Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)
Please can you tell us a little bit about HIV/AIDS and how many people in the world it affects?
The best estimates at the moment reckon that there are about 25 million people infected with HIV. Most of those are in resource-limited settings, including sub-Saharan Africa, South East Asia and India.
The infection continues to be uniformly fatal unless treated in almost all individuals. So, treatment of the disease is an important goal for public health.
What therapies are currently used to treat HIV/AIDS?
Currently the standard treatment is combination-anti-retroviral therapy. Usually these consist of three drugs; but there are investigational regimens that have tried to use two drugs or four drugs.
Most patients who begin treatment, so-called treatment-naïve patients, start on a combination of three drugs.
The current standard of care is to use co-formulated drugs, where the patient takes one pill either once a day or twice a day.
You are quoted as saying, “We can do more with less of the active pharmaceutical agent in many anti-HIV drug compounds and we can adopt more efficient techniques to make the drugs more quickly and for less money than before”. Please could you explain to us how this would work?
There are three basic approaches to delivering more anti-retroviral therapy to more people for the same amount of money.
The first is the simplest. It is decreasing the cost required to synthesise the active pharmaceutical ingredient in the drug. This can be done by streamlining the chemical synthesis of the drug in a way that makes it less expensive. There are now some very good examples of this in the efforts that we are involved with.
The second approach is to use the same ingredient, but improving the extent to which the body absorbs the drug. This means you can use less of the drug to achieve the same effect.
There are chemical techniques which can improve the bio-availability of the drug; this is the proportion of the drug that is absorbed into the systemic circulation. Those techniques usually involve manipulation of the formulation of the drug.
This does not involve altering the chemical structure of the drug that has the anti-HIV effect. Instead you modify everything else that is in the pill. For most pills or tablets, more than 50% of the weight of the tablet is excipient, it is not active ingredient.
You can manipulate the excipient, which is the inactive or inert ingredients in the drug, in a way that will improve the absorption of the active ingredient in the drug.
The third way is to try to take advantage of what we know about the way in which new drugs are developed. That involves rapid escalation of the dose of the drug to find the dose most likely to achieve the desired effect in people involved in initial clinical trials. This ensures that the drug can get to market in the shortest amount of time.
This is a very efficient way to get a drug to market, but it often means that the marketed dose of the drug, at least initially, is higher than it needs to be.
If you can find a situation in which the dose is clearly higher than it needs to be and that it can easily be reduced, say by 30% or 50%; the generic versions of that drug would then be substantially less expensive. Consequently, for the same amount of money one could treat more people, because the dose per person per day would go down.
How do you know that lower-dose prescriptions would work in the treatment of HIV/AIDS? Have you tested this?
There are certainly examples in the history of treating HIV/AIDS where the initially marketed dose of a drug has been decreased. The best example is AZT. This is the drug that is famously taken by Roger, the protagonist, in the film Rent every four hours.
The originally marketed dose of that drug was 1500 mg per day. The dose of that drug has now been reduced to 300 mg twice a day, this equates to roughly a two thirds reduction in the amount of drug the patient has to take every day.
That is because when the drug was first marketed, the dose they thought was needed to control HIV was way too high and as a consequence many people developed toxicity from AZT unnecessarily. Today the dosage is much smaller, and still has the desired anti-HIV effect but with much less toxicity.
Would the dosage vary depending on the particular patient? And would patients with more advanced stages of HIV/AIDS need higher doses?
There are some examples of drugs whose recommended dose for a treatment experienced or advanced patient is higher than for a treatment –naïve patient or a patient whose disease is less advanced.
In planning strategies for treating HIV in the developing world, generally speaking we try to find the simplest strategy as it is most likely to be taken up by the greatest number of people in the greatest number of countries.
Therefore, personalised dosing may not work as well in resource-limited settings as it does in resource-rich settings such as the United States and Europe.
This highlights one of the complications of reducing the dosage of an approved drug. First of all it takes large clinical trials to show the reduced dose is just as effective as the approved dose; and secondly, you need to make sure that you have a dose that is going to cover all treated patients, including those who will take the drug after failing their first regimen as well as those taking that drug as part of their very first regimen.
How significant would using lower-dose prescriptions be on the expense of the therapy? And how many more people do you think this would mean could be treated?
We know that the majority of the cost of generic drugs, which are the forms of these drugs that are being used in these resource-limited settings, is in the active pharmaceutical ingredient.
So, if you could reduce the required daily dose of the active pharmaceutical ingredient by say 50%, you could reduce the cost of that tablet by almost 50%. This means that for the same cost per year you could treat twice as many people.
Even if you could lower the cost of the therapies, would there not still be a restriction on the number of people that could be treated, due to the limiting number of medical personnel?
We know that it is not just a drug problem, but also a delivery problem in resource-limited settings. I think these problems are in the process of being addressed.
Although this was not the topic of our research, I think they are making great strides in solving the problem of delivery by using non-physicians to identify people in need of HIV treatment and to get drugs to those people and monitor them.
For example, nurses, or even people that don’t have medical degrees are being considered for delivering drugs.
Are there any other ways you think manufacturers could lower the cost of existing drugs for HIV/AIDS?
One of the things being investigated is nano-formulation of existing drugs in a way that would allow them to be given very infrequently at lower dose.
Nano-formulation would involve chemical techniques for reducing the particle size of a drug in a way that allows the drug to be deposited into tissue and be released very slowly into the patient’s body.
This is a very exciting approach to drug delivery and one that is being evaluated for some anti-HIV drugs, but none of those are very far along clinically yet.
What type of tissues would these drugs be potentially placed into?
This depends on the formulation and on the drug. Some of those formulations are designed so that they are taken up by the lymph nodes for example and released slowly from the lymph nodes.
Some of the particles are designed to be taken up by muscle and released slowly from muscle. And some particles are even being designed for delivery to special organs like the brain.
What other plans do you have for further research into this field?
I think a big goal is to determine whether or not the existing approved drugs are going to be enough to manage the HIV epidemic worldwide or whether we need new drugs.
What we would like is a combination of three drugs, all of which:
- could be given once a day
- are highly effective
- are not susceptible to drug resistance
- would have little or no toxicity
Currently, we are not there yet.
There are some very encouraging new developments, including some very interesting new drugs in the pipeline, but we still have a lot of work to do to find a regimen that we are happy to give to the majority of patients around the world.
Despite this, although 5 years ago it seemed impossible for us to treat everyone on the planet infected with HIV with combination-anti-retroviral therapy; I think it is now a real possibility and is within our grasp.
We are thinking by 2015 or maybe a little beyond, most of the people who need HIV treatment and/or want access to it, will be able to get it.
Where can readers find more information on your work?
Our research paper can be found here: http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(12)70134-2/abstract
Much of this work is being driven by the Clinton Health Access Initiative: http://www.clintonfoundation.org/what-we-do/clinton-health-access-initiative/
It is also being driven by the World Health Organization’s HIV/AIDS programme: http://www.who.int/hiv/en/
About Charles Flexner
Charles W. Flexner, M.D., is Professor of Medicine in the Divisions of Clinical Pharmacology and Infectious Diseases, and Professor of Pharmacology and Molecular Sciences in the Johns Hopkins University School of Medicine. He is also Professor of International Health in the Johns Hopkins University Bloomberg School of Public Health.
Dr. Flexner is an expert on the basic and clinical pharmacology of drugs for HIV/AIDS and related infections, including viral hepatitis and tuberculosis. His scientific contributions include work on the important roles of pharmacokinetic enhancement, adherence, and dosing frequency in the long-term management of HIV/AIDS. He has published extensively on anti-infective drug transport and metabolism, and metabolic drug interactions.
Dr. Flexner is currently the Deputy Director of the Institute for Clinical and Translational Research at Johns Hopkins, where he serves as Program Director for Clinical Research Units. He also serves as Associate Vice-Chair for Academic Fellowship Programs in the Department of Medicine, and Associate Director of the Graduate Training Programs in Clinical Investigation of the Johns Hopkins University School of Medicine and Bloomberg School of Public Health.
Dr. Flexner is the Principal Investigator of the Johns Hopkins University AIDS Clinical Trials Unit (ACTU) supported by the NIH, and was Chair of the AIDS Clinical Trials Group (ACTG) Translational Research and Drug Development (TRADD) Committee from 2009-2011. Dr. Flexner served as President of the American Federation for Medical Research (AFMR) in 1999-2000, and was President of the AFMR Foundation from 2001-2002. He is a member of the editorial board of 10 scientific journals. He currently serves as a consultant to the Bill and Melinda Gates Foundation and the Clinton Health Access Initiative, and served as a consultant on FDA reform to the United States House of Representatives.