Where next in PrEP and microbicides? Europeans discuss research pipeline

Thursday 18 June saw the final research meeting in Brussels of CHAARM (Combined Highly Active Anti-Retroviral Microbicides), the EU-supported research consortium which for the last five and a half years has been researching and developing possible new biomedical methods of preventing HIV.

With the success last year of the European PrEP trials PROUD and Ipergay as well as the overwhelming evidence of the potential efficacy of simply putting as many people on treatment as possible – reinforced last month by the results from the START trial – it might be asked why there needs to be further research in this field.

However while we now have PrEP’s proof of concept in gay men, the evidence that PrEP may be an option women can use is much less firm, with only two trials – Partners PrEP and the Caprisa 004 vaginal gel trial – reporting statistically significant positive results for women. With suggestions that hormonal contraception could impact on vulnerability to HIV, we need something that protects against both HIV and pregnancy. With fears that PrEP in gay men could lead to mass migration from condoms and a rise in STIs, we need substances that can work against other viruses. We have no proof of concept for PrEP in adolescents or specifically in female sex workers. We need to broaden the range of drugs that can be used for prevention, especially into classes not used for treatment, because of the possibility of drug resistance. And with models implying that PrEP might only be cost-effective for very restricted groups, we need simpler molecules that can be cheaply manufactured.

Future EU research funding

All these needs have to some extent been considered by CHAARM programmes (and by many other researchers). Before they presented their work, however, since the FP7 EU funding programme has reached its end, Alessandra Martini of the European Commission and Ole Olesen of the European and Developing Countries Clinical Trials Partnership (EDCTP) outlined plans for the Horizon 2020 programme, the next cycle of EU scientific research funding, and the second round of EDCTP grants.

Glossary

microbicide

A product (such as a gel or cream) that is being tested in HIV prevention research. It could be applied topically to genital surfaces to prevent or reduce the transmission of HIV during sexual intercourse. Microbicides might also take other forms, including films, suppositories, and slow-releasing sponges or vaginal rings.

hormone

A chemical messenger which stimulates or suppresses cell and tissue activity. Hormones control most bodily functions, from simple basic needs like hunger to complex systems like reproduction, and even the emotions and mood.

phase I

The first stage of human testing of a new drug or intervention, typically involving a small number (10-100) of participants who do not have the condition the drug is intended to treat. Phase I clinical trials evaluate safety, side-effects, dosage and how a drug is metabolised and excreted in the body.

oral

Refers to the mouth, for example a medicine taken by mouth.

vaginal ring

A device that is worn inside the vagina for a month at a time, which women can insert and remove themselves. A vaginal ring for HIV prevention that slowly releases the antiretroviral drug dapivirine is being developed.

These programmes have been criticised in the past by organisations like the International Aids Vaccine Initiative (IAVI) for leaving a ‘translational gap’ in European research funding. The successive FP programmes have tended to fund preclinical and safety studies and the EDCTP is specifically designed to help poor countries in Africa develop the capacity to put on large prevention and treatment trials. There has been a lack of funding for the drug-development programmes that for lucrative diseases would be funded by pharmaceutical companies and the private and philanthropic sector is much weaker in Europe than the US. Alessandra Martini unveiled a couple of new Horizon 2020 initiatives that are designed to support more sustained  translational research programmes while Ole Olesen said EDCTP, which was originally designed purely as a joint “public-public” research programme between the EU and its individual countries was opening up ways for private and philanthropic funders to contribute.

As the CHAARM day was for researchers to present their recent work to their colleagues and potential funders, most results are as yet unpublished and data cannot be given here in detail: watch out for news on these initiatives from various conferences.

Forthcoming efficacy trials

Before the results from CHAARM programmes, the two biggest public/private partnerships in microbicide research presented some future research ideas. Mitzy Gafos of the Microbicides Development Programme (and PROUD) presented a proposal for an innovative trial of a microbicide or oral PrEP in female sex workers in Africa. This would have the same delayed open-label design as PROUD whereby half of participants would receive the intervention immediately and half one year later. However, given that so many microbicide and PrEP trials had been stymied by the difficulty of women fitting the prevention method on offer into their lifestyles, the innovative aspect of the proposal was that there would be an initial phase where key women in a position of social leadership in their community would be given a chance to try out three different prevention methods – a tenofovir gel, an oral pill, and a vaginal ring – in succession, and then choose which of them to advance into the full trial.

Wendy Blanda of the International Partnership for Microbicides unveiled their pipeline of research. Their first project after the Ring study, which should announce its results in early 2016, is a study of another vaginal ring that adds the hormonal contraceptive levonorgesterol to the NNRTI anti-HIV drug dapivirine. This is partly in order to continue to research on if and how hormonal contraception impacts on HIV vulnerability, but primarily to see if adding a contraceptive will give the product added value to women and possibly improve adherence if it combined both.

Other future projects include trials combining dapivirine with anti-HIV drugs of three other classes: tenofovir, darunavir, maraviroc or combinations of all four, in rings and other devices. This would be, in the first place, for reasons of simple potency; combining the drugs leads to an anti-HIV effect that is greater than the sum of its parts, thus enabling a more powerful effect and smaller amounts of individual drugs to be used. However it is also in order to combat any possibility of HIV resistance arising in response to microbicide use. As we see below, one of CHAARM’s projects has been to take the first dual-ARV gel – one using darunavir plus dapivirine – into a phase 1 trial.

CHAARM’s research programmes

Before that, other CHAARM researchers presented innovative preclinical work. Koen Augustyns of the University of Antwerp and Delphine Desjardins of the Commissariat à l'Énergie Atomique et aux Énergies Alternatives presented protection data from studies of UAMC-01398, a novel NNRTI ARV drug based on dapivirine. Pepe Alcami from Instituto Carlos III in Spain and Elisa Vicenzi from Universita San Raffaelle in Italy presented data on the AIM-HIV project, a separately-financed research programme affiliated to CHAARM. The studies of a non-antiretroviral drug, 5 hydroxytyrosol (5HT), show that this natural compound displays anti-HIV activity in vitro and also has some anti-inflammatory properties. It displays strong synergy with tenofovir, and would be cheap to make.

Veteran HIV scientist Robin Weiss presented the first monkey-study results from a project that caught the imagination of the press last year. It is a monoclonal antibody to the gp120 surface protein of HIV called J3 that would act as an entry inhibitor. The press interest was spurred by the fact that J3 and other antibodies that it could work in concert with were derived from ones found in llamas. These and other members of the camel family produce unique ‘heavy chain’ antibodies whose properties mean that they could be manufactured in bulk and more cheaply than similar monoclonal anti-HIV antibodies. Animal studies will soon announce data on potency; the next research phase needs to look at how best to formulate and package this drug if it shows promise.

Finally Charles Lacey and his colleagues from the University of York presented the first human trials of a combined dapivirine-darunavir (“Dapidar”) vaginal gel. This was a phase 1 safety study in a limited number of women but, without giving details, it did not throw up any safety concerns that might lead to a halt in the development of this particular combination.