Important note: Information in this article was accurate in June 2000. The state of the art may have changed since the publication date.Microbicides 2000 brings "a level of seriousness and credibility that the field hasn't had before," UNAIDS Executive Director Peter Piot, MD, told the opening session of the conference. "We cannot wait until the day we have a vaccine. . . . We have to apply today what we know works" in reducing the spread of HIV.
Neal Nathanson, MD, had more than a hint of resignation in his voice when he described vaccine development as "an incremental, slow process that will take some years." Nathanson, who is the director of the Office of AIDS Research (OAR) at the US National Institutes of Health (NIH) showed a steely determination as he continued, "In the interim, it is terribly important to bring to bear as many prevention technologies as we can."
Interest in microbicides appears to be rising like a child's seesaw, counterbalanced by declining optimism about vaccine development. The adrenaline generated by President Bill Clinton's 1997 commitment to develop an AIDS vaccine within a decade is fading in the face of continued scientific obstacles to that goal. Something else must be done. Microbicides are the orphans that may finally get the support they deserve.
A capacity crowd of 620 attended the Microbicides 2000 conference held March 13-16, 2000, near Washington, DC. It was a mix of basic science and clinical researchers, public health officials, and social marketers who engaged in four days of intense exchanges. Generous support from the OAR allowed for travel fellowships as part of an ongoing North-South dialogue on HIV. Forty-four percent of the participants were from outside the United States.
The term microbicide is not confined to agents that simply kill microbes, specifically HIV. It also includes therapeutic interventions that can block or prevent infection, as well as amplification of the body's natural defenses to prevent infection through sexual acts.
Condoms are an effective barrier to transmission. But cost, custom, pleasure, rape, and other factors inhibit their use. Many see a major problem with condom use in the need for cooperation from the male. Negotiating use can be a tricky matter anywhere, but especially in more traditional societies where women have few rights by custom or by law.
Health advocates have sought an unobtrusive means by which women could protect their own health, independently of men. Microbicides are the theoretical Holy Grail of this quest for female-controlled protection. But they offer protection to both parties--the woman from infection by semen laced with HIV, the man from viral shedding from the woman's vaginal secretions, or in anal intercourse where parallel transmission dynamics occur.
The dream is for a silver bullet that will act cleanly in all instances. The reality of HIV is that a combination approach, as with HIV therapy, is the more likely route for the greatest microbicidal protection. Some active ingredients may fortify innate immune defenses, some will be virucides that directly kill the pathogen, others will take a barrier approach to deny entry.
Combinations of these agents are likely to have an additive and perhaps even a synergistic effect when mixed in a topical product. While microbicides ideally will be used as a complement to condoms for enhanced protection, probably they will often simply substitute for condoms.
The field of microbicide research is relatively advanced. At least 64 compounds are in some known stage of development, said Ronald E. Rodday, PhD, an epidemiologist with Family Health International. But few novel approaches have gone beyond phase I trials. Nonoxynol-9 and octoxynol-9 are approved for sale in the United States as spermicides, while European and some other nations also have approved benzalkonium chloride and menfegol. None of these products have proven particularly effective in killing HIV in vivo.
One management issue in developing microbicides is the wealth of options in ph ase I trials. "But we can't move all 60-plus products forward" into large, expensive phase III clinical trials, said Zeda F. Rosenberg, ScD, with Family Health International. She urged a decision-making process that mixes small trials that will yield intermediate results and help winnow candidate compounds, as well as comparison and open-label trials.
This report is by no means a comprehensive examination of all of the chemicals with microbicidal options. Rather it is a selective look at some of the more interesting and most advanced approaches and compounds presented at Microbicides 2000. (The NIH is negotiating publication of papers from the meeting.)
"Vaginal and cervical mucosa and epithelium are major barriers to infection," said Preston A. Marx, MD, of the Aaron Diamond AIDS Research Center. They reduce the risk of infection about a thousand-fold compared with direct injection exposure to a pathogen. "Estrogen promotes vaginal epithelial keratinization, decreases intravaginal pH, increases epithelial thickness, and increases intracervical mucus production."
Progesterone, by contrast, decreases all of these protective activities. Women getting shots of Depo-Provera, the synthetic progesterone used to prevent ovulation, are two to three times more likely to become infected with HIV than women not using Depo-Provera. Postmenopausal women not taking estrogen replacement therapy are four to eight times more susceptible to infection than those taking estrogens.
Marx assessed the impact of hormones in hysterectomized rhesus macaque monkeys exposed to SIV, which shares the same envelope as HIV. After an appropriate washout period, six control monkeys received no therapy, six received systemic progesterone, and six estrogen. Later they were vaginally challenged with the virus.
A biopsy 14 days after challenge revealed a thin vaginal epithelium in the control group, a thin 2- to 5-micron epithelium in the progesterone group, and a robust 80- to 200-micron thick layer in the estrogen group. All control animals became infected, as did five of the six treated with progesterone. But none in the estrogen arm became infected. Other experiments found that estrogen had no effect on viral load.
"We did not find a role for estrogen in a physiologic sense," said Marx, "which means that everything focuses on the microenvironment of the vagina."
His next study will look to see if topical estrogen can work as a microbicide, increasing vaginal barrier protection without the unwanted effects of systemically administered hormone.
Lactobacilli are nonpathogenic bacteria that produce lactic acid. They are a natural part of the vaginal environment, crucial to controlling bacterial vaginosis, a chronic inflammation of the vagina. In vitro work shows that lactobacilli inhibit HIV. Sharon L. Hillier, MD, a University of Pittsburgh researcher, calls lactobacilli "the Xena Warrior Princess of the vagina."
She emphasized the importance of understanding the vaginal ecosystem in developing a useful microbicide. "Vaginal flora actually alters the vaginal inflammatory response," she said. "Not only are the organisms interacting with the pathogen, they are interacting with the host in altering the immune function."
Work presented by Hortense Faye-Kette, MD, with the Institut Pasteur in Côte d'Ivoire, showed that women with vaginal discharge had a low level of lactobacilli colonization. They were particularly lacking in strains that produce hydrogen peroxide.
Hillier cited research by Barbara Richardson1 among commercial sex workers in Kenya as first "suggesting that a microbicide can have a completely different effect depending on the flora in the vagina."
She used the example of nonoxynol-9 (N-9). Extensive use can result in increased inflammation of the vagina, activating neutrophils, while lactobacilli donate hydrogen peroxide to the mix "and result in a beautiful killing system locally. So N-9 can promote sustained colonization and promote killing even though it causes inflammation." But in a woman lacking this flora, or with an overgrowth of an anaerobe, there is "no peroxide there to work with the MPO [myeloperoxidase, an enzyme found in white cells and neutrophils] to exert the killing mechanism."
"When we talk about resistance to HIV on a mucosal level, it is dependent on the epithelium, bacteria, inflammation, and how those interrelate," said Hillier. Any topical product must be evaluated in terms of its impact on these changing variables. "When we talk about putting products in the vagina, we should maintain the pH and the flora because that preserves both the pH and the epithelium."
Clinical populations are likely to have differing vaginal colonization, she said, recalling Richardson's work. That implies the need to identify and track those subsets in clinical trials of microbicidal products and possibly later in their clinical use.
Hillier is working on a lactobacillus product for restoration of flora to see if it will be a useful adjunct to other microbicides. A bacterial vaginosis prevention protocol is now under review by the FDA.
"Cytokine expression increases with bacterial vaginosis, HPV [human papilloma virus], and chlamydial infection," said Kenneth H. Mayer, MD, a researcher at Brown University in Providence, Rhode Island. Expression of CCR5, a coreceptor of HIV, seems to be upregulated by these and other sexually transmitted disease (STD) infections, offering HIV more targets on the cell surface by which to enter.
In a two-year study of women with HIV or at risk for HIV, multivariate analysis showed that only race--being African American--predicted abnormal vaginal flora and bacterial vaginosis. Mayer also found that HIV-positive women on HAART "who had any genital lower track infection were four times more likely to have detectable HIV in their vaginal secretion." That was particularly true of women who had bacterial vaginosis.
Tying the strands together, Mayer said that HIV-positive women and high-risk HIV-negative women are more likely to have "increased cervical-vaginal CD4+ lymphocytes and mononuclear cells independent of having a sexually transmitted infection." They may have increased proinflammatory cytokine levels, altered microflora, and, as a result, elevated pH. These factors must be taken into account when developing microbicides.
BufferGel is an acidic polymer developed to maintain the vaginal environment at a pH below 5, even in the presence of alkali semen. It neutralizes sperm and many STD pathogens in vitro and has the additional benefit of promoting lactobacilli. Animal and phase I human trials have been encouraging.
Nonoxynol-9 causes vaginal irritation in some users. The inflammation probably results from IL-1
and activation of the NF-
ß proinflammatory pathway, Deborah Anderson, MD, said, based on her research at Harvard Medical School. It suggests to her the advisability of monitoring the pro- and anti-inflammatory responses generated by vaginal products in an attempt to maintain equilibrium. She saw downregulation of NF-ß as a possible component of future microbicidal products.
In earlier in vitro studies, her lab showed that SLPI could inhibit HIV entry into CD4+ and CCR5-expressing cells by interacting "not with the virus but with the targeted cells." It binds to the cells, blocking access "in a barrier function." That may help explain why the rate of HIV infection through oral sex is so low.
Data from studies of various mucosal tissues--mouth, gut, rectum, vagina--suggest an inverse relationship between infectious HIV and the presence of SLPI, Wahl said. In breast milk, levels of SLPI rise dramatically at birth and begin to drop two to three weeks later, to a point where they are not sufficient to inhibit HIV.
A study of transmitters and nontransmitters of HIV at birth found no significant difference between the two groups in levels of HIV RNA in vaginal fluid. However, the levels of SLPI did affect transmission in vaginal deliveries. "If SLPI levels were greater than 100 ng/mL, then the rate of transmission was 5.9 percent," compared with 48 percent in those below that threshold, Wahl reported. A subsequent study found that levels of SLPI increase during the third trimester of pregnancy, evidently in anticipation of birth.
In early March, Wahl's lab successfully manipulated "cells that don't make SLPI genetically to make SLPI." Now they have to see if that level is sufficient to afford protection. She urged further study of SLPI as "a natural endogenous product" that may function as an effective microbicide.
Moench sought to determine the "residence time" of topical vaginal monoclonals--the time until they are excreted, degraded, or absorbed below levels of effectiveness--by using RhoGAM, an agent that prevents sensitization to Rh antigen. There was "an exponential decline in antibody concentrations starting at one hour," with a half-life of nine hours.
Thus application of a 100-fold threshold dose will offer some protective activity for up to three days. That will allow for daily dosing. Moench said the practical implication is that one "does not have to plan for sex" or make the application near the time of intercourse. He believes that monoclonals probably will work in the rectum, though there are unanswered questions concerning coverage in a system that is not a closed pouch.
Human anti-HSV (herpes simplex virus) monoclonal antibodies IgG, IgA, dIgA, and sIgA have been genetically engineered into a variety of rice plants, and a succeeding generation of those plants has expressed the antibody. Topical application of these antibodies protected mice from vaginal challenge by HSV.2 The end objective of this work is to develop a protective topical gel for humans. Some believe that "planticeuticals" are the most viable method of producing such antibodies at prices affordable to the populations of poorer countries.
Parniak's in vitro work with several NNRTIs identified UC-781 as "a true virucide that inactivates HIV-1." Virus exposed to the drug is no longer infectious, even after UC-781 is removed from the culture system, he explained. Cell-to-cell transmission is prevented. Cells exposed to the compound for as little as 10 minutes, after which it is washed away, have an enduring resistance to HIV when that pathogen is introduced to the culture. The protective effect correlates with dose and time of exposure to the compound.
This all suggests to Parniak that the small molecule is residing in some subcellular compartment that they have not yet identified. He believes that "tight binding is the single most important parameter for a virucidal NNRTI" in conferring resistance to infection.
The approved NNRTIs nevirapine and delavirdine are not particularly tight binders, "So you can't just take them off the shelf" to use as microbicides, Parniak said. But since efavirenz does have impressively strong binding, "This is where we start looking because the toxicity work has been done."
CSIC, an NNRTI developed by Merck but dropped early in clinical work because of poor bioavailability, has shown superior protective ability in vitro. Parniak suggested that the poor bioavailability that doomed it as a systemic drug may be an asset when it comes to topical use, because a topical agent should not be absorbed.
The small virucidal protein binds irreversibly to HIV envelope protein gp120, and with lesser affinity to gp160 and gp41. Cyanovirin-N appears to change the shape of HIV surface proteins and prevent the virus from entering cells. Boyd called it "the most widely neutralizing, the most potent neutralizing substance known," much more so than neutralizing antibodies. Yet at the same time it is extremely safe to cells; the lab has not been able to induce toxic death in cell cultures.
Cyanovirin-N is "remarkably resistant to physical degradation," water soluble, and stable in solution on the shelf for at least six months, "probably, literally indefinitely," Boyd said. It does no harm to lactobacilli, nor does it bind to sperm. The latter trait may allow protection from HIV while allowing conception. It can be produced in modified E coli through traditional recombinant procedures and industrialized "at literally pennies per gram."
Boyd was at Microbicides 2000 seeking a corporate suitor for his prize compound, available under license from NIH. While there has been some interest, none has come from companies with the financial resources to develop cyanovirin-N into a market product on their own. (See "Where is industry?" on page 166.)
PC-515 is Phillips' formulation of a topical gel containing 3 percent carrageenan. It is being developed as a noncontraceptive microbicide that will offer disease protection while allowing women to become pregnant.
Phillips measured its protective properties in the vagina of mice challenged with HSV, a standard model used to test microbicides. HSV, an envelope virus like HIV, is fatal to mice, killing them in seven to 14 days.
Phillips found that PC-515 offers protection superior to nonoxynol-9 and other microbicides in development. Even at 100 times a lethal dose of HSV, 40 percent of the mice were protected from infection. The protective effect was seen across a wide range of pH levels and seems to last up to 18 hours.
PC-515 has undergone a handful of small developmental trials in humans to fine-tune the formulation. In early 2000 the Population Council, with support from the CDC and in collaboration with local organizations, began a phase I/II trial in South Africa and Thailand. The best-case scenario will roll that over into a phase III trial by the end of 2001.
If sex is the terra incognita of human physiology, then anal sex is the Forbidden City of that land. The small session devoted to the topic bore the discreet title "Non-Vaginal Microbicide Use."
"There are many people in the political arena who are quite reluctant to speak about anything that is not penile-vaginal sex, preferably in the missionary position," explained session chair Alex Carballo-Dieguez, PhD, an HIV researcher with the New York State Psychiatric Institute at Columbia University. He urged that scientists study the world as it exists.
The presumption is that only gay men engage in the act; the reality is quite different. Data gathered through the US HIV Network for Prevention Trials (HIVNET) from 1400 HIV-negative women at high risk for infection showed 32 percent acknowledging having anal sex within the last six months, said Michael Gross, PhD, who works with HIVNET at the University of Washington. This rate is significantly higher than other surveys have reported.
Gross believes the difference is explained by their use of a computer interview rather than a human interview to record the sensitive information. His interpretation was reinforced by "a little opportunistic subset of 60 women" who initially were interviewed by a person and three to nine months later were re-enrolled using the computer survey.
Their willingness to report anal sex "increased by a factor of eight" when using the computer, Gross said. Additional contact with HIVNET likely also contributed to an increased comfort level in disclosing taboo sexual practices.
Anal sex is fairly common among men having sex with men (MSM). Gross was surprised to find that their observational study of 3200 MSM in six American cities found that they "were much more apt to selectively use lubricant than condoms during anal sex." That finding held even after excluding monogamous seroconcordant couples.
Furthermore, 41 percent actively selected lubricants containing nonoxynol-9, despite their skepticism concerning the anti-HIV properties of that agent. Roughly three-fourths of the lubricants available in the United States contain nonoxynol-9. Little safety data is available on use of this product in the rectum.
Connie Celum, PhD, described a pilot safety study of nonoxynol-9 in anal sex undertaken by HIVNET at the University of Washington in 1996-97. It enrolled 25 HIV-negative and 10 HIV-positive monogamous homosexual couples in stable relationships of at least one-year duration. They were asked to be a "designat ed insertive or receptive partner" for the 10-week lubricant study, which consisted of a week of placebo, six weeks of standard-dose nonoxynol-9, and a week of high dose nonoxynol-9, with a week of washout between the two doses. They were asked to have sex at least three times a week.
The product used was Advantage 24, an individual dose applicator lubricant that contains 52.5 mg of nonoxynol-9. The receptive partner applied an escalating schedule of one to four doses a day, regardless of whether the couple had sex. The insertive partner was asked to put the gel on his penis for 30 minutes a day to test for toxicity. Both were instructed to use condoms during sex.
About a third of the receptive subjects in both the nonoxynol-9 and placebo phases of the study complained of "rectal fullness," a nonspecific sensation that lasted for about 30 minutes. It did not cause discomfort or any change in activity. Celum attributed it to volume rather than to an active ingredient. Some also complained of minor irritation to the rectum or penis, though it did not lead to any change in activity.
Rectal tissue was examined visually and samples were taken at baseline, the end of the placebo phase, the end of the low-dose phase, and soon after conclusion of the trial. Celum found some slight evidence of trauma; one example probably was related to use of the applicator. "Mild mucosal abnormality," primarily inflammation, was observed in nine subjects, though abnormality was also noted at baseline. She lamented that there is no good standard for what constitutes the range of "normal" in rectal mucosa and called for development of standardized criteria for evaluation of "inflammation that is clinically relevant."
Celum concluded that "toxicity was minimal" when nonoxynol-9 is used in the rectum. Given the volumes used and the percent of nonoxynol-9 contained in them, Celum's results suggest that currently available products likely are safe. But read on.
The Population Council's David Phillips reached a frighteningly different conclusion about rectal use of nonoxynol-9. Because he had found that vaginally applied nonoxynol-9 and other products offered some protection against HSV, which is normally fatal in the mouse model he used, Phillips wanted to see if these microbicides would protect against rectal challenge.
He swabbed the rectums of mice with the microbicidal compounds, then challenged them with HSV. All of the mice "protected" by nonoxynol-9 died. It did not matter what dose of HSV Phillips used--from one strong enough to infect all normal mice, down to one that should infect only 5 percent--all of the mice died. And they died faster, in four days versus the seven to 14 days it usually takes HSV to kill mice. Phillips wanted to know why.
Once again he applied nonoxynol-9 to the animals' rectums and 10 minutes later performed a lavage. He found significant quantities of epithelial cells floating about. A biopsy of mouse rectal tissue showed "places where there is no epithelium at all, just connective tissue," said Phillips. Nonoxynol-9 "had stripped the epithelial cells off of these animals" (Figure 1). A longitudinal look found that mouse mucosal rectal tissue repairs itself within an hour.
Phillips explained that the rectal mucosa of mice and humans is very similar. Earlier studies determined that human gut mucosa also repairs itself very rapidly. "One way it does this is, if the cells on the top are removed, cells in the crypts slide up along the connective tissue and replace them. So we knew we had to look very quickly, as we did in the mice." The next step was to look at humans. Phillips and colleagues chose two commercially available products, Foreplay with 1 percent nonoxynol-9, and KY Plus with 2 percent nonoxynol-9, as well as the nontoxic carrier gels carrageenan and methylcellulose.
Four volunteers performed a baseline rectal lavage with a syringe. Each of the four then applied 5 mL of product, waited 15 minutes and performed another lavage, then performed a final lavage eight to 10 hours later. They repeated the procedure with each of the four products.
"In the baseline we saw just feces material and bacteria," said Phillips. The same was true of the carrageenan and methylcellulose controls and all of the final lavages, which indicated normal mucosa.
"But we saw striking differences with the N-9, sheets of epithelia, hundreds of them, in each one of these samples," he said. The response was somewhat dose dependent, with higher numbers of cells after use of KY Plus, which contains a higher concentration of nonoxynol-9.
"We don't think this is a definitive study; it is only four subjects," Phillips cautioned. "Although it is very striking that we saw the same in all four subjects," he noted, and results were consistent with those from the animal model. "It is very troublesome," he added, because stripping off the epithelium "could lead to increased HIV transmission." He called for further study of nonoxynol-9 and other products to determine their effect on the rectum.
Microbicide advocates have long expressed the need to conduct safety and efficacy trials of products in the rectum along with the vagina. The products inevitably will be used at this site regardless of the label indication, so the earlier in product development these issues are resolved, the better.
"Most AIDS widows have given up hope of living a normal sexual and emotional life," said Lynde Francis, who spoke movingly as a woman living with HIV in Zimbabwe, at the close of the conference. One's serostatus often remains a taboo subject for discussion, she said. A microbicide would allow women to better protect their partners from HIV and themselves from STDs that might accelerate their disease, and it might offer the possibility of safely conceiving a child.
Polly Harrison, PhD, and the Alliance for Microbicide Development are lobbying the US Congress for increased funding for microbicide research at NIH. Approximately $20 million was spent on microbicide research and clinical trials in 1998. The Alliance wants to increase that to $50 million in 2001 and to no less than $75 million in each of the three succeeding years.
Money, not technology, is the major barrier that stands in the way of developing effective microbicides, said Geeta Rao Gupta, director of the International Center for Research on Women. "If women and their families are to have a fighting chance of surviving this epidemic, we need a microbicide."
There is a narrow window of opportunity to prevent or blunt infection in mucosal tissue of the vagina, said Ashley Haase, MD, in the opening plenary session. The University of Minnesota researcher drew on his experience looking for productive infection of SIV in rhesus macaques to estimate the progress of HIV in humans after mucosal transmission.
Three days after vaginal exposure in monkeys, Haase could detect viral replication in cervical areas; by day 7 there is "a 70-fold increase in the frequency of productively infected cells" beneath the surface; by day 12 where was "an explosion of infection" into draining lymph nodes "as well as very distant sites, the afferent lymph nodes."
In the endocervical region and lymph nodes, 80 to 90 percent of productive infection involved CD3+ and CD4+ T lymphocytes. Macrophages were not so much infected themselves but were critical for priming and activating the T cells.
Haase called HIV and SIV "quite diabolic" because of their ability to infect T cells, particularly quiescent ones. His lab recently showed that "this virus more or less re-engineers its environment to provide itself with those substrates that it prefers for propagation." Those are Ki67+ cells, chronic low producers of virus that are not recognized and killed by the immune system.
Haase first detected an immune response by virus-specific cytotoxic T lymphocytes (CTLs) at the portal of entry 72 hours after exposure. But a recurring theme of lentiviruses like HIV and SIV is that "they present too little antigen on the surface of infected cells for efficient detection and elimination. Maybe there is too little virus-specific CTL response both locally and systemically," Haase suggested. "The numbers are insufficient to prevent systemic spread and eradicate infection without some kind of inducing boost."
By day 12, proliferating cells predominate and 90 percent of macaques have symptoms of acute infection. "The basic conclusion is that our window of opportunity is quite narrow." That finding led Haase to stress the importance of preventing initial mucosal infection.
(Haase and coworkers published this study in Science: Zhang Z, Schuler T, Zupancic M, et al. Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells [published erratum appears in Science 1999;286:2273]. Science 1999;286:1353-1357.)
"We will fail to make significant progress" in the development of microbicides "unless we have the commitment and support of the pharmaceutical and biotechnology industries," said Mark Wainberg, PhD, in his opening remarks. The conference chair and president of the International AIDS Society recognized that industry participation is based on "a reasonable expectation of profit." Wainberg was encouraged that pharmaceutical companies are expressing more interest--or perhaps more accurately, less disinterest--in microbicides today than they were five years ago.
Alan Stone, PhD, a medical research consultant in the United Kingdom, surveyed 13 large pharmaceutical companies with annual sales above US$3 billion in 1996 concerning their interest in developing microbicides. In the fall of 1999 he canvassed a second set of 26 large companies. The conversations were confidential so he did not offer names of firms or products. Stone found that while there is a shift in attitudes about microbicide development, the industry as a whole is still wary of the field.
Some felt that microbicides were outside their company's area of medical concentration. Most believe that there is not a big enough market, identified as at least $1 billion in annual sales. Others felt that the market was there for an over-the-counter (OTC) product. But OTC products historically yield lower profit margins than prescription agents and hence hold less interest for the pharmaceutical industry, one of the most profitable industrial sectors of the world economy.
Family planning advocates have noted industry's reluctance to deal with contraceptive and reproductive health issues in general. One reason is that some elements of society find these issues controversial and do not hesitate to make their positions known. Another is a perceived greater risk of product liability and the fear of juries awarding large damages to victims of birth defects attributed to a medical product.
Unstated industry hesitation might also include the suspicion that microbicidal products will prove to be too low tech. Once the concept is proven, there will be few barriers to entry for competitors, thus limiting ability to demand and get a premium price and profit in the developed world.
Stone found that pharmaceutical company aversion was waning because HIV infection continues to spread and grow in importance; vaccine development lags, and optimism is fading for a quick, effective product; the field of microbicides has advanced; and industry's perception of a potential market is becoming more optimistic. Four major companies are now discussing entering the field. He concluded, "Big pharma is beginning to see the light."
The recurring themes of what industry considers "pivotal" are clinical evidence or proof of principle that microbicides work in humans; levels of anti-HIV activity sufficiently high that regulators will grant approval; and market interest.
Heather Boonstra presented survey research from the US National Microbicide Survey of 1000 sexually active women of reproductive years, conducted by the Alan Guttmacher Institute in 1998. The desire to control protecting themselves from STDs was near universal; 92 percent of women responded positively, while 4 of 10 expressed an interest in purchasing a microbicidal product.
Those expressing greater interest in microbicides tended to be younger and more sexually active; those with less interest tended to be older and married or in long-term monogamous relationships. The results paralleled survey work from Europe and anecdotal reports from women in developing nations.
Surveys of gay men in the US show that they use lubricants more frequently than condoms for anal sex. Price does not seem to be a major inhibitor, as indicated by the price of existing lubricants that offer no microbicidal protection. Bob Roehr is a medical writer based in Washington, DC (BobRoehr@aol.com).
1. "Martin HL Jr, Nyange PM, Richardson BA, et al. Hormonal contraception, sexually transmitted diseases, and risk of heterosexual transmission of human immunodeficiency virus type 1." J Infect Dis 1998 Oct;178(4):1053-9.
2. Briggs K, Zeitlin L. An anti-HSV antibody produced in transgenic rice plants prevents HSV-2 infection in mice. Presented at: Microbicides 2000; March 13-16, 2000. Alexandria, VA. Abstract A10.
3. Pearce-Pratt R, Phillips DM. Sulfated polysaccharides inhibit lymphocyte-to-epithelial transmission of human immunodeficiency virus-1. Biol Reprod 1996 Jan;54(1):173-82.
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