Transcript Optimism or pessimism in microbicides research?

Optimism or pessimism in
microbicides research?
Anatoli Kamali
MRC/UVRI Uganda Research Unit
on AIDS
Introduction
• Microbicides: products designed for topical
application (vaginal or rectal) to reduce
HIV/STIs
• Women at higher risk of HIV infection
– transmission dynamics
– inability to negotiate safer sex e.g. condoms
– condoms infrequently used among couples –
desire to conceive
• Microbicides viewed as a Female controlled
method
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12
16
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HIV Prevalence with 95% CIs, by Gender (20-24 yr olds)
1990
1992
1994
1996
1998 2000 2002
Survey Year
Prevalence(Male)
95% CIs (Male)
2004
2006
Prevalence(Female)
95% CIs (Female)
2008
“Female-controlled” concept
• Advantages:
– self insertion before sex
– could be left in place after sex
– effective for multiple intercourses
– men “unaware” and no consent required
– potentially prevent other STIs
– increase sexual pleasure
APPLICATION INSTRUCTIONS
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Role of men in microbicides
• Microbicide gel also increase sexual
pleasure in men – in communities where
“dry sex” is not popular
• A role in stable relationships e.g discordant
couples
Acceptability studies
Safety and acceptability
studies
Summary of findings
• Carraguard: safe and acceptable among
Thai women up to x4/week with or
without sex warranting phase III efficacy
trial
• PRO 2000 (0.5% and 2%): safe and well
tolerated, justifying large-scale
effectiveness trials
Safety and acceptability of
penile applications
• BufferGel and PRO 2000 Gel daily (7 days)
application to the penis
– safe and well tolerated among healthy lowrisk men and HIV-positive men (Stephens et
al. JAIDS: 2003;33:476-83)
• Acceptable safety profiles
• Encouraging safety and acceptability data
both in women and men justifying largescale efficacy trials in various populations
• Optimistic that efficacy trials would show
protection
Three generations of
Microbicides
• 1st generation: Nonoxynol-9 and Savvy
– Surfactants disrupt microbial cell membranes
– Vaginal defence enhancers (BufferGel)- maintain or
boost the acidity of the vagina
• 2nd generation: (PRO2000, Carraguard, CS)
– entry inhibitors block cellular receptors and prevent
HIV from attaching to and infecting target cells
• 3rd generation: ARV-based (tenofovir gel,
dapivirine, and UC-781)
– prevent HIV from replicating once inside a cell
First generation products
• No effect on HIV transmission
• Nonoxynol-9: Evidence of toxicity that
enhanced HIV transmission particularly
among frequent users of gel (Lancet
2002; 360: 971–77)
Second generation products
• Cellulose sulphate: A high rate of HIV
acquisition - 25cs/16p 1.61 [0.86-3.01]
(N Engl J Med 2008; 359: 463-72)
• Carraguard: No effect on HIV transmission
134c/151p 0.89 [0.7-1.13] Lancet 2008;
372: 1977–87
Summary
• No effect on HIV/STI transmission
• Evidence of toxicity and increased risk of
transmission with some products
• “Worrying findings” to scientists, advocacy
groups, policy makers and funding
HPTN 035 Phase II/IIB trial
• 4 arm trial in 4 African countries and USA
• PRO 2000 gel, buffer gel, placebo gel
and no gel arm
HPTN 035 results
• Presented at CROI 2009; AIDS 2011;
25:957-66
• HIV incidence rates:
– PRO2000: 2.7 [1.9-3.7];
– Buffer gel: 4.1 [3.1-5.4]
– Placebo: 3.9 [2.9-5.1]; No gel: 4.0 [3.0-5.3]
• PRO2000 gel: HR 0.70 [0.46-1.08], p=0.10
• Buffer gel HR: 1.10 [0.75-1.62], p=0.63
HPTN 035 PRO 2000 trial
results
• “The results on PRO2000 are a ray of
hope for women“
• “A glimmer of hope for a possible proof
of concept”
• “MDP 301 should help refine estimate of
how effective PRO2000 actually is, x 3
number of women, will yield an even more
precise estimate of effectiveness”
MDP 301 trial
•
HIV-negative women
A phase 3 trial (20052008), enrolled 9385 at
13 clinics, at 6 research
centres in four African
countries under the
MDP
MDP 301 trial
• Efficacy and safety of 0.5% and 2% PRO
2000 gels
• Feb 2008, IDMSC stopped the 2% gel
arm (futility)
• Recommended 0.5% gel arm to continue
0.5% PRO 2000 gel
• Incidence 4.5 [3.8-5.4]; placebo 4.3 [3.65.2], HR 1.05 (0.82-1.34)
Why lack of efficacy of PRO
2000 gel?
• Well demonstrated anti-HIV activity in
preclinical studies
• Post coital diminished anti-viral activity (PD)
and lower concentrations (PK) of PRO 2000
gel (Keller PLoS ONE 2010;5:e8781)
– Semen, cervico-vaginal secretions and sex
activity
• Lower concentration of products in vagina
and mucosa than predicted
Next generation microbicides
• ARV-based microbicides offer optimism
• 1% Tenofovir gel
• Dapivirine gel and ring
• Maraviroc
1% Tenofovir gel acceptability
• Kenneth et al, AIDS 2006; 20:543-51
– 2-week course of 1% tenofovir vaginal gel 2x
daily was well tolerated in sexually abstinent
and sexually active HIV-negative and HIVpositive women
• Rosen et al. J Women’s Health 2008; 17:
383-92
– Tenofovir gel among women in a Phase I Trial
was well acceptable to almost all users
CAPRISA-004
• 1% tenofovir gel – coitally dependent regimen (BAT24)
• HIV: overall 39% reduction (6-61%, p=0.017)
• HSV-2: 51% reduction (95% CI 22%-70%, p=0.003)
• “Proof of concept”, an exciting milestone and
historic results!
CAPRISA 004 effectiveness by
adherence
• High adherers (>80% gel use): 54% lower,
p=0.025
• Intermediate (50-80% gel use): 38% lower,
p= 0.34
• Low (< 50% gel use): 28% lower, p=0.30
• Need to achieve high Tenofovir vaginal
concentrations
Post CAPRISA 004
• WHO/UNAIDS meeting – priority next
steps
– Additional safety studies e.g among young
women
– FACTS trial to confirm findings (same
regimen)
– Simplified dosing and less frequent HIV
testing (MDP 302)
FACTS 001, South Africa
• Phase III testing 1% tenofovir gel, same
regimen as CAPRISA 004
• Launched October 2011 and results
expected 2014
MTN-003 (VOICE)
• Safety and effectiveness among women
• Daily 1% Tenofovir gel, oral Tenofovir and
Truvada once a day
Oral tenofovir and gel safe but not
effective against HIV transmission
Oral Truvada arms continues, late
2012
“Disappointing findings and a large
blow to the HIV prevention field!”
Conflicting CAPRISA and
VOICE results
• Same product 1% Tenofovir
• Different dosing regimen daily vs BAT24
• Possible explanations, but no answers yet
– Adherence levels
– Drug levels in genital tract
– Risk behaviours of trial participants
– Will be available at end of VOICE trial
Other microbicide formulations
• Gel formulations been mainly evaluated as
“coitally-dependent”
• “Coitally –dissociated” formulations – offer
sustained delivery (IVR, injectable,
implants)
– IVR most advanced of all
Why a ring?
• Long-acting: monthly or longer
– improve adherence, hence better effectiveness
• Easy to use, comfortable
– Flexible ring, can be self-inserted
– Rarely felt by women or their male partners
– Little or no impact on sexual activity
• Suitable for developing world
– low manufacturing cost
– Good safety and acceptability data
• Potential for drug combinations
Rectal microbicides
• Anal sex is a risk factor for HIV infection in
both men and women
• Rectal mucosa different from the vagina and
more vulnerable to HIV
– single cell layer thick; contains many more CD4
receptors; more alkaline pH which is less
protective than the acidic vaginal pH
• Rectal tract has greater surface area
the Future ….
• Requires both vaginal and rectal products
• Research is required to find the right drug
at the right and in the right place
• Require a lot of support from funding
agencies
• ARV-based combination products
• Challenges: drug toxicity, resistance
Combination Microbicides
• Advantages:
– Potential increased efficacy
– Potential synergy and need for less drug
• Possible disadvantages
– Difficulties in co-formulation
– Increased cost
– Potential for toxicity and resistance
Combination Microbicides
• Various combinations in development
– Dapivirine/Tenofovir ring
– Dapivirine/Maraviroc gel, film and ring form
Conclusions
• Data supports that high gel and condom
use
– Gel: 96.2% Carraguard, 95.9% placebo
– Condom: 64·1% in both groups at last sex
– MDP 301, mean reported gel use was 89%
and condom 55-57%
• ? Consistent gel use in real world
Conclusions
• More potent ARV-based products and new
formulations
• Long term effects of IVR
– could disturb the vaginal environment and
increase HIV acquisition risk?
• Need to keep major donors interested and
political will
• Optimistic that a microbicide dream will be
a reality and turn the HIV epidemic in
women and men
Optimistic
• A dream to a reality of a safe, effective
and affordable microbicide
• “All our dreams can come true, if we have
the courage to pursue them”
• Together we can turn the HIV epidemic in
women and men
Acknowledgements
• Funders: MRC (UK), DFID, other agencies
• Allan Stone, Annalene Nel, Elizabeth
Bukusi, Janneke van de Wijgert and
Sheena McCormack