RESUMEN
Microbicides are a new tool, still under investigation, which could help prevent infection by the human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs). Increasing evidence shows that the complexity of sexual transmission of viral pathogens requires the identification of compounds able to block the early events during the cycle of viral infection. In this manuscript we provide a comprehensive review of the different microbicide strategies that have been studied or are currently being considered for STI prevention, particularly emphasizing those having the potential to block HIV infection. The manuscript also reviews the complex process that is required to conduct future clinical studies in humans and concludes with a brief discussion of the strategies that could be part of the immediate future in microbicide research.
Asunto(s)
Antiinfecciosos Locales/farmacología , Evaluación Preclínica de Medicamentos/métodos , Enfermedades Bacterianas de Transmisión Sexual/prevención & control , Enfermedades Virales de Transmisión Sexual/prevención & control , Administración Intravaginal , Administración Rectal , Animales , Antiinfecciosos Locales/química , Antiinfecciosos Locales/clasificación , Antiinfecciosos Locales/aislamiento & purificación , Antiinfecciosos Locales/toxicidad , Ensayos Clínicos como Asunto , Modelos Animales de Enfermedad , Aprobación de Drogas , Inhibidores Enzimáticos/farmacología , Femenino , Infecciones por VIH/prevención & control , Infecciones por VIH/transmisión , Herpes Genital/prevención & control , Herpes Genital/transmisión , Humanos , Masculino , Estudios Multicéntricos como Asunto , Infecciones por Papillomavirus/prevención & control , Infecciones por Papillomavirus/transmisión , Tensoactivos/farmacología , Tecnología Farmacéutica/métodos , Proteínas Virales/antagonistas & inhibidores , Internalización del Virus/efectos de los fármacosRESUMEN
Microbicides are a new tool, still under investigation, which could help prevent infection by the human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs). Increasing evidence shows that the complexity of sexual transmission of viral pathogens requires the identification of compounds able to block the early events during the cycle of viral infection. In this manuscript we provide a comprehensive review of the different microbicide strategies that have been studied or are currently being considered for STI prevention, particularly emphasizing those having the potential to block HIV infection. The manuscript also reviews the complex process that is required to conduct future clinical studies in humans and concludes with a brief discussion of the strategies that could be part of the immediate future in microbicide research.
Asunto(s)
Antiinfecciosos Locales/farmacología , Evaluación Preclínica de Medicamentos/métodos , Enfermedades Bacterianas de Transmisión Sexual/prevención & control , Enfermedades Virales de Transmisión Sexual/prevención & control , Administración Intravaginal , Administración Rectal , Animales , Antiinfecciosos Locales/química , Antiinfecciosos Locales/clasificación , Antiinfecciosos Locales/aislamiento & purificación , Antiinfecciosos Locales/toxicidad , Ensayos Clínicos como Asunto , Modelos Animales de Enfermedad , Aprobación de Drogas , Inhibidores Enzimáticos/farmacología , Femenino , Infecciones por VIH/prevención & control , Infecciones por VIH/transmisión , Herpes Genital/prevención & control , Herpes Genital/transmisión , Humanos , Masculino , Estudios Multicéntricos como Asunto , Infecciones por Papillomavirus/prevención & control , Infecciones por Papillomavirus/transmisión , Tensoactivos/farmacología , Tecnología Farmacéutica/métodos , Proteínas Virales/antagonistas & inhibidores , Internalización del Virus/efectos de los fármacosRESUMEN
Topical microbicides that block the sexual transmission of HIV and herpes simplex virus 2 (HSV-2) are desperately needed to reduce the incidence of HIV infections worldwide. Previously we completed phase 3 testing of the carrageenan-based gel Carraguard. Although the trial did not show that Carraguard is effective in preventing HIV transmission during vaginal sex, it did show that Carraguard is safe when used weekly for up to 2 years. Moreover, Carraguard has in vitro activity against human papillomavirus (HPV) and HSV-2 and favorable physical and rheological properties, which makes it a useful vehicle to deliver antiviral agents such as zinc acetate. To that end, we previously reported that a prototype zinc acetate carrageenan gel protects macaques against vaginal challenge with combined simian-human immunodeficiency virus reverse transcriptase (SHIV-RT). Herein, we report the safety and efficacy of a series of zinc acetate and/or carrageenan gels. The gels protected mice (75 to 85% survival; P < 0.001) against high-dose (10(6)-PFU) HSV-2 vaginal or rectal challenge. In contrast, zinc acetate formulated in HEC (hydroxyethylcellulose; or the Universal Placebo) failed to protect mice against the high-dose vaginal HSV-2 challenge (similar to aqueous zinc acetate solution and the placebo controls). The gels were found to be effective spreading gels, exhibited limited toxicity in vitro, caused minimal damage to the architecture of the cervicovaginal and rectal mucosae in vivo, and induced no increased susceptibility to HSV-2 infection in a mouse model. Our results provide a strong rationale to further optimize and evaluate the zinc acetate/carrageenan gels for their ability to block the sexual transmission of HIV and HSV-2.