Slide 1 of 9
Update on Pre-Exposure
Prophylaxis: Never a Dull Moment
Jeanne Marrazzo, MD, MPH
Professor of Medicine
University of Washington
Seattle, Washington
From J Marrazzo, MD, at Los Angeles, CA: April 22, 2013, IAS-USA.
IAS–USA
Slide 2 of 9
What is PrEP, and Why Might it Work?
• Definition: Provision of chemopreventive agent at vulnerable
site(s) prior to infection
• Rationale:
• Infection of healthy
mucosa requires
relatively large dose of
virus (10-6 to 10-8
particles)
• In theory, the right drug
could prevent founder
population from
establishing infection,
but time is of the
essence!
• Animal data is very
supportive; stresses
need for PEP
Garcia-Lerma JG, et al. Trends Pharmacol Sci. 2010
component
From J Marrazzo, MD, at Los Angeles, CA: April 22, 2013, IAS-USA.
Slide 3 of 9
Evidence for PrEP Efficacy with
Tenofovir-Based Regimens, 2012*
Study
iPrEx
Population
N
Efficacy (%)
Men Having
2499
Sex with Men
44%
Daily oral FTC/TDF
Young men &
1200
women
62%
Daily oral FTC/TDF
Partners PrEP Heterosexual
4758
Study
couples
67% daily oral TDF
75% daily oral
FTC/TDF
Brazil, Ecuador,
Peru, South Africa,
Thailand, US
TDF2 Study
Botswana
Kenya, Uganda
•
At time of FDA meeting
Baeten J, Celum C. Current Opinion HIV AIDS, 2012
From J Marrazzo, MD, at Los Angeles, CA: April 22, 2013, IAS-USA.
Slide 4 of 9
FDA Antiviral Drugs Advisory
Committee Meeting, May 10, 2012
• Recommended approval of daily TDF/FTC for
HIV prevention in 3 groups:
– MSM: 19-3 YES
– HIV-uninfected partner in discordant couples: 19-2 YES
– Other populations: 12:8 YES
16 July 2012
From J Marrazzo, MD, at Los Angeles, CA: April 22, 2013, IAS-USA.
Slide 5 of 9
Oral FTC/TDF PrEP Studies
Effect size
(95% CI)
FTC/TDF for HIV
discordant couples
(Partners PrEP)
75% (55; 87)
FTC/TDF for young
Heterosexuals
(TDF-2)
63% (22; 83)
FTC/TDF for MSM
(iPrEx)
42% (15; 63)
Wide confidence intervals
outside of discordant
couples, with lower limit
<20% in iPrEx
0
10
20
30
Efficacy
40
50
60
70
From J Marrazzo, MD, at Los Angeles, CA: April 22, 2013, IAS-USA.
80
90 100%
Slide 6 of 9
Oral FTC/TDF PrEP Studies, 2012
Effect size
(95% CI)
FTC/TDF for HIV
discordant couples
(Partners PrEP)
75% (55; 87)
FTC/TDF for young
heterosexuals
(TDF-2)
63% (22; 83)
FTC/TDF for MSM
(iPrEx)
42% (15; 63)
FTC/TDF for
women
(FEM-PrEP)
6% (-69; 41)
Efficacy
0
10
20
30
40
50
60
70
From J Marrazzo, MD, at Los Angeles, CA: April 22, 2013, IAS-USA.
80
90 100%
Slide 7 of 9
Divergent PrEP trial results:
Contributions of Adherence + Biology?
Adherence
Biology*
•
•
•
•
Behavior
Low genital drug levels (pK/pD)
Inflammation, STI
Acute HIV (high VL in partner)
Disrupted vaginal microbiome
* These factors may make PrEP
efficacy more sensitive to
imperfect adherence
Slide adapted from J. Baeten
Efficacy
From J Marrazzo, MD, at Los Angeles, CA: April 22, 2013, IAS-USA.
• Frequency of
anal vs.
vaginal
intercourse
• Vaginal
hygiene
practices
PrEP
Slide 8 of 9
HIV Incidence in CAPRISA 004
No K65R resistance mutations among seroconverters
Abdool Karim, Q, et al. Science. 2010;329:1168-1174.
From J Marrazzo, MD, at Los Angeles, CA: April 22, 2013, IAS-USA.
Slide 9 of 9
Candidate Drugs in PrEP Pipeline
Phase
IIB
Phase
II
• NNRTIs: Dapivirine intravaginal ring
• Effectiveness trials for dapivirine ring under way (MTN, IPM)
• Entry inhibitors: Maraviroc with NRTI or NNRTI
• Oral maraviroc +/- FTC/TDF (HPTN 069)
• Maraviroc & dapivirine vaginal ring (IPM, MTN)
• NNRTIs: Rilpivirine (TMC 278), long-acting injectable
Phase
I
• Once monthly injections; in phase I safety studies in UK
• Integrase strand transfer inhibitors
Animal
Studies
• Macaque & humanized mice protected with topical & oral
raltegravir (Dobard CROI 30; Neff PLoS ONE 2010); macaques
protected with parenteral long-acting agent (GSK744) (Andrews
CROI 2013)
• NRTIs: Tenofovir intravaginal ring (Smith CROI 2013)
From J Marrazzo, MD, at Los Angeles, CA: April 22, 2013, IAS-USA.