The global need for microbicides

It is my pleasure to welcome you all to the Microbicides 2000 Conference. This is, we all believe, an extremely important event and we want to thank you for being here. The reason it is important is that it is the largest meeting of its type to have been held to date in the context of being a highly focused conference on the topic of microbicides and on their potential to help stem the course of the HIV epidemic. There have been many individuals who have contributed to this meeting and to the success that we all hope it will be. At present, we have 620 registered delegates for this conference which is more than we had anticipated. And, in fact, the number of attendees mushroomed, as more and more people wanted to attend. Eventually, we had to limit registration by order of the fire marshal who said that the venue could not safely hold more people than 620. The International AIDS Society, of which I am President, is proud to be a co-sponsor of this conference. However, I want to begin by thanking Dr. Neal Nathanson of the Office of AIDS Research (OAR), as well as the National Institutes of Health (NIH) for their major support. This support has been of several types. First, it has been financial. The OAR has provided staff for the logistics of the meeting to ensure that the job got done. Second, we have had strong moral support, and we thank you for each of these. I want to point out as well that the financial support has included a strong commitment to a scholarship program that has enabled us to bring many individuals concerned with microbicide development from around the world. This program has been executed successfully and efficiently by the Harvard AIDS Institute, and we thank them as well. There are a number of individuals who have worked tirelessly to ensure the success of this conference and I would now like to recognize some of them for their efforts. Unfortunately, one of them is ill and cannot be with us today; that is Dr. Victoria Cargill of the Office of AIDS Research. Let me tell you that Vicki has really worked to capacity on this event. In fact, I had wanted to present her, among others, with a bouquet of flowers. Since she is not here, I would like her colleague at OAR, Dr. Bob Eisinger, to accept these flowers for her. Bob has also worked for long hours on this meeting, and we also have a small gift for him. Bob, you don't get a bouquet of flowers, but a tie instead. Thanks so much. I also want to call up Ann Borlo who works for Social and Scientific Systems, which is the organization that has helped us to put this conference on. I cannot tell you the sacrifices that Ann has made for this meeting, including-permit me to say this-the postponement of her wedding date in order to make sure that this meeting would go off without a hitch. That represents commitment beyond the call of duty. I also want to call up Helen Rees, my co-chair for this conference. Helen, we have a bouquet for you as well. And lastly, I want to present flowers to Dr. Judith Auerbach of OAR for the enormous work which she did. Let me also remind you that no meeting of this type can ever take place without the help and involvement of many people and organizations. Your program book lists our corporate sponsors, whom we thank for their financial support of this meeting, as well as the names of commited organizations that have taken this task to heart. The list includes the International AIDS Society, the American Foundation for AIDS Research (AmFAR), the Centers for Disease Control and Prevention (CDC), the Harvard AIDS Institutes, UNAIDS, the United States Agency for International Development, the Contraceptive Research and Development Program (CONRAD), Family Health International, the Populations Council, the Alliance for Microbicde Development, and the Center for Health and Gender Equality. And, of course, I have already mentioned the superb leadership of OAR. I want to tell you a bit about how this meeting was conceived. In this context, I want to thank Dr. Pat Reichelderfer of the National Institute of Child and Health Development, because this meeting arose, in part, through discussions that took place last year at the Retrovirus Conference in Chicago, where Pat and I together discussed the need to organize a highly focused conference of this type. Pat also did a fantastic job in organizing teleconferences and early planning meetings related to this event. Laura Spofford also deserves recognition through having designed the conference logo. I think you will all agree that the logo is striking and symbolizes the goal of women to reach up and control much more of their destiny than is possible in too many places in the world at this time. Thank you, Laura, for the superb conference design. And, last, I want to thank the co-chairs, track chairs, and other people who served on our committees. The list is too long to mention but their names are all published in the program book. I would now like to make several points by way of introduction. First, I want to emphasize a reason that we are all here. Namely, granting agencies must prioritize research into the field of antiviral microbicides to a far greater extent that has hitherto been the case. These interventions should focus on empowering women in disadvantaged situations to do more to protect themselves against HIV. I next want to show a type of experiment that we have done in the lab. Mike Parniak of our group at McGill University was actually the first to do this type of work, and Jan Balzarini at the Rega Institute in Leuven, Belgium, has done similar studies. The experiment is very simple: you take the virus, mix it together with a drug and then centrifuge down the virus to eliminate any drug that hasn't been bound. Then you resuspend the viral pellet in the absence of drug, and simply ask whether or not the virus still retains the ability to be infectious. Among the drugs that have rationale in this regard, as we will discuss during this meeting, are non-nucleoside reverse transcriptase inhibitors. Other candidate molecules include dextran sulphate. PMPA is another drug that probably has the best proven record of all in regard to protecting macaques against transmission of simian immunodeficiency virus (SIV). The centrifugation experiment shows that a NNRTI termed UC-781 can literally kill the virus because it binds exquisitely well to the viral reverse transcriptase, as Mike first showed. Table 1 shows that Ifaverenz (Sustiva) can likewise perform this task. The reason that this is important is because Efaverenz has already been approved for treatment of HIV disease. Thus, at least one drug that is already widely used in the clinic is known to have the ability to kill viral reverse transcriptase. This compound has already passed a wide array of toxicity texts and has strong rationale as a potential microbicide.Table 1: Effect of Various Compounds on HIV InfectiousnessaPMPA, as I've said, also has strong rationale because it has a proven track record in animal models. Yet when PMPA is studied in the centrifugation experiment, it does not succeed in killing the virus; this is actually not surprising, since PMPA requires metabolism in order to be effective against reverse transcriptase. In brief, it must be metabolized from its pro-drug form to a phosphoryalated derivative in order to act as a chain terminator. I show this to highlight how we need to move forward. In short, we need to do experiments that are based, in part, on the compounds that are already available to us and what we know of their mechanism of action. As mentioned as well, several very cheap products, such as dextran sulphate, may also have strong rationale for microbicide development. It should also be obvious to us that we will fail to make significant progress in this field unless we have the commitment and support of the pharmaceutical and biotechnology industry. Microbicide research may, in fact, be unable to significantly move forward without the involvement of industry. The reasons for this relate not only to the cost of product development, but also to the expertise of companies in regard to each of product formulation, experience in conducting clinical trials, and the costs involved in the conduct of such trials. However, we cannot expect pharmaceutical companies to become more seriously involved (and we know that they have not become involved until now), unless this field can be shown to be profitable. At present, company executives may consider it likely that they will have to give away a microbicide that has been shown to be effective, because the vast majority of women at need, who live in developing countries, may not be able to afford this type of product, even if it were available. Therefore, there also needs to be a reasonable expectation of profit on the part of companies, if we are to encourage their involvement to begin with. That is why other parties need to become involved. Indeed, international agencies, such as the World Bank, working together with UNAIDS, can play a major role in enabling developing countries to institute biologically mediated HIV prevention policies. This can best be done by ensuring the affordability of relevant medical devices once these have been shown to be effective. In this context, the pledge by the World Bank to both purchase and distribute a successful microbicide product, once developed, is of the utmost importance. It means, among other things, that companies that invest in microbicide development can realistically expect their efforts to be profitable. I think that it is obvious to all of us that three of the cornerstones of HIV prevention research are vaccine development, the use of drugs to prevent mother-to-child transmission of HIV, and the development of microbicides to prevent the sexual transmission of HIV. These objectives must always be seen as complementary and never as mutually exclusive. A fourth area, that is also extremely important, is that of HIV education and awareness. In this regard, government leadership is essential, and the leaders of HIV-endemic countries must learn to articulate that HIV is their number one enemy. Unfortunately, far too many such leaders continue to prioritize other problems such as relatively minor border disputes with their neighbors. In regard to microbicide development, the data to be presented at this meeting will convincingly demonstrate that we now have the scientific ability to make a difference. The real question is whether the world will have the political will to translate scientific achievement into practical success.

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