Microbicides for HIV Prevention

Pamina M. Gorbach, Epidemiology & Infectious DiseasesUCLA

What is a microbicide?

….a product applied inside the vagina or rectum that are intended to protect against HIV though sex. Microbicides that incorporate antiretroviral (ARV) drugs are showing particular promise.

Microbicides First generation:

Gels & creams for rectum or vagina

Inserted daily or before and after sex

Current generation: Vaginal rings: Inserted and remain in place for > 1 month

Pills: PrEP (Pre-exposure prophylaxis)

Future: Injectables, film?

What Do Participants Need from HIV Prevention Methods?

To reduce risk of HIV and other STIs

To prevent pregnancy and not prevent pregnancy!

To be safe and non-irritatingTo be inexpensive and available over the counterTo be possibly used without partner’s cooperation or even awareness

Photo courtesy of http://www.mtnstopshiv.org/

If microbicides work…

1. Only taken if you KNOW you are HIV negative.So regular HIV testing is necessary.

2. May be available by prescription only.So access to a qualified health care provider is

necessary.

3. Different dosing is being tested in trials.These include application daily or before and

after sex.

Why would HIV+ people want microbicides?

Reduce risk of:

Infection with multiple strains of HIV

Infection with other STIs, yeast or bladder infections

Women can get pregnant while still protecting their partner from HIV.

Findings from Recent Microbicide Trials: Effectiveness – Do they work?

Who is doing the research?

Research entity Examples Funding sources

Not-for-profit health groups and academic institutions

MTN, CONRAD, FHI, CAPRISA

Governments (South Africa DST, US NIH, UK DFID), philanthropic foundations

Public-private partnerships

IPM European/US/Canadian governments, philanthropic foundations, UNFPA, World Bank

Smaller pharmaceutical companies

EndoStarPharma

Venture capital, some government grants

Outcomes of first trials – not good

Signs of efficacy No efficacy

SafeCarraguard®BufferGel®

PRO 2000 0.5%

Trend toward harm

Nonoxynol-9Savvy

Cellulose sulphate

FACTS 001: Follow-on African Consortium for Tenofovir Studies

Compared HIV infection rates between 2 groups of sexually active HIV-women aged 18–30 in nine sites in South Africa (n=2,059): those assigned a vaginal gel containing

tenofovir for use before and after sex those who received a placebo gel

New HIV infections occurred at the same rate in both groups: The HIV incidence was 4% in both groups

Showed that the results of CAPRISA 004 could not be replicated in a large study population comprising diverse women across South Africa.

In this trial, overall use of the gel by participants was low.

VOICE 2.0 (MTN 003)

5,000 Women

Tablet(3,000)

Vaginal Gel(2,000)

Truvada(1,000)

Tenofovir(1,000)

Placebo Tablet(1,000)

Tenofovir Gel(1,000)

Placebo Gel(1,000)

VOICE: Primary Efficacy Results.

Marrazzo JM et al. N Engl J Med 2015;372:509-518

Marrazzo, J. et al. Pre-exposure prophylaxis for HIV in women: daily oral tenofovir, oral tenofovir/emtricitabine, or vaginal tenofovir gel in the VOICE study (MTN 003). 20th Conference on Retroviruses and Opportunistic Infections. Atlanta. March 3 –6, 2013. Abstract #26LB.

Conclusions: VOICE Incidence of HIV substantially higher than

anticipated No study drug significantly reduced risk of HIV Adherence to study products was low, especially

among younger, unmarried women Results consistent with FEM-PrEP

Consider PrEP agents/delivery systems that are long acting and require minimal daily adherence

Understanding HIV risk perception and biomedical, social and cultural determinants of adherence in this high-risk population urgently needed

Marrazzo, J. et al. Pre-exposure prophylaxis for HIV in women: daily oral tenofovir, oral tenofovir/emtricitabine, or vaginal tenofovir gel in the VOICE study (MTN 003). 20th Conference on Retroviruses and Opportunistic Infections. Atlanta. March 3 –6, 2013. Abstract #26LB.

Rectal Microbicides

MSM Throughout the World Need HIV Prevention

Chandra A, Mosher WD et al. Sexual Behavior, Sexual Attraction, and Sexual Identity in the United States: Data From the 2006–2008 National Survey of Family Growth. National Health Statistics Reports n Number 36 n March 3, 2011

Anal Intercourse: Lifetime (ever)NSFG US General Population

Lubricants are Popular for AI

Peri-sexual behaviors: Rectal Douching Common

Rectal and Vaginal Mucosa Are Very Different

Histology ImmunologyMicrobiology

Differential susceptibility to candidate microbicides

MTN 017 A Phase 2 Randomized Sequence Open

Label Expanded Safety and Acceptability Study of Oral Emtricitabine/Tenofovir Disoproxil Fumarate Tablet and Rectally-Applied Tenofovir Reduced-Glycerin 1% Gel.

So Where Now?

MTN -017 Progress – Enrolled!

ASPIRE – Enrolled! Multi-site randomized controlled Phase III

trial of Dapivirine vaginal ring for HIV prevention

3,476 women enrolled in South Africa Phase I Safety Study of Post-Menopausal women in US completed

Phase I Safety Study of Adolescent girls in US (done with ATN) in process

59/96 enrolled.

Coming Up

Issues with Microbicides Many provide only partial protection : How will people

interpret this?

What will be best medication schedules (daily, weekly, activity-based, long-acting (30-90 days)?

How often & who will track: Adherence/consistent use Drug resistance New HIV infections by users (seroconversion)

Other Issues Who will get the products? Should adolescents?

Pregnant women? Transgender?

For how long should/could they be used?

Who will pay for them?

Will there be an increase in risk behavior?

Drug resistance from microbicides?

Most likely when using only one drug or one type of ARV.

Can become HIV+ while using microbicide.

Continued use (you don’t know you’re HIV+) may lead to resistance.

Options for treatment may be more limited—you might pass on resistant virus.

There are unanswered questions at this point.

In a nutshell: Acceptability

The Good News Rectal Microbicides looking promising Rings seem to have high adherence

The Bad News Some participants may not satisfied with current

product characteristics and dosing Adherence vastly under-reported & products not

used in trails enough to detect effectiveness

The “Ugly” news Not everyone (dis)likes the same things, and there

will need to be product choices

Creating Desire for Microbicides

To enjoy (the gel) first you need to

use it

Summary: State of the Science Vaginal gel---unclear effectiveness in preventing HIV in

women due to low adherence – not moving forward

Vaginal rings and injectables seem to show promise for women – under “Microbicides” umbrella

Rectal gel---shown to prevent HIV in Phase I trial in men and women

Cultural differences: African women may prefer a vaginal gel U.S. women may prefer a pill

Bottom Line: People may have choices!