The first day of the
14th European AIDS Conference, which opened yesterday in Brussels, featured a
satellite symposium on development of HIV microbicides, broadly defined to
include a variety of approaches to pre-exposure prophylaxis (PrEP).
The session, sponsored
by the CHAARM (Combined Highly Active Antiretroviral Microbicides) Project and
the European AIDS Treatment Group (EATG), focused on the status of microbicide
research in Europe, which some speakers suggested was not keeping up with
research in the US and Africa.
is one of the most promising areas of HIV research, with large clinical trials
recently demonstrating the effectiveness of oral Truvada (tenofovir/emtricitabine) and tenofovir vaginal gel.
The main challenge for
PrEP is the need for a high level of adherence. Researchers are optimistic that
different formulations and schedules of administration might help overcome this
barrier. Approaches now under study include vaginal rings, long-acting
injectables and oral PrEP, or gels used before or after sex rather than every
Sheena McCormack of the
UK Medical Research Centre Clinical Trials Unit reviewed the status of
biomedical prevention including a recent study of Truvada PrEP prescription in the US – which showed that nearly half of PrEP users
are women – and clinical trials now or soon to be underway.
The advantages of oral
PrEP include familiarity and decades of experience with adherence, McCormack
explained. Topical products, on the other hand, "get where they need to
go", rapidly achieving high drug levels in genital tissues whilst lower
blood levels mean less toxicity. Topical products also offer more opportunity
for multipurpose use, for example combining antiretrovirals and hormonal
contraceptives in a single gel or ring.
For oral PrEP, the
entry inhibitor maraviroc is now under study, both alone and in combination
with tenofovir or emtricitabine. The IPERGAY trial is looking at Truvada PrEP
taken within 24 hours after having unprotected sex rather than once daily.
Vaginal gel studies
include the DAPIDAR trial, looking at the NNRTI dapivirine with or without
darunavir (Prezista). Tenofovir gel –
already shown to be effective for vaginal use in the CAPRISA 004 trial – is now being studied for rectal use (either
daily or before and after sex) in the phase 2 MTN-017 trial, with sites in the
US, Thailand, South Africa and Peru.
Other ongoing studies
are evaluating vaginal rings that release antiretrovirals over time. A study presented earlier this year showed that a tenofovir ring, worn for a month,
protected macaque monkeys against infection with a hybrid HIV-like virus. Two
trials of vaginal rings containing dapivirine are underway in Africa and have
each enrolled about three-quarters of their target number of women.
Finally, a pair of
long-acting injectable antiretrovirals – extended-release formulation of
rilpivirine (TMC278) and GSK1265744 – appeared safe in pre-clinical studies and are now entering phase 2 trials.
Results from most of
these studies, McCormack predicted, should be available by the end of 2015 or
trials of microbicides in different populations will be still be necessary,
however, and may present challenges such as whether to use oral Truvada PrEP as a standard-of-care
"It's the responsibility
of [researchers] to come up with better designs that will allow us to do these
trials faster and find better ways to move these products through the development
pipeline," McCormack concluded.
Guido Vanham of the
Institute of Tropical Medicine in Antwerp followed with an overview of some of
the compounds under development by CHAARM, including M48U1 CD4 mini-proteins,
single-chain antibodies found in llamas, triazine NNRTIs and LEDGF
inhibitors, or LEDGINs.
Many of these novel
compounds target the entry, reverse transcription and integration steps of the
HIV lifecycle. An advantage of novel agents is that they remain active against
HIV that has developed resistance to older drugs, Vanham explained. These new
compounds probably will not be used as single agents but offer potential for
In a similar vein,
Alessandra Martini discussed the role of the European Commission in microbicide
research. The European and Developing Countries Clinical Trials Partnership
(EDCTP) is supporting a variety of microbicide projects both at the
capacity-building and the clinical trial stages.
Janneke van de Wijgert
of the University of Liverpool gave a presentation on the safety challenges of
vaginal and rectal microbicides. It is important that products not disrupt the
vaginal flora, or 'microbiota,' in ways that discourage friendly bacteria or
encourage growth of harmful pathogens. The rectal micro-environment is
"much more vulnerable" than the vagina, she explained, because it has
a thinner layer of cells and is less protected by mucus. In both the vagina and
rectum, inflammation increases susceptibility to HIV infection.
In an effort to do no
harm, microbicide research must take into account a range of interconnected
factors including the presence of other sexually transmitted infections, the
role of hormonal contraception, the effects of semen and traditional practices
such as vaginal washing after sex.
Harriet Langanke of
the German Sexuality and Health Foundation took a turn away from the science to
discuss the marketing of microbicides. To encourage adherence, she said, new
products should be "at least as easily available as male condoms" and
packaging should be either discreet or sexy – "something you wish to show
off, like a smart phone."
Products for HIV
prevention should be adaptable to individual preferences and use in a variety
of settings ranging from casual encounters to sex work to long-term
relationships. "When talking about microbicides we should be talking about
sex and sexuality and whether these products improve pleasure," she
Summing up, session
chair Gus Cairns of EATG and NAM noted that the field is increasingly turning
towards multi-purpose products that also address the need for contraception or
protection against other sexually transmitted infections
NAM is sending four news summary bulletins by email from the 14th European AIDS Conference, available in English, French, Spanish, Portuguese, Italian and Russian. Sign up on our conference page at www.aidsmap.com/eacs2013