A microbicide for HIV does not yet exist, but the idea is currently being researched and developed.

What is a microbicide?

A microbicide is something designed to destroy microbes (bacteria and viruses) or to reduce their ability to establish an infection. A microbicide for preventing HIV infection would be applied to the vagina or rectum to prevent the virus being passed on during sex.

What are the advantages of HIV microbicides?

A microbicide would share many of the advantages of an AIDS vaccine. It would be especially useful for women unable to insist on their partner using condoms, who might be able to use a microbicide without their partners knowing. However, a microbicide would not be able to prevent all forms of HIV transmission, and would require regular reapplication. Unlike vaccines, an effective microbicide must be made into a commodity that people will want to use regularly, such as a cream, gel or vaginal ring.

How might an HIV microbicide work?

A microbicide could work in at least four different ways:

• Kill or inactivate HIV
• Stop the virus entering human cells
• Enhance the body’s normal defence mechanisms against HIV
• Inhibit HIV replication

The first microbicide candidates developed were made from barrier gels, among them nonxoynol-9 and cellulose sulfate. More recent trials have been testing antiretroviral-based microbicides, which aim to prevent HIV infection in the same way as PrEP might.

What are the challenges in developing HIV microbicides?

There are many chemicals that kill HIV, including undiluted household bleach. But what is needed for a microbicide is something that works against HIV without causing discomfort or irritation. For example, when researchers investigated using the spermicide nonoxynol-9 as an HIV microbicide they were surprised to find it actually increased the rate of transmission, probably because it caused vaginal lesions and inflammation, which made it easier for HIV to establish an infection, even though nonoxynol-9 killed the virus in lab tests.¹

For a microbicide to become popular, researchers must develop not only the active ingredient but also a microbicide that is socially acceptable, affordable and easy to apply. Ideally it would provide protection for several days or even weeks at a time.

Another major issue is how a microbicide affects sperm. To reach all those in need, scientists will have to develop both contraceptive and non-contraceptive microbicides.

How are the possible microbicides tested?

There are three phases of clinical trials that a potential mircobicide must pass through before it is judged effective and safe. Phase I tends to last between twelve and eighteen months, whereas the final phase can take up to three or four years.

• Phase I involves a small number of volunteers to test the safety of various doses
• Phase II involves hundreds of volunteers to further assess safety and, in some cases, positive responses
• Phase III involves thousands of volunteers to test safety and effectiveness

The Phase IIb trial, a recent innovation, is a larger variant of the Phase II trial.

All microbicide trials provide condoms and prevention counselling to all participants, as an ethical obligation. As a result, the overall rate of HIV transmission is lowered, which means more volunteers are needed to produce a significant result. Most volunteers must be HIV-negative at the beginning of the trial, though it is also important to test safety in those who are already infected.

How many microbicides trials are under way?

Several microbicide candidates are currently being studied in over 20 clinical trials.² The results of a Phase IIb trial, CAPRISA 004, were presented at the 2010 International AIDS Conference in Vienna. The randomized, controlled trial assessed the safety and effectiveness of tenofovir gel in 900 HIV-negative, sexually active women between the ages of 18 and 40 years in South Africa. The results were statistically significant, with the gel reducing the risk of HIV acquisition by 39 percent overall.³ The protective effect increased to 54 percent among women with high gel adherence. The study is the first to provide proof of concept for microbicides.

A Phase IIb safety and effectiveness study of tenofovir gel, oral tenofovir and emtricitabine/tenofovir is due to enroll 4,200 women in various sites in Africa.⁴ First reports are expected in 2011.

Which microbicide trials have recently ended?

In August 2006, Family Health International decided to halt a Phase III trial of a surfactant called SAVVY after preliminary results showed no evidence of a protective effect. The organisation has no plans to further investigate this product.⁵

Two Phase III trials of an entry inhibitor called cellulose sulphate (also known as Ushercell) were halted in January 2007 after some sites recorded a higher HIV infection rate among women who used the gel, compared to those who were given a version that had no medicinal properties (a placebo). This result led to speculation that the gel may have increased the risk of HIV transmission. Later analysis indicated that the higher infection rate may have been due to chance.⁶

In February 2008, researchers announced the results of a Phase III trial of Carraguard, an entry inhibitor based on carrageenan, which is derived from seaweed. The product - the first ever to complete Phase III testing - was shown to be safe, but had no significant effect on HIV transmission.⁷

In 2009 two large-scale trials of the microbicide candidate, PRO 2000, ended. PRO 2000, is a type of entry inhibitor that binds to viruses to prevent them from infecting healthy cells.⁸

Results from the smaller trial of the two were released in February 2009. There were 30 percent fewer HIV infections among trial participants who used PRO 2000, compared to women who used the placebo. Although these results seemed promising, they were not statistically significant and therefore could have been down to chance.^{9 10}

The results from the second larger trial were released in December. Of the 3,156 women who were given PRO 2000, 130 became infected with HIV, while 123 of the 3,112 women given the placebo gel become infected with the virus. There is therefore no evidence the PRO 2000 gel reduces the risk of HIV infection in women.¹¹

Who is supporting research and development?

In 2008 around $244 million was invested in microbicide research and development - up by 8% on the previous year. About 85% of this money came from the public sector, 14% came from the philanthropic sector and 1% was accounted for by commercial companies (only $2.5 million).¹²

At present no major pharmaceutical firm is investing significant amounts of its own money in microbicide research because it is complex and the market is uncertain.¹³ As Professor Jonathon Weber has stated:

"[Microbicides] are perceived as drugs for Africa, and no one makes money from Africa" - ¹⁴

Conclusion

If one of the microbicide candidates were successful in preventing HIV infection, it would be a while before it would become widely available. Any successful product would have to undergo review and licensing by regulatory agencies before becoming available to the public. It would take time to work out the best formulation and dosage; find a suitable delivery method; and distribute the product. Also, if an effective product is produced it may be difficult finding investors, as the microbicide will have to be available to women in low- and middle- income countries and therefore profit margins will be low.¹⁵ In addition, any successful microbicide will only be partially protective and so would have to be complemented with other prevention methods.¹⁶

Whilst it is important to ensure continued funding and support for microbicide development, it would not be helpful to be overly optimistic about the effectiveness and potential availability of such a product. A microbicide will not be a ‘silver bullet’ for ending the epidemic, but rather another tool to add to existing prevention efforts.

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References:

1. Global Campaign for Microbicides ‘Nonoxynol-9’.
2. Alliance for Microbicide Development (2010) 'Microbicide and PrEP candidates in ongoing clinical trials, summary as of September 2009'
3. Karim, Q.A. et al (2010) 'Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women', 19th July 2010, Sciencexpress
4. Microbicides Trial Network (2010) 'MTN-003'
5. Family Health International (2006, 28th August) ‘Phase 3 trial in Nigeria evaluating the effectiveness of SAVVY gel in preventing HIV infection in women will close’
6. Van Damme, L. et al (2008) ‘Lack of effectiveness of Cellulose Sulfate gel for the prevention of vaginal HIV transmission’, NJEM 359:463-472.
7. Skoler-Karpoff, S. et al (2008) ‘Efficacy of Carraguard for prevention of HIV infection in women in South Africa: a randomized, double-blind, placebo-controlled trial’, The Lancet, 372(9654):1977-87.
8. Global Advocacy for HIV Prevention (AVAC) (2009) 'Understanding the results from trials of the PRO 2000 microbicide candidate'
9. National Institute of Allergy and Infectious Diseases (2009, 9th February) ‘Anti-HIV gel shows promise in large-scale study in women’.
10. Global Campaign for Microbicides (2009) ‘Advocates’ frequently asked questions about HPTN 035’.
11. AVAC (2009) 'Understanding the results from trials of the PRO 2000 microbicide candidate'
12. HIV Vaccines and Microbicides Resource Tracking Working Group (2009, July) ‘Adapting to Realities: Trends in HIV prevention research funding, 2000 to 2008’.
13. Global Campaign for Microbicides ‘Financing’.
14. The Guardian (2004, 22nd March) ‘Taking prevention of Aids beyond ABC’
15. UNAIDS (2008) ‘Microbicides: challenges to development and distribution (part 2)’.
16. UNAIDS (2008, 20th February) ‘Microbicides: why are they significant? (Part 1)’