On April 15, 1996, representatives of CDC's Office of Women's Health; the National Center for HIV, STD, and TB Prevention (NCHSTP); the National Center for Chronic Disease Prevention and Health Promotion; and the National Center for Infectious Diseases convened a one-day panel discussion on female-controlled chemical methods for HIV/STD prevention. The goals of this meeting were:
To have experts from governmental and nongovernmental organizations brief CDC staff on accomplishments, work in progress, and future directions in biomedical and behavioral research on and development and marketing of topical microbicides, and development and implementation of policy concerning their use (See attached agenda).
To have CDC staff brief panelists and guests on ongoing research at CDC.
To discuss ways to foster collaboration between CDC and other governmental and nongovernmental organizations.
To seek guidance on developing a CDC research agenda that would establish a science base for developing and implementing policy about use of female-controlled HIV/STD prevention methods.
Panelists recommended several future actions for CDC, including:
Continuing behavioral research on determinants of acceptability and use and on attitudes of consumers and providers toward vaginal and rectal microbicides.
Conducting research on how complex, hierarchical prevention messages are understood and whether recommending other, less effective HIV/STD prevention methods causes 'drifting' away from male condom use.
Increasing support of Phase III human effectiveness trials of nonoxynol-9 (N-9) and other candidate compounds against HIV through collaboration with other agencies and development of CDC-sponsored high and moderate-risk cohorts.
Developing population-based research on vaginal products with both contraceptive and antiinfective action and rectal microbicides.
Publishing and distributing a document for providers, consumers, and HIV/STD prevention specialists on the effectiveness and acceptability of female-controlled methods for HIV/STD prevention, current gaps in knowledge, and recommendations for future research.
Deferring development of a policy to promote N-9 as a topical microbicide until more data are available.
Meeting highlights are summarized below.
Helene Gayle, MD, NCHSTP Director, reviewed the reasons for CDC's growing interest in this topic; these include the growing number of women with HIV/AIDS; the fact that women are disproportionately affected by STDs; NCHSTP's increased emphasis on prevention programs; the limited progress with other preventive strategies, such as vaccine development and male condom promotion; and the growing recognition that women who are at risk for HIV/STD infection through heterosexual contact need methods other than the male latex condom to protect themselves.
Clinical efficacy studies of N-9: status and future directions.
David Sokal, MD, Family Health International (FHI), reviewed results of in vitro, animal, and human testing of nonoxynol-9 (N-9), a candidate microbicide found in spermicides commercially available worldwide. Although N-9 kills HIV in vitro, the effects of N-9 on HIV/STD acquisition in humans are uncertain. The results of three randomized, controlled field trials of the effectiveness of various forms of N-9 indicate that N-9 reduces the risk of acquiring gonorrhea and/or chlamydia by 20% to 70%, but these trials did not evaluate HIV and other bacterial STD. In the only randomized controlled trial of N-9 against HIV, high-dose N-9 in a vaginal sponge showed no protective effect against HIV acquisition among commercial sex workers (CSWs). Two multicenter, randomized controlled clinical trials, including one sponsored by FHI, are underway. Recruitment for the FHI study of the effects of N-9 film on HIV infection among CSWs in Cameroon is complete, and the final analysis is expected in December 1996.
Jos Perriens, MD, UNAIDS, reviewed the status of UNAIDS-sponsored microbicide trials. A study of menfegol, a spermicidal surfactant similar to N-9 that is found in foaming tablets used in many developing countries, was stopped in early stages because of dose-dependent toxicity to the genital mucosa that appeared to be partly due to the toxicity of the vehicle. This finding suggests that foaming tablets containing N-9 may also cause toxicity. He then reported on safety studies with an N-9-containing gel (COL-1492 or Advantage 24). Healthy volunteers in Europe and Thailand were randomly assigned to one of three groups: once-daily use of gel, once-daily use of placebo, or no treatment. The incidence of genital ulcers and abrasions was very low in all three groups, but the incidence of erythema was higher in the COL-1492 group than in the other two groups. In a subsequent study investigating the safety of COL-1492 used four times a day by healthy volunteers in Thailand, the incidence of lesions was still very low but was slightly higher than with once-daily use. However, because of the overall low incidence of lesions, COL-1492 was considered safe for phase III studies. A phase III study is starting in June 1996 in South Africa and Thailand; Project Retro CI in Cote d'Ivoire will also participate if they receive IRB approval. Dr. Perriens also described the accomplishments of the Interagency Working Group on Vaginal Microbicides, a group of representatives from public-sector agencies supporting vaginal microbicide research. At the group's meeting in April 1996, guidance on the preclinical and clinical development of vaginal microbicides was approved and will be published by July 1996. The ensuing discussion concluded that important issues to address in ongoing and future research include:
The generalizability of results of trials among CSWs to the general population of women at lower risk of bacterial STDs.
Potential problems with recruiting sufficient numbers of participants to account for inadequate statistical power and confounding due to high frequency of concurrent male condom use.
The importance of product formulation in determining effectiveness, toxicity, and acceptability.
The correlation of self-reported symptoms and colposcopic, histologic, and immunohistochemical findings in the lower genital tract and the impact of these factors on HIV transmission.
The role of pharmacokinetics (e.g., half-life, duration of effect) in determining effectiveness and adverse effects.
The need to define the "minimum threshold" of effectiveness that would be necessary to support various messages for use of N-9 for HIV/STD prevention (e.g., as a stand-alone product, as a back-up if condoms are not available, or as an adjunct to condom use).
Role of in vitro testing in developing and evaluating female-controlled chemical methods:
Michael Norcross, PhD, Food and Drug Administration, emphasized that in vitro testing is an important first step in evaluating toxicity and efficacy of candidate compounds, especially for determining the diverse types and mechanisms of HIV entry and replication in cells. However, he cautioned that in vitro test results cannot predict results in animal or human studies because of the complex microbiologic and immunologic environment of the lower genital tract. He reviewed the two broad categories of HIV-1 isolates: T-cell line trophic and macrophage trophic. Testing algorithms for N-9 are largely T-cell trophic, but because N-9 has nonspecific cytotoxic properties, algorithms using either cell type are appropriate.
Lee Claypool, PhD, Program for Contraceptive Research and Development (CONRAD), outlined CONRAD objectives and activities in the development of topical vaginal microbicides, including:
Collaboration with Federal agencies.
The testing of experimental compounds and existing products for spermicidal activity.
The evaluation and decision tree used to direct and focus preclinical development of new candidatae compounds.
The testing algorithm and assay methods for evaluating the in vitro anti-HIV activity of test compounds and existing spermicides against cell-free HIV, cell-associated HIV, and viral binding of target cells
Research on vaginal physiology and virus-cell interactions.
He also reviewed the current leading candidate compounds, the pending evaluations for toxicity, and the additional research needed to support product development regarding safety, efficacy, and acceptability.
Role of animal testing in developing and evaluating female-controlled chemical methods:
Nancy Alexander, Ph.D., National Institute for Child Health and Development, described the theoretical advantages of using animal models in developing and evaluating microbicides, including the ability to perform toxicity tests and do necropsies. She reviewed the common animal models used for reproductive and toxicity studies (rabbits) and retroviral transmission studies (cats and macaques).
Christopher Miller, DVM, University of California at Davis, summarized studies showing that N-9 can prevent vaginal transmission of FIV in cats and SIV in macaques. He concluded that, although animal models are useful in developing and evaluating chemical methods to prevent HIV transmission, they cannot predict the outcome of clinical trials. He emphasized that research is needed on the clinical implications of self-reported vaginal irritation associated with microbicide use because data are lacking on the "background" irritation associated with vaginal sex without microbicide use.
New candidate compounds: status and future directions for in vitro and in vitro testing:
Lourens Zaneveld, DVM, Ph.D., Program for Topical Prevention of Conception and Disease (TOPCAD), explained that his program is focusing on developing and testing noncytotoxic antimicrobial contraceptives because nonspecific, cytotoxic compounds such as N-9 have a high potential for disrupting vaginal epithelium and adversely altering vaginal flora. In addition, it is unlikely that another nonspecific cytotoxic agent could be found that would be so much better than N-9 that it would warrant the high cost of drug development. TOPCAD is currently evaluating five noncytoxic contraceptive antimicrobials, two of which are entering preclinical development, as well as two N-9 releasing formulations. He emphasized that formulations are critical in determining the efficacy and acceptability of a product and that several formulations of the same active ingredient may be needed to meet individual preferences. However, clinical trials evaluate a single formulation of a single active ingredient. If this formulation is not acceptable in clinical testing, research and development must return to preclinical testing with another formulation for FDA licensure requirements, slowing the progress of an acceptable product to market.
Zeda Rosenberg, Ph.D., National Institute of Allergy and Infectious Diseases, described the categories of new candidate compounds under development at NIAID and elsewhere, including:
Broad-spectrum microbicides: surfactants (N-9), acid buffers, natural products (lactobacilli, magainins, protegrins).
Inhibitors of viral entry: monoclonal antibodies, soluble CD4, sulfated polysaccharides, naphthalene sulfated polymers, n-docosanol.
Inhibitors of HIV replication: postbinding fusion inhibitors, reverse transcriptase inhibitors.
In vitro, many such products vary widely in their activity against wild versus lab HIV strains, suggesting that testing against various strains is valuable. She emphasized three factors that will be key to successful product development:
the development of "combination products" that may act through more than one mechanism,
the ability to economically synthesize compounds in bulk,
the use of a formulation that adequately covers the vagina and is acceptable to women and their partners.
HIV/STD prevention methods with contraceptive action: advantages and disadvantages:
Penelope Hitchcock, DVM, National Institute of Allergy and Infectious Diseases, noted that outstanding contraceptive methods are available, but no methods (other than Hepatitis B vaccine) are available that prevent STD/HIV infection but allow conception. Currently, couples must risk infection to have children. In addition, the best methods for preventing pregnancy (e.g., hormones, intrauterine devices) are least effective against STD/HIV and may lower consistent condom use. She raised three questions about promoting N-9 as a microbicide:
If N-9 lyses cells, will N-9 trigger the release of cell-bound virus into the vagina as free virus and thus possibly promote infection of other vaginal cells or make women more infectious to partners?
Will reducing the dosage or frequency of N-9 to minimize irritation also reduce N-9's contraceptive efficacy?
If the results of clinical trials of N-9 do not answer questions about N-9's effectiveness against HIV, is this effectiveness best evaluated through postmarket surveillance?
Willard Cates, MD, Family Health International, noted that national surveys indicate that US women desire contraception during 85% of their reproductive years, whereas women in developing countries may desire contraception for shorter durations, albeit still a large part of their reproductive years. These findings suggest the need to develop microbicides with and without contraceptive action and to study the relative value of recommending dual methods of contraceptive/microbicide regimens. He described an FHI-sponsored study of condom use in Colombia in which female CSWs were counseled to use male condoms and/or spermicides as HIV/STD prevention methods. While CSWs were more likely to report ever using condoms than spermicides, they were more likely to report consistent use of spermicides than consistent use of condoms, suggesting "drift" away from consistent condom use. Because studies among CSWs may not be generalizable to populations at lower risk, he encouraged CDC to study the comparative effectiveness of promoting a single method vs. two methods for HIV/STD prevention in population-based cohorts of women at moderate risk for HIV/STD. He also called for CDC studies of the role of microbicides in postexposure prophylaxis for HIV/STD.
Characteristics of the ideal method: what do women need?
Muriel Harris, Society of Women and AIDS in Africa and the Microbicide Research Advocacy Project, reviewed several characteristics of the ideal method: it must be safe, easy to use, available, affordable, nonirritating, and effective in preventing infection. She emphasized that research indicates that the majority of STD and HIV transmission to women can be prevented if women are given the means to protect themselves; that research, especially behavioral research, on female-controlled microbicides is needed; and that advocates are needed to promote the development of methods that meet the most important needs of women.
Chris Elias, MD, of The Population Council, emphasized that research on the acceptability of various formulations is important in determining user preferences and user dynamics and in documenting adverse effects during typical use. He reviewed an N-9 formulation preference study being conducted at five sites in several different countries. Women are instructed to use a different formulation (gel, film, or suppository) each month for 3 months. Preliminary results from four countries indicate that preferences are highly variable within and between countries; are not well correlated with expectations before use; and are strongly influenced by perceptions of 'wet' vs. 'dry' sex, partner's perceptions, and the product's ability to enhance sexual pleasure or frequency. No significant irritation was found with any of the three formulations. Film was the most preferred, suppositories the least. This study suggests that:
- influencing the way a product is introduced and supported among users may be easier than changing the product itself,
- more focus on partner preferences is needed,
- "trade-offs" between promoting a product for disease prevention vs. enhancing sexual pleasure or vaginal health need to be explored.
Sheila Murphy, Ph.D., University of Southern California, reviewed preliminary data from a CDC-sponsored study of the most desirable features of HIV/STD prevention methods among African-American and Latino women attending STD clinics in Los Angeles. The study is evaluating several dimensions, including availability, reliability, female control, interruption of the sexual sequence, and ease of use. In a preliminary subset of African-American women, the most desired characteristics were that the method:
- did not cause vaginal or urinary tract infection
- did not cause physical discomfort
- worked immediately
- was reliable
Women who desired a female-controlled method were at lower risk for HIV/STD infection as measured by age at onset of sexual activity and number of lifetime sexual partners. Focus group analyses suggest that the features that women find important may differ by cultural background and beliefs; this issue is being evaluated in a larger quantitative survey. The study is also evaluating how women process single vs. multiple prevention messages (e.g., male condom alone vs. male condom, female condom, and/or spermicide). Questions being asked include
Does offering a second option such as spermicides undercut the perceived efficacy of the primary option of the male condom?
Does offering multiple options, especially specific hierarchies, create confusion?
She emphasized the need for community-level trials to supply data for policy making but pointed out that data on the effectiveness of products are needed before community-level studies can be done.
Licensing, labeling, regulatory, and marketing issues for female-controlled methods in the United States:
Sheryl Lard, Ph.D., Food and Drug Administration, explained that unlike toxicity testing requirements the type and extent of studies that the FDA requires for approval of new topical antiviral compounds or new labeling claims for existing topical compounds are not defined by law. Rather, preclinical research needs are determined on a case-by-case basis, depending on the amount and quality of existing data, the design of the initial clinical trial, and the mechanisms of drug action (e.g., nonspecific lysis, biochemical barrier, immune-based mechanisms). Relevant characteristics of drug activity in vitro include the dose/response curve against clinically relevant virus types, the results of cytotoxicity testing, and the kinetics of drug action. She encouraged new product sponsors to contact the FDA early in the development stages before bringing products to the most expensive clinical trial phase.
Deborah Birnkrant, MD, Food and Drug Administration, reviewed requirements for clinical testing for new products, for submitting claims for change in dosage or route of administration, and for supporting a new labeling claim for an existing product for use in different patient populations. These include safety studies (Phase I) and efficacy studies (Phases II and III). She encouraged using formulations with demonstrated acceptability in clinical trials.
Lorna Totman, Ph.D., Nonprescription Drug Manufacturer's Association, explained that over-the-counter (OTC) vaginal spermicides are a small, shrinking, non-profitable market: only about 2-3% of married US women use spermicides with or without mechanical barriers. Manufacturers are reluctant to pursue new product development or submit FDA labeling claims of HIV/STD prevention for existing products for many reasons, including liability concerns, especially when OTC products are used in ways not recommended by the label and manufacturers may still be found liable for such "off-label" use. A major current focus of manufacturers is responding to the 1993 FDA-proposed rule that recommends collecting data to support claims of contraceptive effectiveness of specific formulations of OTC N-9-containing spermicides. She emphasized that market surveys indicate that there is virtually no US market for HIV/STD prevention methods without contraceptive action and that adding a labeling claim for HIV/STD prevention to spermicides would at best double a very small market.
CDC's current behavioral and biomedical research on female-controlled HIV/STD prevention methods:
Rebecca Cabral, Ph.D., Division of Reproductive Health, CDC, reviewed the CDC-sponsored study of psychosocial predictors of female condom use among women in STD clinics in Alabama. Preliminary data from first-month follow-up interviews indicate that 17% of women reported using the female condom as their only barrier method during intercourse, 15% only the male condom, and 54% both the female and male condoms (on different occasions). Other findings from baseline data indicate that, although most women expressed favorable opinions about the properties of female-controlled barriers, only 4% currently use spermicides, and that women who have experience with diverse methods like spermicides least. Dr. Cabral concluded that the determinants of barrier use are complex; we need to know more than what women say they like or dislike about product formulation properties. Comprehensive behavioral research is needed.
Katherine Stone, MD, Division of Sexually Transmitted Disease Prevention, CDC, reviewed other CDC-sponsored behavioral and biomedical research on female-controlled HIV/STD prevention methods (See attachment). She reviewed preliminary data from a study in Philadelphia STD clinics evaluating the effect of counseling women about the New York State Department of Health hierarchical prevention message for HIV/STD prevention, which recommends both male and female condoms; if neither are used, spermicides are recommended. Among women exposed to the hierarchical message, the number of acts of intercourse in which at least one recommended method was used dramatically increased.
Development and implementation of policy on HIV/STD preventive methods:
Zena Stein, MBBS, Columbia University, reviewed the development of the New York State Department of Health AIDS Institute hierarchical prevention message of 'Don't do nothing.' She emphasized that, if CDC continues to advocate a policy of preventing HIV/STD through male condom use only, it will be "walking away from the problem." The condom-only policy is not working, especially among women at low to moderate risk, who, unlike CSWs with paying partners, tend to be ineffective condom users. Spermicides were included in the hierarchy for several reasons: male condoms are not an 'exciting' HIV/STD prevention option for most women, the efficacy of N-9 in reducing the risk of gonorrhea and chlamydia has been demonstrated, HIV transmission may be reduced indirectly by reducing risk of these bacterial STD, and there is no convincing evidence that N-9 enhances HIV transmission. However, she cautioned that the efficacy of N-9 in reducing HIV has not yet been demonstrated and the extent to which N-9 guards the cervix, which may be an important target organ for HIV, remains unclear. She emphasized that women need client-centered counseling about options that are appropriate for their specific circumstances. She recommended that CDC play an active role in determining if women offered options other than male condoms "drift" away from condom use and in training providers to counsel women about appropriate prevention methods.
Martha Rogers, Division of HIV/AIDS Prevention, CDC, reviewed the long and arduous process CDC typically goes through to develop and implement health recommendations and policy in collaboration with other governmental and nongovernmental agencies. Factors that are weighted heavily in guideline development are science (as available), expert opinion, cost, and practicality. In considering guidelines for microbicide use, CDC is faced with incomplete data and a dearth of scientific evidence. Questions that need to be answered include
How should results expected from the Cameroon study in June and December 1996 be incorporated into guidelines?
If microbicides are recommended for HIV prevention, how will they fit with other prevention modes?
3) How will the guidelines be implemented?
How will the potential impact of policy be determined?
What is CDC's role in this process?
Finally, she solicited recommendations about CDC's role in the development of topical microbicides.