Microbicides and HIV prevention in women: the state of research

HIV Australia | Vol. 13 No. 2 | July 2015

Jennifer Power

Jennifer Power says that disappointing microbicide trial results among women to date are a reflection of HIV stigma and the complex realities of women’s lives.

Earlier this year in Seattle Washington, participants at the Conference on Retroviruses and Opportunistic Infections eagerly awaited the first public announcement of results from the FACTS 001 microbicide trial.

The FACTS 001 trial – named after the Follow-on African Consortium for Tenofovir Studies (FACTS)¹ who were running the trial – was a large-scale clinical trial of a microbicide gel containing the antiretroviral drug tenofovir.

The FACTS 001 trial involved over 2000 HIV-negative young women from South Africa. Each participant was randomly assigned to the intervention group (receiving the tenofovir gel) or the control group (receiving a placebo gel).

Participants were asked to insert the gel into their vagina prior to and after sexual intercourse while continuing their usual safe-sex and contraceptive methods.

Unfortunately, over the course of the trial, which ran from October 2011 until August 2014, 123 participants acquired HIV and there was no difference in the rate of new HIV infections in the tenofovir gel group compared with the placebo group. This was a disappointing result.

Microbicides are products, usually a gel or cream, inserted into the vagina or rectum prior to, and after, sex to help reduce the risk of HIV infection.

Microbicide research been strongly encouraged by women’s health advocates because – if proven to be effective – it offers an HIV prevention method over which women would have control.

Unlike condoms, microbicides do not need consent or cooperation from a male sexual partner; the male partner may not even know a microbicide is being used.

In countries where there are numerous cultural barriers to condom use, or where women may have less power or capacity to insist on safe sex, products such as microbicides could become central to reducing HIV transmission rates.

But, do microbicides work?

The idea for an HIV microbicide was inspired by the spermicide product Nonoxynol-9 (N-9), the active ingredient in many contraceptive gels.

However, trials of N-9 for HIV prevention conducted back in the mid-1990s indicated that not only did N-9 not prevent HIV, it actually made women more susceptible to HIV infection by stripping away natural barriers within the vagina.

Following this, trials for other forms of microbicides, including products which aimed to create a barrier around target cells or strengthen natural defences within the vagina, have not proven to be effective.

However, the latest generation of microbicides, which contain antiretroviral drugs such as tenofovir, appear to be more clinically effective.

These microbicides work by preventing HIV from reproducing and establishing an infection if it enters the body.

A trial conducted in South Africa between 2007 and 2009, the CAPRISA 004 trial, found tenofovir gel reduced the rate of HIV infection among women by 39%.²

These results have not been replicated in larger studies. The VOICE trial (short for the Vaginal and Oral Interventions to Control the Epidemic) was a major trial of tenofovir gel conducted across Uganda, South Africa and Zimbabwe between 2009 and 2011.³

Similar to the FACTS 001 trial, the VOICE study found no difference in HIV infection rates between women using tenofovir gel and those using the placebo.

This was not necessarily because the tenofovir gel did not work from a clinical or biomedical perspective. Rather, neither of these studies could demonstrate efficacy of the gel because many women enrolled in the trials simply did not use it.

In the VOICE trial, the average rate of adherence to the gel was only 25%.⁴

In both trials, HIV infection rates were lower among women who used the gel consistently, suggesting that it does work if used properly.

However, it is difficult to verify if this group were at less risk of HIV for other reasons. Possibly those who managed to use the gel consistently also had other structures or supports in their life which helped them negotiate safe sex.

More research is needed before tenofovir gel can be approved for distribution.

The findings of FACTS and VOICE highlight the need for greater community education around biomedical prevention methods, and arguably, the need for study design that is more sensitive to the pervasive impacts of HIV stigma and of women’s needs.

A social or clinical problem?

Investigators on the VOICE study conducted interviews with research participants to explore socio-cultural factors which made adherence to microbicide gels difficult or undesirable for women.⁵

Interviews were conducted with around 300 women, focusing on their experiences, behaviours, beliefs and attitudes about HIV risk and ARV-based prevention, and on their relationships with trial staff.

Many women said that they found it hard to coordinate use of the gels with their schedule, often being at work or school at the time they were required to insert it, either before or after sex.

Other women did not use the gel because their partner did not like the feel of it, or because he did not support her participation in the trial.⁶

There was a strong sense of ambivalence and in some cases mistrust of the research among participants.

Many women were convinced the gel would harm their fertility or make them ill; or they worried that researchers would actually infect them with HIV as part of the study, a view reinforced for some women by their partners, friends or family.

Stigma was also a major issue. Women did not want to be associated with a trial or a product that might lead others to assume they were HIV positive.⁷

Armed with these research findings, investigators on the FACTS 001 trial put in place an intensive program to support adherence.

This involved client-centred counselling, motivational text messages and monthly social clubs for participants. Unfortunately, this did not translate into higher levels of adherence.

So at this point in time, the question of whether or not microbicides are effective is largely social, not clinical.

What social and cultural supports would help women use a microbicide gel if one was available? Or is it simply unrealistic to expect there would ever be widespread uptake of this type of product?

The way forward

Oral pre-exposure prophylaxis (PrEP), taken once per day, may be easier for some women to manage than microbicide gels. However, trials of oral PrEP in realworld settings have encountered similarly low rates of adherence to that seen in microbicide trials.⁸

Women don’t want to use oral PrEP because they fear side effects and worry people will assume they are taking antiretroviral medication because they are HIV positive. Tablets are difficult to hide from friends, family or partners.⁹

Microbicide research is increasingly focusing on novel approaches to administration, most notably vaginal rings which could be inserted into the vagina and release anti-HIV medication slowly over a number of weeks.

The potential advantage of this type of product over oral PrEP or microbicides is that it doesn’t require regular adherence, it can be inserted once a month and is more discrete and possibly cheaper than gels or tablets.

Possibly even more promising are long-term injectable antiretrovirals, which are also now in clinical trials.

Commenting on the outcomes of the FACTS 001 trial, Professor Helen Rees, an investigator on the trial, said:

‘Interviews with participants throughout the study taught us that HIV prevention tools for women must be convenient and take account of complex social and economic realities of their lives.

‘A product that is applied around the time of sex may be suitable for some women, but it did not meet the needs of the majority in our study, most of whom were young, single and lived with their parents.

‘Methods that are easier for women to incorporate into their lives are likely to be more effective.’¹⁰

Professor Rees captures well the challenges going forward. There is a pressing need for women-centred HIV prevention methods. But any method must take into account the complex reality of women’s lives as well as the enormous barrier presented by HIV stigma.

References

1 For further information on the FACTS Consortium and FACTS 001, see: factsconsortium.wordpress.com

2 For further information on CAPRISA, see: www.mtnstopshiv.org/node/2004

3 For further information on VOICE, see: www.mtnstopshiv.org/news/studies/mtn003

4 Marrazzo,J., Ramjee, G., Richardson, B., Gomez, K., Mgodi, N., Nair, G., et al; VOICE Study Team. (2015). Tenofovir-Based Preexposure Prophylaxis for HIV Infection among African Women. N Engl J Med., 372, 509–518. doi: 10.1056/NEJMoa1402269

5 Two social and behavioural sub-studies (VOICE C and VOICE D) were conducted. See: MTN-003C and MTN-003D Fact Sheet, retrieved from: mtnstopshiv.org/news/studies/mtn003cd/factsheet

6 van der Straten, A., Stadler, J., Montgomery, E., Hartmann, M., Magazi, B., Mathebula, F., et al. (2014). Women’s experiences with oral and vaginal pre-exposure prophylaxis: the VOICE-C qualitative study in Johannesburg, South Africa. PLOS ONE, 9(2), 1–12. doi: dx.doi.org/10.1371/journal.pone.0089118

7 ibid.

8 van der Straten, A., et al. (2014). op. cit.

9 ibid.

10 Follow-on African Consortium for Tenofovir Studies (FACTS). (2015, 24 February). HIV prevention study does not confirm tenofovir gel effectiveness. Women require convenient and effective HIV prevention methods that work within the context of their lives. FACTS Media release. Retrieved from:www.avac.org/sites/default/files/u3/FACTSfeb24.pdf

Dr Jennifer Power is Research Fellow at the Australian Research Centre in Sex, Health and Society, La Trobe University.