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Julie Clayton argues that the strategy behind promising results now emerging from research into microbicides has implications for other fields of biomedical research.

The author is coordinator of SciDev.Net's HIV/AIDS quickguide and has run SciDev.Net workshops on HIV/AIDS reporting in India and Uganda.

The pace of research into microbicides — gels or creams that aim to protect against HIV infection by being inserted into the vagina or rectum before sex — seems set to outpace efforts to produce a vaccine. This at least was the impression left by the buoyant mood and results presented at the international Microbicides 2004 conference in London last week.

Microbicides research is no longer the poor relation that many considered it to be up to relatively recently, particularly compared to fields such as vaccines. In a relatively short space of time, it has gained impressive levels of funding, advocacy, and, critically, new candidates swelling the research and development pipeline.

With one phase III clinical trial having just started, and three others due to begin later this year — all in developing countries — the field is also beginning to make a significant contribution to scientific capacity building. "We're now a committed, vibrant, scientific, public health, advocating research community," concluded Catherine Hankins of the Joint United Nations Programme on HIV/AIDS (UNAIDS) at the conference's closing ceremony, who admitted that it was she who had coined the 'poor sister' tag six years earlier.

Hankins also revealed that, in recognition of the growing status of microbicides research, the forthcoming biannual international AIDS Conference, due to take place in Bangkok in July will, for the first time, devote a plenary presentation to microbicides research. Despite having started with less funding as a small and scattered set of researchers in the early-1990s, microbicides research has grown at an impressively fast rate, a lack of large-scale funding being the only limiting factor.

Secrets of success

What has enabled such rapid development of the field, which has gone from a trickle of research papers in the mid-1990s, to an average of 66 peer-reviewed publications a year at the start of this century? And what lessons that can be learned for other areas of biomedical research, particularly those directly relevant to the needs of developing countries?

One is that the importance of partnerships and networks of collaborators cannot be overestimated. The Alliance for Microbicide Development, an alliance of scientists, product developers and advocates, began in 1998 to coordinate and promote investment in, and development of, microbicides. Four years later saw the formation of a public-private partnership, the International Partnership for Microbicides (IPM), to assist with financial and regulatory issues and country preparedness. IPM was awarded US$60 million by the Bill and Melinda Gates Foundation last year, and its activities continue to grow. 

Research networks are also thriving, with new support from the European Union for taking novel candidates from European laboratories into phase I clinical trials in Africa, coordinated by researchers at St George's Hospital Medical School and King's College in London. Another network, based at the US National Institute for Allergy and Infectious Diseases, has also gained increasing funding for a 'pipeline' that extends to five ongoing or anticipated clinical trials in Africa and Asia. The vaccine field, which began around a decade earlier, took considerably longer to establish such extensive networks, a lesson that microbicides researchers — some of whom work in both areas — have taken on board.

Learning from the experience of others

Researchers and others engaged in each of the microbicides networks held behind-the-scenes discussions last week on how to learn from each other's experiences and prioritise decisions about advancing their products through the pipeline. The one major hold-up they anticipate is the lack of support from any large pharmaceutical company, which may delay the clinical testing of promising candidates.

With less commercial secrecy or competitive advantage at stake, progress in the basic science of microbicides can have an immediate impact on the design of clinical trials.  Conversely, the outcome of clinical trials can validate the relative value of different laboratory and animal models.

All this will hopefully help the microbicides field to avoid some of the pitfalls that have beset HIV vaccine research, where a phase III trial is currently going ahead in Thailand with private industry backing, but — at least according to its critics — little scientific justification (see World's biggest HIV vaccine trial 'is a costly mistake').

One example of the value of feedback comes from new data presented last week showing that some gel formulations prepared for the placebo arm of phase III trials — tests carried out for comparative purposes with chemicals that are not intended to have any physiological effect — can cause inflammation in the lining of the genital tract. Because this could, in theory, increase the ability of HIV to infect the body, investigators are introducing a new form of monitoring during such trials to check for signs of inflammation in volunteers.

Another pointer comes from evidence that the 'second generation' of microbicides currently in early development will have to be used in combination, rather than individually, if they are to block the different routes of entry of HIV into the body. This in turn raises the issue of intellectual property, as agreement would need to be reached between the owners of patents on individual substances before the marketing of a combined product (see Patent threat to anti-HIV compounds is lifted).

Feedback from vaccines research

As for vaccines, basic research into microbicides is now benefiting from new and improved cell-culture-based and animal models that use wild-type HIV strains, rather than those that have been adapted through prolonged growth in the laboratory.

These are providing greater insight into the biology of HIV, and a clearer idea of the targets for both vaccines and microbicides, as well as providing the opportunity to reconsider the scientific justification for particular clinical trials.

Fortunately for those microbicides candidates now entering phase III trials, the justification remains strong, although there is still need for caution, as these products are somewhat less effective — at least in vitro — against wild-type freshly isolated strains of HIV than they are against the lab-adapted varieties.

Animal studies to investigate this are being carried out. Meanwhile, however, it is important to get data from clinical trials to see whether such in vitro differences provide any clues to how effective the product will be in real life. "Whatever the result, we'll learn from the trials, and I think nobody would want to stop something half way through if they don't know what the end result will be," commented Robin Shattock from St George's Hospital Medical School in London.

As for HIV vaccine trials themselves, progress towards phase III microbicides trials has already been a great boost for capacity building in developing countries. Local laboratories are increasingly taking on responsibility for monitoring the health and clinical status of trial volunteers, particularly in South Africa. And health care infrastructure — including training of health care and community workers — is also benefiting.

But for all the progress being made, one question hovers like a dark cloud: why has it taken so long for microbicides to gain such ground? Stephen Lewis, UN Special Envoy, places much of the blame on the treatment of women, particularly in developing countries, and the way that this has stood squarely in the way of promoting a women-centred approach to HIV prevention.

"For much of my life I have felt that the struggle of gender inequality is the toughest struggle on the face of the earth. And never have I felt it more keenly than in the battle against HIV/AIDS," Lewis told last week's meeting in London. "I ask all of you that you see microbicides not merely as one of the great scientific pursuits of the age, but as a significant emancipation for women, whose cultural, social and economic inheritance puts them so greatly at risk."

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