MICROBICIDES AND OTHER PREVENTION TECHNOLOGIES

GITA RAMJEE

HIV Prevention Research Unit

Durban, South Africa

XVI International AIDS Conference, Toronto 13-18 August 2006

HSV-2 Suppressive

therapy

Testing and treatment of

genital infections (STIs)

Cervical Barriers: vaginal

diaphragms

Male circumcision

Exposure prophylaxis MTCTPEPPrEP

Immunisation: Vaccines

Voluntary Counselling and Testing (VCT)

Behavioural Intervention

(ABC)

HIV PREVENTION

Microbicides

MICROBICIDES: POTENTIAL FOR HIV MICROBICIDES: POTENTIAL FOR HIV PREVENTIONPREVENTION

Chemical products applied in the vagina to prevent HIV acquisition

Female-initiated

Early research on rectal application fo

Compelling evidence from monkey challenge studies:*0.5% PRO2000 – 0/7 macaques infected vs. 7/7 controls infected

**1% Tenofovir (48 hrs pre-challenge) – 0/10 macaques infected vs. 10/10 controls infected

Ref: *Tsai C-C, et al. Science 1995: 270:1197-1199; **Veazey RS et al.

Shattock RJ and Moore JP. Nature Reviews Microbiology, vol. 1 Oct/2003

Anti-HIV activity Toxicity

Activity against other STIs

Contraceptive/non-contraceptive options

MICROBICIDES: POTENTIAL FOR HIV MICROBICIDES: POTENTIAL FOR HIV PREVENTIONPREVENTION

++

+/-

+

+/-

Specificity to HIV

+++-++SurfactantsC31G (SAVVY)

+/-+-ARV-containingTenofovir, TMC120

+++-CS ++Entry InhibitorsCS, PRO2000, Carraguard

+++-++Acid Buffer BufferGel

Coitally Dependent

Systemic Absorption

ContraceptiveProduct

MICROBICIDES: MICROBICIDES: PRODUCTS IN PHASE IIB/III TRIALS

1stG

ener

atio

n2n

dG

ener

atio

n

Early-stage concepts

Pre-clinical development (30 - 40 candidates)

14 in early safety trials

5 in large-scale efficacy trials

Adapted from Alliance for Microbicide Development, Microbicide Watch 2006

MICROBICIDES: DEVELOPMENT PIPELINEMICROBICIDES: DEVELOPMENT PIPELINE

South Africa

Zimbabwe

Malawi

UgandaKenyaBenin

Nigeria

Tanzania

Zambia

Burkina Faso

CARRAGUARD

CELLULOSE SULFATE

2% & 0.5% PRO2000

BUFFERGEL & 0.5% PRO2000

C31G (SAVVY)

India

Philadelphia, USA

Ghana

MICROBICIDES: MICROBICIDES: GLOBALGLOBAL PHASE IIB/III TRIALSPHASE IIB/III TRIALS

Phase IIb/III Clinical Trial Update

USAID

USAID

USAID Gates Foundation

NIH

DfID

USAID

USAID Gates Foundation

Sponsor

May 20089 - 201395/2160FHI Cellulose Sulphate

Sept 2007122070/2142FHI SAVVY (C31G) - Nigeria

Study terminated

92142/2142FHI SAVVY (C31G) - Ghana

Dec 200718 – 436299/6629Population Council Carraguard

Apr 200917 – 281191/3220HPTN 035 BufferGel & 0.5% PRO2000

Dec 200920 - 381312/9673MDP 0.5% and 2% PRO2000

Dec 200910 - 55959/2600CONRAD Cellulose Sulphate

Expected Results

HIV Prevalence

%RecruitedTrial

MICROBICIDES: WHERE ARE WE NOW?MICROBICIDES: WHERE ARE WE NOW?

ARV-containing MicrobicidesMore specific

Longer acting

Vaginal Rings30+ days of drug delivery

Potentially reduces compliance burden

Easy to use

MICROBICIDES: New developments in Microbicides and Formulations

Ref: International Partnership for Microbicides

Lack of markers of protection

Adherence to product use

Trial conduct: pregnancy, retention, HIV incidence, cost

Ethics and care obligations

Note: Many of the same challenges in other prevention trials

MICROBICIDES: KEY CHALLENGESMICROBICIDES: KEY CHALLENGES

MICROBICIDES: MICROBICIDE DEVELOPMENT STRATEGY (MDS)

The MDS was initiated by the Microbicide Donors Committee

Year-long consultative process with key players in microbicide research and development

Purpose: To take stock of the current status of the field, identify gaps, and build consensus on current R&D priorities

Available at:Microbicide Alliance Booth Exhibition Hall Space #H-489, and at www.microbicide.org

CERVICAL BARRIERS: POTENTIAL FOR HIV PREVENTION

Women-initiated method

Proven safe, effective and acceptable contraceptive

Upper genital tract may be more susceptible to HIV infection – covering cervix may HIV infection

Observational studies – reduced STI infectionE.g: Rosenberg et al - Reduced risk of Gonorrhoea among diaphragm users, [OR, 0.32; CI: 0.16-0.45]

CERVICAL BARRIERS: VAGINAL DIAPHRAGM CLINICAL TRIAL

5045

Recruited

June 2007September 2006

12-24 months retention rate

= 87-92%

32%Durban Johannesburg

Harare

MIRA Vaginal Diaphragm with Replens N = 5045

Expected Results

End DateTrial Duration

HIV Prevalence

@ Screening

No. of SitesTrialUCSF Gates

Note: Challenges similar to microbicide trials

MALE CIRCUMCISION: POTENTIAL FOR HIV PREVENTION

Biological data on HIV risk reductionRemoval of HIV target cells from foreskin

Keratinisation of skin surface – rapid drying STI

Epidemiological evidenceHIV prevalence in circumcised men

Meta analysis (Weiss et al, 2000)

38 (mainly African) studies – circumcision risk of HIV

MALE CIRCUMCISION: CLINICAL TRIALS

912

9

7.3

HIV Prevalence (%)

2008780HIV (+) men

Women partners from both cohorts

HIV (-) men

HIV (-) men

Population

September 20072,784Kenya

4,035Uganda

Interim analysis Dec06

5000Uganda

End Date/ResultsRecruitedSite

Challenges

Safety and Ethical Challenges

Cultural and religious acceptability

From evidence to public health action

Auvert et al: HIV incidence: 0.85/100py (n = 20) in circumcised men vs. 2.1/100py (n = 49) in control; RR = 0.40 (95% CI: 0.24 – 0.65); p <0.001 – 60% protection

Ref: Auvert et al. PLos Med 2: e298. DOI: 10.1371/journal.pmed.0020298

PRE-EXPOSURE PROPHYLAXSIS (PrEP): POTENTIAL FOR HIV PREVENTION

Proof of concept, e.g. malaria, PMTCT

Candidates: Tenofovir & Truvada

Good safety profile in AIDS treatment

Once a day regimen

PrEP: CLINICAL TRIALS

21 months

MSMNot yet recruiting (6 July 06)

Peru (N = 1400)

Truvada (FTC/TDF)NIAID

2008/9Heterosexuals71Botswana (N = 1200)

Truvada (FTC/TDF)CDC

Gates

CDC

CDC

Sponsor

EndedHigh risk women400 Ghana, 400 Cameroon, 136 Nigeria

West Africa (N = 1200)

Oral Tenofovir (TDF)

211

1200

Enrolled

2008MSMUSA (N = 400)

Oral Tenofovir (TDF)

End date

Study PopulationSiteProduct

2008Male & Female IDUThailand (N = 1600)

Oral Tenofovir (TDF)

Safety and preliminary effectiveness of tenofovir disoproxil fumarate (TDF) for prevention of HIV infection in womenL. Peterson, D. Taylor, E.E.K. Clarke, A.S. Doh, P. Phillips, G. Belai, K. Nanda, R. Ridzon, H.S. Jaffe, W. Cates. XVI International AIDS Conference, 13 – 18 August 2006, Toronto, Canada Abstract No: THLB0103

Implications of breakthrough infections with resistant viruses for future therapy options

Level of adherence required?

Monitoring for adverse events

Acceptability of chronic medication for healthy people?

Potential for abuse of PrEP among those who cannot/will not use condoms

PrEP: KEY CHALLENGES

HSV-2 SUPPRESSIVE THERAPY: POTENTIAL FOR HIV PREVENTION

HSV-2 increases risk of HIV acquisition2-fold increased rate (Celum et al, 2004)

HSV-2 risk of transmission5-fold increase in per-contact risk due to GUD (Wald et al, 2004,

Corey et al, 2004)

HIV impacts on natural history of HSV-2 – frequent sub-clinical occurrences

HSV-2 associated with HIV viral load0.3 log plasma HIV viral load in early HIV (Duffus et al, 2005,

Schacker et al, 2001)

20082007Anticipated completion

70% (2100 couples)100% (3277 participants)Status of enrollment

HIV transmissionHIV acquisitionPrimary endpoint

3000 HIV discordant couples (6000 participants)

3277 participantsSample size

Daily Acyclovir or placeboHIV discordant couples

(HIV+ partner is HSV-2+)14 sites in Africa

Daily Acyclovir or placeboHIV-, HSV2+ MSM &

women 9 sites (US, Peru, Africa)

Study Design

Effect of HSV-2 on HIV infectiousness

Effect of HSV-2 on HIV susceptibility

Objective

Partners in Prevention (Gates Foundation)

HPTN 039 (NIH)

HSV-2 SUPPRESSIVE THERAPY: CLINICAL TRIALS

HSV-2 SUPPRESSIVE THERAPY: KEY CHALLENGES

Adherence

Continuous vs. episodic treatment

Potential for emergence of HSV-2 resistance

IMPACT OF NEW TECHNOLOGIES ON HIV PREVENTION

Microbicides – 60% effective product could avert 2.5 million new HIV infections in middle to low income countries(1)

Male circumcision – widespread implementation in Sub-Saharan Africa could avert 2 million new HIV infections over the next 10 years(2)

Cervical barriers – inexpensive, registered, women-initiated – impact on reduction of HIV among women

PrEP – reduction of HIV in high risk individualsHerpes suppressive therapy – lower HIV acquisition and

transmission

Ref: 1. Public Health working group: model projects 20022. B. Williams et al; The potential impact of male circumcision on HIV in Sub-Saharan Africa.

PLoS Med 206:3:e262

FUTURE CHALLENGES IN NEW HIV PREVENTION TECHNOLOGIES

Contextualize policy development for appropriate local action

Link to scale-up of VCT

Managing the behavioural disinhibition

Maintaining high levels of adherence

Operational research and feasibility

Regulation and licensure

Access and Affordability

Acceptability

Service provider education

Monitoring and evaluation

Promote collaboration to ensure optimal use of resources

Prioritizing research with promising public health impact

Addressing future clinical trial design

Choice of control interventions

Ethical issues

PUBLIC HEALTH IMPLEMENTATION FUTURE RESEARCH

PROVEN PREVENTION METHODS

BARRIER METHODS

(Male & Female Condoms)

MTCTVCT

BEHAVIOURAL CHANGE

BARRIER METHODS

(Male & Female Condoms)

MTCTVCT

BEHAVIOURAL CHANGE

HSV-2 SUPPRESSIVE

THERAPY

PrEP

MICROBICIDES

CERVICAL BARRIERS (Vaginal

Diaphragms)

MALE CIRCUMCISION

NEW TECHNOLOGIES

BARRIER METHODS

(Male & Female Condoms)

MTCTVCT

BEHAVIOURAL CHANGE

HSV-2 SUPPRESSIVE

THERAPY

PrEP

MICROBICIDES

CERVICAL BARRIERS (Vaginal

Diaphragms)

MALE CIRCUMCISION

IMPACT ON HIV EPIDEMIC

Lead

ersh

ip &

sca

ling

up

of

trea

tmen

t/pr

even

tion

eff

orts C

omm

un

ity involvem

ent

Enhanced by synergistic use of social, behavioural, biomedical and barrier methods

AbstainBe

FaithfulCondomise Counselling & Testing

A B C

CDEFG H I

Circumcision

Diaphragm

Exposure prophylaxis (pre- and post)

Female-controlled microbicides

Genital tract infection control

HSV-2 suppressive treatment

Immunity

ACKNOWLEDGEMENTMicrobicide Clinical Trials

Population Council

HPTN 035

Microbicides Development Programme (MDP)

CONRAD

Family Health International (FHI)

PrEP Trials

Centers for Disease Control (CDC)

Family Health International

HSV-2

Connie Cellum

Male Circumcision

Bertran Auvert

Stephen Moses

Ron Gray

Maria Wawer

Salim Abdool Karim, Tom Coates, Ward Cates, Renee Ridzon

Vaginal Diaphragm Trial

University of California, San Francisco

THANK YOU