Topical microbicides: the real front line of HIV prevention
David Margolis, for natap.org
Topical microbicides, preparations able to kill HIV on contact and prevent infection, are a critical complement to vaccines and other prevention strategies. They can protect women, for example, who cannot protect themselves by other means. Gels are in development and testing, but a plan is needed for future approaches if the results of trials expected in 2006-07 are not encouraging.
John Moore of Cornell provided an excellent overview of what is needed in the field. A microbicide must be safe, effective, affordable, and acceptable. To accomplish this, a preparation must not damage the epithelium, not alter bacterial flora, and must not cause inflammation (as has led to increased HIV transmission following the use of past microbicides).
Several HIV reverse transcriptase inhibitors, AZT-like drugs, are in development. Among them are TMC 120, UC781, and tenofovir. Reagents that block chemokine receptors such as cyanovirin, psc-rantes, and others are under study. In the SIV model, PSC-Rantes formulated in a gel protected monkeys from vaginal and rectal challenge, and did not induce inflammation. The triple-therapy of compound 167 (a Merck CCR5 inhibitor), combined with BMS 387806 (a CD4-blocking molecule from BMS), and c52L (a T-20 like fusion inhibitor molecule produced in engineered bacterial) were tested by Ron Veazey in macaques treated with progesterone to enhance their susceptibility to infection.
8/10, 6/8, and 3/5 monkeys were protected by each agent. 16/20 given two agents, and all 3/3 given all 3 agents were protected from high-dose HIV mucosal challenge. In a delayed challenge SHIV (a SIV-HIV hybrid) experiment, microbicides were 80% effective 30 minutes after application, but only 33% protective at 12 hrs. 2 of 5 animals were protected against 5 daily high-dose challenges by daily triple application.
In addition to being effective, microbicides must be affordable. Moore estimated that a product could only cost $0.25-0.50/application. This is a challenge as the amount of compound needed to be effective varied from as little as 3 mg/application to 50 mg. Compounds must reach the millimolar range to protect in the monkey model, which is several-fold higher than in vitro models. In general, receptor blockers need to achieve higher concentrations than antivirals.
In the real world, the challenges will be great. Viral load (innoculum) is likely to be high in many settings as transmission is associated with other active STDs. A product requiring daily application is unlikely to achieve perfect adherence. The cheapest candidates as polyanion detergent-like antivirals at <0.01$ dose, antiviral drugs come in at $0.01-0.10/dose, and small peptides or molecules are the Rolls Royce at $1-20/dose. An interesting idea that Moore mentioned was Dean Hamers proposal to engineer live bacterial flora to secrete antivirals, a clever and interesting idea that would need proof of concept in a model system, and acceptance by the public.
Moore J. Preventing HIV transmission by topical microbicides. Plenary lecture Wednesday 8 February, 13th CROI, 2006, Denver. Abstract 121. Webcast available on conference website.