Abstract
The predominant route of human immunodeficiency virus type 1 (HIV-1) transmission is across the vaginal and rectal epithelia during sexual intercourse. Yet the development of safe and clinically effective vaginal and rectal antiretroviral microbicides remains an unmet challenge despite more than 25 years of accelerated product development. The clinical failure of seven microbicide candidates points to major unresolved challenges associated with target specificity, safety, potency as well as drug-delivery of validated candidates undergoing preclinical and clinical development as anogenital microbicides. Currently, additional antiretroviral agents are sought as anogenital microbicides to provide potential anti-HIV protection by directly inactivating HIV-1, preventing HIV-1 from attaching, entering or replicating in susceptible target cells, and/or by hindering the dissemination of HIV-1 to the host cells that line the vaginal/rectal walls along with targeting novel HIV-host dependency factors. Among the several types of anti-HIV microbicides currently in preclinical and clinical development, only one clinical trial of an HIV-1 reverse transcriptase inhibitor has shown clinical promise as a potential microbicide. This article reviews the preclinical/ clinical efficacy and safety profiles of current antiretroviral microbicide candidates (Tenofovir, Stampidine, UC-781, Dapivirine/TMC120, MIV-150, HI-443, CCR5 antagonists, neutralizing antibodies, targeted RNA interference, RNA- based aptamers, Aptamer-siRNA-chimeric RNA), as well as advances in multimodal microbicide delivery systems (nanocarriers - liposomes, dendrimers, polymeric, solid lipid and metal nanoparticles, nanospheres, nanocapsules, intravaginal rings and recombinant lactobacilli delivery strategies). The clinical failure of first-generation antiretroviral gels is spearheading efforts to evaluate new mechanism-based antiretrovirals with a rational design and engineering of long-acting and novel delivery systems more appropriate to curb anogenital HIV transmission.
Highlights
Sexual transmission through vaginal and rectal mucosal surfaces has been the most common route of human immunodeficiency virus type 1 (HIV-1) spread throughout the world [1]
Significant systemic absorption of RTI-based microbicides could lead to suboptimal drug pressure and could potentially promote the selective transmission of RTI-resistant viruses, contributing to an already increasing public health problem in developing countries. These findings demonstrate the importance of pursuing alternative nucleoside reverse transcriptase inhibitors (NNRTIs) compounds with superior activity against both NNRTIand nucleos(t)ide reverse transcriptase inhibitors (NRTIs)-resistant isolates
Receptive anal sex is the predominant mode of HIV acquisition among men who have sex with men (MSM), and a significant independent risk factor for HIV infection among women
Summary
Sexual transmission through vaginal and rectal mucosal surfaces has been the most common route of HIV-1 spread throughout the world [1]. There is increasing epidemiological evidence that women as well as men in both the developed [9,10,11] and developing world [12,13,14] practice RAI Both vaginal and rectal microbicides should be seen as an important HIV prevention technology for all individuals who practice RAI. Strategies to prevent the spread of sexual transmission of HIV-1 with first-generation vaginal antiviral agents led to the failure of 11 clinical trails with 6 microbicide candidates, nonoxynol-9, SAVVY®/C31G, cellulose sulfate, Carraguard®/PC-515, PRO 2000 and BufferGel® [15,16,17,18,19]. The recent failure of rectal microbicide candidates can be attributed to the use of vaginally formulated microbicide gels that failed in clinical vaginal efficacy and safety studies
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