Toxicity vs. tolerance: how pharmacogenomic could help – Interview with Amalio Telenti

This is the crude statement that could summarize my talk with Amalio Telenti, professor of Medical Virology at University Hospital and University of Lausanne, in Switzerland. This year he had the opportunity to draw the state of the art of genomics research in HIV/AIDS during the CROI in Seattle and after during the ISHEID conference in Marseille, where he accepted to answer to my questions. Despite progress and relevant amount of publications the use of genomic tools to make easier decision and simplify the daily life of a person dealing with his/her own therapy, in your talk said that genetics is everywhere except in the clinic Yes, I think that was the common motive to my talk. It is to express how as much as it comes out of daily press and there is lots of hopes and there is a lot of interest also outside of the medical environment, surprisingly we are not seeing much of it coming to us, either because it’s not ready or because there is something wrong in the way we are bringing those tools into our help.

In the HIV field, you started working on genomics since 2005. I remember during the IAS conference in Rio you told me the future of this approach. Now, 7 years later, you have lot of new data you have presented in your talk, focusing on individual answer to every specific drug… I think we have to think that, as much as we are all different, we are also different in terms of how we metabolize drugs, how we develop toxicities and some of it is coded and it can be traced back with the new technology to particular genes. Some of the genes are very good at predicting, almost black and white: a particular problem like for example the famous abacavir hypersensitivity and a type of HLA.Some of the genes contribute a small information, but information could be useful.

For example your patient may develop diabetes, if you put him on this drug. It’s very hard to re-educate all the medical community on how to use a large number of new tools, new tests and which one is very good, which one is a bit informative. I think the challenge will be this new generation of physicians that will probably have to slowly integrate predictors in their clinics.

In your talk, you discussed the position of pharmaceutical companies and the perception of the medical doctors vs. the perception of patients.
I think there are important issues to be discussed in our community – doctors, healthcare workers, patients – in what is acceptable toxicity and this can be what the doctors look for. Big things: you don’t want to do harm to a patient, but then when we go away from the big things, we stop listening to the patient, we don’t want the patient to be whining because they don’t sleep well or because they get sad or because they say that their body is changing. Why? Because, of course, accepting those minor complaints will force us to consider new therapies, change therapies, so we just push it away. Now, when you observe the behavior of patients in retrospect, you will realize that if they are given the choice they will drop drugs not because of major toxicity, but just because it doesn’t feel well. In my opinion this is a field where pharmacogenetics could help. Companies don’t want to hear about it because they don’t want their drugs to be pushed aside just by what they call minor adverse events. Doctors don’t want to be busy changing drugs for what they also consider as a kind of minor problems of a therapy, that otherwise works wonderfully against the virus. So, the whole system is built to ignore that therapy may not be well tolerated and that there could be alternatives.

It’s interesting the concept “toxicity vs. tolerance” you have used in your talk…

I think I hope that we think about that: toxicity is what is in the doctor’s head, tolerance is what is in the patient’s head and these two worlds have to reconcile.

The Food and Drug Administration recommends some kind of genetic tests in order to start a therapy with some drugs, the NIAID has said that it could be useful if everybody enrolled in clinical trials will give informed consent about to storage their DNA. Why it’s so difficult to obtain this?
I think because there is still this deep-rooted feeling that genetics is a violation of our last level of privacy and therefore either ethics commissions, patients, countries will oppose what is required, that means a storage, long-term storage and large-scale screening, it makes no sense to ask permission to analyze one gene, it makes sense to ask permission to analyze a whole genome.
Therefore, somehow people say I am exposing myself excessively and this is a risk, or perceived risk, insurance, etcetera. The idea is to try to convince society that when you spend half a billion or one billion to put a drug in the market, the minimum that you can do is already from the beginning try to identify those people that may pay a heavy price from receiving that drug because they will die of a hypersensitivity reaction or a toxicity of the liver or they will accumulate a particular distressing syndrome or will not respond. Now, this is a change in mentality. A clinical trial should attempt to understand the origin and basis of failure or of toxicity from the start, not five years later. Academic groups like ours will try to catch up and try to figure out in retrospect why people were getting a particular problem. This has to be built into the system and, as I mentioned in my talk, there are excellent examples, like for example IL28b, the interferon lambda, and interferon response excellent exemple of successful use of clinical trial materials to find something that is very important for people: am I going to respond to interferon or not? Is it worth to start a costly treatment for something where I know already I will not respond?
It’s a way to maintain the promise of less drugs more efficient.

This is a war of the movements where the pharmaceutical companies have not decided: are we asking pharmaceutical companies to produce drugs for everybody?
Are we asking them to produce effective drugs for some people? Of course, these are two competing economic models and eventually somebody will have to figure out what makes sense in terms of society or economically. Is it cheaper to pay for toxicities or is it cheaper to pay for individualization?

Articolo presente in – HAART and correlated pathologies n. 15

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