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New microbicide enema achieves high levels of drug in rectal tissues in monkeys
Gus Cairns, 2016-10-22 10:00:00
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,
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.
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 a lot of 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 five 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) 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 Villiger of the University of Louisiana presented results for
four different enema formulations. Two 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. Two were hypo-osmolar.
They tested two concentrations of tenofovir, at 1.76 and 5.28 milligrams per
The researchers gave monkeys a simple dose of the enema and measured concentrations
of tenofovir in their blood and in rectal tissue biopsies an hour, a day and
three days after the dose. They also took cells from biopsies at these points and
cultivated them in a lab dish with monkey-HIV (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 five to eleven times higher than any of the other formulations, though the
difference in the levels in cells was not significant at three days after dose.
An important consideration in tenofovir is whether the concentration of the prodrug
in blood, tenofovir disoproxil fumarate (TDF) which is the version actually dosed, correlates with the biologically
active, metabolised version of the drug that has to be 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 five times higher with the larger hypo-osmolar dose, one hour after
dosing, than they were with any other formulation. There was no damage
observed to rectal tissues with any formulation either.
In the HIV prevention assays, the hypo-osmolar high dose
formulation was highly effective in preventing HIV infection by two different
strains of SIV
Cells taken from biopsies one hour after microbicide dosing were
completely protected from HIV infection and in cells taken 24 hours after
dosing, biopsies taken from two out of six monkeys were infected compared with
all of them with 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 for.
Nonetheless there 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.