HIV prevented from entering the body

Although oral administration of these drugs has in recent years downgraded HIV from a death sentence to a chronic medical condition, Professor Charles Lacey at the University of York in the UK still describes HIV as one of the deadliest pandemics the world has ever seen.

‘The virus cannot yet be cured and it continues to claim thousands of lives each day,’ he said. ‘We have to work out ways to slow down and then stop new cases.’

In 2010, the Centre for the Aids Programme of Research in South Africa showed that a single antiretroviral drug delivered to the vagina or rectum during sexual intercourse could reduce HIV infection rates by close to 40 %.

Over the past five years, Prof. Lacey has taken part in the EU-funded CHAARM project to build on this and try to reduce infection rates even further with several antiretroviral drugs combined into a single, easy-to-use delivery method, such as a gel or a vaginal ring. This new form of prevention could boost the appeal and efficacy of microbidices among vulnerable communities.

As coordinator of the project, Professor Charles Kelly at King’s College London in the UK explained that rectal and vaginal microbicides contain the same drugs that are used in systemic HIV treatments, but releasing them under more favourable circumstances could turn the tide in the struggle against HIV.

‘The difference is that by applying the drugs topically we can deliver higher doses of them with fewer side effects,’ he said. ‘Also, microbicides make it possible to hit the virus when it is vulnerable.’

Stopped at the gate

Tackling the process of infection erodes one of HIV’s greatest assets. In contrast to systemic treatments that have to combat generations of viruses that are already replicating inside the body, a microbicide limits to a single shot the chances of the virus getting past its defences.

‘If HIV is stopped at the gate, that’s the end of the infection,’ said Prof. Kelly.

Condoms remain the gold standard in terms of HIV prevention, but communities among which their use is inconsistent urgently need alternatives.

Gus Cairns, from the European AIDS Treatment Group in Brussels, Belgium, said that discreet prevention methods such as microbicide gels and vaginal rings could offer millions of young women in lower income countries better chances to protect themselves against HIV infection.

‘The virus is spreading in many countries where gender equality is not a given and where the stigma attached to HIV is severe,’ said Cairns. ‘Many women cannot challenge their partners by asking them to wear a condom.’

If researchers can make microbicides that are both safe to use and accessible, these women could take charge of their own sexual health.

The work has also led to new discoveries about how drugs administered through the vagina enter the body and how to combine different drugs in a single gel.

Whereas the proteins that transport drugs inside and out of cells of the digestive and circulatory system are well documented, little was known about those in the vagina before the CHAARM project began.

‘We found, for instance, a protein that naturally pumped the drugs that we were testing out of vaginal cells,’ said Prof. Kelly.

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‘This is step toward a larger challenge of achieving total body control and is applicable to many diseases.’

To complicate matters further, the genetic adaptability of HIV limits the therapeutic effect of any single drug. Medical practitioners work around this challenge by administering different kinds of antiretroviral drugs at the same time.

Following the same strategy with microbicides means combining active chemical compounds while keeping their pharmaceutical effects separate. According to Prof. Kelly, this is no minor undertaking.

‘The two first antiretroviral drugs that we tested, Darunavir and Dapivirine, initially reacted in undesirable ways with each other,’ said Prof. Kelly. ‘They also responded in different ways to the medium within which we were formulating them.’

Rather than compromise on the active ingredients, CHAARM enlisted the expertise of Particle Sciences, a biotech firm in Bethlehem, Pennsylvania, in the US. The company developed a series of physicochemical tricks to combine the two drugs harmoniously.

These achievements were broadened to different kinds of antiretroviral drugs in the recently finished MOTIF project, also led by Prof. Kelly, which explored how optimised formulations and dosing could spread microbicides over all internal surfaces in the vagina and rectum, and into the human cells that need protection.

Before the CHAARM project came to an end, Prof. Lacey oversaw a trial of the gel, which proved that a microbicide combining Darunavir and Dapivirine was safe for use in humans.

Laboratory tests on graft tissue and in animal models suggest that the formulation could reduce HIV infection rates further than the single drug microbicides tested to date, but Prof. Lacey remains cautious on the matter.

‘When you translate a medical intervention from cells in a test tube, to animal models, to real life human populations, you always get different numerical read outs of protection,’ he said. ‘Only clinical trials on human patients can now reveal the full impact that microbicides will have on HIV.’