Rapporteur reports
Track A: HIV Basic Science report by John Zaunders
HIV transmission across the columnar epithelium may result from direct
infection, transcytosis or even carriage by cells from within the
lumen. Transmission across the multicellular stratified epithelium
layer may occur by attachment to Langerhans cells or by possible
preferential adhesion of HIV to sites of physical abrasion.
Importantly, whichever process is used, the resulting transmission is
rapid, exposure of only 30-60 min is sufficient, localized infection
can be found within 16-72 hrs, and infection in the draining lymph
nodes within 1-3 days.
Triggering of innate immunity was predicted to be beneficial from in
vitro results, but has been found in some studies to enhance
transmission, and reduce transmission in others. New candidate
microbicides need to be screened for induction of pro-inflammatory
cytokines that may recruit target cells and enhance infection. Further
study is also needed to clarify if modulation of innate immunity can be
intermittent or needs to be continuous, and also whether perturbing
innate immunity has an adverse effect on subsequent adaptive immunity.
The role of the adaptive immune response in the mucosa also needs to be
clarified. Topical application of neutralizing antibodies can be
protective, but important questions remain as to whether IgG, IgM or
IgA are most effective, whether they need to be systemically or locally
produced, and whether this is Fc region mediated. Such adaptive immune
responses may be more effective if combined with other classes of
antiretroviral agents such as RT inhibitors, or blockers of
co-receptors or dendritic cell surface attachment molecules such as
DC-SIGN. Combinations of the different classes of agents may
synergistically prevent transmission. Future studies will require
rational drug design, and need rigorous testing in animal models
Track C: Biomedical Prevention report by Iona Millwood
New products and strategies in the microbicide research and development pipeline were discussed by Zeda Rosenberg (USA). Vaginal microbicides the chance to deliver locally high drug levels at the site of transmission, while systemic levels remain low. Their success depends on delivery of the right drug (potent, safe, mechanism of action, combination), level (pharmacokinetic study needed), and at the right time (the window of opportunity after exposure is small). Long acting sustained release delivery types, such as vaginal rings, are likely to be most useful. First generation products which block the interaction with host cells, act over shorter time spans requiring coital dependent use, whereas the second generation of more specifically targeted anti-retorviral agents may act over a longer time span and allow for different dosing regimens. Combinations of products are under development, with potential increased potency, potentially blocking multiple transmission pathways, however increased toxicity and the difficulties of co-formulation must be considered. There is a range of products in the development pipeline acting at various stages of the viral life cycle, including monoclonal antibodies, small molecule inhibitors and new anti-retroviral based products of various classes, which can take advantage of an established base of safety data built up as during the development of the drugs for therapy.
Lut Van Damme (USA) presented an update of current and recently ended phase IIb/III microbicide trials, other planned trials, and the challenges and issues arising from large scale prevention trials using the experiences gained during the current trials. Two phase III trials of Savvy, in Nigeria and Ghana, were stopped early due to lower than expected HIV incidence and predicted inability to detect an effect. Two phase III trials of cellulose sulfate were also stopped early, but this was due to an increased risk of HIV with treatment (to be presented in Late Breaker session WESS3). Four ongoing trials being conducted among several thousand women at risk in Africa involve the buffering agent Buffergel, the fusion and entry inhibitors Carraguard and PRO 2000, and the second generation product, tenofovir gel. Trials are planned for an anti-retroviral product, Daviripine, possibly involving vaginal ring delivery, and a further trial of tenofovir gel, to be evaluated with oral tenfovoir and Truvada, the VOICE study, is also planned. The challenges of large scale prevention trials were discussed using the experiences of current trials to pose solutions, such as providing contraception at clinic visits to prevent the high pregnancy rates that are seen in many of the trials, and provision of a high level of care and services to encourage retention.
A presentation on rectal microbicides was given by Ian McGowan (USA). The need for rectal microbicides is demonstrated by epidemiological evidence showing high levels of anal intercourse among heterosexual populations in several countries, in addition to the established risk of unprotected anal intercourse among MSM. The anatomy and histology of the rectal and anal canal renders it susceptible to HIV infection, and also to cytotoxicity when potential microbicide agents are used. There has been limited clinical research into rectal microbicides, although a phase I study for rectal safety is planned for UC-781. It was recommended that rectal safety be an established component of the development of new products, given the strong likelihood of off label use if a vaginal product is marketed, as well as the need for development and evaluation of specific rectal formulations.
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