Back HIV Prevention Microbicides HIVR4P 2016: New Microbicide Enema Achieves High Levels of Drug in Rectal Tissues in Monkeys

HIVR4P 2016: New Microbicide Enema Achieves High Levels of Drug in Rectal Tissues in Monkeys


Rectal microbicides that protect against HIV transmission via anal sex are a bigger technical challenge than vaginal ones. The rectal lining is more delicate than the vaginal lining, so safety has been an issue; research has shown that many of the gel formulations used in lubricants damage rectal cells and may actually enhance HIV transmission.

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But the biggest challenge is coverage. A rectal microbicide has to cover a considerably greater area of mucous membrane as the gut is an open-ended tube; devices such as rings cannot be used and CAT scans have shown that semen may travel a considerable way up into the colon after anal sex.

Since many gay men use enemas and douches, it seemed logical to try and make a microbicide formulated as an enema, and scientists have been developing one for at least 5 years. The issue has been getting the enema formulation right. Standard lubricants are hyper-osmolar; this means they suck the water out of rectal tissue cells, which not only causes irritation but means the HIV drug in the gel has to fight against a current, so to speak, going the other way.

Researchers at the second HIV Research for Prevention Conference (HIVR4P) this week in Chicago presented the first results on tissue concentration and potential anti-HIV efficacy in monkey studies of a tenofovir-containing gel that is hypo-osmolar. This means that the cells absorb water from the gel and therefore actively transport the drug it contains through the cellular membrane.

François Villinger of the University of Louisiana presented results for 4 different enema formulations. Of these, 2 were iso-osmolar, meaning they contained the same balance of salts as cells do; this means their effect on the direction of water transport between enema and cell is neutral, and 2 were hypo-osmolar. The researchers tested 2 concentrations of tenofovir, at 1.76 and 5.28 mg/mL.

The researchers gave macaque monkeys a single dose of the enema and measured concentrations of tenofovir in their blood and rectal tissue biopsies an hour, a day, and 3 days after the dose. They also took cells from biopsies at these points and cultivated them in a lab dish with an HIV-like monkey virus (SIV) to see if they could be infected -- a so-called explant test.

With both doses of the hypo-osmolar formulation, drug levels in cells reached their peak faster than with the iso-osmolar formulation.

The higher dose of the hypo-osmolar formulation produced drug concentrations in both blood and inside cells that were 5 to 11 times higher than any of the other formulations, though the difference in the levels in cells was not significant at 3 days after dosing.

An important consideration with tenofovir is whether the concentration of the pro-drug in blood, tenofovir disoproxil fumarate (TDF), which is the version actually administered, correlates with the biologically active, metabolized version of the drug that has to get inside cells, tenofovir diphosphate (TFV-DP), and the levels correlated at all doses. The concentrations of TFV-DP -- specifically in CD4 cells, which are the important cells to get into -- were 5 times higher with the larger hypo-osmolar dose at 1 hour after dosing than they were with any other formulation. There was no damage observed to rectal tissues with any formulation.

In the HIV prevention assays, the hypo-osmolar high dose formulation was highly effective in preventing infection by 2 different strains of SIV

Cells taken from biopsies 1 hour after microbicide dosing were completely protected from SIV infection; in cells taken 24 hours after dosing, biopsies from 2 out of 6 monkeys were infected, compared with all biopsies when using other microbicide doses. The issue of how long semen stays in the gut and can infect cells is important here, as it dictates how long the microbicide needs to be effective.

Nonetheless, these are promising results, showing that it is possible to make an enema microbicide that causes cells to actively absorb drug, and human studies are planned.



P Xiao, S Gumber, M Marzinke, F Villinger, et al. Hypo-osmolar Formulation of TFV Enemas Promotes Uptake and Transformation of TFV to TFV-DP in Tissues and Prevents SHIV/SIV Infection. HIV Research for Prevention (HIVR4P 2016). Chicago, October 17-21, 2016. Abstract OA04.03.