Interview With Robin Shattock, M.D.
St. George's Hospital Medical School, London, UK
P4P: We're pleased to have as our guest Dr. Robin Shattock of Saint George's Hospital Medical School in London, England. Dr. Shattock presented yesterday on microbicides. Doctor Shattock, I know that there have been some gains in knowledge that have lead to new approaches in tackling the problem of development of microbicides. What are some of those new developments, and what barriers still remain?
Dr. Shattock: Well, it's an exciting time for microbicide development, partly because the field is being taken more seriously, and that's due, in part, to the fact that at the moment there isn't an effective vaccine that's likely to be rolled out in a global way in the near future. Microbicides have the advantage that they may well be able to be developed quicker and faster than an effective vaccine. Ideally, at moment, they're being targeted to be developed for the developing world, so that they can give women a means of protection that they can choose and control themselves, so that where there is inconsistent or no condom use they still have other options. One of the significant things is we know that a major risk factor for women is to actually be in a stable monogamous relationship, and in those relationships condoms are used far less, partly because fertility is very important in many parts of the world. But it is in those relationships often where HIV transmission appears to occur. This is a critical concept that could have big impacts in terms of prevention therapy or prevention treatment.
P4P: In terms of the "A-B-C," it kind of like puts a dampening effect on the "B" part of that term -- being faithful?
Dr. Shattock: Yes. Absolutely. So if you're in a monogamous relationship you may be faithful, you're certainly not going to want to abstain if it's a relationship. But being faithful doesn't necessarily protect you.
P4P: And in many parts of the world that's placing women at higher risk.
Dr. Shattock: Absolutely.
P4P: In terms of where the development of microbicides is at this point, could you discuss some of the mechanisms that we are exploring now, especially as they relate to preventing entry?
Dr. Shattock: What we would call first-generation microbicides, the things that have been worked on for the longest and are about to enter Phase 3 clinical trials, the majority of those work on a charge basis, so they would be called polyanionic molecules. On a cell sheet they're very long chain molecules that have a high level of negative charge, and these compounds work by blocking HIV fusion with susceptible target cells. They work in a very nonspecific fashion, so they're likely to be active against a wide range of viral types. Unlike, for example, antibody approaches, mutation of the virus is less likely to be a problem for such an approach. They're ideal because they're very cheap to manufacture and cheap to distribute. But what have no proof of concept at the moment, as to whether they'll work, so we need to try these in a Phase 3 trial to see if they are efficacious.
Alongside those, there is still one compound that's been taken to Phase 3 trial that destroys the virus by lysing1 its envelope. This is a relatively new molecule and has a much higher selective index, so it's much more selective about the lysing virus particles and epithelial2 cells than the nonoxynol-9. Hopefully it has a better safety profile, and again, we need to try it in a clinical trial to see whether it works or not.
And then there's one other approach, which is using a pullout called "buffer gel," that simply maintains a very low pH3 in the vaginal lumen4 -- that's a pH of about 4.5 -- that in itself can inactivate viral particles.
So those are the first-generation things are going to clinical trials this year. But then, following them up very quickly are alternative approaches. A lot of drugs that have been used in therapeutics are now crossing over and being considered as microbicides. Certainly some of the antiretroviral compounds, particularly tenofovir (viread) has been formulated as a gel as a vaginal microbicide, and also some of the newer NNRTIs are being considered as microbicides. Those are compounds that have a good chance of working, but one of the issues with those will be their impact on other therapeutic use of antiretrovirals, and that's still an unknown in terms of resistance issues.
P4P: Are we looking at a certain percentage of efficacy? And, can you estimate a timeline when we might be able to obtain a microbicide that achieves that percentage of efficacy?
Dr. Shattock: At the moment what we would like to achieve with a first-generation product would be something that shows 60 percent efficacy. That will be complex, because proving that in a clinical trial setting will require good compliance by the subjects, so something might be much more effective than 60 percent if it's used consistently. But in a trial setting I think that 60 percent is probably a good goal to go for. We also know from some of the modeling that a product that has 60 percent efficacy, if it were actually distributed through distribution channels that already exist to 20 percent of people who would use that product, within a 3-year time period it could have actually prevented 2 and a half million infections, which is quite an achievement.
In terms of timelines, if the first-generation compounds show efficacy in a clinical trial they could be rolled out into the marketplace by 2010. But we have no proof of concept of a microbicide against HIV, so it's much harder to know whether we'll be successful. I think what the microbicide community needs to gear up to do is to make sure that we can try as many different types of products to give us the highest chance of success. One of the problems is that a Phase 3 clinical trial is extremely expensive. It would cost in the region of $30 to $40 million dollars, and would enroll anywhere between 3,000 and 7,000 women. So there's only a certain capacity for doing clinical trials, and clearly to date there isn't enough funding to support all the clinical trials we'd like to do. The perhaps more pessimistic viewpoint would be that it would need several rounds of Phase 3 clinical trials, which would mean that it could be delayed up until 2016. The difference between an approach where you try as many different things early on, and perhaps get an achievable target of 2010, and a pessimistic viewpoint that would say 2016, would be, in practical terms, a difference of preventing 5 million infections.
P4P: Would you say the take home message from that is, people need to be speaking to their legislators and governments about adequate appropriations for this type of research?
Dr. Shattock: Absolutely. Clearly everybody wants more funding, but the relative amount of funding that goes into microbicides research versus vaccine research is very small. Although we're talking perhaps hundreds of millions of dollars, we're not talking billions of dollars. And it is -- with enough funding, enough political will, enough cooperation between different funding agencies and governmental agencies -- certainly an achievable goal.
P4P: When we're talking about polyanionic molecules, those could have an effect on other sexually transmitted diseases as well?
Dr. Shattock: Yes. Certainly they seem to be quite effective against herpes simplex, and they may be effective against other STDs as well. There are some differences between some of the different candidates. But an impact on other STDs is good news in terms of human health, but also may have an impact on HIV transmission itself, because there's such a close association between other STDs and HIV transmission.
The other, I think, important concept is that, although these have been pushed very much as allowing women to be able to make their own choices in terms of protection, they're also likely to prevent transmission from women to men. Especially in a developing world situation where we know that lots of women are unaware of whether they are HIV positive or not, if an HIV positive woman is applying a product that may actually prevent her transmitting the virus to her male partner. This is an important concept, because, again, if men think it will be protecting them, they're more willing to encourage their female partners to start using these products.
P4P: That's an interesting point. In closing, aside from money, what are the major hurdles that you see in the development of vaccines?
Dr. Shattock: One of the major hurdles is the regulatory pathway. Clearly nobody wants to take something into the developing world that will be dangerous. But it's very hard to do a clinical trial along FDA standards, and most of the developing world looks to the FDA to set those standards. There is an ongoing conversation between those people who are planning these Phase 3 trials and the FDA, and I think it needs to continue to be an ongoing dialog, because with a new type of drug what the FDA would usually expect is that it would be administered as a prescription-only drug for up to 10 years. Now clearly a product like this is only going to work if it can be sold on every street corner and is readily available. That's going to be a major hurdle that needs to be talked through with the regulatory bodies, both in the U.S., in Europe, but also in the countries where these products are going to be used.
P4P: The FDA regulates in the United States. In Great Britain you have an equivalent to the FDA ...
Dr. Shattock: Yes.
P4P: ... and the situation is pretty much the same for the EU community as well.
Dr. Shattock: It's similar. There are some subtle differences, and it may be that an approach through the European regulatory bodies may be a way to go. But also the other factor is that some of these products are being funded or developed by small biotech companies, and although they are willing to provide these for use in the developing world, they would still like to get drug registration in the developed world. So they are also keen that it goes down an FDA route.
P4P: Doctor Shattock, I want to thank you so much for the time that you've taken here with us, and certainly on behalf of all those people who could not be here.
Dr. Shattock: Thank you.
Johnson & Johnson to Grant License to International Partnership for Microbicides for Experimental Microbicide
This article was provided by Wyoming: Positives for Positives. It is a part of the publication Positives for Positives.