Microbicides for sexually transmitted infections are pharmacologic agents and chemical substances that are capable of killing or destroying certain microorganisms that commonly cause sexually transmitted infection (for example, the human immunodeficiency virus). Microbicides are a diverse group of chemical compounds that exert their activity by a variety of different mechanisms of action. Multiple compounds are being developed and tested for their microbicidal activity in clinical trials. Microbicides can be formulated in various delivery systems including gels, creams, lotions, aerosol sprays, tablets or films (which must be used near the time of sexual intercourse) and sponges and vaginal rings (or other devices that release the active ingredient(s) over a longer period). Some of these agents are being developed for vaginal application, and for rectal use by those engaging in anal sex. Although there are many approaches to preventing sexually transmitted infections in general (and HIV in particular), current methods have not been sufficient to halt the spread of these infections (particularly among women and people in less-developed nations). Sexual abstinence is not a realistic option for women who want to bear children, or who are at risk of sexual violence. In such situations, the use of microbicides could offer both primary protection (in the absence of condoms) and secondary protection (if a condom breaks or slips off during intercourse). It is hoped that microbicides may be safe and effective in reducing the risk of HIV transmission during sexual activity with an infected partner.
Mechanisms of action
Detergents Detergent and surfactant microbicides such as nonoxynol-9, sodium dodecyl sulfate and Savvy (1.0% C31G), act by disrupting the viral envelope, capsid or lipid membrane of microorganisms. Since detergent microbicides also kill host cells and impair the barrier function of healthy mucosal surfaces, they are less desirable than other agents. Additionally, clinical trials have not demonstrated these agents to be effective at preventing HIV transmission. Consequently, laboratory and clinical trials testing this class of products as microbicides have largely been discontinued.
Vaginal defense enhancers Healthy vaginal pH is typically quite acidic, with a pH value of around 4. However, the alkaline pH of semen can neutralize vaginal pH. One potential class of microbicides acts by reducing the pH of vaginal secretions, which may kill (or otherwise inactivate) pathogenic microorganisms. One such agent is BufferGel, a spermicidal and microbicidal gel formulated to maintain the natural protective acidity of the vagina. Candidates in this category (including BufferGel) have proven to be ineffective in preventing HIV infection.
Polyanions
The polyanion category of microbicides includes the carrageenans. Carrageenans are a family of linear sulfated polysaccharides chemically related to heparan sulfate, which many microbes utilize as a biochemical receptor for initial attachment to the cell membrane. Thus, carrageenan and other microbicides of its class act as decoy receptors for viral binding. Carrageenan preparations (such as 0.5% PRO 2000 and 3% Carraguard vaginal microbicide gels) have failed to demonstrate efficacy in preventing HIV transmission in phase III clinical multicenter trials. PRO 2000 was demonstrated to be safe, but it did not reduce the risk of HIV infection in women (as explained in the MDP 301 trial results, released in December 2009). Similarly, the phase III efficacy trial of Carraguard showed that the drug was safe for use but ineffective in preventing HIV transmission in women. Cellulose sulfate is another microbicide found ineffective in preventing the transmission of HIV. On February 1, 2007, the International AIDS Society announced that two phase III trials of cellulose sulfate had been stopped because preliminary results suggested a potential increased risk of HIV in women who used the compound. There is no satisfactory explanation as to why application of cellulose sulfate was associated with a higher risk of HIV infection than placebo. According to a review of microbicide drug candidates by the World Health Organization on March 16, 2007, a large number of compounds (more than 60 in early 2007) are under development; at the beginning of that year, five phase III trials testing different formulations were underway.
Nanoscale dendrimers
VivaGel is a sexual lubricant with antiviral properties manufactured by Australian pharmaceutical company Starpharma. The active ingredient is a nanoscale dendrimeric molecule (which binds to viruses and prevents them from affecting an organism's cells). Experimental results with VivaGel indicate 85–100% effectiveness at blocking transmission of both HIV and genital herpes in macaque monkeys. It has passed the animal-testing phases of the drug-approval process in Australia and the United States, which will be followed by initial human safety tests. The National Institutes of Health and the National Institute of Allergy and Infectious Diseases have awarded grants totaling $25.7 million for VivaGel's development and testing. VivaGel is being developed as a standalone microbicide gel and an intra-vaginal microbicide. It is also being evaluated for use in condoms. It is hoped that VivaGel will provide an extra resource to mitigate the sub-Saharan AIDS pandemic. It is also hoped that microbicides will block the transmission of HIV and other sexually transmitted infections, such as those caused by certain human papillomaviruses (HPV) and herpes simplex viruses (HSV). In 2009, Starpharma released its results for a study investigating VivaGel's antiviral activity against HIV and HSV in humans by testing cervico-vaginal samples in vitro (in a test tube). The compound displayed a high level of efficacy against HIV and HSV. While the results are encouraging, the study did not evaluate VivaGel's effect in the body. It is still unknown what the results mean for women who would use the product in real-life settings; for example, the effect of sexual intercourse (or semen) on the gel (which often affects the protective properties of a drug) is unknown. The CAPRISA 004 trial demonstrated that topical tenofovir gel provided 51% protection against HSV-2.
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