Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens...
-
Upload
beryl-dean -
Category
Documents
-
view
215 -
download
0
Transcript of Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens...
![Page 1: Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh.](https://reader036.fdocuments.net/reader036/viewer/2022062516/56649d9c5503460f94a852a2/html5/thumbnails/1.jpg)
Use of Antivirals in Prevention
Oral and Topical Prophylaxis
Ian McGowan MD PhD FRCP
Magee-Womens Research Institute
University of Pittsburgh
![Page 2: Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh.](https://reader036.fdocuments.net/reader036/viewer/2022062516/56649d9c5503460f94a852a2/html5/thumbnails/2.jpg)
Recent Events FEM-PrEP study stopped for futility
April 18th, 2011 HPTN-052 delayed treatment arm
stopped for efficacy May 12th, 2011
Partners PrEP placebo arm stopped for efficacy July 13th, 2011
CDC announce positive TDF2 results July 13th, 2011
![Page 3: Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh.](https://reader036.fdocuments.net/reader036/viewer/2022062516/56649d9c5503460f94a852a2/html5/thumbnails/3.jpg)
Overview
HIV prevention strategies in 2011 Current status of ART PrEP
Oral Vaginal Rectal
Challenges Future Directions in PrEP
![Page 4: Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh.](https://reader036.fdocuments.net/reader036/viewer/2022062516/56649d9c5503460f94a852a2/html5/thumbnails/4.jpg)
HIV Prevention Research in 2011
Behav
iora
l
Positiv
e
Mic
robic
ides
Positiv
e
Oral P
rEP
Positiv
e
ART Rx
Positiv
e
Circum
cisi
on
Positiv
e
STI Rx
Positiv
e
Vacci
ne
Positiv
e0
5
10
15N
um
ber
of
Tri
als
Adapted from Padian et al. Lancet 2011
![Page 5: Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh.](https://reader036.fdocuments.net/reader036/viewer/2022062516/56649d9c5503460f94a852a2/html5/thumbnails/5.jpg)
Effectiveness of Prevention
HPTN-052
Partners PrEP
CDC TDF2
Circumcision
iPrEX
STI
CAPRISA
RV144
96%
73%
63%
54%
44%
42%
39%
31%
Abdool Karim & Abdool Karim. Lancet 2011
![Page 6: Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh.](https://reader036.fdocuments.net/reader036/viewer/2022062516/56649d9c5503460f94a852a2/html5/thumbnails/6.jpg)
A Brief History of ART PrEP1995
PMPA effectivein macaque
model
2005HPTN-050
Phase 1
2006HPTN-059Phase 2
2010CAPRISA 004
Phase 2B
2010iPrEX
2011FEM-PrEP
2011HPTN-052
2011Partners
PrEP
2011TDF2
2011Partners
PrEP
2012MTN-003VOICE
2007TDFPrEPStudy
2011FACTS-001
![Page 7: Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh.](https://reader036.fdocuments.net/reader036/viewer/2022062516/56649d9c5503460f94a852a2/html5/thumbnails/7.jpg)
McGowan I, Biologicals, 2006
PrEP Mechanism of Action
![Page 8: Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh.](https://reader036.fdocuments.net/reader036/viewer/2022062516/56649d9c5503460f94a852a2/html5/thumbnails/8.jpg)
Compartmental PK
Oral
Topical
Concentration of ARV
Blood Mucosa
![Page 9: Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh.](https://reader036.fdocuments.net/reader036/viewer/2022062516/56649d9c5503460f94a852a2/html5/thumbnails/9.jpg)
MTN-001Lo
g 10
TF
V &
TF
Vpp
(fm
ol/m
g or
pm
ol/m
L*)
8
7
6
5
4
3
2
1
0
-1
-2
Route
Dual
Oral
Vaginal
Serum TFV Cmax
PBMC TFVpp Cmax
CVL TFV
ECC TFVpp
Tissue TFVpp
Tissue TFV
Hendrix et al. CROI 2011
![Page 10: Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh.](https://reader036.fdocuments.net/reader036/viewer/2022062516/56649d9c5503460f94a852a2/html5/thumbnails/10.jpg)
RMP-02 / MTN-006TFV DP Homogenate Comparison ~30min Post-Dose
Oral Dose Single Rectal Dose Multiple Rectal Dose
TV
F D
P T
issu
e H
omog
enat
e C
once
ntra
tion
(fm
ol/m
g)
100
101
102
103
104
105
N detectable 7/18 10/12 12/12
Co
nce
ntr
atio
n o
f TV
F-D
P(f
mo
l/mg)
Route Oral Rectal (S) Rectal (7D)
N Detectable 7/18 10/12 12/12
Anton et al. CROI 2011
![Page 11: Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh.](https://reader036.fdocuments.net/reader036/viewer/2022062516/56649d9c5503460f94a852a2/html5/thumbnails/11.jpg)
iPrEx Study 2,499 MSM and male-
to-female transgendered women randomized to Truvada or placebo
44% reduction in HIV acquisition
Higher drug concentrations associated with increased protection
Grant et al. NEJM 2010
![Page 12: Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh.](https://reader036.fdocuments.net/reader036/viewer/2022062516/56649d9c5503460f94a852a2/html5/thumbnails/12.jpg)
FEM-PrEP 1,951 women randomized to receive Truvada
or placebo Kenya, South Africa, and Tanzania Study stopped because of futility
56 HIV endpoints Truvada: N = 28 Placebo: N = 28
Possible explanations for lack of efficacy Poor adherence or drug sharing Differential compartmental PK Chance
![Page 13: Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh.](https://reader036.fdocuments.net/reader036/viewer/2022062516/56649d9c5503460f94a852a2/html5/thumbnails/13.jpg)
Partners PrEP Study 4,758 HIV serodiscordant couples
randomized to receive Viread, Truvada, or placebo
Kenya and Uganda
HIV EP % CIPlacebo 47
Viread 18 63 34-78
Truvada 13 73 49-85
IAS 2011
![Page 14: Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh.](https://reader036.fdocuments.net/reader036/viewer/2022062516/56649d9c5503460f94a852a2/html5/thumbnails/14.jpg)
CDC TDF2 Study
1,200 men and women randomized to Truvada or placebo
Botswana
HIV EP % CI
Placebo 24
Truvada 9 63 22-83
IAS 2011
![Page 15: Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh.](https://reader036.fdocuments.net/reader036/viewer/2022062516/56649d9c5503460f94a852a2/html5/thumbnails/15.jpg)
CAPRISA 004 889 women randomized to receive tenofovir
1% gel or placebo with BAT regimen South Africa Protection significantly higher with
concentrations of TNF in cervical fluid (> 1,000 ng/mL)
HIV EP % CI
Placebo 60
Tenofovir 38 39 6-60
Abdool Karim et al. Science 2010; Lancet 2011
![Page 16: Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh.](https://reader036.fdocuments.net/reader036/viewer/2022062516/56649d9c5503460f94a852a2/html5/thumbnails/16.jpg)
MTN-003 (VOICE Study)
Total Enrollment = 5,029Overall Screen to Enroll Ratio = 2.4:1
2,308 identified as HIV infected at
Screening
12,320Screened
4,983Screened Out
(not HIV+)
Uganda322 Enrolled
South Africa4,077 Enrolled
Zimbabwe630 Enrolled
![Page 17: Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh.](https://reader036.fdocuments.net/reader036/viewer/2022062516/56649d9c5503460f94a852a2/html5/thumbnails/17.jpg)
Rectal Microbicides Receptive anal sex common practice in
MSM and heterosexuals Proof of concept in NHP SIV/SHIV model
Cyanovirin-N, tenofovir, MIV-150/carageenan Phase 1 evaluation includes safety,
acceptability, PK, and PD RMP-01 (UC781) RMP-02 / MTN-006 (tenofovir VF) MTN-007 (tenofovir RGVF)
![Page 18: Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh.](https://reader036.fdocuments.net/reader036/viewer/2022062516/56649d9c5503460f94a852a2/html5/thumbnails/18.jpg)
RMP-02/MTN-006
BaselineEvaluation
Open labelOral tenofovir
(N = 18)
Single rectal
tenofovir(N = 18)
2:1
7 DayRectal
tenofovir(N = 18)
2:1
Safety, PK / PD, acceptability
Anton et al. CROI 2011
![Page 19: Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh.](https://reader036.fdocuments.net/reader036/viewer/2022062516/56649d9c5503460f94a852a2/html5/thumbnails/19.jpg)
PK/PD Relationship
0 1 2 3 40
5000
10000
15000
r2 = 0.33P = 0.0011
Oral Dose Single Rectal Dose Multiple Rectal Dose
Log10[Tissue TFV-DP ]fmol/mg
Cum
ulati
ve p
24 (p
g/m
L)
![Page 20: Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh.](https://reader036.fdocuments.net/reader036/viewer/2022062516/56649d9c5503460f94a852a2/html5/thumbnails/20.jpg)
Project Gel
www.rectalmicrobicides.org
![Page 21: Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh.](https://reader036.fdocuments.net/reader036/viewer/2022062516/56649d9c5503460f94a852a2/html5/thumbnails/21.jpg)
Unanswered Questions PrEP and ART resistance
MTN-009 & MTN-015 Differential safety and efficacy between
oral and topical PrEP VOICE study
Use of topical PrEP in adolescents MTN-021
Use of PREP in pregnancy MTN-002, MTN-016, and MTN-019
![Page 22: Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh.](https://reader036.fdocuments.net/reader036/viewer/2022062516/56649d9c5503460f94a852a2/html5/thumbnails/22.jpg)
Key Challenges for ART PrEP Increasing adherence in PrEP trials
Use of objective measures of adherence Development of PK/PF correlates of
protection Obtaining licensure for tenofovir 1% gel Life after placebo Bridging between the end of PrEP
effectiveness trials and community availability of PrEP agents
Reducing cost of PrEP delivery
![Page 23: Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh.](https://reader036.fdocuments.net/reader036/viewer/2022062516/56649d9c5503460f94a852a2/html5/thumbnails/23.jpg)
Future Research Priorities (1) Development / optimization of
biomarkers for use in clinical trials Sexual exposure Adherence Safety Efficacy
Phase 2/2B development of rectal microbicides MTN-017
![Page 24: Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh.](https://reader036.fdocuments.net/reader036/viewer/2022062516/56649d9c5503460f94a852a2/html5/thumbnails/24.jpg)
Future Research Priorities (2)
Evaluation of extended release PrEP agents Dapivirine intravaginal ring TMC-278
Combination HIV prevention strategies T4P + PrEP + circumcision PrEP + HIV vaccination PrEP + contraceptive products
Moving to implementation
![Page 25: Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh.](https://reader036.fdocuments.net/reader036/viewer/2022062516/56649d9c5503460f94a852a2/html5/thumbnails/25.jpg)
NIH/NIAID/ DAIDS U19 AI060614 U19 AI082637 U01 AI068633-01
NIH/NIAID/DMID U01 AI066734
NIH/NICHD & NIH/NIMH R01 HD059533-01A1
![Page 26: Use of Antivirals in Prevention Oral and Topical Prophylaxis Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh.](https://reader036.fdocuments.net/reader036/viewer/2022062516/56649d9c5503460f94a852a2/html5/thumbnails/26.jpg)