Microbicides:

New Hope for Prevention of HIV and other STIs

Pamina M. Gorbach UCLA- SPH & Medicine

The Global Impact of HIV Worldwide

Sub-Saharan Africa Asia & Eastern Europe North America & Western/Central Europe Other People living with HIV in 2006

39.5 million

24.7 million 10.25 million 2.14 million 2.49 million New infections in 2006

4.3 million

2.8 million 1.23 million 65,000 242,100 Women are disproportionately affected by AIDS: In Sub-Saharan Africa, young women are 4 times more likely to be infected than young men.

Why We Need Female Controlled Methods

Biology

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Women are 2-4 times more likely than men to get HIV from unprotected sex Economics

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Economic need or dependency

–

Less able to assert their rights Social & Cultural

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Gender norms about sexuality

–

Gender based violence Current methods (abstinence, fidelity, and condom use) often require male consent, participation & cooperation

Protection in Primary Partnerships: Difficult to Achieve

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People generally are willing to to use condoms with new partners, or during casual or commercial sex

•

But once “trust” enters the equation the condom comes off

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Sex with a primary partner is the biggest source of HIV infection among women globally

What is a Microbicide?

A substance that can reduce the transmission of HIV and other STI pathogens when applied topically to genital mucosal surfaces vaginally and, possibly, rectally.

They are not yet available.

First Generation:

• Gels and creams

In the future:

• Sponges, vaginal rings • Gels with barrier devices •Possibly use of oral antiretroviral therapy, (tenofovir), for pre exposure prophylaxis (PrEP) to prevent HIV infection.

What Do We Need from Microbicides?

•

To be contraceptive and non-contraceptive

•

To reduce risk of other STIs

•

To be safe and non-irritating

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To be inexpensive and available over the counter

•

To be possibly used without partner’s cooperation or even awareness

How could microbicides work?

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Kill/inactivate/immobilize the virus

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Boost body’s natural defenses

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Prohibit viral entry by blocking fusion

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Inhibit viral replication

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Create a physical barrier

or some combination of these approaches

1. boosts vagina’s natural defenses - Buffergel 2. surfactants 4. anti-retrovirals =Tenofovir, UC781, TMC120 3. entry inhibitors = CS, Carraguard, Pro2000 Source: Shattock, R.; Moore, J. Inhibiting Sexual Transmission of HIV-1 Infection . Nature Reviews Microbiology. Vol 1, October 2003.

MICROBICIDES IN CLINICAL TRIALS May ‘07

© Alliance for Microbicide Development

3 Products Furthest Along

Product

Trial sponsor

Buffer Gel

HPTN035-NIH

Carraguard

Population Council

PRO2000 (.5%)

HPTN035-NIH

PRO2000 (.5 and 2%)

DFID, MRC

# women to be enrolled

3,100 women 6,299 women

Location

South Africa, Malawi, Tanzania, Zambia, Zimbabwe and Philadelphia South Africa – 3 locations

Preliminary results expected in

April 2009 December 2007 April 2009 3,100 women 9,673 women South Africa, Malawi, Zambia, Zimbabwe and Philadelphia South Africa, Uganda, Zambia, Tanzania December 2009

Planned Microbicide Trials

There are 11 microbicide candidates in clinical development and over 30 in preclinical development

How Effective Will Microbicides Be?

First microbicides may be

40-60%

protective

Second

generation may be

60-80%

Promoted as a

back-up

replacement.

to condoms, not as a

“Use a microbicide with your condom for added pleasure and protection.” “Use a male or female condom every time you have sex; if you absolutely can’t use a condom, use a microbicide.” The Economics of Microbicide Development: A case for investment. THe Rockefeller

Potential Public Health Impact

If a 60% effective product Offered to 73 lower income countries Is used by 20% people reached by health care during 50% of unprotected sex acts = 2.5 million HIV infections averted in 3 years including women, men and children

The Product Pipeline in 2007 3 products 3 products 4 products 30+ products

Phase I (safety) Phase II (safety) Phase III (efficacy) Laboratory Testing 2-6 Years 1 to 6 Months

25 – 40 people

Up to 2 Years

200-400 people

2 to 4 Years

3,000-10,000 people

Simultaneous studies in some cases: HIV+, penile & rectal safety 10 or more years Source: Alliance Pipeline Update, first week of every month - http://www.microbicide.org/publications

Clinical Trial Sites in 2007 THE AMERICAS:

-United States: Phase I, II, IIB -Brazil: Phase II

EUROPE

- Belgium: Phase I/II

WEST AFRICA:

-Cameroon: Phase I, II

ASIA

-India: Phase II -Thailand: Phase I

AUSTRALIA

- Phase 1

SUB-SAHARAN AFRICA:

-Botswana: -Kenya: planned -Madagascar: Phase -Malawi: Phase II, IIB -Rwanda: Phase I/II -South Africa: Phase I, IIB, III -Tanzania: Phase III -Uganda: Phase III -Zambia: Phase IIB, III -Zimbabwe: Phase I, II, IIB Source: Alliance for Microbicide Development

When can we expect a microbicide?

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Earliest results from current Phase 3 trials in 2008-2009

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If shown to be effective, a microbicide may be available in a few countries via introductory studies in the next 5 years

• If not, we will have to wait for results from second generation products

The Microbicide Trials Network (MTN) is a worldwide collaborative clinical trials network that evaluates the safety and efficacy of microbicides designed to prevent HIV transmission and will support licensure of topical microbicide products. The MTN plans to develop and/or execute 15 separate clinical trials of microbicides between 2006 and 2013.

Network led by Sharon Hillier at Magee Women’s Health Foundation/U Pitts: Dr. Ian McGowan is a Co-principal investigator. PMG – Chair of Behavioral Research Committee

Topics on BRC Scientific Agenda: Adherence & Acceptability

Topic Measurement

Context Partners Microbicide Administration Biomarkers Pregnancy Measurement approaches for contexts of microbicide use Partner types and relationship dynamics Methods Use of biomarkers for comparison with or validation of behavioral measures of adherence Pregnancy intentions at screening, affects of trial participation at individual and community level

Experience of a Phase III Participant Family Planning

Informed consent for screening Informed consent to enroll.

Condoms + experimental gel Recruitment: Participant receives information about the trial in their own language Screening Visit 1: Education about the trial, HIV and pregnancy test, STI tests and treatment, baseline data collected Screening Visit 2: Results of tests, counselling, reinforce education about trial Condoms + placebo Randomisation: Participant assigned by chance to a group.

Handheld screen with 035 adherence question (n=400 in Malawi

Courtesy of Barbara Mensch, Population Council

Malawi – Pop Council School Study

Courtesy of Barbara Mensch, Population Council

Microbicide Research in LA

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Focus on rectal microbicide development

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Principle research effort led by UCLA:

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Microbicide Development Program (MDP) – U19 funded by NIAID

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Preparedness:

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NARLA: Project 2 -

Rectal Microbicides

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Many people (women and men) need microbicides for anal intercourse

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Creating an effective rectal microbicide is scientifically more complicated

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Vaginal microbicides must be accurately labeled

Photo courtesy of www.lifelube.org

•PI: Peter Anton & Ian McGowan.

Collaborative

effort with NIH and industry to initiate multidisciplinary research on rectal microbicides through multiple projects including:  Preclinical Evaluation of HIV Rectal Microbicides  Rectal Health, Behaviors and Product Acceptability  Phase I trial of a rectal microbicide UC-781 a reverse transcriptase (RT) microbicide •

These studies are designed to help develop a product that people will find acceptable and actually use. Findings will help guide the selection of the formulation used in human trials.

Rectal Health, Behaviors and Microbicide Acceptability – U19 Project 3 - Gorbach

Two Components: (1) Integrated behavioral and clinical study of receptive anal intercourse (2) Applicator method acceptability (preference) study

•

2 sites: LA, Baltimore

“AMP” Ano-rectal Microbicide Project

896 participants ½ in LA ½ men & ½ women ½ HIV positive ½ report recent RAI All complete: STI/HIV testing HRA Clinical exam Behavioral Questionnaire Already ~ 219 studied!

• • • • •

Why This Study? Preparedness…

Rectal microbicides are in development. The public knows little about rectal microbicides.

There will soon be clinical trials of rectal microbicides that will need participation from those who need and will use them. A Phase I trial started in LA (U19).

There is a need for specially designed materials to introduce the public to rectal microbicides (both within clinical trials and beyond) to optimize their value as a method of HIV prevention. Preliminary work with communities is necessary to prevent misinformation and enhance acceptability.

Study Goals

1. Assess the best

format

to deliver educational materials about rectal microbicides to potential participants in clinical trials, and 2. Consider potential barriers to microbicide trial participation by analyzing factors that facilitate enrollment and retention in a microbicide trial registry in a cohort of men in Los Angeles N=>106 already!

Total cohort 450 men

Materials Developed (Video & Brochure) in LA in 2006

Community sites: Friends, APLA, UCLA-CARE

What if microbicides don’t work?

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Build on the lessons in development of new technologies – process is iterative.

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But….keep perspective. Failure of one product that utilizes one mechanism of action in microbicide does not mean all microbicides are doomed. Many other products and other mechanisms in the pipeline

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Future microbicide will likely use combination mechanisms and will likely include coitally & non coitally dependent methods

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Setbacks may happen but science must move forward – there is an epidemic…

Imagine a Full Spectrum of Interventions Prior to exposure Point of transmission Treatment

•Rights-focused behaviour change •VCT •STI screening and treatment •Preventative

Vaccines

•PREP •Male circumcision •Male and female condoms and lube •PMTCT •Clean injecting equipment •Vaginal and rectal

microbicides

•Cervical barriers •PEP •Anti-retroviral treatment •Treatment for opportunistic infections •Basic care/nutrition •Prevention for positives •Education and behavior change •Therapeutic vaccines

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The global and local need for microbicides is urgent as women and men continue to become infected and suffer from HIV

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There are vaginal & rectal microbicides in clinical trials now

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Microbicides offer great potential to impact HIV epidemics –one more prevention tool - self not partner controlled