Download ARV-based Microbicides and Resistance

ARV-based Microbicides
and Resistance
Jeanne Marrazzo, M.D., M.P.H.
University of Washington
John Mellors, M.D.
University of Pittsburgh
Who we are?
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Jeanne Marrazzo, MD, MPH
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Associate Professor of Infectious Diseases, University
of Washington
Medical Director, STD/HIV Prevention Training Center
Research focus on vaginal health, vaginitis, STI
diagnosis and prevention
MTN-003 (VOICE) Study Co-chair
John Mellors, MD
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Chief of Infectious Diseases,University of Pittsburgh
Oversees HIV-AIDS clinical research and primary care
Research focus on ARV drug resistance
MTN Virology Core Director
About the MTN
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Funded by the U.S. National Institute of
Allergy and Infectious Diseases until 2013
Co-funded by the National Institute of
Mental Health and the National Institute of
Child Health and Development
Based at the University of Pittsburgh and
Magee-Womens Research Institute
18 clinical research sites in 7 countries
The MTN Mission
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To reduce the sexual transmission of
HIV through the evaluation of
products applied topically to mucosal
surfaces or administered orally
Presentation Overview
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Key concepts: ARV and resistance
PrEP Resistance: A one-act play
ARV-based microbicides
Oral PrEP
Is resistance a risk? How can we reduce
any potential risk?
Questions and open discussion
Key Concepts: HIV Life Cycle
1. Binding – HIV binds to T-cell via CD4 receptor.
2. Fusion – HIV fuses with cell, dumps contents.
3. Reverse Transcription – HIV genetic code (RNA)
changed into DNA by reverse transcriptase
enzyme.
4. Integration – HIV DNA is inserted into infected
cell's DNA by integrase enzyme.
5. Transcription – HIV DNA is transcribed (made
into) HIV RNA
6. Translation - HIV RNA is translated into proteins
7. Assembly and Release – Components of new
virus particles assemble and leave the cell.
HIV Life Cycle
1. Binding
2. Fusion
3. Reverse
Transcription
4. Integration
5. Transcription
6. Translation
7. Assembly
and Release
From IAVI: Vaccine Blueprint 2006
Key Concepts: ARVs
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ARVs are drugs to treat HIV designed to interfere with virus’s ability
to replicate
They are best used in combination,
i.e., anti-retroviral therapy (ART)
Different ARVs target different steps in
the HIV life cycle
Generally, ARVs are safe and effective
Key Questions
What is resistance?
How does it happen?
Are you concerned about it?
Why are you concerned?
Key Concepts: Resistance
Definition: ability of a microorganism to
survive and multiply in the presence of
drugs that would normally kill or weaken it.
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For HIV, drug resistance means the virus
is no longer sensitive to one or more ARV
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HIV is “resistant” to a medicine if it keeps
reproducing even while a person is taking
that medicine
Key Concepts: Resistance
How does it happen?
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The enzyme HIV needs to replicate is error
prone, resulting in mistakes (mutations)
Some mutations make the virus not
sensitive to a drug
The drug-resistant virus can now replicate
and take over other drug-sensitive virus
Resistant Virus: Like Hearty Weeds
What if you spray a garden with
weed killer that works only on
some weeds?
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The other weeds will thrive, grow
bigger and take over.
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The bigger weeds will get bigger
and bigger if the weed killer
continues to be used -- the weed
“killer” is like fertilizer for resistant
weeds.
How do we suppress resistance?
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Take away the “fertilizer” drug
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Introduce a new drug that
suppresses that HIV variant along
with the others
Resistance is not all doom
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Resistance is common in HIV-infected people
being treated with ART
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Where ART is widely used, 5-20% of new HIV
infections can involve drug-resistant virus
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Can be managed when detected early –
suppressed by other ARV combinations
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However, treatment options may be limited
for some types of resistance.
Resistance: A Play in One Act
The cast (in order of appearance):
HIV “wild-type” virus:
Audience volunteers
ARV #1: Lisa
HIV “mutant” (drug-resistant) virus:
Sharon
ARV #2:
Sean
Resistance: A Play in One Act
Scene 1 – Infection
Scene 2 – Treatment with ARV #1
Virus suppression
Scene 3 – Resistance
Scene 4 – Treatment with ARV #2
Virus suppression
Curtain Call (Audience Applause)
What just happened and why?
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The mutant virus was not sensitive to ARV#1,
allowing it to replicate and start taking over the
other virus sensitive to ARV#1.
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When ARV#1 was taken away, the mutant virus
no longer had an advantage and the wild-type
virus could replicate, increase in number and
become stronger than the mutant virus.
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ARV#2 worked to suppress all virus, including the
ARV#1 drug-resistant virus.
Will resistance be a problem?
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We don’t know
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No scientific or clinical information is
available about the nature or incidence
of resistance among those using ARVbased microbicides or oral ARVs for
prevention
What do we know?
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Resistant virus overtaken by sensitive virus
within weeks of stopping ARVs
 Monkey studies: virus initially transmitted
is usually not drug-resistant, but
resistance is more likely with time if the
PrEP ARV is continued
What do we know?
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Mothers who took single dose nevirapine for
pMTCT and developed nevirapine resistance: no
decrease in response to ARV treatment if initiated
after 6 months (Mashi Study)
Adding single-dose Truvada to the standard
method of preventing mother-to-child HIV
transmission is a “new, effective and feasible
approach to reducing maternal nevirapine
resistance.”
The Lancet 2007; 370:1698-1705
What do we know?
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Resistant virus overtaken by sensitive virus
within weeks of stopping ARVs
 Monkey studies: virus initially transmitted
is usually not drug-resistant, but
resistance is more likely with time if the
PrEP ARV is continued
Resistance with PrEP?
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Impact on future care for people infected
while on PrEP is unknown
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FHI trial in 936 HIV-negative women in
Ghana (primarily), Cameroon and Nigeria
with daily tenofovir:
 Tenofovir safe – no serious side effects
 8 seroconversions occurred: 2 in the
active arm and 6 in placebo arm
 HIV infections too few to draw
conclusions on efficacy
Moving Forward
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Resistance will be a risk associated with
being in a study like VOICE
We have some information from
different animal and human studies
suggesting how resistance may develop
in a participant
At the same time, much more research
is needed because we know very little
The risks are not considered high
enough to think that PrEP studies
should not be done
Microbicides
What about ARV-based
microbicides?
Evolution of the Microbicide Field
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Focus on potent antiretrovirals rather than
nonspecific inhibitors of HIV
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Development of microbicides for use
independent of the timing of sex:
 daily use
 sustained release delivery
Key Concepts: HIV Infection
Where different microbicides act
Shattock & Moore Nature Rev Microbiol 1:25-34, 2003
Many Microbicide Candidates
Pre-Clinical
Entry Inhibitors
Cyanovirin
BMS806
Plant lectins
New
Polyanions
ARV - NRTI
ARV - NNRTI
Safety
VivaGel
Pro2000
CAP
Carraguard
Polystyrene sulfate Buffergel
Tenofovir
DABO
MIV-150
Membrane active
UC-781
TMC-120
SLS
Unclassified
Bacteria
Combination
PC-815
Truvada
NRTI/NNRTI
NRTI/P
NNRTI/P
Efficacy
Praneem
Tenofovir
Tenofovir Gel
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Active ingredient is tenofovir, an ARV
Oral tenofovir has good safety profile
Gel has specific action against HIV
Low levels of drug in the blood
Low frequency of side effects
Farthest along in clinical testing of ARVbased microbicides
Tenofovir Gel: 8 Clinical Trials
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HPTN 050 – Phase I safety
HPTN 059 – Phase II expanded
safety/acceptability
Male tolerance
Tissue PK
CAPRISA 004 – Phase IIb
MTN-002 – Phase I PK (pregnant women)
MTN-001- Phase II (oral tenofovir and gel)
VOICE – Phase IIb
Tenofovir Gel - HPTN 059
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Phase II study assessing local and
systemic safety and acceptability of
tenofovir gel used daily or before sex over
6 months
Study completed in 200 sexually active
HIV- women at 3 sites in U.S. and India.
Results (at M2008):
 Daily use over 6 months not harmful
 Some women preferred daily use
Tenofovir Gel - MTN-001
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Phase II adherence and PK study
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Comparing 3 daily regimens (oral, vaginal, and
dual use) in 144 sexually active, HIV- women at 6
sites in Uganda, South Africa and U.S.
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Each regimen used for 6 weeks with 1 week off
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Differences in drug absorption (systemic and
local) to be evaluated at U.S. sites (48 women)
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Anticipate enrolling April/May/June 2008
Tenofovir Gel - MTN-002
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First microbicide study in pregnancy
Phase I study:
 How does pregnancy affect drug
absorption?
 Is the drug transferred to the fetus?
Tenofovir gel to be applied as one-time dose
in 16 HIV- women prior to scheduled
caesarean delivery
IRB approval pending minor modifications
Tenofovir Gel - MTN-003 VOICE
Vaginal and Oral Interventions to Control
the Epidemic (VOICE)
 Phase IIb safety & effectiveness trial,
5 study groups, 2 HIV prevention
approaches:
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Once-a-day ARV tablet (PrEP)
Once-a-day application of vaginal gel
4,200 women in Africa
Start date October 2008
VOICE Study
Two sequential randomizations.
Women will use product daily for average of 21 months.
TOTAL
SAMPLE
(4200)
Oral Pill
(2520)
Truvada
(840)
Tenofovir
(840)
Vaginal Gel
(1680)
Oral Placebo
(840)
Tenofovir
Gel
(840)
Placebo Gel
(840)
Why VOICE?
Tenofovir
Tenofovir Gel
Truvada
Which is safer?
Which is effective?
Which will women use?
ARVs used in PrEP (and VOICE)
Tenofovir
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NRTI approved for treatment of HIV-1
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Dose - 300 mg tablet taken once a day
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Used in combination with other oral agents
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Safety profile comparable to placebo
Also called Viread® or TDF
ARVs used in PrEP (and VOICE)
Truvada
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NRTI approved for treatment of HIV-1
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Combination drug - tenofovir and emtricitibine
(FTC)
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One tablet contains 200mg of FTC and
300 mg tenofovir, taken once a day
Also called Truvada®, FTC/TDF or tenofovir+FTC
Tenofovir Gel - CAPRISA 004
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USAID funded
Phase IIb study of tenofovir gel
Will enroll 980 women: family planning, STI
clinics, sex workers (3:2:1)
Screening started 18 May 2007
Regimen: Gel used within 12 hours before and 12
hours after sex;
max. 2 applications within 24 hours
Drug absorption studies are ongoing
Effectiveness studies
Prevention of HIV when gel used with sex
Prevention HIV when gel used daily
Tenofovir gel summary
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Studies completed in:
 HIV+ women – safety, 2 weeks use
 HIV- women – safety and acceptability,
6 months use
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Drug absorption, other safety studies ongoing
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Effectiveness studies ongoing or planned:
 Prevention of HIV when used with sex
 Prevention HIV when used daily
UC-781 Gel: 5 Phase I studies
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Active ingredient is UC-781
NNRTI type-ARV
Gel has specific action against HIV
Phase 1 studies underway
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Information on safety and acceptability
Pharmacokinetic studies underway
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Information on amount of drug absorbed
UC-781 Gel: 5 Phase I studies
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Safety and persistence in HIV- women
(NIAID/CONRAD)
Safety and acceptability in HIV- women and male
partners (CDC/CONRAD)
Safety and acceptability for rectal use in HIVmen and women (NIAID/CONRAD)
Male tolerance (CONRAD)
Safety and acceptability of 2 different doses in
HIV- women and acceptability in male partners
(CDC/CONRAD)
Dapivirine (TMC120)
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Active ingredient is dapirivine
NNRTI-type ARV
Gel has specific action against HIV
Dapivirine (TMC120)
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International Partnership for Microbicides
developing as gel and vaginal ring
Phase 1 and Phase 1/2 drug absorption,
safety and acceptability studies of both –
completed or planned
Phase III study planned
ARV-based Microbicides
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14 of 17 planned clinical trials are
ARV-based microbicides
(Alliance for Microbicide Development)
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Other HIV-specific compounds are in
the pipeline
ARV-based Microbicides and PrEP
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We’re in this together
What happens in PrEP trials can be
instructive
Resistance being studied in current
trials
Current PrEP Studies
Candidate
name
Sponsor Formulation /
Design
Population
Sites
Tenofovir
CDC
Once daily dose
Tenofovir
Phase III
2,000
injecting drug
users
Thailand
Truvada
CDC
Once daily dose
Truvada
Phase III
1,200 men &
women
Botswana
Tenofovir
CDC
Clinical safety and 400 men who United
behavior in once
have sex with States
daily dosing of
men
Tenofovir
Phase II
Truvada
NIH
Once daily dose
Truvada
Phase III
Switched from
tenofovir
3,000 men
Peru /
who have sex Ecuador/
with men
Other sites
Planned PrEP Trials
Candidate
name
Sponsor
Population
Sites
Start
Tenofovir
Truvada
Gates
3,900 HIV
discordant couples
Kenya and
Uganda
Early 2008
Tenofovir
Truvada
and
Tenofovir Gel
NIH
(VOICE)
4,200 heterosexual Southern Africa Mid 2008
women
Truvada
Gates/
USAID
3,900 high risk
women
Southern Africa 2008
Moving Forward Responsibly
We must minimize as much as
possible ARV exposure by a
woman who has become
infected.
The VOICE Study: Taking Precautions
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To avoid enrolling anyone who is already HIVinfected, all prospective participants will be
screened for HIV
Participants will have HIV tests every month.
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HIV infections will be diagnosed quickly
Study drug or microbicide will be stopped
immediately
Participants will only receive 30 doses of
study drug at a time
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Participants can’t keep taking study drug for more
than 30 days without coming in for an HIV test.
The VOICE Study: Taking Precautions
Participants who become HIV-infected:
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Resistance testing
 Indicates if person’s HIV is resistant to any
drugs
 Help healthcare providers decide which HIV
drugs will work best or to avoid
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Referred to local care and support services
 Medical care, including ART
 Psychosocial services
 Other programs, e.g., offered by CBOs
Invited into MTN-015
 Frequent lab tests can help local provider better
manage HIV care of participant
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Purpose of MTN-015
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Assess potential long-term effects of exposure
to study product among women who become
infected with HIV while taking part in MTN trials
 Characterize the natural history of HIV
infection and response to ART
 Assess differences in clinical progression
and response to ART among women
assigned to an active study product
compared to women assigned to a control
product (or to no product)
Take-home Messages
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ARV-based microbicides are promising for HIV
prevention – HIV-specific
Allow daily use, which may be more effective and
some women may prefer
As pills, ARVs safe for treatment
Resistance fairly common in treatment of HIV and
can be managed; lessons learned useful
We don’t know risks for prevention – need to be
honest about what we know, don’t know
We are being cautious – trials include several riskreduction measures
Thank You!
Key Concepts: HIV is Error Prone
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HIV makes many millions of copies of
itself in the body
The virus makes many mistakes when
copying its genetic information
This means many, many types or variants
of HIV existing in a person
Some of these variants are resistant to
drugs (drug-resistant)
Your Questions
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Will those who get infected have HIV
resistant to the ARV in oral PrEP or
ARV-based microbicide ?
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We don’t know anything for sure, but we will
monitor monthly for infection and stop gel or
oral PrEP as soon as infection is detected.
Will this affect their subsequent care
and choice of ARV treatment?
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We don’t know if this will be the same for
prevention as it is in the treatment setting
How will we talk about resistance?
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We will state clearly in the consent:
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If you become infected and continue taking
study drug you may develop resistant virus.
We think participants who take study drug
during an infection that hasn’t yet been
diagnosed will not likely be on study drug long
enough to hurt future treatment options, but
we cannot guarantee this.
The message will be repeated and explained
throughout the study.