% Gel
st
1
•
•
•
•
Generation Microbicides:
eg nonoxynol-9 (N-9), SAVVY
Detergents – dissolve lipid membranes
No specificity
Active in vitro and in vivo, but NEGATIVE in large human
trials (eg, COL 1492), SAVVY trial discontinued
Normal vagina
Slide courtesy of Charles Lacey and Jonathon Weber
Effect of N-9
2nd generation microbicides:
• PRO 2000
• Discontinued, No difference
• Cellulose sulphate
• Discontinued, increased HIV in active group
• Dextrin sulphate
• Discontinued, no funding
CAPRISA 004: 1% Tenofovir Microbicide
Gel for Prevention of HIV in Women
• Randomized, placebo-controlled, double-blind, proof-of-concept study
conducted at 2 sites in South Africa
HIV-uninfected women,
at high risk of HIV,
≥ 2 vaginal sex acts within
30 days of screening
(N = 889)*
1% Tenofovir Gel†
(n = 445)
Placebo Gel†
(n = 444)
Abdool Karim Q, et al. Science DOI: 10.1126/science.1193748.
Abdool Karim Q, et al. AIDS 2010. Abstract TUSS0202.
Study
continued
until 92
HIV
infections
observed
Tenofovir Gel Effective in
Preventing HIV Acquisition
# HIV infections
Women-years (# women)
HIV incidence
(per 100 women-years)
Tenofovir
Placebo
38
60
680.6 (445)
660.7 (444)
5.6
9.1
Incidence rate ratio: 0.61 (CI: 0.4 to 0.94); p = 0.017
39% lower HIV incidence in tenofovir gel
group
Tenofovir Gel More Effective
with Higher Adherence
HIV incidence
# HIV
N
High adherers
(>80% gel adherence)
36
Intermediate adherers
(50-80% adherence)
Low adherers
(<50% gel adherence)
Effect
TFV
Placebo
336
4.2
9.3
54%
20
181
6.3
10.0
38%
41
367
6.2
8.6
28%
Infected On Treatment Fluid
Based on CVF
Concentration
TNF Percent
Cervicovaginal
Concentrations
(Werner 1 Versus Werner 2A)
Correlate with HIV Infection
100
BLD
infected
PercentINFECTED
PERCENT
80
BLQ
84
75
60
50
57
50
40
33
20
20
0
0
10-2
10-1
100
Total # women
19
8
Number infected
16
6
101
102
103
104
105
CVF Concentration
(ng/mL)
6
7
2
5
3
4
1
CVF Concentration
(ng/mL)
1
106
107
6
1
2
0
108
Source: Kashuba (2010)
New Antiretroviral Topical Microbicides
Compound
Mechanism
Developers/
Sponsers
Status
Dapivirine
NNRTI
Tibotec/IPM
Phase I/II (gel,
ring)
UC-781
NNRTI
Conrad/NIH/
MTN
Phase I/II
MIV-150
NNRTI
Population
Council
Phase I
BMS-793
gp 120 blocker
BMS/IPM
Pre-Clinical
L644 Peptide
gp 41 blocker
Merck/IPM
Pre-Clinical
Maraviroc
CCR5 blocker
Pfizer/IPM
Pre-Clinical
M167, M872,
M882
CCR5 blocker
Merck, IPM
Pre-Clinical
Slide courtesy of Kenneth Mayer, M.D. CROI 2010
Development of stable slow released products
1. Vaginal rings: Sustained delivery, one to three month dosing
2. Depot injection: TMC278, One to thee month dosing
Slide courtesy of Charles Lacey and Jonathon Weber
Dapivirine Ring: Potent NNRTI
Attractive Technology
•30+ days of drug delivery
•Easy to use and “low”
cost
•Drug combinations
feasible
•Biodegradable/novel rings
Slide Courtesy of Robin Shattock
Does genital tract penetration matter ?
THE IDEAL DRUGS for PEPSE...
• Non toxic
• Achieves high levels in genital tissues
tissues quickly after a single dose
• Rectum, Vagina, Tonsils
• Is active against sexually transmitted
variants (R5)
• Is unlikely to cause resistance in the
recipient if found to be HIV positive
Oral PREP agents must effectively
penetrate vaginal or rectal tissue
1% gadolinium 1:100 in a sterile system with Dextrin sulphate gel, 2hrs post application (C. Lacey, Imperial College)
Post exposure prophylaxis must be initiated within
24-36 hours of exposure, 48 hours may be too late.
NSI HIV (M-tropic)
SI HIV (T-tropic)
Semen
HIV-1
“swarm”
Lamina propria
Dendritic cell
CD4+
CCR5+
DC-SIGN+
CD4
DC-SIGN
Migration
to lymphoid organs
Geijtenbeek TBH, et al. Cell 2000;100:587-597
CCR5
T-cell
Transmitted HIV:99% R5,
82% 1 variant
Maraviroc
as PrEP?
Day 7-10 Mean/SD
Profile
Maraviroc Concentration (ng/mL)
1000
CVF/BP MVC 200 -400 %
Plasma
CVF
Cervicovaginal Fluid
Vaginal Tissue
100
VT/ MVC 200 %
10
Blood Plasma
1
0
N = 12
12
24
36
Time (hr)
N=12
Dumond et al. CROI 2008
48
72
Protein-free
IC60
90 = 0.5 ng/ml
Angela Kashuba et al. UNC
Bob Coombs et al. Seattle
Charles Hendrix et al. Boston
Developed a New Sport Science
“Extreme Sampling”
PRE EXPOSURE PROPHYLAXIS (PREP)
Does genital tract drug penetration matter ?
Slide courtesy of Robin Shattock
PREP: Does drug penetration matter ?
• Safety profile - use for years in healthy individuals
• Ease of use (once daily, weekly, intermittent, missed
dose)
• Good drug penetration - at the viral portals of entry
(rectum and genital tract)
• High effectiveness - in real world situations
• High barrier for resistance (requirement for multiple
mutations to cause virologic failure)
• Limited impact on therapy (low or no level of cross
resistance).
• Cost effective and accessible
Derdelinckx et al PLosMedicine 2006
FDA-Approved Drugs for HIV Therapy: 2010
Nucleos(t)ide Reverse Transcriptase
Inhibitors (NRTIs)
Abacavir (ABC)
Didanosine (ddI)
Emtricitabine (FTC)*
Lamivudine (3TC)*
Stavudine (d4T)
Tenofovir (TDF)*
Zalcitabine (ddC)
Zidovudine (ZDV)
3TC/ABC
3TC/ABC/ZDV
3TC/ZDV
FTC/TDF*
Nonnucleoside RTIs (NNRTIs)
Delavirdine (DLV)
Efavirenz (EFV)
Nevirapine (NVP)
Amprenavir (APV)
Atazanavir (ATV)
Darunavir (DRV)
Fosamprenavir (FPV)
Indinavir (IDV)
Lopinavir/ritonavir (LPV/r)
Nelfinavir (NFV)
Ritonavir (RTV)
Saquinavir (SQVhgc)
Tipranavir (TPV)
Fusion Inhibitors (FIs)
Enfuvirtide (ENF)
Multiple Class Agents
EFV/FTC/TDF
Integrase Inhibitors
Raltegravir
Protease Inhibitors (PIs)
Chemokine Receptor 5 (CCR5)
Inhibitors
Maraviroc*
Yellow* = Current PREP Candidates
Protection of Rhesus Macaques from Vaginal
Infection by Maraviroc, an Inhibitor of HIV-1
Entry via the CCR5 Co-receptor
Veazey1, T Ketas2, J Dufour1, P Klasse2, and John Moore*2
•Results: Gel-formulated MVC derived from prescription-grade
tablets provided dose-dependent protection,
• The duration of protection was transient; the longer the delay
between MVC application and virus challenge, the less protection
(T1/2 ~ 4 h).
•Conclusions: Of note is that a single 300 mg tablet of
prescription-grade MVC, which retails for ~$15 in the USA,
contains enough active drug to fully protect about 25 macaques
CROI Paper # 84LB
PrEP in Macaques
% Uninfected Animals
100
High-Dose Injectable Truvada (n = 6)
75
Oral Truvada (n = 6)
50
Injectable FTC (n = 6)
Oral TDF (n = 4)
25
Controls (n = 18)
0
0
2
4
6
8 10 12 14
Number of Rectal Exposures
Garcia-Lerma et al. PLoS Med 2008
Repeat exposure macaque model of rectal
SHIV transmission
• More closely mimics human HIV exposures
• Low doses of an R5 tropic SHIV162p3 isolate
• Virus exposures repeated weekly to better
assess the robustness of the intervention
• Possibility to evaluate iPrEP efficacy under
highly controlled conditions
Slides courtesy of Gerardo Garcia-Lerma*1 CROI 2010 Paper # 83
Otten et al., JID 2005
Efficacy of intermittent PrEP with Truvada in the
repeat low-dose macaque model: design
Slides courtesy of Gerardo Garcia-Lerma*1 CROI 2010 Paper # 83
Risk reduction by iPrEP with oral Truvada
% Uninfected macaques
6 groups challenged with physiologic inoculum of R5 virus (10 TCID50)
2 doses of TDF/FTC given before (-) or after (+) challenge
100
-22h/+2h
-3 days/+2h
-7 days/+2h
HR = 16.7, p = 0.006
HR = 15.4, p = 0.008
HR = 9.3, p = 0.003
+2h/+26h (PEP)
-2h/+22h
HR = 4, p = 0.03
HR = 4.1, p = 0.02
75
50
25
Untreated controls (n=32)
0
0
2
4
6
8
10
12
14
(9 real time and 23 historical)
Number of rectal exposures
Extended window of protection associated with long IC
No drug resistance on macaques failing PrEP/PEP
Slides courtesy of Gerardo Garcia-Lerma*1 CROI 2010 Paper # 83
* Sci
Transl Med 2010;2:14ra4
TRUVADA
i PrEP
Demonstrated efficacy of several iPrEP dosing
strategies with Truvada with a wide window of
protection
Favorable pharmacokinetic profiles for FTC and
TFV likely complement and maximize PrEP efficacy
Rapid detection of FTC in secretions. Peak levels at 24h
TFV only seen at 24h in secretions
•
High TFV concentrations at 24h associated with high
intracellular TFV-DP and long TFV-DP persistence in
tissue
Slides courtesy of Gerardo Garcia-Lerma*1 CROI 2010 Paper # 83
Can single pre-exposure dosing with long-acting
drugs be sufficient for protection?
- Arm 1. Truvada (n = 6): One dose given 3d before virus
exposure
- Arm 2. Untreated controls (n = 6)
- Arm 3. GS7340 (n = 6): Tenofovir prodrug with desirable
characteristics for PrEP
• Potent (-1.6 log10 decline in plasma RNA)
• Higher TFV-DP concentrations in PBMCs compared to oral
TDF dosing
• Macaque PrEP dose: One single dose given orally 3d
before virus exposure (13.7 mg/kg or 2/3 of the TDF dose)
Slides courtesy of Gerardo Garcia-Lerma*1 CROI 2010 Paper # 83
Lee WA, AAC 2005
Lack of protection by a single pre-exposure dose
(-3 days) of Truvada or GS7340
100
Percent survival
Oral Truvada (-3d/+2h)
75
50
Oral Truvada (-3d/no post)
Oral GS7340 (-3d no post )
Controls (n=32)
25
0
0
2
4
6
8
Exposure
10
12
14
Slides courtesy of Gerardo Garcia-Lerma*1 CROI 2010 Paper # 83
Local and systemic TFV and TFV-DP levels in
macaques after a single GS7340 dose
Blood
Oral GS7340
1000
100
~100-fold higher
10
1
Oral TDF
24h 3d 5d 7d
Time
12d
Oral TDF
Oral GS7340
Rectal
secretions
100000
TFV (ug/ml)
TFV-DP (fmols/106 cells
10000
10000
1000
100
10
0
Slides courtesy of Gerardo Garcia-Lerma*1 CROI 2010 Paper # 83
2
Time
5
24
Conclusions
• Combined with a post-exposure dose, iPrEP with
Truvada was highly protective
• A single -3d pre-exposure dose with Truvada or longacting GS7340 was not sufficient despite long
intracellular drug half-lives
• Rapid FTC penetration in tissues suggests that FTC
plays an important role in the protection contributed by
the PEP dose with Truvada
Slides courtesy of Gerardo Garcia-Lerma*1 CROI 2010 Paper # 83
PrEP Clinical Trials: 2010
Study Name
Location
Funder Population
(Slide courtesy of Ken Mayer CROI 2010)
Intervention
Results
Available
2010
CDC 4940
Botswana
CDC
1,200 Het. Daily Oral TDF,
Men &
TDF/FTC
Women
CDC 4323
USA
CDC
400 MSM
Daily Oral TDF
2010
CDC 4370
Thailand
CDC
2400 IDU
Daily Oral TDF
2010
CAPRISA 004
South Africa
IPREX
Peru, Ecuador,
Brazil, USA,
Thailand,
South Africa
USAID
900
women
Pre/Post Coital
1% TFV Gel
3,000 MSM Daily Oral
TDF/FTC
2010
NIH,
BMGF
2010
PrEP Efficacy Trials: Beyond 2010
Study Name
Location
Partners PREP
Kenya, Uganda
Funder
BMGF
Population
Intervention
Results
Available
3,900 Het.
Discord.
Couples
Daily Oral TDF 2012
FEM PREP
USAID,
BMGF
Kenya, Malawi,
South Africa,
Tanzania, Zambia
3,900
Women
Daily Oral TDF 2012
Voice
South Africa,
Uganda, Zambia,
Zimbabwe
5,000
Women
Daily Oral TDF, 2013
TDF/FTC, and
Tenofovir Gel
MTN/
NIH
(Slide courtesy of Ken Mayer CROI 2010)
HIV-1 Prevention Opportunities
UNEXPOSED
EXPOSED
EXPOSED
(precoital/coital)
(postcoital)
Vaccines
Vaccines
ART PrEP
PEPSE
Behavioral,
Structural
Microbicides
RX STIs
RX STIs
INFECTED
Treatment of HIV
Reduced Infectivity
RX STIs
Circumcision/ Condoms
YEARS
HOURS
Cohen et al. JCI 2008; Cohen. IAS Journal online 2008
72 HRS
YEARS
4 Drugs, Decay Dynamics in Semen
8
2 phases of decay:
T 1/2 1st phase 1.1 days
T 1/2 2nd phase 12 days
plasma
7
semen
log10 viral load
6
model
5
4
3
A = viral load at initiation of 1st phase decline
(pt 1 blood and semen: pt 2 blood)
B = viral load at initiation of 2nd phase decline
(pt 1 blood and semen)
C = viral load at initiation of 1st phase decline (pt 2 semen)
2
a = 1st phase decay (log/day)
b = 2nd phase decay (log/day)
1
0
0
10
20
30
Time (days)
AIDS 2001; 15(3):424-6
40
50
Semen HIV With ART
% Patients With Detectable
HIV in Semen
100
Controls (drug naive)
n = 55
Potent ART
n = 114
p < 0.0001
80
p = 0.025
60
40
20
0
HIV RNA
Vernazza, Cohen et al. AIDS 2000
HIV DNA
STI’s and Seminal Super
Shedders
Plasma
STI’s
Genital Tract
Taylor et al 00, Hart et al 02, Eron et al 00, Tachet et al 00 ,
Pilcher et al 01, Gupta et al 97, De Pasquale et al 99
“Seminal Super Shedders”
Patient
BPVL
•
•
•
•
•
GL
AS
PH
MJ
JB
1,600,000
92,000
200,000
18,000
54,000
•
•
•
•
MG
KH
MH
LF
69,000
13,000
540
2,300
Core Transmitters ?
S. Taylor et al 10th CROI Boston 2003
SPVL
>2,000,000
>5,000000*
460,000*
190,000*
130,000
100,000*
60,000
23,000*
11,000*
Treatment
none
none
none
none
none
NVP,ABC,d4T
RTV,SQV,d4T
RTV, SQV,d4T
NFV/SQV/ddI/d4T
Semen Versus Blood HIV-1
RNA
Semen HIV RNA (log10 copies/ml)
6
Untreated
5.5
Treated
5
Urethritis
4.5
4
3.5
3
42
2.5
2.5
3
3.5
4
4.5
5
Blood HIV RNA (log10 copies/ml)
Winter, Taylor, workman et al. Sex Trans Inf 99; 75 261-263
5.5
6
Detection of SP HIV-1 during ART
and Urethritis (n=24) Cases
18/19
Undetectable
in semen
Plasma
HIV-RNA
3/5
SP HIV RNA
+ve
(SP < BP)
5+ve
1
SP HIV
RNA+ve
Sadiq T , Taylor S et al AIDS 2002
-19
2/5
SP HIV RNA
+ve
(SP >BP )
VIRAL LOADS AND RESISTANCE MUTATIONS IN BLOOD PLASMA AND SEMEN PLASMA
IN MEN TAKING ANTIVIRALS AT THE TIME OF SYMPTOMATIC URETHRITIS
PRE TREATMENT AT TIME OF URETHRITIS
Case
19
Treatment
STI
BPVL
Visit 1
SPVL
Visit 1
Resistance Mutations in blood plasma
(BP) and seminal plasma (SP) Visit 1
POST ANTIBIOTIC TREATMENT
BPVL
Visit 2
SPVL
Visit 2
Resistance
Mutations
BP and SP Visit 2
4-6 Men on ART with Urethritis and
detectable HIV RNA in semen
had multiple drug resistance
associated mutations in both blood
and semen
ddI, ABC,
NFV,SQV
GC
13,913
6412
RT: M41L, L74V, V118I, M184V,
T215Y
PR: L10I, K20I, l24I, M36I, M46L,
154V, L63P, A71V,T74S, V82A
11,249
4,012
No change from Visit
1
AZT, 3TC,
ddC
GC
98,882
15,770
RT: M41L, A98G, M184V, L210W/L,
T215Y
85,262
23,786
No change from Visit
1
AZT, 3TC,
ddI
GC
85,470
26,422
RT: M41L, E44A, D67N, K70R,
M184V, T215Y, K219E,
PR:. L10I, L63P, I93L
26,422
21,916
No change except
V77I, in SP at Visit 2
d4T, ABC,
NVP
GC
69,000
100,000
RT: K65R, K103N, Y181C
49,000
4,300
No change from visit
1
SP No Amp
23
d4T,3TC,
NFV,SQV
GC
713
5,928
No Amp
986
<1000
No Amp
24
d4T, 3TC,
NVP
NSU
<500
1,512
No Amp
<1000
<1000
No Amp
20
21
22
S.TAYLOR, T, SADIQ et al Antiviral Therapy
A few more questions...
• What about PI monotherapy?
• What about iPREP for discordant couples
wishing to conceive?
• What about the Swiss Statement?
• What about viral shedding in women on
ART?
Genital Tract HIV-1 RNA
Shedding among Women
with Below Detectable
Plasma Viral Load
Susan Cu-Uvin, Allison DeLong,
Joseph Harwell, Joseph Hogan,
Jessica Ingersoll, Stacey Chapman,
Joselyn Cerezo, Carla Moreira,
Jaclyn Kurpewski, Heather Burtwell,
Angela Caliendo
Results: Non-shedder
ID
C-213
C-213
C-213
C-213
C-213
C-213
C-213
C-213
C-213
C-213
C-213
C-213
Visit
1
2
3
4
5
6
7
8
9
10
11
12
PVL
≤80
≤80
≤80
≤80
≤80
≤80
≤80
≤80
≤80
≤80
≤80
≤80
Endocervix
0
0
0
0
0
0
0
0
0
0
0
0
Slide Courtesy of Susan Cu-Uvin
Ectocervix
0
0
0
0
0
0
0
0
0
0
0
0
Vagina
0
0
0
0
0
0
0
0
0
0
0
0
HAART
3TC, DDI, d4T, NVP
3TC, DDI, d4T, NVP
3TC, DDI, d4T, NVP
3TC, DDI, d4T, NVP
3TC, DDI, d4T, NVP
3TC, DDI, d4T, NVP
3TC, DDI, d4T, NVP
3TC, DDI, d4T, NVP
3TC, DDI, d4T, NVP
3TC, DDI, d4T, NVP
3TC, DDI, d4T, NVP
3TC, DDI, d4T, NVP
Results: Persistent Shedder
ID
Visit
PVL
Endocervix
Ectocervix
Vagina
HAART
C-221
1
≤80
0
0
0
DDI, TDF, NVP
C-221
2
≤80
0
0
0
DDI, TDF, NVP
C-221
3
≤80
0
0
6480
DDI, TDF, NVP
C-221
4
≤80
0
0
5600
DDI, TDF, NVP
C-221
5
≤80
0
0
4720
DDI, TDF, NVP
C-221
6
blood draw failed
0
96000
0
DDI, TDF, NVP
C-221
7
lost specimen
0
0
0
DDI, TDF, NVP
C-221
8
≤80
0
29600
0
DDI, TDF, NVP
C-221
9
≤80
0
0
0
DDI, TDF, NVP
C-221
10
≤80
0
0
0
DDI, TDF, NVP
C-221
11
150000
136000
2880000
2880000
off HAART
C-221
12
Slide Courtesy of Susan Cu-Uvin
missed visit
Conclusions:
• Women on HAART with below detectable plasma viral
load may continue to shed HIV-1 RNA in all genital tract
sub-compartments (52%)
• Among those who do shed, the majority will shed
intermittently
• The odds of genital tract HIV-1 RNA shedding are
increased in each genital tract sub-compartment when
plasma viral load is detectable
• These findings may have implications on possible
continued risk of sexual transmission from women with
well controlled plasma viral load
Genital Drug penetrations ,
does it matterrs... or what ?
YEAH
WHAT EVVVAAR ........
Acknowledgements
Slides: Robin Shattock, Myron Cohen, Angela Kashuba, Pietro Vernazza
Bob Coombs, Gerado Garcia Lerma, Charles Lacey, Chris Pilcher,
Jonathon Weber, Ken Mayer, Debbie Flanigan, and John Watson
“PATIENTS: on going contributions”
HPA Birmingham .
Birmingham Heartlands HIV Service UK University of Birmingham UK.
Sophia Davies, Ashini Jayasuria
Ngozi Dufty, Ras Smit , Maxine Owen,
MIDRU Gerry Gilleran and team
UCL Ian Weller, Deenan Pillay
St Georges: Tariq Sadiq,
Department of Pharmacology and
Therapeutics University of Liverpool, UK
David Back, Saye Khoo
Sara Gibbons, Helen Reynolds
Ras Smit ,,
Judith Workman, Daina Ratcliffe,
Li Xu,
HPA Collindale Pat Cane
Department of Pharmacy and Pharmacology
Slotervaart Hospital, Netherlands.
Rolf van Heeswijk
Richard Hoetelmans