As microbicides gain more footing in the pipeline since the conference in Bangkok, the advocacy community prepares for the future in Toronto
LifeGuide
[Treatment Horizons]
by Chael Needle
The clarion call of the XV International AIDS Conference in Bangkok, Thailand, in 2004 was “Access for All.” In his opening address, United Nations Secretary-General Kofi Annan advocated for one of a myriad of meanings of “access”: women’s access to microbicides, joining the calls for the empowerment of girls and women in the prevention and treatment of HIV/AIDS.
With the majority of the world’s HIV-positive population now composed of women, an urgent need has arisen for heterosexual women to be able to easily protect themselves against HIV without relying on male partners using condoms or reporting their sexual histories accurately, as well as during nonconsensual sex, if at all possible. Microbicides may potentially protect male partners as well, allowing positive women more sexual and conception options. While some prevention strategies might possibly mean a regimen of a preexposure chemoprophylaxis such as tenofovir or the use of female condoms, microbicides are high on the list of prevention options. A microbicide protecting against HIV infection has yet to make it through the clinical pipeline, however.
Microbicides are substances applied prior to sex, and have been formulated as a vaginal gel, cream, or contained within a sponge or vaginal ring, releasing the drug over days or weeks. (Some research on rectal microbicides has begun as well.) Mechanisms of action include blocking HIV attachment to CCR5 receptors, inhibiting viral replication, strengthening the body’s natural defenses, creating a physical barrier between pathogens and vulnerable cells in the cell wall, and killing or inactivating pathogens. Microbicides can either be contraceptive or noncontraceptive.
Recent NIAID-funded research has demonstrated that combination microbicides may be more efficient than single microbicides at preventing vaginal transmission of simian HIV (SHIV) in rhesus macaques. Forecasting the possibility that first-generation microbicides may only be thirty to fifty percent effective against something as complex as HIV transmission, researchers suggest that microbicides in synergistic combination might be needed to touch most, if not all, efficacy bases.
Two years after Bangkok, “when” is still an important concern as the world waits for research to make candidates into full-fledged products. But judging from the planned sessions at Toronto, “when” has joined a coalition of “how,” “what,” “where,” and “why.” Instead of waiting for microbicides to come to us, many in the microbicide advocacy community are stepping up to meet microbicides at the door, so to speak. Sessions in Toronto include modeling Phase III microbicide trials costs, building support for microbicides in Europe and North America, promoting investment in female-initiated or controlled prevention methods, unveiling a microbicides development strategy, as well as discussions of ethics and exploitation in women-enrolled prevention trials and fostering inclusion of positive women in trials, among other topics.
In the following interview, A&U talks with Pam Norick, Chief of External Relations, International Partnership for Microbicides (IPM), about setting the stage for access and for supporting research.
Started in 2002, IPM is a nonprofit product development partnership with a mission to accelerate the development and availability of a safe and effective microbicide for use by women in developing countries.
“The XV International AIDS Conference was a watershed event for microbicides. The issue of women and AIDS and the potential for microbicides gained wide attention and, for the first time, provided a forum for microbicide advocates to be heard globally,” says Pam Norick, when asked to reflect on the impact of Bangkok then and now. “At this year’s XVI International AIDS Conference, in addition to presenting new data on a vaginal ring delivery system, IPM is hosting a day-long expert consultation on understanding microbicide introduction in Africa and India. With five microbicide products in Phase III trials and a second generation of products well into safety testing, preparation for the introduction of microbicides as an addition to other HIV prevention strategies is urgently needed.”
IPM is preparing for access in multifaceted ways—“establishing innovative intellectual property agreements that enable delivery of microbicides in resource-limited settings; selecting for development products that are mindful of the realities of women’s lives; and designing policies and delivery strategies to promote successful product distribution,” notes Norick. The ultimate goal is to maximize the HIV-prevention impact of microbicides by making them widely accessible to women at risk of HIV infection in resource-limited countries throughout the world.” This undertaking ultimately depends on researching and understanding “the needs of women as well as the cultural and social situations in which they live and operate every day” and applying these realities in the design and delivery of microbicides. “The effectiveness of microbicides will be influenced by acceptability,” she adds. “Even the most effective microbicide in the world will not work if it is not used correctly.”
So far, “feedback from safety studies in many developing countries points to the need for microbicides that do not interfere with sexual intercourse and may be used discreetly. IPM has just completed one of several consumer studies aimed at determining the preferences and opinions of African women and their male partners regarding different types of gels, and is also planning for an acceptability study for the vaginal ring.” IPM and other microbicide developers will be able to use this information “to appropriately address women’s preferences for different types of microbicide delivery methods.”
Part of laying the foundation for access also involves developing clinical trial sites. “Extensive preparation is needed to ensure clinical trials of microbicides meet all regulatory and ethical requirements and produce meaningful results. IPM’s site development and clinical work is focused on the operational aspects of carrying out its initial safety trials and developing additional trial sites for future large-scale efficacy trials,” says Norick.
“When existing capacity is not sufficient, IPM works to build infrastructure and train host country staff to establish the necessary research sites and technical capacity. A critical element of this step is providing training for transferable skills with the goal of leaving behind buildings, equipment, technical capacity, and other resources that can be used by the communities for other types of research and trials in the future.”
In response to what IPM and the microbicide advocacy community hope to accomplish in Toronto, Norick responds: “Prevention and the feminization of the epidemic will be two of the key themes in Toronto. Because microbicides are at the intersection of these critical issues, microbicide development is expected to receive significant attention.” IPM expects the increasingly recognized need for a comprehensive response to HIV/AIDS to be a “major theme” at the conference. “The ABCs of prevention—Abstinence, Be faithful, Condoms—can work, but all depend on a man’s cooperation. Safe and effective microbicides would provide women with an urgently needed new tool to prevent HIV, complementing prevention strategies such as treatment for sexually transmitted infections, condoms, behavior change, abstinence, and some day, a vaccine. In Toronto, there will be important new attention paid to other potential prevention options, including male circumcision, diaphragms, preexposure prophylaxis, and herpes suppression.”
Of course, Toronto will continue to nurture innovative directions in microbicide research. Norick singles out the research and development of next-generation microbicides based on highly active antiretrovirals and novel delivery systems “to ensure that a microbicide is both accessible and something that women want to use once it is proven effective.”
“The earliest microbicide products, developed in the 1990s, are hoped to provide at least partial protection against HIV infection. These products work by forming physical barriers to the virus and by changing the chemistry of a woman’s vagina to make infection less likely. Currently, there are five first-generation microbicide products in large-scale efficiency trials throughout Africa and India.” These five are Carraguard, Savvy, cellulose sulphate, Buffer Gel, and Pro2000.
But the “development of ‘noncoitally dependent’ (independent of sex) microbicides is essential. Because many women lack the power to determine when they have sex, it is important to develop microbicides that are effective for longer periods of time. No one delivery method will be acceptable to all women, so multiple formulations must be developed. For example, IPM is developing the ARV-based dapivirine (TMC120 gel) formulated in a once-a-day gel designed to be used independent of sexual activity.” Currently conducting safety studies of this product in Africa, IPM is exploring alternative methods including intravaginal rings, films, suppositories, sponges and diaphragms. “Like the semisolid products (e.g., gels and creams), these alternatives are also versatile in terms of their ability to deliver combinations of drugs with multiple mechanisms of protective action. Importantly, these alternative delivery vehicles hold the promise of greater dosing versatility and potentially lower costs.” Dr. Joe Romano, a lead investigator of one of IPM’s safety studies, will be reporting on of one of these microbicide-containing intravaginal rings at the International AIDS Conference.
“A microbicide delivered in a vaginal ring may be able to deliver a drug for periods greater than thirty days. Recently, IPM completed two, first-ever clinical safety studies of microbicide-containing, silicone vaginal rings. IPM will be following these initial safety studies on an ARV-containing ring in Europe with an acceptability study later in 2006 in several African countries. A new, multichambered ring is also under early development which could allow for the inclusion of combinations of drugs in the same ring, mirroring the use of drug combinations which has become the standard in HIV/AIDS treatment. While still in the early stages of research and development, this structure could also allow for the inclusion of contraceptive properties, as well as protection against other STIs. The ring could be used discreetly, and may need to be changed as infrequently as every three months. Issues still to be considered in using a vaginal ring include multidrug compatibility, production limitations, environmental impact and product acceptability.”
Chael Needle reported on IAPAC’s survey about physicians’ and patients’ treatment perceptions in the July issue.
August 2006
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