PreclinicalThe high rate of HIV and other infections acquired through sexual activity and the concurrent need to avoid or delay pregnancy warrant development of novel compounds displaying contraceptive and microbicidal properties. Some of the molecules and mechanisms used by sperm to fertilize the egg are similar, if not identical, to those used by HIV and other STD-pathogens to infect host cells.
Research on this topic has been ongoing since 2003 and has yielded significant discoveries that led to the filing of a patent by CONRAD. The purpose of this work was the development of noncytotoxic bifunctional anti-HIV-1 microbicides with sperm-immobilizing activity. Furthermore, conjugation of anionic polymers with fatty acid derivatives of AZT has shown contraceptive properties both in vitro and in vivo, in addition to HIV entry and RT inhibitory activity. Dual-activity compounds will be formulated and delivered as described below.
Contraceptive microbicide. CONRAD will develop an intravaginal ring (IVR) that releases levonorgestrel (LNG) and UC781. LNG is a 19-nortestosterone derivative of proven safety and efficacy. It is available in the market in different dosage forms including a LNG-releasing intrauterine system, which releases LNG directly into the uterine cavity at a constant rate of 20 µg per day. Preliminary data indicate that release rates of LNG from an IVR are adequate to achieve contraceptive efficacy. The controlled release of LNG and UC781 from a vaginal ring device will protect women against sexual acquisition of HIV and unplanned pregnancies.
In addition to the contraceptive microbicide LNG/UC781-releasing ring, dual-activity compounds described above will be formulated in polycarboxylic acid (e.g., Carbopol) and cellulose derivatives (e.g., Q-2 and HEC) to form a gel. A formulation containing specific carbomers at appropriate concentrations will display contraceptive properties similar to those of BufferGel.® The use of sperm-inhibiting vehicle ingredients in conjunction with microbicidal or dual-activity agents constitutes another strategy to develop dual-protection contraceptive microbicide products.
Dual-activity microbicide (anti-HIV and -HSV activity). Genital herpes is the leading cause of genital ulcer disease worldwide, and it is one of the most common sexually transmitted diseases. Genital herpes is caused by herpes simplex virus (HSV) type 2 in 60–80% of cases, while HSV-1 is responsible for as many as 35%. Acyclovir suppressive therapy, which leads to a reduction in relative risk for recurrence, has been used since the early 1980s. Several trials of suppressive therapy with acyclovir derivatives daily found significant reductions in genital and plasma HIV loads. Adherence to daily dosing, however, is key to the success of the therapy. Using a polyurethane-based ring and the same technology developed to incorporate UC781 and TFV, we plan to vary drug loadings until release rates match those desired to achieve effective doses in vivo. The development of a simple gel will be used to test the active agents for safety and efficacy (especially against HSV-2) in small animal models. The development of a product that offers protection against HIV and other STIs, such as the highly prevalent genital herpes, will significantly benefit the population of women at risk of acquiring HIV/STIs but desiring conception.