State of the ART of microbicides

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The microbicides field has undoubtedly moved and shifted a lot in the past decade. Now, with first generation microbicides candidate products up and gone, antiretroviral treatment (ART)-drug based microbicides in spotlight, and only three major microbicides efficacy studies remaining, the need to lobby for increased funding of microbicides research and development, was never so compelling.

The need to bolster HIV prevention has certainly not dimmed - and so has the need to up HIV treatment, care and support which is becoming acute on daily basis. The International Microbicides Conference (M2010) opened with the plenary that cited UNAIDS data, from New York Times news (At Front Lines, AIDS War Is Falling Apart), "For every 100 people put on antiretroviral treatment (ART), 250 people are getting newly infected with HIV." Read more

"People were already questioning that whether universal access to treatment is achievable without significantly reducing the number of new infections" said Professor (Dr) Robin Shattock, who is a Professor of Cellular and Molecular Infection in the Department of Cellular and Molecular Medicine at St George's University of London, UK.

"Donors were questioning too whether it is sustainable to continue the roll out of treatment across the globe" said Prof Shattock.

There is no doubt that HIV prevention, treatment, care and support programmes all need to be fully funded, supported, and rolled out in all possible ways so as to reach the hardest-to-reach affected communities.

"This is the first microbicides conference to talk about HIV prevention technologies in a broader context. It also includes Pre-Exposure Prophylaxis (PrEP) and really the two fields of microbicides and PrEP are starting to become very blurred" said Prof Shattock.

"The research is going on taking the same tenofovir based drug orally to prevent infection or applying a similar drug topically - the distinction between PrEP and microbicides have become more blurred" said Prof Shattock.

In September 2009, the world's largest AIDS vaccine trial (Thai Prime-Boost study) to date showed the first evidence that an experimental AIDS vaccine could lower the risk of HIV infection. The results were complex; the observed benefit from the vaccine was modest; and the field is still years away from a highly protective vaccine. "The caveats to the Thai Prime-Boost study results are important and true. But letting them become the entire story does a severe, even dangerous, disservice to the field, the trial and especially the 16,000 people who participated in the trial," said Mitchell Warren, Executive Director of AVAC: Global Advocacy for HIV Prevention.

"The Thai AIDS Vaccine trial needs to be repeated which could change things dramatically" said Prof Shattock.

"With microbicides, when the first generation microbicides were successfully tested, and we should not underestimate what a significant advancement it was, but it appears to either lack sufficient potency or not be used appropriately enough to show statistical end-points" shares Prof Shattock.

"Then it led the microbicides field to move towards potent products specifically those that are targeted against the virus. It also shifted the microbicides field to develop a programme of systematically testing the biological plausibility of different targets in the primate model to validate whether a target is appropriate for prevention approaches. It also accelerates and emphasizes the need for drug distribution studies and tissue activity studies in both primates and humans. It also led the microbicides field to prioritise new formulations that maximise adherence to give the best possible chance of showing efficacy in a clinical trial" explains Prof Shattock.

"These developments led to increasing emphasis on combination products. Combination products not only to ensure that any microbicide will hit the wide possible diversity of virus but also potentially to reduce the risk of resistance" said Prof Shattock.

"It has also led us to recognizing the need to prioritise several efficacy testing in clinical trials because it is only human data that already helped us understand when the basic science is pointing us in the right direction" added Prof Shattock.

"So right now at this conference I believe we stand at the critical standpoint in microbicides development, critical because the first generation products have been and gone, and next generation products are poised to be tested in clinical trials, that represents quite a vulnerable position to the field because without some proof of efficacy in future trials it may become harder and harder to sustain funding for microbicides development" said Prof Shattock.

With ART based microbicides, there is a need to have appropriate drug delivery mechanisms - Many of these ART targeted microbicides are operating at the level of preventing HIV infection at the target cell, which means it needs to be delivered at the right time at the right tissue. But also can be taken for combination with products that have a high barrier for resistance and will have a limited impact on therapy.

"What we do know is that the transmission takes place very rapidly. So it is absolutely critical for the science of microbicides development, to make sure the product is there, covering and protecting the target cells, at the time of exposure" said Prof Shattock.

There are many antiretroviral drugs already being used in HIV treatment and this is perhaps the biggest success story in HIV history with development of as many ART drugs as the number of years have passed by since the discovery of HIV. "This also means significant investment into research and drug development that has gone over years.

"One reason for engaging antiretroviral drugs into microbicides development is to accelerate the candidates that are ready to go into clinical trials because they come from a very rich product development profile. So now we have so many good candidates, can we provide the much needed bridge to establish biological plausibility - to find out will these things actually work in clinical trials" said Prof Shattock.

"So we now have extremely good biological plausibility that microbicides could work and how can we use this knowledge in performing better human trials. Well more emphasis is being placed on drug distribution and tissue activity studies and we hear people talking about PK and PD. Pharmacokinetics (PK) is how much drug is needed and where is it needed to provide protection. Work is also being done to determine tissue drug activity - Pharmacodynamics (PD) - whether the drug which is delivered is active" explains Prof Shattock.

Prioritisation of new products is receiving particularly more attention in order to maximise adherence so that we have the best chance of seeing efficacy in a clinical trial. And this has led many people to trying to move microbicides from time-of-exposure products to pre-exposure products.

ARV-based Microbicices be prescription-only products?
Should ARV based microbicides be prescription only product? This sounds disappointing especially for those who came from microbicides field because the original vision was to have an over-the-counter (OTC) product. But the benefit of prescription-only product that requires testing is that it will have a positive impact on the voluntary counselling and testing.

Emphasis will be placed on a combination that reduces the threat of resistance. "It is not entirely inconceivable that if we have an ART-based mono-drug product that shows efficacy that eventually it could become an over-the-counter (OTC) product" said Prof Shattock.

We are at the advent of multiple different products, multiple different delivery strategies, but lack of sufficient funding to take them all to the clinical trials. So we need to be very smart on what goes into the efficacy trials. This has led the field to prioritising on what's best-in-class. So how do we go about choosing the best in class?

Firstly we need to choose the best-in-class inhibitor in a different category. There is no sense of testing multiple drugs in the same category.

Secondly, we need to choose at the level of potency and selectivity.

Thirdly, these products need to be stable.

Fourthly, looking at products that reduce resistance and can combine with other drugs, will be prudent.

Fifthly, we need to look at the stage of development of this product - if we don't have a product that shows a degree of efficacy in the next five years, some product 10 years behind the queue will never have the opportunity to try a clinical trial.

And many such factors that scientists use to prioritise different potential microbicides candidate products.

"There are only three potential microbicide efficacy trials remaining... now that is quite concerning because although there is a strong biological plausibility we all know that science is full of surprises. And efficacy is not just about potency of the drug, but also about the way it is delivered and the way it is used" said Prof Shattock.

"Many of you are aware that after the Thai AIDS Vaccine trial, the vaccine advocates are lobbying to get funding to do a phase 2b trial every year, whether they will be able to get the money for that is debatable but I don't see microbicides field standing up and lobbying hard enough to do more clinical trials to get the human data that will inform the basic science" said Prof Shattock.

Some new data on ART-based microbicide studies may be announced at the forthcoming International AIDS Conference, Vienna, Austria. 2009 Thailand's AIDS Vaccine study results were promising indeed. Yet there is a very long way to go for the HIV prevention research field and perhaps, might succeed in turning the tide of the new HIV infection.

Bobby Ramakant - CNS

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