Microbicides: INFO New Potential for Protection REPORTS What are microbicides? Microbicides are substances that are designed, when The INFO Project applied vaginally, to reduce transmission of HIV or Johns Hopkins Bloomberg other sexually transmitted infections (STIs). Some School of Public Health microbicides under development also function as Center for Communication Programs spermicides to provide contraceptive protection. 111 Market Place, Suite 310 Eventually, microbicides are likely to be available as Baltimore, MD 21202 gels, creams, films, suppositories, or vaginal rings. USA 410-659-6300 www.infoforhealth.org KEY POINTS • Scientists currently are studying over 60 substances as possible microbicides. Some 45 of these substances are in laboratory or animal testing, and 17 are in var- Contents ious stages of human testing. Five are in or about to enter phase III clinical trials— Five Microbicides the final stage of testing—which will determine how well these microbicide candi- in Final Stages dates prevent HIV infection and how safe they are for long-term use. If safety and of Testing effectiveness are established in clinical trials, a microbicide could be marketed per- page 2 haps as early as 2010 (26). Research Process • Effectiveness remains uncertain. It is not yet known whether any of the five microbi- Prolonged cides in phase III clinical trials will prove able to protect against HIV at all. If so, it page 5 may only be 50–60% effective in preventing HIV and other STIs, providing substan- Microbicides to tially less protection than condoms when used consistently and correctly. But future Join Condoms in generations of microbicides are likely to be more effective than the first generation, Saving Lives less costly, and better able to meet people’s needs (106). page 6 • Microbicides could save millions of lives. A vaginal microbicide that is used more Women consistently than condoms might prevent more HIV and STI infections than con- Could Control doms do in actual use. Many sexually active people are at risk for HIV/AIDS because Microbicide Use they do not use condoms or do not use them consistently and correctly, while peo- page 7 ple probably would be more likely to use microbicides than condoms. One estimate is that 2.5 million lives would be saved in the first three years after microbicides are Investment and Funding Are Crucial introduced (28, 97). page 8 • Women could control microbicide use. One advantage of microbicides over condoms is that women could use them without their partners’ cooperation. Microbicides Studies Suggest would offer women, who often lack the power to control sexual activity or condom Substantial Interest page 9 use, a method to reduce their vulnerability. • Public interest could be substantial. Many women and men would have great Ensuring Access interest in using microbicides, studies show. People differ widely, however, in the Is Essential page 11 characteristics of the ideal microbicide they would prefer—a fact suggesting that manufacturers should provide a wide range of choices. Bibliography • Introduction strategy is crucial to access. For microbicides to fulfill their promise, page 14 they must be accessible and affordable. A successful introduction strategy would involve manufacturers, suppliers, public health systems, and governments and would include communication, marketing, logistics, and pricing plans. January 2005 • Issue No. 3 INFO Five Microbicides REPORTS in Final Stages of Testing icrobicides, like drugs 1. Vaginal defense enhancers semen, which is alkaline, neutral- and medical devices, boost the body’s natural defenses izes the acidity of the vagina, mak- M must go through several against infection by increasing ing it more likely that sperm—and stages of rigorous testing for safe- lactobacilli or by rapidly acidifying also HIV and other pathogens—will ty and effectiveness in order to the ejaculate, reinforcing the natu- survive. Acid-buffering microbi- obtain approval from regulatory ral mild acidity of the vagina that cides make the semen acidic, agencies such as the US Food and inactivates both sperm and STIs. which keeps the vagina acidic, thus Drug Administration (US FDA). BufferGel is a vaginal defense inactivating sperm and several STI The first stages focus on safety of enhancer. organisms, including HIV (65, 86). use and product acceptability. The 2. Surfactants damage the BufferGel (carbomer 974P)1, final stage focuses on effective- surface membranes of disease developed at Johns Hopkins ness—that is, the ability of a pathogens, thereby disabling University and ReProtect, Inc., a microbicide in typical use to them and preventing them from biotechnology firm, reinforces reduce the average rates of infec- causing infection. C31G is a tions when compared with control surfactant. This report was prepared by Ushma Upadhyay, MPH. Indu Adhikary, groups, as well as long-term safety 3. Entry and fusion inhibitors Research Analyst. Bryant Robey, Editor. Richard D. Blackburn, Senior Research Analyst. and acceptability (11) (see Table 1). bind to disease pathogens or to Catherine Richey, Program Assistant. If successful, one or more of healthy cells before pathogens Designed by Prographics, Inc. the five products entering phase have a chance to invade and INFO Reports appreciates the assistance of the following reviewers: Willard Cates, III clinical trials is likely to reach attach to them. Carraguard, PRO Lee Claypool, Richard A. Cone, Patricia Donovan, Polly Harrison, the market. These five products 2000, and cellulose sulfate are Michelle J. Hindin, Henry Gabelnick, ® ® Pape Gaye, Monica Jasis, Karusa Kiragu, are: BufferGel , Carraguard , PRO entry and fusion inhibitors. Judy Manning, David M. Phillips, 2000®, C31G, and cellulose sulfate 4. Replication inhibitors prevent Malcolm Potts, Gita Ramjee, Susheela Singh, Harris Solomon, J. Joseph Speidel, (2, 44) (see Table 2). viruses from replicating in cells Jeff Spieler, Alan Stone, Lut Van Damme, and Cynthia Woodsong. A sixth product, dextrin-2-sulfate that they have entered. Replication Suggested citation: Upadhyay, U. Microbicides: (Emmelle®), was poised to enter inhibitors are still in preclinical New Potential for Protection. INFO Reports, No. 3. Baltimore, Johns Hopkins Bloomberg School phase III clinical trials in 2005, but studies or in phase I or phase II of Public Health, The INFO Project, Jan. 2005. the organization running the trial, clinical trials. None has yet The INFO Project Center for Communication Programs the UK Medical Research Council's reached phase III. The Johns Hopkins Bloomberg School of Public Health Microbicides Development Ward Rinehart, Project Director Programme (MDP), pulled it from Vaginal defense enhancers Stephen Goldstein, Chief, Publications Division Theresa Norton, Associate Editor the clinical trial. In a statement the boost natural defenses Linda Sadler, Production Manager organization explained that three against diseases. The vagina is INFO Reports is designed to provide an accurate and authoritative report on important develop- other products of a similar type normally too acidic for sperm to ments in family planning and related health issues. The opinions expressed herein are those of the were already entering phase III survive. During sexual intercourse authors and do not necessarily reflect the views of the US Agency for International Development or clinical trials, and dextrin-2-sulfate the Johns Hopkins University. 1 Some microbicide candidates are typically did not prove as effective as the known by their brand name, such as BufferGel, others in preclinical tests (78). while others are known by their chemical agent, such as C31G. In this section each microbicide is Most microbicides under devel- introduced by the name most commonly used, followed by its other name, whether product or opment, including the five in chemical, in parentheses. Thereafter, throughout phase III clinical trials, act in one or the text the product is referred to by the name most commonly used. Product names are in ital- Published with support from USAID, Global, GH/POP/PEC, under the terms of Grant No. GPH-A-00-02-00003-00. more of the following ways (44): ics, while chemicals are in roman type. 2 TABLE 1 Clinical Trial Phases Applicable to Microbicides Phase Number of Length of Objectives Participants Treatment and Follow-up Phase I 10–100 1 to 2 weeks To assess local and systemic safety and acceptability and to determine dose and formulation. May run into a phase II trial (called phase I/II). Phase II 50–200 2 to 6 months To assess safety and acceptability over a longer time. Phase II/IIb 50–500 6 months to To screen for products reaching a minimum level of effectiveness. 2 years Smaller, less costly than phase III, but numbers of participants and length of follow-up indicate whether a subsequent larger trial would be worthwhile. If so, participants continue from one trial to the next, and additional participants are recruited (called phase II/III). Phase III 1,000–30,000 1 to 2 years To evaluate effectiveness in preventing HIV infection and other STIs and to assess long-term safety and acceptability. Some phase III trials will involve multiple products, which will require more participants than those testing only one product. Note: Phases I/II, II/IIb, and II/III are variants of study designs or studies that move from one clinical trial phase to the next. Number of participants and length of treatment and follow-up vary. Sources: Adapted from Stone, 2003 (112), Fleming, 2004 (27), Mauck