CHALLENGES IN MICROBICIDE DEVELOPMENT

July 24, 2005, Caesar Park Ipanema Hotel, Rio de Janeiro, Brazil

On Sunday, 24 July 2005, the UCLA AIDS Institute and the Brazilian STD/AIDS Program convened a symposium in Rio de Janeiro prior to the 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment. In his opening remarks, Dr. Ian McGowan, organizer of the symposium, noted that microbicide development is entering an exciting phase, with a number of potentially promising compounds in late-stage effectiveness clinical trials. This progress is especially significant given how little funding the field has received: an aggregate of only US$142 million in 2004, compared with roughly US$650 million for HIV vaccine research.

Even the most optimistic projections suggest that we are a decade or more away from having a sterilizing HIV vaccine. Microbicide research, by contrast, may yield one or more marketable products within the next five ­ 10 years, although Dr. McGowan reminded attendees that bringing these products to market will require a huge logistical undertaking and studies involving tens of thousands of women, most of them in sub-Saharan Africa.

Cristina de Albuquerque Possas, Director of Research for the Brazilian STD/AIDS Program, who co-chaired the first half of the symposium with Dr. McGowan, provided attendees with an overview of her country’s response to the AIDS epidemic—a sensible, science-based, compassionate, comprehensive approach to prevention and treatment that is a model for developing and developed countries alike. Dr. Possas observed that the Brazilian AIDS/STD program is keen to begin working in collaboration with US-based groups such as the UCLA AIDS Institute and the International Partnership for Microbicides. Because Brazil already provides universal access to HIV testing and treatment, much of the infrastructure for microbicide research and development already exists.

According to Robin Shattock (St. Georges Medical School), microbicide research is focused on identifying the most effective targets—on the virion itself, and in the human body. To date, most of this work has been done with NNRTIs and the nucleotide analog tenofovir, because of their long half-lives and relative stability, but a number of small molecules now in development—chief among them CCR5 entry inhibitors and fusion inhibitors including T-20-like compounds—also appear to hold real promise. The very newest data suggest that there is a synergistic effect when these compounds are used in combination, an effect that mimics that seen when antiretroviral agents are given in combination.

It is already apparent that some of these agents may have better efficacy in preventing migration of infected cells from the mucosa to regional lymph nodes. It is equally clear that some of the tested agents, the NNRTIs in particular, demonstrate significant memory effects. All of this is encouraging, but as Dr. Shattock noted, candidate microbicides need to do more than show efficacy. If they are going to be effective in containing the worldwide epidemic, they also need to be inexpensive (4 cents or less per application), stable, heat-resistant, and available in enormous quantities. (The first and last caveats would seem to rule out agents based on proteins or peptides, unless ways can be found to manufacture such compounds economically, which is currently not the case.)

What we are looking for, Craig Hendrix (Johns Hopkins University) told the assembly, is the right drug in the right concentration in the right place at the right time. Our objective, he said, is to “outdistance and outlast the virus.” This sounds simple enough and may be readily achieved in the vagina, but is likely to prove daunting when one considers what kind of distribution and duration, concentration, and clearance would be needed to protect the rectum and lower colon during anal intercourse. Dr. Hendrix’s current research is centered on ways to provide the coverage that will be needed, for as long as it will be needed. Given how long simulated ejaculate remains in the lower gut—and how far up the transverse colon it migrates—it appears that effective agents will have to blanket more of this area, and do so for far longer, than was initially thought.

In effect, NNRTI-based prevention strategies are already being tested, as Kenneth Mayer (The Miriam Hospital/Brown University) pointed out in his review of the current status of pre-exposure prophylaxis (PREP) studies using tenofovir. Although a number of these studies are stalled or have been cancelled due to miscommunications about the risks of PREP and the long-term design of the studies, Dr. Mayer expressed confidence that close to 4,600 sexually-active adults would soon be enrolled in preliminary trials of tenofovir as pre-exposure prophylaxis.

One concern about PREP has been that enrollment in such studies would encourage risk-taking on the part of participants. This concern may prove to be unfounded, according to Dr. Mayer, who reported that fewer than 5% of the MSMs enrolled in a trial that offers post-exposure prophylaxis (PEP) to participants who engage in unprotected anal intercourse have actually availed themselves of PEP treatment.

There is no question that innate immunity protects some individuals from HIV infection some of the time—and a much smaller number from infection all of the time. The corollary question, which currently engages Leonid Margolis at the US National Institute of Child Health and Human Development, is whether there are also "innate microbicides." Dr. Margolis presented preliminary evidence that HHV-6 and measles both suppress HIV replication in vitro by inducing secretion of chemokines known to be inimical to the virus. The recent discovery that Toxoplasma gondii also down-regulates CCR5, and does so in a dose-dependent fashion, is as intriguing as it is counterintuitive, given that T. gondii also causes fatal infections in individuals with advanced HIV disease.

Nonetheless, Dr. Margolis feels that microbes may one day be used as microbicides to prevent HIV entry and infection by creating a hostile cytokine milieu for HIV. Indeed, these microbes might function as "proto-vaccines" and would probably be less expensive to produce than any of the candidate vaccines currently in development.

Whatever forms microbicides eventually take, they will need to be safe and efficacious when used rectally, as Peter Anton (UCLA) underscored in his presentation. The rectum is 200 times more vulnerable to HIV infection than is the vagina, a physiological fact that makes unprotected anal intercourse exponentially more risky than vaginal sex. Further, anal sex is far more widely and routinely practiced than is commonly recognized. Dr. Anton presented preliminary data from a study being conducted by his UCLA colleague Pamina Gorbach, who has enrolled more than 1,100 young adults (ages 18 to 26) in a survey of contemporary sexual practices. Fully 41% of these young heterosexuals report that they have at some point engaged in anal intercourse, and 29% report having done so with one or more of their last three sexual partners.

Using mathematical modeling, it is clear that even a modestly effective microbicide could have a significant impact on the course of the global epidemic, as Dr. Anton demonstrated: a compound that is only 50% effective, used only 50% of the time, will still result in a 17% reduction in the rate of new infections. This may seem like a modest diminution, but it is still enough to shift the growth rate of the pandemic to less than 1.0, the mark of an epidemic in decline.

At this juncture there are still many more questions than answers, Dr. Anton admits. We need to know what to measure and where to make those measurements. We need to characterize the baseline mucosal indices for MSMs, in order to know what characteristics a rectal microbicide will have to possess in order to confer protection on all those who engage in anal intercourse. These questions need to be answered soon, because Dr. Anton and his colleagues at UCLA hope to initiate Phase 1 rectal microbicide studies in the next two years.

Assessment of microbicide safety and efficacy, though critical, are not the only questions that need to be answered. As Alex Carballo-Diéguez (Columbia University) indicated in the final presentation of the afternoon, if at-risk individuals will not use microbicides when they do become available—or will not use them consistently—then it will not matter how effective they are. And when the question turns to acceptability, there are scores of questions…and very few answers. At the outset there are the issues of taste, odor, color, and viscosity to be considered, Dr. Carballo-Diéguez noted, and after that there is a host of questions, as yet unanswered, about how these agents would be applied.

Of necessity, Carballo-Diéguez and his colleagues are looking at sexual hygiene and sexual practices across cultures, since the ideal microbicide will be one that is more or less universally acceptable. He is factoring into his analysis the use of prescription drugs and over-the-counter products such as anti-hemorrhoidal agents and compounds to relieve vaginal dryness; recreational drugs, especially those taken as suppositories; and products for pre- and post-coital hygiene, since any or all of these could have a negative or positive impact on the effectiveness of a candidate microbicide.

Clearly, there are a number of obstacles to overcome: in understanding what happens when HIV comes in contact with mucosal surfaces, in developing compounds that can thwart entry and infection, and in formulating those compounds in ways that encourage their widespread and routine use. But none of these hurdles is insurmountable, and as Dr. McGowan said at the outset of the symposium, we are entering an exciting phase in the collective effort to create these life-saving agents.