Identifying Priority Research Questions

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Transcript Identifying Priority Research Questions

Potential role of PEP, PrEP and ART for
HIV Prevention among Men who have
Sex with Men
Frits van Griensven, PhD, MPH
Division of HIV/AIDS Prevention
US Centers for Disease Control and Prevention
and
Thailand MOPH - US CDC Collaboration
Disclaimer: The views expressed herein are solely the responsibility of the
author and do not necessarily represent the official views of the CDC
In this presentation
1) Non-occupational (or sexual) post exposure prophylaxis
(NPEP)
2) Pre-post exposure prophylaxis or PrEP
Oral
Topical
3) Antiretroviral treatment for prevention
Non-occupational post exposure
prophylaxis (NPEP) for MSM
Efficacy concerns
 No solid data supporting efficacy in MSM; controlled studies are not
available
 Observational studies in MSM show no clear effect on transmission
(Kahn et al, 2001; Schechter et al, 2004; Poynten et al, 2009)
 Animal data show no protection against rectal SHIV challenge if
started too late (+24 hrs) but some protection if started timely
(+2hrs) (Garcia-Lerma et al, 2010)
 Men fail to timely recognize high risk exposure, even in the
presence of direct access to ARVs (Schechter et al, 2004)
 Public health impact of NPEP is considered limited and only costeffective in very specific situations (MMWR, 2005; Poynten et al,
2007)
Non-occupational post exposure
prophylaxis (NPEP)
In conclusion
 NPEP not feasible for programmatic scale-up in MSM
 Can be offered as an individual service on a case-by-case basis
Non-occupational post exposure
prophylaxis (NPEP)
 BUT eventually PEP led to PrEP
 If you need to take so soon after, why not take it before?
 Series of animal studies looking at the timing of drug intake


versus exposure, 2 hrs before, 24 hrs after etc, etc.
Particularly relevant are the rectal challenge models
The results of these experiments are driving the PrEP research
agenda for MSM today
% Uninfected macaques
Efficacy of daily and pre- and post-exposure oral
Truvada in preventing SHIV infection following rectal
challenge in macaques
FTC/TFV daily (n=6)
100
(HR>20, p<0.0001)
FTC/TFV -2h/+22h (n=6)
75
(HR>20, p<0.0001)
50
25
0
0
2
4
6
8 10 12
Number of weekly rectal exposures
Controls (n = 21)
Garcia-Lerma et al, PLOS, 2008
iPrEx:
PrEP Initiative
Sponsored by NIH/NIAID/DAIDS
With co-funding from the
Bill and Melinda Gates Foundation
And drug donated by
Gilead Sciences
Slides, courtesy of Dr Robert Grant
Men who have sex with
men
MSM with a heavy burden
•
•
•
In the Americas
In Asia
In Africa
Lima, Peru
Different from HXY, IDU
• Differing penetration of
virus or drug into rectal
tissue
iPrEx is the only study of
PrEP efficacy in MSM
PrEP Initiative (iPrEx)
 Men who have sex with men
 Randomized 1:1 FTC/TDF vs Placebo
 Daily oral
 Followed for:
•
•
•
•
•
•
•
HIV seroconversion
Adverse Effects
Metabolic Effects
HBV exacerbations
Risk behavior and STIs (including HSV)
Adherence
If infected
 Drug resistance
 Viral load
 Immunological responses and CD4 counts
Intermittent PrEP (iPrep)
 May be more in line with sexual life style
 Reduce pill burden
 Reduce drug burden
 Reduce side-effects
 Decrease costs
 May increase adherence and coverage
 And may be increase safer sex behavior

And is supported by animal models
Efficacy of intermittent PrEP with Truvada in the
repeat low-dose macaque model: design
Garcia-Lerma et al, 2010
% Uninfected macaques
Risk reduction by iPrEP with oral Truvada
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
Garcia-Lerma et al, 2010
2
Sex frequency among 823 HIVFigure
negative
MSM in Bangkok Thailand
(“On how many days in the past week did you have sex?”)
40
36.6
35
33.3
% reporting sex
30
25
20
15.9
15
10
7.3
5
3.2
1.9
1.1
0.7
5
6
7
0
0
1
2
3
4
Number of days
van Griensven F, et al. 2010
4 MSM in Bangkok Thailand
Sex planning among 823 HIV Figure
negative
(“On the last day you had sex, was the first sex on that day planned?”)
80
70.5
76.4
65.5
63.3
64.0
58.2
60
50
40
30
20
10
e
Tu
M
on
n
Su
t
Sa
Fr
i
Th
ur
s
0
W
ed
% reporting planned sex
70
72.9
Day of the week
van Griensven F, et al. 2010
Multivariate analysis of sex planning among 823 HIV
negative MSM in Bangkok, Thailand
(first sex on last sex day was planned)
Multivariate
OR
(95% CI)
Younger age (<30 years old)
1.67
1.12 – 2.48
Lower education (<high school)
2.97
1.51 – 5.83
Not indentifying as gay
1.58
1.04 – 2.38
Receptive in anal sex
1.67
1.16 – 2.40
Group sex (ever)
0.54
0.34 – 0.85
van Griensven F, et al. 2010
Intermitent PrEP (iPrep)

Post IPREX generation of studies will be
comparing continuous versus intermittent PrEP
• Non-inferiority or equivalency studies (costly, large N)
•
•
•
Daily vs pre-post exposure
Daily vs standing doses plus post exposure dose
Daily vs standing doses
 HPTN 067: the “ADAPT Study”
•
•
•
•
•
•
“Alternative Dosing to Augment Pill Taking Study”
Phase II, Randomized, Open-Label, Pharmacokinetic and
Behavioral Study of the Use of Intermittent Truvada
3-armed study: daily, vs pre-post, vs bi-weekly standing plus
post exposure dose
N=360, MSM n=180 Bangkok; HW n=180, Capetown
Adherence, coverage, PK and risk behavior
Start January 2011
Safety and adherence to intermittent Emtricitabine/Tenofovir for
HIV pre-exposure prophylaxis (PrEP) in Kenya and Uganda.
Mutua et al. IAC 2010, MOPE0369
In the shadow of Caprisa
Strong push for evaluation of rectal microbicides, e.g.,
TDF gel, possibly in combination with oral formulations
Figure: Courtesy of Dr Ian McGowan
Rectal Specific Products
 CHARM Program
•
•
•
•
Combination HIV Antiretroviral Rectal
Microbicide Program
DAIDS IPCP Program
Tenofovir, UC781, tenofovir + UC781
Consortium
• University of Pittsburgh
• UCLA
• Johns Hopkins
• CONRAD
PI: Ian McGowan MD PhD
Courtesy of Dr Ian McGowan
In the shadow of Caprisa
Where Would We Conduct Phase 2/3
Studies?
 Phase 2 studies
• RAI sexually active men and women
• Higher risk populations
 Phase 2B studies
•
3% sero-incidence MSM populations
• North America
• Latin America (Peru, Brazil)
• Asia Pacific (Thailand)
• Africa (South Africa)
Courtesy of Dr Ian McGowan
MTN 017




Phase II, multi-site, randomized, six sequence,
three period, open label crossover study of
adherence and pharmacokinetics of oral and
rectal formulations of tenofovir
120 MSM
Bangkok, Thailand; Lima, Peru; 2 US Sites
Possibly roll-over into Phase IIB, III efficacy trial
Rectal Microbicide Timeline*
2010 2011 2012 2013 2014 2015 2016 2017 2018
Phase 1
Phase 2
Phase 2B
Review
Available
Vaginal
microbicides
*An approximation based on 1% tenofovir
Courtesy of Dr Ian McGowan
ART as prevention


Test and link
Test and treat
HPTN 065 – Wash DC and Bronx:
Test-Link-Care-Plus Study
Test
Enroll in Care
Initiation
of ART
Testing
HIV Positive
Positive
Linkage
Prevention
to care
Adopt safer behaviors sites
Treat
Adherence
to ART
Maintain viral
suppression
Decrease in HIV
Transmission
Treatment as Prevention for MSM
Rationale: lower viral load reduces transmission; ART
reduces viral load, thus ART reduces transmission
Dr Myron Cohen will give an excellent review and
summary on this
However:
•
•
No transmission studies in discordant MSM couples
No information about the reduction in transmission probability
in discordant MSM couples in the presence of ART
We need scientific evidence to support this
intervention in MSM
•
Study of 350 discordant couples is being prepared in Sydney,
Australia (Prof Andrew Grulich); behavior, transmission
events, phylogenetic analysis
Treatment as Prevention for MSM

In the mean time:
 April 2010 - San Francisco guidelines issued: offer treatment
to all HIV positives, regardless of CD4 and VL

Strong association between mean community viral load, total
community viral load and reduction in newly identified HIV
cases from 798 in 2008 to 434 in 2008

Very special situation with good surveillance data on HIV
infection and viral load, almost universal access to ART
Mean community viral load in San Francisco, by
neighborhood, 2005-8
Das, et al, 2010
Total community viral load in San Francisco, by
neighborhood, 2005-8
Das, et al, 2010
Reductions in VL, newly diagnosed and reported cases and
estimated HIV incidence in San Francisco 2004-8
Das, et al, 2010
Challenges for ARV prevention in MSM
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
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


Adherance
Risk compensation and behavioral disinhibition,
individually and at the community level
Targeting and duration of programs
Programming outside the Western world
Implementation and programming in low HIV
prevalence communities
Costs and competition with curation
Pill burden, drug burden, side-effects, toxicity,
resistance
How to monitor impact
In conclusion

PEP not ready for programmatic scale up, but
good as an individual service on a case by case
basis

Daily PrEP results expected soon; if efficacious,
studies will try to identify non-inferior alternative
regimens
 Many implementation issues
Rectal PrEP – promising, but still long way to go

 ART for prevention, seems reasonable, ecological
evidence available, MSM transmission studies are
urgently needed
Acknowledgements
Ian McGowan
University of Pittsburgh
Lynn Paxton
US CDC
Peter Kilmarx
US CDC
Tim Mastro
Family Health International
Bob Grant
University of California, San Francisco
Eduard Sanders
University of Oxford/KEMRI/IAVI
Susan Buchbinder
SFDPH/UCSF
Anchalee Varangrat
Thailand MOPH–US CDC Collaboration
Kathie McCarthy
ASPH/CDC Global Public Health Fellow
Disclaimer: the results and conclusions presented in this presentation are those of the
author, and do not necessarily represent those of the US Centers for Disease Control and
Prevention
[email protected]
Status of Completed, Ongoing and Planned Advanced Stage Clinical Trials of
Antiretrovirals for Prevention (Oral and Topical), 2010
Study
Product
N, Population
Countries
Enrollment
Started
Status as of
Jan 2010
Expected
Results
West Africa
Tenofovir Trial
TDF oral
936
Women
Ghana,
Cameroon,
Nigeria
2004, Q2
Completed
Published
2007
US Extended
TDF Safety
Trial
TDF oral
400
MSM
US
2005, Q1
Fully enrolled
2010, Q2
Bangkok
Tenofovir
Study (BTS)
TDF oral
2400
M&F IDU
Thailand
2005, Q2
2364 (99%)
enrolled
2010
TDF-2
TDF/FTC
oral
1200
M&F,
heterosexuals
Botswana
2007, Q1
Fully enrolled Changed to
safety study, 2009
2010
iPREX,
UCSF
TDF/FTC
oral
3000
MSM
Peru, Ecuador,
Brazil, US,
Thailand, SA
2007, Q1
2451 (82%)
enrolled
2010
CAPRISA
004 Trial
TFV 1% gel
900
Women
South Africa
2007, Q2
Completed,
Released
2010
Partners PrEP
TDF oral,
TDF/FTCoral
3900 Disco
Heterocouples
Kenya, Uganda
2008, Q2
3100 (79%)
couples enrolled
2011
FEM-PrEP
TDF/FTC
oral
3900
Women
Kenya, Malawi,
South Africa,
Tanzania
Expected:
2009, Q2
461 (12%)
enrolled
2012
VOICE,
MTN-003
TDF oral,
TDF/FTC
oral,
TFV 1% gel
4950
Women
Malawi, Uganda,
South Africa,
Zambia,
Zimbabwe
Expected:
2009, Q2
137 (3%)
enrolled
2013
Non-occupational post exposure
prophylaxis (NPEP)
 Concern about negative behavioral side-effects
• In some studies NPEP recipients were at higher subsequent risk
•
for HIV seroconversion due to continued exposure or reexposure (Poynten et al, 2009)
No increases in high risk behavior after NPEP were observed
(Schechter et al, 2004; Martin et al, 2004), but no decreases
were observed either (Poynten et al, 2007)
Non-occupational post exposure
prophylaxis (NPEP)
 Drug side-effects
•
uncommon with current generation of ARVs available for NPEP
 ARV resistance
•
•
unlikely, because HIV infection after NPEP is uncommon
current ARV’s less likely to cause resistance
 Public health impact of NPEP is considered limited and only costeffective in very specific situations (MMWR, 2005; Poynten et al,
2007)
In conclusion
 NPEP not feasible for programmatic scale-up in MSM
 Can be offered as an individual service on a case-by-case basis