Since the early days of microbicide development, this preventive strategy has been considered promising in the battle against sexually transmitted HIV infection. Now, more than a decade has passed and all major clinical trial results show that these vaginal formulations not only failed to achieve their objectives, but also, in some cases, actually enhanced HIV transmission. Confronted with these unexpected outcomes, the scientific community is now trying to find explanations and rethink strategies to circumvent these poor results. Recently, van de Wijgert and Shattock  addressed an interesting review of likely explanations for microbicide failure. However, we believe that important issues related to the performance of microbicide-containing drug delivery systems used in the past and currently ongoing clinical trials were not discussed, which we would like to address next.
Consider the following illustrative example: an HIV-positive patient is prescribed a new oral antiretroviral and a highly emetic drug. After 3 months, HIV-infection has progressed and the patient complains of regular vomiting after drug intake. Should we immediately consider that the newly instituted antiretroviral drug was ineffective against HIV? Indeed, it would be more reasonable to first presume that the patient's outcome could be related to gastric removal due to emesis. In our opinion, this example pretty much illustrates what happens with current microbicides, namely in the form of vaginal semisolid formulations (e.g. gels). After vaginal administration of a microbicidal formulation, it is essential that it distributes evenly throughout the vaginal and cervical mucosa, providing a protective, active substance-containing barrier. In addition, this coating must resist shearing effect of penile penetration and dilution with fluids present in the vagina (e.g. vaginal fluid or semen). Indeed, forces experienced by vaginal formulations during coitus are exceptionally high, corresponding to shear rates of 1000 s−1 and above ; these values match, for example, the forces applied when pumping a microbicide gel through a 1-mm diameter nozzle. In the case of fluid dilution, polymers responsible for the semisolid nature of gels can be diluted to approximately 25% and more of their original concentration, causing loss of structure and drug leakage . The conjugation of these two late factors acts in the same way as the ‘highly emetic drug' in the example given above as they reduce gels’ viscosity, forcing them to flow, contributing to the removal of the microbicide coating. In this manner, poor outcomes obtained in clinical trials may result mostly from poor drug delivery systems design, not from increased women's vulnerability to HIV due to microbicide local toxicity or differences in nonadherence between study arms as argued by van de Wijgert and Shattock .
In recent years, drug delivery systems optimization has been a major approach to optimize pharmacotherapeutic performance of both existing and new drugs, being able to solve many of their drawbacks. In the case of microbicides, investigation on smart drug delivery systems has not yet reached clinical trialing, therefore failing to meet the specificities of vaginal drug delivery and sexual intercourse. However, several innovative and promising strategies have been proposed, namely vaginal rings , environmentally sensitive gels (particularly to pH or temperature) , or genetically modified commensal bacteria that are able to secret anti-HIV substances , which can help in solving poor vaginal retention and/or distribution of current microbicides. Also, new in-vivo methodologies have been recently developed in order to assess the actual capability of vaginal preparations to effectively distribute, retain and maintain an effective drug-containing barrier in the vaginal and cervical mucosa before, during and after sexual intercourse [7,8]. It is urgent that these techniques be included in the clinical assessment of microbicides.
It is clear to all that one or more pieces of the puzzle are still missing in the quest for effective microbicides. After the first disappointing results and while waiting for the outcome of ongoing clinical trials, researchers are currently promoting major reflection and debate in order to determine future directions. Therefore, our view is that foremost priority should be given to the development and evaluation of old and new drug delivery systems in order to assess the real potential of first- and second-generation microbicidal substances in preventing HIV vaginal transmission.
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2. Katz DF, Henderson MH, Owen DH, Plenys AM, Walmer DK. What is needed to advance vaginal formulation technology? In: Rencher WF, editor. Vaginal microbicide formulations workshop. Philadelphia: Lippincott-Raven Publishers; 1998. pp. 90–99.
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