Early tests of maraviroc as microbicide produce less activity than expected

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Preclinical ex-vivo tests of the entry inhibitor drug maraviroc as a possible microbicide have found that the drug only produced a moderate protective effect against HIV - a 50-60% inhibition of HIV infection of penile tissue and an 85% inhibition in colorectal tissue, when given at high doses.

Dr Katherine Young, clinical safety physician for the International Partnership for Microbicides said that the results indicated that maraviroc would have to be used in combination with other drugs in any microbicide.

Hopes had been high that entry inhibitors like maraviroc would be excellent candidates as the active ingredient in microbicides because they stop HIV getting inside cells at all.

Glossary

microbicide

A product (such as a gel or cream) that is being tested in HIV prevention research. It could be applied topically to genital surfaces to prevent or reduce the transmission of HIV during sexual intercourse. Microbicides might also take other forms, including films, suppositories, and slow-releasing sponges or vaginal rings.

replication

The process of viral multiplication or reproduction. Viruses cannot replicate without the machinery and metabolism of cells (human cells, in the case of HIV), which is why viruses infect cells.

receptor

In cell biology, a structure on the surface of a cell (or inside a cell) that selectively receives and binds to a specific substance. There are many receptors. CD4 T cells are called that way because they have a protein called CD4 on their surface. Before entering (infecting) a CD4 T cell (that will become a “host” cell), HIV binds to the CD4 receptor and its coreceptor. 

tropic

When HIV selectively attaches to a particular coreceptor on the surface of a host CD4 cell. HIV can attach to either the CCR5 coreceptor (R5-tropic) or the CXCR4 coreceptor (X4-tropic) or both (dual-tropic).

CCR5

A protein on the surface of certain immune system cells, including CD4 cells. CCR5 can act as a co-receptor (a second receptor binding site) for HIV when the virus enters a host cell. A CCR5 inhibitor is an antiretroviral medication that blocks the CCR5 co-receptor and prevents HIV from entering the cell.

Maraviroc works by blocking the CCR5 co-receptor on the surface of cells. Despite it being the first of a new class, clinical uptake of this drug has been slow because it only works against the types of HIV that use CCR5 as a co-receptor (R-tropic) and does not work against viruses that use the other co-receptor CXCR4 (X-tropic), or use both co-receptors (dual-tropic). A tropism test to determine receptor use is therefore necessary before prescribing maraviroc.

Tropism may possibly be less of a problem for maraviroc as a microbicide, as the vast majority of viruses transmitted are CCR5-tropic.

To test maraviroc's efficacy as a microbicide, Young and colleagues used explants – cell samples of penile and colorectal tissue kept alive on small rafts floating in a nutrient medium.

They exposed the explants to maraviroc for one hour before also exposing them to a CCR5-tropic strain of HIV called HIV-1BaL for two hours. They did this daily for 11-21 days.

They followed three protocols:

  • Removing the maraviroc at the same time as the virus (total exposure to maraviroc: three hours)
  • Allowing the maraviroc to remain overnight (total exposure to maraviroc: twelve hours, nine after viral removal)
  • Incubating the explants with maraviroc for the entire duration of the experiment.

Four different doses of maraviroc were used: one, ten, 100 and 1000 nanomols. In studies of maraviroc used as an anti-HIV treatment, the IC90 - the concentration needed to inhibit viral replication by 90% - was found to be 273 nanomols and the IC50 - the concentration needed to halve viral replication –was 33 nanomols.

With the three-hour dose, 100 nanomols of maraviroc inhibited HIV infection and replication in penile tissue by about 40% and 1000 nanmols by 60%. With the overnight dose, one-tenth as much maraviroc was needed, with 10 nanomols inhibiting HIV infection and replication by 35% and 100 nanomols inhibiting it by 60%.

In colorectal tissue maraviroc exhibited a degree more potency, with overnight and continuous exposure inhibiting HIV infection and replication by 80-90% at doses of 100 nanomols and three-hour exposure inhibiting it by 85% at a dose of 1000 nanomols. The IC50 of the three-hour dose in colorectal tissue was calculated to be 79.7 nanomols.

Microbicides researcher Dr Ian McGowan described the results as “OK, but not that great, when compared to the results from some of the other antiretrovirals.”

Further information

A powerpoint presentation by Katherine Young and a webcast of the conference session in which it was presented are available on the IAS 2009 website.