A small removable plastic implant resembling a tiny piece of
dry spaghetti is capable of delivering sustained levels of the drug tenofovir,
researchers told last month’s HIV Research for Prevention conference (HIVR4P 2018) in Madrid.
The drug delivery capability of the implants was tested on
rabbits and will now advance into tests on dogs and non-human primates before
phase 1 trials in humans, researcher Ariane van der Straten told the
conference. Van der Straten belongs to an initiative called the Women’s Global Health Imperative, which
promotes research into sexual health and safe motherhood in women and girls
globally.
There has been considerable
interest in developing removable implants for HIV pre-exposure prophylaxis
(PrEP). Long-term injectable versions of anti-HIV drugs have
already shown efficacy as treatments and have
reached phase II trials as PrEP. PrEP injections are
popular among users but suffer from the fact that cabotegravir, the drug
used in the trials, persists in the body for an extraordinarily long time –
years in some cases, as another
study presented at Madrid showed.
This sets up the conditions for
the ex-user of injectable PrEP to develop drug-resistant HIV if they are exposed
to an infection, and
one case of this happening was reported in 2014. Even though an injectable
version of the drug concerned, rilpivirine, is
no longer being taken forward, the possibility still exists with other
drugs. The only way to ensure this does not happen it to cover the “long
tail” of drug level decay with oral PrEP – which obviously makes no sense if
people choose injectables because they prefer them to pills.
For this reason, there is intense
interest in developing PrEP as a removable implant. The technology exists for
these, and removable contraceptive implants containing levonorgestrel
have been in use for 30 years; one implant can be effective for three to five
years.
However, all drugs have different
distribution and excretion characteristics, so trials need to be done of the
most effective formulation of a PrEP implant.
Even before these are done, as
previous PrEP studies have shown, it is important to do acceptability research
to establish what people want from a PrEP implant. Van der Straten told the conference that 14
focus groups were conducted with 105 potential implant users and 30 healthcare providers were interviewed, all in South Africa.
A preference was expressed for a
smaller and thinner implant than the one already devised, discreetly matched to
skin tone, and participants said they would be willing to have two implants at
once if it meant changing them less often. As a result, the initial implant,
which was more like a drinking straw containing drug, was reformulated as a thinner
but stiffer extruded-polymer version measuring 40mm by 2.5mm.
The implant is inserted with a trocar, a medical device
commonly used to insert cannulas, and can be removed easily with one too,
though it is planned to make the implants with a biodegradable plastic that
will be absorbed by the body. Users also said they would like smaller ‘test’
implants to be made that can be used on a trial basis, and also asked if they
could be made with some kind of monitoring system that would show when they had
run out of drug.
The Women’s Global Health Imperative have been testing rabbits with drug
implants that deliver the ‘newer’ version of tenofovir, tenofovir alafenamide
or TAF. This drug was chosen because it gets delivered so efficiently
into tissue cells. They used three different versions designed to deliver a
low, medium or high dose of TAF, which means that 0.2, 0.4 or
0.8 milligrams of drug per day are delivered – the high dose requiring two implants.
In total
24 rabbits received one of the three doses. Because the high dose necessitated
two implants, the rabbits on the lower doses received one ‘dummy’ implant as
well as a real one.
The implants were inserted into
the rabbits' front legs for nine weeks and then removed. Each week, drug levels were
measured weekly in blood and in PBMCs – T-lymphocytes in the bloodstream. Two of the eight rabbits in each group were humanely killed and had drug
levels in vaginal, cervical and rectal tissues biopsied at week six, as were three rabbits in each group at
week nine.
The rate that drug diffused out
of the implant into saline in a lab dish was also measured to find if the way
it diffused in animal tissue was different: it was not significantly so.
Drug levels in blood reached
steady state – above 8.2 nanograms per millilitre – in blood after seven days and
were maintained throughout, or had even slightly increased by week nine. Drug
levels in PBMCs did not build up to a steady state (maximum) till week six or even week seven but
were already well above the expected effective concentration for PrEP at the first
measurement, seven days after the implants were inserted.
The expected effective
concentration for PrEP in PBMCs is 48 femtomols per million (fmols/106)
cells. Levels were well above this at all time points; the average level for
high, medium and low doses was 1203, 990 and 440 fmols/106 cells
averaged from week one to week nine, and the mean lowest level seen was 790,
655 and 175 fmols/106 cells respectively.
Levels in tissues were expressed
as fmols per milligram. In the rabbits receiving the lowest dose they were about 10 fmols/mg at
week five, 15-60 fmols/mg at the medium dose and 15-70 fmols/mg at the high
dose. It was notable that tissue concentrations in the rectum tended to be lower than concentrations in the vagina
or cervix, contrary to some other PrEP studies. At week nine the levels in the low and medium doses were only
slightly higher, but levels in the animals receiving the high dose were
markedly higher at about 75-320 fmols/mg in the vagina, 65-120 fmols/mg in the
cervix and 25-75 fmols/mg in the rectum (though it is worth noting these were
not the same animals).
All the implants were retrieved
intact. Some reactivity to a foreign body under the skin is to be expected and
has been seen in people using other implants, ranging from slight redness to
mild fibrosis (scarring). There was no reaction in the rabbits that gave cause
for concern.
The next step in the implant
studies is to do longer studies – six months or more – in rabbits, dogs and
monkeys before progressing to phase I human trials.