An intravaginal ring containing tenofovir protected
all but one macaque monkey given hormonal contraceptives and repeatedly exposed
to a hybrid human/simian virus similar to HIV, according to a late-breaker
presentation at the 53rd
Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) this month in
The field of biomedical HIV prevention has seen major
advances in recent years. A number of studies have shown that pre-exposure
prophylaxis (PrEP) using oral tenofovir or Truvada
(tenofovir/emtricitabine) can dramatically reduce the risk of HIV infection in
various populations, but it only works with good adherence.
Researchers are therefore exploring other delivery
methods that might be more convenient than daily pills. The CAPRISA
004 trial showed that a 1% tenofovir gel applied before and
after sex decreased HIV acquisition by about 40% overall. Risk of infection was
significantly reduced if the tenofovir concentration in cervical-vaginal fluid
exceeded 1000 ng/ml.
Another approach uses a hollow urethane intravaginal ring
containing tenofovir disoproxil
fumarate (TDF) powder and sodium chloride. Vaginal fluid is absorbed into the
ring, forms a solution with tenofovir and the drug then flows back out.
In an earlier
presented at this year's Conference on Retroviruses and Opportunistic Infections (CROI), researchers with
the US Centers for Disease Control and Prevention (CDC) tested the tenofovir
vaginal ring in female pigtail macaques, a species that has regular menstrual
cycles, like humans, rather than seasonal fertility.
In that analysis, six macaques were fitted with
intravaginal rings containing 120mg TDF. Six control monkeys did not receive
rings and the researchers also looked at six historical control animals. The macaques
were subject to 16 weekly vaginal exposures to a CCR5-tropic human/simian
hybrid virus designated SHIV162p3. The first exposure occurred six days after
the first vaginal ring was inserted and rings were exchanged every four
The ring produced intracellular levels of tenofovir diphosphate
in lymphocytes similar to those obtained using a 30mg dose of tenofovir gel.
Drug concentrations in vaginal fluid reached levels thought to be protective
based on prior studies.
The intravaginal ring fully protected macaques from
SHIV infection throughout the 16 weeks. In contrast, eleven of the twelve untreated control
animals became infected by the end of the study, after a median of four
In the latest analysis, James Smith from the CDC and
colleagues aimed to determine whether the tenofovir vaginal ring remains protective
in the presence of high-dose hormonal contraception.
Many women at risk for HIV use hormonal contraceptives
such as the long-lasting injectable depot
medroxyprogesterone (DMPA or Depo-Provera).
Though data have been conflicting, some evidence suggests hormonal
contraception may make women more susceptible to HIV infection, possibly by thinning
the vaginal epithelium, suppressing progesterone or prolonging the luteal phase
of the menstrual cycle. Researchers want to ensure that
PrEP does not interact with contraceptives in any unexpected or harmful ways.
In this analysis, six macaques were fitted with
tenofovir intravaginal rings and six with placebo rings. All monkeys received 30mg
DMPA by intramuscular injection every six weeks. Smith noted that this is a
higher dose than women use for contraception. The macaques were subject to twelve
SHIV exposures, with the first occurring four weeks after DMPA administration
and one week after insertion of the first vaginal ring. Rings were exchanged
every four weeks, two days after virus exposures.
Looking at the control animals, those receiving DMPA
were infected after a median of two SHIV exposures, compared with a median four
exposures in the earlier analysis without DMPA, but the difference did not reach
Again, the tenofovir ring provided protection against infection.
One macaque became infected at week 8, for an efficacy rate of 83%. All six
macaques with placebo rings were infected. Among infected animals, the viral
load set-point was higher in those receiving DMPA.
The tenofovir intravaginal ring offered
"significant protection against SHIV acquisition", the researchers
concluded. "Sustained topical delivery afforded mucosal protection."
They added that the mechanism for the single
breakthrough infection is unknown, as that macaque had high tenofovir levels
and no apparent inflammation; further analysis is underway.
"With PrEP, adherence is everything," Smith said.
"With many routes of administration, the more choices you
give women. The more options that will fit their lifestyle, the better
adherence is going to be."
He noted that adherence was an issue even in the
animal study, as one macaque repeatedly removed her ring and was replaced with
a more compliant animal.
A phase 1 clinical trial of this vaginal ring in women
is schedule to start by the end of 2013, James said.