Background: The new millennium has seen a rapid evolution and transformation of the microbicide field with new impetus and vigor. Presentation of the nonoxynol-9 trial results at the Durban AIDS Conference served as a catalyst and led to important new developments in the diversity of products being developed, their mechanisms of action, formulations, vehicle of delivery, and clinical trial design. In a mere 7 years, the microbicide field has been redefined, despite significant obstacles, including lack of clinical proof of concept, lack of surrogate markers of protection, or a validated animal model. Significantly, the lack of clinical trial data showing protection in women has stimulated new developments to enhance the conduct of future trials in terms of trial design, selection of trial participants, measurement of product use, safety monitoring, and HIV risk reduction and contraceptive counseling. In terms of product development, the shift away from non-specific, broad-spectrum contraceptive and anti-microbial agents, to more specific anti-viral, including antiretroviral, formulations has been a significant advance, especially in improving product safety profiles and shifting the field from a focus on extra-cellular activity to products which act intra-cellularly and hence systemically as well.

Conclusions: This has enabled the expansion of product formulation and delivery from topical gels in individual, pre-filled applicators to oral and long-acting injectable formulations, physical barriers, slow-release vaginal rings, and potentially implants— all reminiscent of developments in hormonal contraceptive options. While the major beneficiaries of an efficacious microbicide will remain women, the more recent increase in trials that assess safety during rectal use may provide an additional option for women engaging in anal sex and men who have sex with men. With clinical trial results on HIV protection for several products becoming available over the next 24 to 30 months, demonstration of at least partial effectiveness will provide the needed thrust to validate animal models, including new animal models, such as BLT humanized mice. Upon proof of concept, the next microbicide frontier will likely be the development of combination products that target various points of viral entry in the genital tract, antiretroviral combinations and/or more specific anti-HIV co-receptor blockers.