MICROBICIDES 2004
Revised draft of a report for NAT and the Global Campaign for Microbicides
by Julian Meldrum, 30 April 2004
References in this report are to abstracts which can be searched and read online at www.microbicides2004.org.uk
REPORT SUMMARY
Microbicides 2004 was a successful interdisciplinary meeting attended by 800 people from 53 countries over the last three days of March 2004 in London, England.
Microbicides are desperately needed because the HIV pandemic continues to spread and girls and women lack options to protect themselves from HIV. In many African countries, girls and women are now the majority of those living with HIV and dying with AIDS. The “ABC” strategy – abstain (or delay sex), be faithful, or use a condom – is limited in its impact on HIV because women who marry have little or no control over their husbands’ past or future behaviour.
The main emphasis of current research is on experimental products, six of which are due to enter full-scale trials to test their effectiveness against HIV during 2004. These trials are costly and very complex undertakings. However, they are seen as vital to create confidence among pharmaceutical companies and others that such products can actually work, will have a real market, and are worthy of private investment. At present, almost all work in the microbicide field relies on public funding.
Scientists working in the UK, with British government support, have pioneered HIV microbicide research and play a leading role in global efforts in this area, working closely with their counterparts overseas. The US and other governments, charitable foundations, and the European Union, are funding equally important work.
Within the UK, there is a need for more and better methods to prevent transmission of HIV among gay men. Rectal microbicides, to be applied before or during anal sex, may eventually be developed and may have value for the even larger number of heterosexuals who also engage in anal sex.
There is also a potential market in the UK and other western countries for a microbicide that could protect heterosexual women and men against other infections, especially genital herpes.
Planning for field trials was discussed at length during the meeting and there are disagreements about the need for, and value of, a “condom only” arm in clinical trials that will all compare possible microbicide gels with what are thought to be “inactive” placebo gels. The standard of care for trial participants has been very actively debated and there is clearly a need for access to better treatment both for HIV and other conditions than is generally provided in the countries where trials are to be held. However, this topic (standard of care) is not covered further in this report.
Of the six leading candidates, there were extensive reports of preliminary safety studies and laboratory tests on four of them (Carraguard, cellulose sulphate, Emmelle, PRO 2000). There were also extensive reports of social research and feasibility studies for trials on four of the products (BufferGel, Carraguard, Emmelle, PRO 2000). The sixth product, Savvy, was not discussed although there are safety issues which may not favour its use in populations highly exposed to HIV.
There are several products at earlier stages of testing as microbicides which show some promise and one, cellulose acetate phthalate (CAP) is about to be entered in a safety trial recruiting 60 women volunteers in London.
An alternative route to a microbicide is being explored in India. This centres on testing existing medicines for their anti-HIV potential and has identified an antifungal cream which is already on the market in India, as a possible microbicide. Further testing is essential to evaluate the safety and efficacy of this or other such products.
Condoms are not the only barrier method of contraception, and it is possible that the diaphragm, a device inserted in the vagina to cover the cervix, could give limited protection against HIV in its own right and also serve as a delivery method for microbicides. Some research in this area was reported at the meeting.
Another approach is based on locally applied hormones that change the properties of the mucus and the vaginal wall to reduce the risk of infection and, incidentally, limit absorption of the drug. An oestrogen-based cream marketed for the control of menopausal symptoms has been shown to protect some monkeys against HIV-like viruses. Its short-term and long-term safety for women and babies and its effects during prolonged use in younger women are unknown. The priority for testing will be for women using Depo Provera as contraception, who are now known to be at increased risk of HIV and for whom the reproductive health concerns may be lower.
Microbicides for men, in the form of penile wipes to be used after sex, have been developed and may be of value against some infections. Unfortunately, the chemicals chosen for the first products of this kind to be described increase susceptibility to viral infection when mice are exposed to them and so cannot currently be recommended.
A number of anti-HIV drugs are being evaluated as potential microbicides and several are already in early stage clinical trials. One of these has been licensed free of charge to a not-for-profit organisation, the International Partnership for Microbicides, by the pharmaceutical company Tibotec (part of Johnson & Johnson). Johnson & Johnson retains rights to license any successful product back from IPM for sale in wealthier markets and has thereby become the first major international company with any commercial stake in microbicide development.
Many other experimental approaches have been proposed, and some show promise in human cell and tissue cultures and in animal models for infection with HIV and other viruses. All of these are at early stages of development and have many hurdles to overcome before they could be adopted as methods of HIV prevention.
ABOUT THE MEETING
The Microbicides 2004 conference was held at the Hilton Metropole on London’s Edgware Road in the last three days of March. Some 800 participants from 53 countries were treated to 300-odd presentations organised into three main tracks: basic science, clinical research, and social science and advocacy. A scholarship programme supported researchers and community representatives, primarily from developing countries which are increasingly involved in microbicide research.
Satellite meetings covered rectal microbicides to protect people who engage in anal sex and manufacturing issues which will become important if one or more microbicides are shown to be effective against HIV transmission. There was also a meeting to help community advocates orientate themselves to the conference.
The next meeting in this series, Microbicides 2006, will be held in South Africa. South Africa is the location for full-scale clinical trials of several candidate microbicides, with a continuing high HIV incidence among girls and women.
THE NEED FOR MICROBICIDES
There were a number of powerful speeches in Microbicides 2004 plenary sessions, not least by UK government Ministers (see UK Contribution, below), describing the plight of women and families affected by HIV, for whom current prevention, care and treatment options are often grossly inadequate.
Dr Geeta Rao Gupta from the International Center for Research on Women in Washington DC described persistent violations of women’s reproductive and sexual health rights in India, to illustrate the need for microbicide development to be located in a wider agenda to empower women. This is reflected in the UNAIDS-supported Global Coalition on Women and AIDS [http://womenandaids.unaids.org/], which includes the development of women-controlled HIV prevention as one of its seven platform issues. She described a moving encounter with an HIV prevention worker from Ghana, who had spoken of her demoralisation at “leading sheep to the slaughter” in relation to the HIV risks that women encounter on marriage.
HRH the Princess Royal (Princess Anne) spoke as President of the Save the Children Fund and Chancellor of the University of London to express her support for the aims of the conference, which had a close relationship to the experience of women affected by HIV in countries such as Ethiopia where she had visited SCF projects.
Stephen Lewis, the UN Secretary-General’s special envoy on AIDS in Africa, spoke of children literally watching their parents die, and of his continuing rage at what he saw as unnecessary and avoidable deaths. He had flown from Canada specifically to attend the conference since he regarded microbicide development as one of the most important achievable measures that could be taken to address AIDS. The full text of his speech is available on the website of the Stephen Lewis Foundation [http://stephenlewisfoundation.org/] (follow link for news, and date: 30 March 2004).
ADVOCACY AGENDAS
An important strand of the conference was, as already mentioned, about advocacy. Presentations in this area identified a number of points, beyond those already made. One is that the arguments made in a particular country may need to take account of the existing history of discussion of female-controlled HIV prevention. For example, some countries (such as Ghana) have made serious efforts to evaluate and give access to the female condom, while others (such as Thailand) have not. This has both positive and negative implications for the way that microbicides will be viewed by policy makers. The legal and social status of women and the agenda of women’s organisations on issues such as sexual violence must equally be taken into account. In South Africa, a radical constitution which insists on gender equality opens theoretical possibilities for women to assert their rights to control their own bodies. However, some question what may happen to vulnerable women who try to put this into practice, without adequate support from women’s organisations and government. Another important area of discussion is how to ensure that advocacy for microbicides, for expanded access to treatment, and for vaccine development, is pursued in a way that acknowledges the importance of all three – and, indeed, other responses to HIV such as making best use of available prevention technologies and knowledge.
Cavanagh D et al. Advocating for microbicides using a sexual rights framework: lessons from South Africa. Microbicides 2004, London. Oral presentation, abstract 02556.
Patterson D et al. HIV treatments, microbicides and vaccines: advancing a rights based agenda for research, development and access. Microbicides 2004, London. Oral presentation, abstract 02694 [presented by Saul Walker].
Sleap B et al. Advocating for microbicides in the global south: approaches and methods. Microbicides 2004, London. Oral presentation, abstract 02653 [presented by Dusita Phuengsamran].
THE PRESENT STATE OF PLAY
A number of experimental products have been developed which seem to prevent HIV infection of cells and tissues grown in the laboratory. Several of these can protect monkeys from infection with HIV-related viruses to which they are exposed vaginally under controlled conditions. Will these findings translate into real-life effectiveness against HIV? Clearly, we need to know the answer as soon as possible.
In 2004, six novel microbicides are due to enter clinical trials designed to test their ability to prevent the transmission of HIV from men to women through vaginal sex. All six of these products take the form of gels, to be applied to themselves by the women, typically up to an hour before sexual intercourse. For clinical studies, gels are usually supplied as individual doses packed in plastic devices that can be inserted in the vagina, so the amount used is consistent – and in the region of 3 to 5 ml.
For each trial, several thousand HIV negative volunteers have to be recruited. All must be tested – with their full knowledge and consent - for pregnancy, for HIV and a range of other infections. As volunteers are being recruited from populations heavily affected by HIV, many women learn in the course of initial screening that they are already HIV positive. This places a great burden not only on the women themselves but also on the counsellors and research staff, and requires that effective referral to health services is available from the outset. In countries where HIV treatment is still in its infancy this is not easy to ensure.
Once enrolled, all volunteers will have to attend clinics – or to be seen by outreach workers - on a monthly or quarterly basis, for anything between 9 and 24 months. Some may be asked to undergo internal vaginal and cervical examinations (colposcopy). While all women will be supplied with condoms and encouraged to use them, some will receive an inactive placebo and others an active version of the product. The commitment and level of understanding needed is far greater than, for example, is required for a vaccine trial.
Large amounts of data are generated and must be processed accurately and promptly. The need to keep records that will be of sufficient quality to enable a new product to be registered for medical use is a serious challenge and requires considerable resources in equipment and training. The UK-funded Microbicide Development Programme is unusual in having decided that the data management should be located in South Africa as part of its commitment to building research capacity. Similarly, there is considerable investment in establishing in-country laboratory facilities and training scientists and technicians to global standards.