Microbicides: Science, research, and overview of the field Dr Kamini Walia, Indian Council of Medical Research, New Delhi Bindiya Patel, Global Campaign for Microbicides

A "microbicide" is any substance that can substantially reduce transmission of sexually transmitted infections (STIs) and HIV when applied either in the vagina or rectum.

Why Microbicide? Many women acquire HIV or STDs from a steady partner Consistent condom use difficult to achieve in the longer term relationships Few interventions have achieved consistent use in more than 30% of couples Contraceptive aspect of existing prevention methods is a major barrier to their use

The search for the ideal microbicide Rationale: Unprotected Sex-reproduction, coercion, pleasure Active against a range of sexually transmitted pathogens Not irritating to mucosal surfaces +/- spermicidal formulations Acceptable (odor, color, taste, lubricity, portability, “stealth factor”)

Imagine a Full Spectrum of Interventions Prior to exposure Point of transmission Treatment Male and female condoms and lube PMTCT Clean injecting equipment PEP Vaginal and rectal microbicides Cervical barriers Anti-retroviral treatment Treatment for opportunistic infections Basic care/nutrition Prevention for positives Education and behavior change Therapeutic vaccines Rights-focused behaviour change VCT STI screening and treatment Male circumcision Preventative vaccines PREP

Science and Research Overview

What is the most critical need in research? Proof of Concept There is no definitive data as yet establishing that any product applied topically in humans can prevent HIV infection. There is no definitive data as yet establishing that any product applied topically in humans can prevent HIV infection.

Desirable Properties of an Ideal Vaginal Microbicide Retain activity in the presence of semen and over a broad pH range, ideally for several hours Products must not disrupt the normal vaginal flora Agents and vehicles for delivery must be compatible for use with condoms and delivery systems Ensure adequate distribution and retention in vagina

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

Steps in research Drug discovery Drug discovery In vitro testing In vitro testing Animal model testing (safety) Animal model testing (safety) Formulation Formulation Scale up manufacturing Scale up manufacturing Phase I early safety Phase I early safety Phase II expanded safety Phase II expanded safety Phase IIb Phase IIb Phase III efficacy Phase III efficacy Social science research Social science research

Laboratory Testing 2-6 Years Phase III (efficacy) 2 to 4 Years Simultaneous studies in some cases: HIV+, penile & rectal safety 10 or more years 3 products 4 products 30+ products Phase I (safety) 1 to 6 Months Phase II (safety) Up to 2 Years 25 – 40 people people 3,000-10,000 people The Product Pipeline in 2008 Source: Alliance Pipeline Update, first week of every month -

Clinical Trial Sites in 2007 AUSTRALIA - Phase I WEST AFRICA: -Cameroon: Phase I, II THE AMERICAS: -United States: Phase I, II, IIB -Brazil: Phase II 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 ASIA -India: Phase II -Thailand: Phase I Source: Alliance for Microbicide Development EUROPE - Belgium: Phase I/II

Products Furthest Along Product Trial sponsor # women to be enrolledLocation Preliminary results expected in Buffer Gel HPTN035-NIH 3,100 women South Africa, Malawi, Zambia, Zimbabwe and Philadelphia April 2009 Carraguard Population Council 6,202 women South Africa – 3 locations Feb 2008 PRO2000 (.5%) HPTN035-NIH 3,100 women South Africa, Malawi, Zambia, Zimbabwe and Philadelphia April 2009 PRO2000 (.5 and 2%) DFID, MRC 9,763 women South Africa, Uganda, Zambia, Tanzania December % Tenofovir Gel CAPRISA 980 womenSouth Africa2010

Experience of a Phase III Participant 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, counseling, reinforce education about trial Randomization: Participant assigned by chance to a group. Family Planning Informed consent for screening Informed consent to enroll. Condoms + comparator gel Condoms + experimental gel

Microbicides which are antiretrovirals Have high specificity and potency Have high specificity and potency Not effective against other STIs Not effective against other STIs Potential for drug resistance with a single drug Potential for drug resistance with a single drug

The case for combination microbicides The arguments for using inhibitors in combination for prevention are as strong as they are for treatment. Increased breadth of coverage against divergent strains. Possible synergy, creating dose-sparing effects. Reduced probability of transmitting viruses resistant to any single inhibitor. BUT the approval process not yet clear

When can we expect a microbicide? Earliest results from current Phase III trials in Earliest results from current Phase III trials in If shown to be effective, a microbicide may be available in a few countries via introductory studies in the next 5 years 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

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 Actors in the Microbicides Field

Range of Players Researchers (lab, trials, social science) Researchers (lab, trials, social science) Trial sponsors Trial sponsors Funders Funders Advocates Advocates

Who is doing Microbicide R&D? Public–sector entities Public–sector entities Non-profit research entities Non-profit research entities Small biopharmaceutical companies Small biopharmaceutical companies Large pharmaceutical have steered clear… Large pharmaceutical have steered clear… o o Perceived low profitability o o Lack of proof of concept o o Few expert in vaginal products o o “Developing world” considered to be primary customers

Who is paying for this work? Public institutions (86%) Public institutions (86%) Philanthropic sources (12%) Philanthropic sources (12%) Commercial sector (2%) Commercial sector (2%) Total of US $222 Million in

Indian players ICMR: NARI, Pune, NIRRH, Mumbai ICMR: NARI, Pune, NIRRH, Mumbai CSIR:CDRI, Lucknow CSIR:CDRI, Lucknow DRDO:DIPAS, New Delhi DRDO:DIPAS, New Delhi YRG, Chennai YRG, Chennai Indian Network of NGOs Indian Network of NGOs

Advocacy Aims Sufficient resources for the entire field R&Ds Social science research Advocacy Community involvement Community and political support so that trials can take place Individuals and communities have a voice in the decisions that affect their lives Access to products once they are available

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