use of antivirals in prevention oral and topical prophylaxis
DESCRIPTION
Use of Antivirals in Prevention Oral and Topical Prophylaxis . Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh. Recent Events. FEM-PrEP study stopped for futility April 18 th , 2011 HPTN-052 delayed treatment arm stopped for efficacy May 12 th , 2011 - PowerPoint PPT PresentationTRANSCRIPT
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Use of Antivirals in Prevention
Oral and Topical Prophylaxis
Ian McGowan MD PhD FRCPMagee-Womens Research Institute
University of Pittsburgh
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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
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Overview HIV prevention strategies in 2011 Current status of ART PrEP
Oral Vaginal Rectal
Challenges Future Directions in PrEP
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HIV Prevention Research in 2011
Behav
ioral
Positive
Microbici
des
Positive
Oral PrE
P
Positive
ART Rx
Positive
Circumcis
ion
Positive
STI Rx
Positive
Vaccin
e
Positive
0
5
10
15N
umbe
r of T
rials
Adapted from Padian et al. Lancet 2011
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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
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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
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McGowan I, Biologicals, 2006
PrEP Mechanism of Action
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Compartmental PK
Oral
Topical
Concentration of ARV
Blood Mucosa
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MTN-001Lo
g 10 T
FV &
TFV
pp (f
mol
/mg
or p
mol
/mL*
)
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
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RMP-02 / MTN-006TFV DP Homogenate Comparison ~30min Post-Dose
Oral Dose Single Rectal Dose Multiple Rectal Dose
TVF
DP
Tis
sue
Hom
ogen
ate
Con
cent
ratio
n (fm
ol/m
g)
100
101
102
103
104
105
N detectable 7/18 10/12 12/12
Con
cent
ratio
n of
TV
F-D
P(fm
ol/m
g)
Route Oral Rectal (S) Rectal (7D)
N Detectable 7/18 10/12 12/12
Anton et al. CROI 2011
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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
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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
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Partners PrEP Study 4,758 HIV serodiscordant couples
randomized to receive Viread, Truvada, or placebo
Kenya and Uganda
HIV EP % CIPlacebo 47Viread 18 63 34-78Truvada 13 73 49-85
IAS 2011
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CDC TDF2 Study
1,200 men and women randomized to Truvada or placebo
Botswana
HIV EP % CIPlacebo 24Truvada 9 63 22-83
IAS 2011
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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 % CIPlacebo 60Tenofovir 38 39 6-60
Abdool Karim et al. Science 2010; Lancet 2011
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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
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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)
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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
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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)
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Project Gel
www.rectalmicrobicides.org
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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
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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
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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
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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
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NIH/NIAID/ DAIDS U19 AI060614 U19 AI082637 U01 AI068633-01
NIH/NIAID/DMID U01 AI066734
NIH/NICHD & NIH/NIMH R01 HD059533-01A1
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