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Update on microbicide research

The AIDS vaccine field faces many unique scientific hurdles but still it is closely tied to treatment and other areas of AIDS research. In particular, the AIDS vaccine field has much in common with the field of microbicide research, which is seeking to develop an effective gel, cream or suppository that could be used vaginally or rectally to prevent sexual transmission of HIV.

AIDS vaccines and microbicides are both being developed because of the urgent need for new prevention strategies in addition to existing interventions like male and female condoms and clean needles. AIDS vaccines and microbicides could both be powerful prevention strategies for women, who are infected with HIV through sexual contact at high rates often because they cannot negotiate condom use with their partners.

At present there are no effective preventive AIDS vaccines or microbicides, but the next few years will bring several large-scale efficacy trials of candidates. Some of the planned (see Research and Trials) and future microbicide trials will take place in the same countries, and perhaps the same communities, as vaccine trials. This increases the importance of coordination between the two fields to share resources like laboratories and clinics and to collaborate on outreach and education campaigns.

Measuring microbicide efficacy

Large-scale microbicide efficacy trials share similarities with AIDS vaccine efficacy trials (see VAX August 2003 andMay 2004). In both cases, the candidate is tested in a population with a known rate of HIV infection or ‘incidence rate.’ Microbicide trial volunteers are randomly assigned to different groups, with one group receiving the experimental candidate while the other receives an inactive “placebo” gel. In some trials there is also a group that is “randomized” to a condom-only arm. All groups receive intensive ongoing counseling on the importance of using condoms and on the fact that none of the women receiving gel should assume that they are protected against HIV infection.

Trial volunteers are monitored and receive regular HIV tests over the course of the trial. At the end, researchers analyze the data to find out if the incidence rate was lowered among women who used the microbicide candidate. Neither the trial staff nor the volunteers know who has been assigned to receive the microbicide candidate or the placebo until the study is over.

For a microbicide to provide protection it will have to be used correctly (e.g., in the right volume and at the right time) and consistently over time. One of the key challenges in designing microbicide efficacy trials is how to measure frequency and consistency of use. This is important because even a very effective microbicide will not provide protection if it is used incorrectly. If many trial volunteers did not use the candidate regularly and correctly then it is possible that a candidate with some protective benefit would appear to be ineffective at the end of the study.

Microbicide trial sponsors are using a variety of strategies to measure and ensure consistent use. In some instances sponsors are conducting short pilot studies in which women are given intensive counseling and education about proper use of the candidate. These pilot studies can be used to identify women who are likely to use the gel consistently throughout the trial and to develop education and information strategies that can increase consistency of use. Researchers also use diaries, interviews and questionnaires to gather information about use over the course of the trial.

The need to gather data on consistent use also affects the length of the trial since it is possible that use may become less consistent over time. Most microbicide trials are also relatively short, often following women for only 12 months.

In contrast, AIDS vaccine trials may ask for a two to three year commitment from volunteers and may involve several years of follow up for volunteers who become infected with HIV through highrisk sexual behavior, to learn more about how a vaccine affects the course of HIV disease. Microbicides do not affect the immune system and are not expected to modify the course of HIV disease, so microbicide trial volunteers who become HIV infected are not involved in longterm follow up. Trial sponsors in both fields are working to ensure that all HIV-infected volunteers have access to antiretroviral (ARV) treatment when needed.

The rationale for upcoming trials

Four out of the six candidates in the planned microbicide efficacy trials are from the same “class” of compound, and several of the trials involve similar or identical candidates. At first glance this may seem strange: given the cost and complexity of mounting a large-scale trial, why would product developers conduct two trials of the same candidate? The answer lies in part with the regulatory guidelines for microbicide development that were recently issued by the US Food and Drug Administration (FDA). The guidelines describe the types of information that the FDA would like to see in an application for licensure and approval if a candidate does show efficacy in a large-scale trial. Sometimes this will require more than one trial. Also, some studies are using slightly different formulations of the same microbicide candidate.

It is important to remember that the FDA only issues guidance for products to be used in the US. Additional or alternative regulatory agencies will also be involved in approving microbicides for use in other countries, particularly resource-poor countries which may have limited regulatory capacity. The World Health Organization and the European Agency for the Evaluation of Medical Products recently announced plans for a collaboration that would provide regulatory review for new medical technologies (including microbicides and vaccines) at the request of developing countries.

New approaches to next generation candidates

As the microbicide field prepares for large-scale trials of current candidates it is also looking for new approaches to blocking sexual transmission of HIV (see Primer). Recent scientific advances have allowed researchers to pinpoint the types of cells that HIV infects during male-to-female sexual transmission. This knowledge is guiding the design of new candidates that could block some of these virus-cell interactions.

Some of these candidates are called “co-receptor blockers” and they prevent HIV from attaching to molecules, or “receptors,” that cover the surface of cells so that the virus cannot enter and infect the cells. Another approach uses ARV drugs in a gel formulation. These drugs are very similar to those used to control HIV in people who are already infected with the virus. There are also plans to test combinations that contain compounds with different modes of blocking viral activity. Many microbicide researchers think that the highest levels of protection will be achieved with a combination approach.

In the future an effective preventive microbicide could also be used in combination with an AIDS vaccine. In both cases the first effective products are not likely to provide complete protection against HIV infection when used alone. But used together they might be able to significantly reduce vulnerability to HIV infection in situations where it is not possible to use a condom.

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All articles written by Emily Bass