Positive Life NSW

What’s news in Microbicides and Biomedical HIV Prevention? Neil McKellar-Stewart reports on the recent Microbicides, Gender and Vulnerability and HIV Biomedical Prevention Symposium organised by The National Centre in HIV Epidemiology & Clinical Research (NCHECR) and the Australian Federation of AIDS Organisations (AFAO).

In Australia we are familiar with new developments in treating HIV. We generally hear much less about new ways of preventing transmission of HIV.

Biomedical prevention is a process of interfering with ‘normal’ biological interactions between an infected host, an infectious pathogen and a possible new host for that pathogen. In the case of HIV: between a person infected with HIV and a person at risk of being infected.

A prevention technology we all know about would be the humble male condom. Access to condoms and clean injecting drug equipment, along with behavioural change (safe sex and injecting behaviours), have been the main reasons for the low number of new HIV infections in Australia.

The Condom is highly efficacious (probably around 98% efficient) and highly effective in stopping transmission of HIV, when used consistently and correctly. “Efficacious (or efficient)” means it actually achieves what it is designed to do: contain seminal fluid, preventing it from entering the vagina or rectum. It also stops infection in the other direction: preventing vaginal or rectal secretions from infecting the tissues of the penis. The condom is an “effective” technology because it is simple to use, rarely fails, and is acceptable to many people (at least in our culture).

In Australia using condoms works. This is not the case elsewhere in the world where access to condoms is poor, condoms are not acceptable to many people, and they are not consistently used. "Only 9% of risky sex acts worldwide are undertaken while using a condom, and the global supply of condoms is millions short of what is needed". (2007 report from the WHO/UNAIDS Global HIV Prevention Working Group) They go on to report: “To ensure a sufficient condom supply to halt the AIDS epidemic by 2015, the level of funding for condom procurement and distribution must increase threefold.” Useful to remember next time you or your partner slip on a condom, which you may have got free from your friendly sexual health provider, community agency like ACON, or even a sex on premises venue.

New prevention technologies in other parts of the world could complement and extend people’s choices beyond the humble condom. More choices could also empower women and put them firmly in control of protecting themselves against HIV.

There are other types of biomedical prevention technologies currently under investigation, these are listed below however none of these have yet proved to be effective but research continues on all.

• Microbicides
• Vaccines
• Pre-Exposure Prophylaxis (PrEP) using HIV antiretroviral drugs
• Male Circumcision
• Suppression of viruses which make HIV infection more likely (eg STIs and Herpes Simplex Virus-Type 2)
• Other Barriers (female condom, ‘invisible’ condom)
• Treatment with HIV antiretroviral drugs which reduce an HIV positive partner’s viral load.

The sobering news is that all the other biomedical technologies (apart from the condom) have a way to go yet. Here’s some recent news on the first of these (we may address the others in a future article):

Microbicides

In the future, if it proves effective, using a gel or similar agent to prevent HIV transmission in the vagina or rectum would be a useful alternative to the condom in many parts of the world. Women in particular would be able to protect themselves when forced to engage in risky sex with men who refuse to use a condom, or where condoms are not available.

Microbicides are designed to make HIV inactive in the vagina or rectum of people using them. A microbicide could take the form of a gel, cream, film, tablet or sponge, or be contained in a vaginal ring that releases the active ingredient gradually.

One of the first microbicide trials was of the spermicide Nonoxynol-9 in women in sub-Saharan Africa and Thailand in 2000. Unfortunately it showed no benefit in preventing HIV infection. Similar results came out of a further eight N-9 trials, which included over 5000 women, predominantly commercial sex workers. Overall, it showed an increased risk of acquiring HIV. An international board considered these results and concluded in 2001 that N-9 should not be used or promoted for the prevention of HIV or STIs.

This was followed in 2004-6 by the trial of SAVVY (C31G) gel for prevention of HIV infection in women. This was a Phase 3 trial of about 2100 women in Ghana. Trial results showed higher reporting of vaginal irritation. The trial data were insufficient to conclude whether SAVVY is effective in preventing HIV infection.

Two trials of Cellulose sulphate (the CONRAD and Family Health International trials) were stopped prematurely in 2007 because more women became infected with HIV on the microbicide arm of the trial than on the placebo arm. Further investigation in 2008 showed that it caused loss of tissue integrity by destroying proteins that bind cells together. This allows HIV to leak into the underlying tissues and increase HIV transmission.

Further trials of other agents have had similar disappointing results: Carraguard is made of carrageenan, a seaweed derivative which in laboratory studies is shown to be effective in blocking cells from becoming infected by HIV and in protecting mice from other STIs. Phase 3 clinical trials by the Population Council in over 6,000 women in sub-Saharan Africa found Carraguard to be safe for vaginal use, but not effective in preventing male-to-female HIV transmission during vaginal sex.

Though disappointing, these trials have contributed significantly to the field’s body of knowledge regarding product development, trial design, and women’s and their partners’ willingness to use a microbicidal gel consistently.

Other microbicides still under investigation include 0.5% PRO 2000 in two studies, one of which adds BufferGel (a vaginal defence enhancer). A stronger dose (2%) PRO 2000 trial was stopped in February because of futility (meaning it would produce no meaningful results). The trial, which is comparing both PRO 2000 and BufferGel with a control, is expected to produce preliminary results later this year. PRO 2000 is an agent that prevents entry and attachment of HIV and others STIs to cells in the vaginal mucosa.

All the agents discussed above are first generation microbicides which don’t act against HIV’s replication processes. The second generation of microbicides, about to start major trials, will attempt to deliver antiretroviral drugs into the vaginal tissues and fluids. Although this approach, called topical PrEP, may be potent, it could have drawbacks too: drug toxicity, and leakage of the drug into the bloodstream, with a potential risk of drug resistance if the user becomes infected.

There are three major programmes which will lead up to efficacy trials of antiretroviral-containing microbicides for vaginal use:

First to report (probably in early 2010) will be CAPRISA 004 (Centre for the AIDS Programme of Research of South Africa) study of 1% tenofovir gel in nearly 1000 women in South Africa. This is the only study looking at ‘coitally-dependent’ use, in which women are told only to use the gel when they think they will have sex.

The Microbicides Trials Network (MTN) is co-ordinating the VOICE (Vaginal and Oral Interventions to Control the Epidemic) study, which will directly compare a tenofovir gel with oral tenofovir PrEP in 4200 women in sub-Saharan Africa. Early studies suggest that tenofovir will be absorbed to a sufficient depth in the vagina wall to defend against HIV infection. The trial proper is due to start in late 2008 and may report by 2011.

The International Partnership for Microbicides (IPM) is co-ordinating a series of studies using the new HIV treatment, dapivirine (TMC120) both as a gel and as drug infused into a silicone vaginal ring which can be left in place for a month. These studies are expected to report in 2012, if they pass early safety trials.

If these microbicides prove to be effective in preventing male-to-female HIV infections vaginally, they may have flow on effects for microbicides which might work in the rectum. Delivering an effective agent will be very difficult. Unlike the vagina, the rectum has only a thin layer of surface cells, and an involuted columnar structure, with lots of surface area, and the molecules to which HIV can attach are much more accessible.

In addition to these vaginal studies, a possible rectal microbicide using UC-781 (a new HIV antiretroviral drug) is undergoing safety trials. These will precede actual trials to test its efficacy, that is, whether it works and does no harm. Preliminary data presented at the Microbicides 2008 conference in February hint that it may be safe and perhaps efficacious; however, much work stills needs to be done.

The take home message from this short overview is that more research is needed. While microbicides have a long way to go in terms of clinical trials and understanding issues around safety, modes of operation and efficacy, they still represent a possible future prevention option. In the meantime condoms (and lube) continue to be the most effective safe sex strategy.

For further reading:

http://www.microbicide.org/ The Alliance for Microbicide Development
http://www.rectalmicrobicides.org/ International Rectal Microbicide Advocates (IRMA)
http://www.avac.org/ AIDS Vaccine Advocacy Coalition (AVAC)

Neil McKellar-Stewart is the HIV Health Maintenance Officer at ACON Northern Rivers

Glossary:

PrEP
Pre-exposure prophylaxis (PREP) involves the use of oral antiretroviral treatment to prevent HIV infection

Microbicide
Microbicides are compounds (formulated as gels, creams, films, or suppositories) that can be applied inside the vagina or rectum to protect against sexually transmitted infections (STIs) including HIV. At present, an effective microbicide is not available.

Pathogen
A pathogen is a biological or infectious agent, or germ, which causes disease or illness to its host.

Phase 1 trial
A phase 1 trial is first step in testing a new treatment in humans. These studies test the best way to give a new treatment (for example, by mouth or injection) and the best dose.

Phase 2 trial
A Phase 2 trial is a study to test whether a new treatment has an effect, whether it works and improves results.

Phase 3 trial
A Phase 3 study compares the results of people taking a new treatment with the results of people taking the standard treatment, and is designed to prove the safety and efficacy of a new treatment.