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Microbicides

HIV replication: A computer generated image of HIV exiting a cell

A microbicide for HIV does not yet exist outside of clinical trials, 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 HIV and 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.

Other major issues include how a microbicide might affect sperm and whether it might cause adverse effects for a woman's reproductive health. 2

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?

There are several different microbicide candidates currently being studied. As of May 2013 there were 11 phase I trials, 1 phase I/II trial, and 4 phase III trials. The current status of ongoing microbicide trials can be found here.

IPM027 (The Ring Study)

MTN 020 (ASPIRE)

CAPRISA 008

FACTS 001

Which microbicide trials have recently ended?

CAPRISA 004

This phase IIb trial assessed the safety and effectiveness of tenofovir gel in 900 HIV-negative, sexually active women between the ages of 18 and 40 years, living in South Africa. Results for this trial were announced in July, 2010. 3 4

The statistically significant results found:

  • Tenofovir gel reduced the risk of HIV infection by 39 percent overall
  • Protective effect increased to 54 percent among women with high gel adherence

The CAPRISA 004 study was the first to provide proof of concept for microbicides. The study found statistically significant results showing microbicides can prevent the sexual transmission of HIV.

MTN-003/ VOICE (Vaginal and Oral Interventions to Control the Epidemic)

This phase IIb trial investigated the safety and effectiveness of both an oral pre-exposure prophylaxis (PrEP) and a vaginal microbicide gel to prevent the transmission of HIV. 5

The trial group, consisted of 5,029 sexually active HIV-negative women living in South Africa (4,077), Zimbabwe (630) and Uganda (322). Mean age of participants was 25.3 years and 79 percent were unmarried. Participants were divided into 5 sub-groups of around 1,000 women. Each group received either tenofovir tablets (Viread), tenofovir + emtricitabine (FTC) tablets (Truvada), a placebo pill, a vaginal tenofovir gel, or a placebo gel; each to be taken or applied daily regardless of sexual activity. Results found 6:

  • Oral Tenofovir tablet (Viread). This part of the trial was halted in September, 2011. The drug was found to be safe, but not effective.
  • Vaginal tenofovir gel. This part of the trial was halted in November 2011. The drug was found to be safe, but not effective.
  • Placebo gel. This part of the trial was halted in November 2011.

Results found that HIV incidence among women using the vaginal tenofovir gel was almost identical to that among women using the placebo gel. 7

  • Tenofovir + emtricitabine (FTC) tablet (Truvada). Ended at scheduled time, August, 2012. The drug was found to be safe, but not effective.
  • Placebo pill. Ended at scheduled time, August, 2012.

Results found that the drug was safe, but not effective. HIV incidence was found to be almost the same among women taking Truvada as those taking the placebo pill.

Key outcomes

The VOICE results 8 were largely received as a step back in the progress towards developing an effective microbicide. 9 Despite this, the VOICE trial highlighted key issues, associated with the efficacy of microbicides as a major form of HIV prevention, to be considered in other mi. Low adherence emerged as one of the key issues associated with the high HIV incidence among women taking the Truvada and placebo pill. Age and marital status were found to be strongly associated with levels of adherence.

  • Truvada was detected in only 21 percent of blood samples of younger, single women
  • Truvada was detected in 54 percent of married women, aged over 25 years
  • HIV incidence was 8.8 percent for unmarried women under age 25
  • HIV incidence was 0.8 percent for older women who were married.

VOICE behavioural studies

Sub-study VOICE C is investigating the impact of community-based factors and beliefs on the women's ability and willingness to adhere to the treatment. Sub-study D is investigating how individual behaviours, beliefs and attitudes to HIV risk affected adherence to the treatment. 10

Who is supporting research and development?

In 2011 around $186 million was invested in microbicide research and development - a 25 percent decrease on the previous year. This decline has been associated with the cycle of funding disbursement, rather than a decline in investment. About 95 percent of this money came from the public sector, 5 percent came from the philanthropic sector, and <1 percent was accounted for by commercial companies (only $1 million). 11

Conclusion

A safe and effective microbicide has potential to become a key method of HIV prevention. As the trials above demonstrate, microbicide research and development brings us ever closer to having a successful candidate.

Importantly, however, if an phase III microbicide candidate successfully prevented HIV infection, it would still be a while before it became 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. Moreover, to ensure microbicides were available to women in low- and middle-income countries, profit margins would need to be low. 12 13

 

References

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