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9 Robin J Shattock St George’s Hosp Med Sch, London, UK |
Background: Heterosexual transmission is the leading mode of HIV-1 infection worldwide, with women particularly vulnerable to HIV-1 infection as they often cannot control sexual encounters or insist on condom use. In the absence of an effective vaccine there is an urgent need to develop alternative prevention strategies. It is only now, more than 20 years into the epidemic, that immediate events between exposure to infectious virus and the establishment of infection are becoming clear. Defining the mechanisms of HIV-1 transmission, the target cells involved and how the virus attaches to and fuses with these cells is revealing new ways to block the sexual spread of the virus. Initial efforts to develop vaginal microbicides focused on killing the virus through membrane disruption using surfactants, and blocking viral entry using polyanionic compounds that interact with the positively charged areas of the viral envelope proteins, many of which are currently entering phase II/III trials. However recent advances in HIV pathogenesis and therapeutics are now bringing a wide range of new products into the development pipeline that specifically target different stages in the viral life cycle. Rigorous pre-clinical evaluation of candidate microbicides is now required to select the best compounds for clinical trials, since this will provide savings in costs and time, given the expense and length of formal efficacy trials. Selection criteria include: high activity against viral clades predominant in the areas where clinical trials are to be conducted; low irritation potential based on a range of preclinical irritation assays; high in vitro activity in the presence of semen; and effectiveness in animal models using challenge virus that is relevant to sexual HIV transmission. In addition assessment of product formulation, stability, cost, acceptability and ease of manufacture are important in candidate selection.
Keywords: dementia; treatment; HAART
