R. M. Grant et al. (Special Section on HIV/AIDS: Follow the Money, Perspectives, "Whither or wither microbicides?", 25 July 2008, p. 532) raise provocative points on how candidate microbicides are evaluated and selected for testing in effectiveness studies, and how microbicide research should be redirected for success. The authors make valid observations and provide a valuable platform for candid discussion of the challenges in microbicide research—challenges also germane to other HIV prevention research approaches, including pre-exposure prophylaxis.
Product selection: We agree that stringent criteria must be applied to the selection of microbicide products for testing in effectiveness trials. BufferGel, Carraguard, cellulose sulfate, PRO2000/5, and SAVVY were selected for evaluation early in this decade based on the best scientific tools and knowledge then available. Since then, testing algorithms and assays have become more sophisticated. This evolution and what we are learning from current trials are already guiding the identification and selection of newer candidates.
Animal models: The authors recommend preclinical studies in Non-Human Primate (NHP) models as essential to establishing the biological plausibility of candidate microbicides. As with use of NHP models to evaluate HIV vaccines, NHP models for microbicides are not yet validated, no consensus protocol exists, and the model is subject to substantial variability. While NHP studies are critical to generating and testing hypotheses, we see them as parallel, not primary, streams of evidence supporting selection of products for effectiveness testing.
Development of combination approaches: Strategies for HIV prevention must consider both risk and benefit, a balance that, simply put, differs considerably for HIV-infected vis-à-vis -uninfected individuals. Development of combination approaches to treatment has been critical to the improvement of HIV therapies. Uninfected individuals who will use drugs for prevention, whether applied topically or orally, must have assurance that chronic exposure to two or more drugs has proved to be not only effective but extraordinarily safe. As combination microbicides advance in preclinical testing, it will be critical to work with regulators on how best to evaluate the relative safety and effectiveness of single vs. combination approaches for use by HIV-uninfected individuals.
Need for greater coordination: The microbicide field has established multiple mechanisms for active communication and coordination to ensure that knowledge gained from past successes and failures informs future decisions. These include the Clinical Trials "Quick" Working Group and Microbicide Donors Committee, both coordinated by the Alliance for Microbicide Development. Despite the relative absence of large pharmaceutical companies from the microbicide field, new chemical entities and formulations, new models, innovative approaches to improve adherence, and more efficient trial designs are shared through these cross-coordination efforts. This is made possible by a valuable diversity of funders, including the U.S. government (CDC, NIH, USAID), U.K. Department for International Development and Medical Research Council, and philanthropies such as the Bill and Melinda Gates Foundation. Cross-agency coordinating functions recently established by the NIH Office of AIDS Research should also enhance future decision-making.
"Whither or wither microbicides?" asks the microbicide field to contemplate its past and future. Some of its recommendations are being implemented; others, such as combination strategies, are in early stages. We recognize that we must pursue only the best scientific leads; better integrate basic, behavioral, and clinical research; and leverage and deploy human and monetary resources efficiently. What we cannot do is wait. The need for effective HIV prevention methods is too great.
Polly Harrison
Alliance for Microbicide Development, 8484 Georgia Avenue, Suite 940, Silver Spring, MD 20910, USA.
John W. Mellors
HIV/AIDS Program, 818 Scaife Hall, University of Pittsburgh Medical Center, 3550 Terrace Street, Pittsburgh, PA 15261, USA.
Barbra Richardson
University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA.
Benoit R. Masse
Statistical Center for HIV/AIDS Research and Prevention, 1100 Fairview Ave. N., LE-400, Seattle, WA 98109, USA.
Quarraisha Abdool Karim
HIV Prevention Trials Network, Centre for Epidemiological Research, Medical Research Center, PO Box 17120, Durban 4013, South Africa.
Salim S. Abdool Karim
CAPRISA, University of KwaZulu-Natal, King George V Avenua, Durban 4041, South Africa.
Ward Cates
Institute for Family Health, Alpha Building, Family Health International, 2224 East Highway 54, Durham, NC 27713, USA.
Anne S. Coletti
Family Health International, 12 Madison Street, Medford, MA 2155, USA.
Janet Darbyshire
Microbicide Research Council, MRC Clinical Trials Unit, Medical Research Council, 222 Euston Road, London NW1 2DA, UK.
Laneta J. Dorflinger
Clinical Research, Family Health International, Post Office Box 13950, Research Triangle Park, NC 27709, USA.
Paul Feldblum
Family Health International, 2224 East Highway 54, Durham, NC 27713, USA.
Henry Gabelnick
CONRAD, 1611 North Kent Street, Suite 806, Arlington, VA 22209, USA.
Vera Grigorieva Halpern
Clinical Research Department, Family Health International, 2224 East Highway 54, Durham, NC 27713, USA.
Sharon L. Hillier
Department of Obstetrics, Gynecology, and Reproduction, Magee-Womens Hospital, University of Pittsburgh School of Medicine, 300 Halket Street, Pittsburgh, PA 15213, USA.
Vicky Jespers
Institute of Tropical Medicine, Nationalstraat 155, Antwerp, Belgium.
Ayesha B. M. Kharsany
CAPRISA, Nelson R. Mandela Medical School, University of Natal, Private Bag 7,Durban 4013, South Africa.
Sheena McCormack, Andrew Nunn
MRC Clinical Trials Unit, 222 Euston Road, London NW1 2DA, UK.
Ian McGowan
Magee-Womens Hospital, University of Pittsburgh School of Medicine, 204 Craft Avenue, Room B505, Pittsburgh, PA 15213, USA.
Rabeea F. Omar
Centre de Recherche en Infectiologie de l'Universitaire de Quebec, Centre Hospitalier Universitaire de Québec (CHUQ), 2705 Boulevard Laurier, Ste-Foy, Quebec G1V 4G2,
Canada.
Nancy S. Padian
Women's Health Imperative, Research Triangle Institute, 114 Sansome Street, Suite 500, San Francisco, CA 94104, USA.
Louise Pedneault
Centre for Biomedical Research, HIV and AIDS Program, Microbicides Population Council, 1230 York Avenue, New York, NY 10065, USA.
Melissa Pope Robbiani
Population Council, 1230 York Avenue, New York, NY 10021, USA.
James Sailer
Population Council, One Dag Hammarskjold Plaza, 9th Floor, New York, NY 10017, USA.
Douglas Taylor
Family Health International, Post Office Box 13950, Research Triangle Park, NC 27709, USA.
Elizabeth E. Tolley
Family Health International, 2224 East Highway 54, Durham, NC 27713, USA.
Lut Van Damme
Family Health International, 4401 Wilson Boulevard, Suite 700, Arlington, VA 22203, USA.
Sten H. Vermund
Institute for Global Health, Vanderbilt University School of Medicine, 319 Light Hall #0242, Nashville, TN 37235, USA.
Janneke van de Wijgert
Academic Medical Center, Center for Poverty-Related Communicable Diseases, Meibergdreef 9, T0-120, Amsterdam 1105, Netherlands.
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