Oral pre-exposure prophylaxis (PrEP) based on tenofovir disoproxil
fumarate/emtricitabine (Truvada) has set a high bar for prevention effectiveness, but a range of alternative PrEP
products are in development, Raphael Landovitz of the University of California
told the HIV Research for Prevention conference (HIVR4P 2018) in Madrid last week. They
variously promise less frequent dosing, multi-purpose uses and different modes
of action, although the development process for each has its challenges.
Speaking at the same plenary session, Craig Hendrix of Johns
Hopkins University made an eloquent plea for research to continue into PrEP formulations
which are topical (applied vaginally or rectally, at the site of potential HIV
exposure) rather than systemic (spreading the drug throughout the body).
Topical products such as films, inserts or gels would provide immediate, rather
than long-term protection. However, the US National Institutes of Health is
reducing its investment in topical PrEP research.
Landovitz said that there had been hope that the CCR5 entry
inhibitor maraviroc, an oral tablet
that is sometimes used as part of antiretroviral therapy, could also be used as
part of PrEP. However, a study found that rectal
tissue samples of men who had taken maraviroc could be more easily infected
with HIV in a test tube than tissue samples of men taking other PrEP regimens.
For this reason, maraviroc has not been taken forward for further development.
Tenofovir alafenamide
(TAF) is a newer, modified formulation that causes less kidney and bone side-effects
than tenofovir disoproxil fumarate (TDF) and is included in a number of fixed
dose combinations for antiretroviral therapy. Landovitz said that while TAF is
an attractive option for HIV treatment, it remains to be seen whether it will work
well for PrEP. TAF delivers high levels of tenofovir to cells, without
requiring high levels in blood plasma. This explains the reduced side-effects,
but could also mean that protective
levels of the drug are not reached in rectal and vaginal tissues.
It’s not clear whether the key determinant of prevention
efficacy is drug levels in plasma (low with TAF), tissue (low with TAF) or
cells (high with TAF). The efficacy of TAF as part of PrEP will be unknown
until the phase III DISCOVER trial is completed. The trial is comparing tenofovir
alafenamide/emtricitabine (Descovy) and
tenofovir disoproxil/emtricitabine (Truvada)
as PrEP regimens.
Landovitz addressed broadly
neutralising antibodies (bNAbs) as
part of his talk. These rare antibodies can neutralise multiple genetic
variants of HIV and may have a role in HIV treatment and (hopefully) remission. In addition, vaccination with bNAbs may have a role in HIV prevention. The
Antibody Mediated Prevention (AMP) studies are investigating whether infusion
of one of these antibodies could provide passive immunisation and protect
against HIV infection. Landovitz said the study will generate important data
that will inform future vaccine development. However, a combination of several
antibodies (rather than the single antibody being tested in AMP) would probably
be needed to fully defend against repeated viral exposures.
Landovitz said that views were polarised about long-acting injectable formulations of
PrEP. They may solve some, but not all the adherence challenges of oral PrEP.
As they cannot be removed from the body in the case of intolerance, a
lead-in period taking the same drug as oral tablets is recommended to
check for side-effects. Moreover, after a last dose is taken, there is a
lengthy, slowly declining ‘tail’ in which drug levels are unlikely to be
protective but may still cause problems in relation to side-effects, drug-drug
interactions and – should HIV infection occur – the selection of drug-resistant
strains.
The non-nucleoside reverse transcriptase inhibitor rilpivirine was a candidate for
injectable PrEP, but is no longer being taken forward. One
participant in an early trial developed drug resistance after acquiring HIV
during the long tail. It still holds promise for use as part of HIV treatment.
The injectable form of the integrase inhibitor cabotegravir is being developed both for
HIV treatment and for PrEP (in the latter case, with dosing every eight weeks).
In another presentation at the conference, Landovitz showed that cabotegravir
can remain in the body for as long as three years after the last injection.
Two large phase III studies, HPTN 083 and HPTN 084, will tell us whether
cabotegravir is efficacious – as well as whether the long tail does cause
problems with drug resistance. Landovitz said that long-acting injectables are likely to become
available imminently – scientists, policy makers and advocates need to be prepared to ensure equitable access.
Long-acting implants
may not have the same drawbacks as injectables. Similar to a contraceptive
implant, the device is placed below the skin and provides a slow, continuous
release of the drug over several weeks or months, without creating a long tail.
It can be removed in the event of side-effects or if the user wants to stop.
The technology of implants is progressing rapidly, with
several different devices in development. One particularly exciting aspect is
the potential for an implant to be a multi-purpose technology, delivering a
contraceptive or another medication alongside PrEP. Early studies are working
on implants to deliver TAF, cabotegravir and the new nucleoside reverse
transcriptase translocation inhibitor MK-8591 (also known as EFdA).
Landovitz said that early work on microneedle patches was promising. The patch would work by painlessly
penetrating the top layer of skin to deliver a drug and then dissolving; a study into a patch for
cabotegravir is underway.
Turning to topical products, vaginal rings are designed to be worn inside the vagina for a month
at a time; women can insert and remove the devices themselves. The dapivirine vaginal ring has
demonstrated partial efficacy and an ongoing open label study suggests
that use of the ring has increased since study participants have been told that
they are using an active product that has already been through clinical trials.
It is currently under review by regulatory agencies.
Rings containing other antiretrovirals have also been
studied and the conference heard about work to develop a multi-purpose ring
that would also provide the contraceptive levonorgestrel. Craig Hendrix added
that he is particularly interested in the development of the ‘pod’ ring – this
has holes which could take numerous drugs, including antibiotics against STIs and
contraceptives, and so would be ideal for multi-purpose use.
A vaginal film is
a small product a little bit like a fresh breath strip. A woman can easily
insert it herself and as it dissolves rapidly on contact with moisture, a sexual
partner would be unlikely to notice it. Acceptability has been high among the thousand
or so women who have taken part in early studies. The films achieve high levels of
drug concentration in the vaginal mucosal tissues, without unnecessary exposure of the whole body to
the drug. They could be engineered either to protect against sex within a few
hours (for on-demand use) or for longer a period of time.
Similarly, vaginal or
rectal inserts are small, fast-dissolving tablets or suppositories that
might work in both body compartments. Hendrix noted early studies into inserts
using the gp120 entry inhibitor DS003, a protein derived from algae called griffithsin
and tenofovir alafenamide/elvitegravir.
The development of rectal
gels has not yet stopped, Hendrix said – there are eight products which
have recently begun phase I studies or will soon do so. He remains optimistic
about their potential – scientists have a much greater understanding of the
safety, pharmacokinetics, pharmacodynamics and user acceptability of potential
products than was the case when the first tenofovir gels for vaginal or rectal
use were developed, he said. The rectal-specific formulation of tenofovir
tested in the CHARM-01 and CHARM-02 studies was worth taking forward, he
suggested.
Moreover, delivering PrEP in the form of a rectal douche would be ‘behaviourally
congruent’ – people would not need to make substantial changes to their
behaviour as the PrEP drug would be added to a product that many people use
anyway. Similarly, adding PrEP to a lube would be behaviourally congruent, but
there are more challenges in developing a PrEP lube.
Craig
Hendrix called on the National Institutes of Health, the HIV Prevention Trials
Network and other actors to ensure that topical products can be chosen for PrEP.
He said the lesson from contraception was clear – an
increased range of contraceptive options is associated with increased use of
contraceptives and better health outcomes. Women who have been able to
choose their contraceptive method use it for longer than women who have been
denied a choice. For
each additional contraceptive method provided, there is a 12% increase in
the proportion of women using contraception.
He asked: “I wonder how much this increase will be for every
additional product we license for PrEP?”.