Topical microbicides may be useful in preventing HIV transmission

September 2006

Existing drug classes can be used as topical microbicides to prevent infection, according to John P. Moore, PhD, who spoke recently at the XVI International AIDS Conference in Toronto.

“Microbicides are an important arm of prevention science strategy because they are needed. With more than 95% of new HIV-1 infections occurring in developing countries and with 80% due to heterosexual transmission, the need for something to block vaginal transmission is extremely obvious,” said Moore, who is a professor of microbiology and immunology at the Weill Medical College of Cornell University in New York, N.Y.

Although an effective vaccine is the first answer to preventing transmission, it will be years before one is available. In the meantime, other prevention methods, such as microbicides, are taking center stage since most HIV infections are spread by unprotected sex.

“Abstinence and faithfulness are not likely to protect married women or those who are sexually abused,” Moore said. “Women often cannot ensure that men use condoms, and condoms are also contraceptive, which means they cannot be used when one of the desired outcomes is pregnancy. Instead, a microbicide could fulfill many of the prevention science gaps if one could be developed and applied properly.”

Microbicides

According to Moore, it is possible but not certain that an effective vaginal microbicide would also work when applied rectally.

A microbicide can be applied as a gel, which is the most common form, or as a cream, suppository, sponge or vaginal ring that gradually releases active ingredient. To be useful, a microbicide must be safe, effective, acceptable and affordable. “It [has to] be priced in cents-per-usage for the developing world, and it has to be acceptable for use in a sexual setting. A product that is runny or smelly will not be used,” Moore said.

Microbicides based on entry inhibitors already in clinical trials as antiretrovirals may meet many of these criteria. Entry inhibitors are generally likely to be reasonably safe, effective and affordable, and there is good evidence of efficacy in a macaque monkey model. Entry inhibitors now being studied in the macaque model include compound 167, BMS-378806, T-1249, AMD3465, C52L and CD4-IgG2.

• Compound 167 – Small molecule CCR5 inhibitor that is clinically relevant, high-quality, and potent. It is highly potent in vitro and has pharmacological and toxicological properties suitable for macaque studies.
• BMS-378806 – small molecule attachment inhibitor that binds to gp120 to inhibit CD4-binding and the subsequent conformational changes associated with co-receptor binding. It is active against both R5 and X4 HIV-1 strains.
• C52L – gp41 peptide fusion inhibitor that is related to T-20, but has been engineered for expression in bacteria. It blocks fusion by inhibiting late-stage conformational changes within gp41 and has broad activity against R5 and X4 HIV-1 strains.
• T-1249 – designed 39-amino acid synthetic peptide that is potent in vitro and in vivo with fusion inhibitor naïve viruses. It has substantial in vitro and in vivo antiretroviral activity against ENF resistant viruses.
• CD4-IgG2, or PRO 542 – tetravalent CD4-immunoglobulin fusion protein that binds gp120 and blocks virus attachment to CD4. It potently neutralizes HIV-1 in a subtype-independent manner and is in phase 2 testing as an antiviral drug.
• AMD3465 – specific inhibitor of CXCR4. It antagonizes SDF-1 mediated calcium influx and is broadly active against X4 HIV-1 strains. It is not cross-reactive with other chemokine receptors, and it has a pharmacokinetic profile similar to AMD3100. It is in early phase pre-clinical development.

Challenge viruses now being used include SHIV-162P3 (R5) and SHIV-89.6P (X4 virus with some R5 use). According to Moore, single-entry inhibitors are strongly protective against vaginal challenge with SHIV-162P3.

Combination microbicides

“The case for combination microbicides is absolutely obvious,” Moore said. “It is the same as the arguments for using combinations for therapy. You do not use monotherapy. For the same reason, it doesn’t make a lot sense to use monotherapy for a microbicide. Using combinations of inhibitors increases the breadth of coverage against divergent strains. In the real world, that is an important issue.”

Using microbicides in combination reduces the probability of transmitting viruses that are resistant to any single inhibitor, and in several circumstances, particularly with the entry inhibitors, could generate genuine synergy. In a recent study, 75% of animals given one inhibitor were protected, 80% of animals given two inhibitors were protected, and 100% of animals given three inhibitors were protected.

For more information:

• Moore J. Entry inhibition as models for microbicide development. Presented at: The 2006 International AIDS Conference; August 13-18, 2006; Toronto.