HIV pharmacology: How to get data quickly to decide – Interview with David Back

“I think the issue that we always want to address is risk benefit of any therapy, be it a single drug or a regimen, and a major principle is that you want the benefit to clearly outweigh the risk- states David Back, Professor of Pharmacology, Department of Molecular & Clinical Pharmacology at the University of Liverpool, starting our conversation about new possible paradigms in HIV therapy. Every time we have new drugs in the market we start to think how to change or innovate: we have to save the way towards innovation as well as the way towards standard therapy. In any case tolerability remains the main issue… We know that there are adverse effects, we have seen adverse effects, if we go back through the development, for example, of the nucleoside analogues, the D drugs were always drugs that concerned us about mitochondrial toxicity, which then linked through to lipodystrophy, so we have got better, I think at understanding some of the key areas. We then had abacavir hypersensitivity of course with the nuke, and we understood the basis of abacavir hypersensitivity brought in the HLAB* 5701 testing. When you look at the other classes of drugs, I think now we are more concerned about long-term toxicity, so that we think of tenofovir and what are the implications of small changes which are seen in renal function and the odd case report of Fanconi syndrome… We are concerned long term and we have new drugs, so that the tenofovir GS-7340, which is the new form of tenofovir, if you like, which is a pro-drug looks an exciting drug but we have a lot to learn. I think we have learned but we are learning and we need to continue to learn.
In these periods there is lot of noise about dual therapy and monotherapy…
Yes. So, the basic principle has always been that you have to have enough drugs in the regimen to suppress the virus and we learned very early on that combination therapy clearly was the way forward. What I think has now gradually emerged is that, once you suppress the virus, the question then is can you maintain the suppression of the viral load by reducing the number of drugs in their regimen, if you really need to have three drugs, what about two drugs and even then… Of course, we have monotherapy studies with one drug.
It’s an area that has caused a degree of polarization of views, not everyone has agreed that this is the way that we need to proceed, but we clearly have data which suggests that there are certain areas that we can use, maybe reduced numbers of drugs.

What kind of parameters we have to consider in order to make therapy easier and simply?

As far as dose simplification is concerned, one is looking all the time to make a regimen as simple as possible for the patient so that patient will be adherent to the therapy, that’s a key, adherence to therapy, and to maintain a reduced impact of any adverse effects. So, simplification of therapy, which is why with Atripla, for example, one pill once a day, with the new Quad which will emerge is one pill once a day, and fixed-dose combinations being the simplest type of regimen. In a sense, if you got a fixed dose at one pill once a day, you could argue it doesn’t matter whether there are three drugs in that one pill or whether there is only one drug in that one pill because you got a simpler regimen which is much easier for the patient to take, as long as you haven’t got adverse effects and intolerability issues. We know that tolerability issues have revolved to a large extent around certain drugs: ritonavir has always been a tolerability question mark in people’s minds because of the diarrhea, the gastrointestinal effects, etcetera. Will cobicistat, the new booster, be any better? I think time will tell, there is always an excitement around a new drug but then there is always the realization that at this moment in time there is no perfect drug: every drug has got its benefits and we have to work out what the issues are around some of the side effects.

In planning a chronic therapy, in oncology it’s used a concept of induction and maintenance, do you think that also in the HIV field we should use a similar approach?

Logically, that should work in my view. If you can induce and make sure the patient’s virus is suppressed, can you then suppress it with less drug or less numbers of drugs.
Clearly the clinical data will always be the key that we rely on, it’s not just a theory, it’s got to be shown in practice in long-term, three-year, five-year trials. You can really suppress the viral load with, if you are going to reduce the number of drugs in that regimen you really got to make sure that is true, but there are data to suggest that we can do that under certain circumstances, but it’s not, you have to define which patients will benefit by that strategy.

The simplification approach is a good tool in order to deal with the aging process caused by HV and occurring as overall effect in HIV/AIDS people that – because of HAART- are living longer…

Aging is a real challenge as well because there are so many changes taking place with aging. There are changes in the way that the body handles the drugs, the body responds to the drugs, the implication of maybe increased adverse reactions to the drugs, there are all the co-morbidities that are been treated as well, so one has to think as patients get older of strategies to maintain the optimum management.
From my clinical pharmacological background, it is always optimize the management of the patient who is in front of you: it is not just looking at patients as a group, it’s always to say can we do better for an individual patient and I think that is the way that we have to look.

In this context, also polypharmacy is a key issue.

Sure, polypharmacy is a key issue. We did a survey recently with a Swiss cohort of over 50s and under 50s in terms of the number of co-medications and, unsurprisingly, if you are over 50 you are on more other medications for co-morbidities, particularly around cardiovascular disease, so in terms of high blood pressure treatment, in terms of lipid lowering agents, there were clear differences between the under 50s and the over 50s. In that context, you have to think about the co-morbidities being treated and what drugs can you use, what drugs would be unadvisable to use because of drug-drug interactions, which is still an area that we have to manage well and manage better with all drug interactions: indeed, aging is an issue.

Last question is related to CNS. We don’t have so many drugs that are able to reach the HIV everywhere where is replicating.

No, that is true. It’s clear, the data that we have comes from CSF, so that we look at penetration into the CSF and then the debate is “is a drug in the CSF necessarily the same as a drug actually in brain tissue” and all the different considerations that we need to think about because we know that some drugs can penetrate into the CSF, other drugs don’t seem to penetrate so well into the CSF. But we have to then think about all the drugs in a regimen: do you need all three drugs or maybe you can have less in terms of the regimen as long as you have got really effective drugs, because you got low viral replication.
Again: I think there is a lot we don’t know and we sometimes tend to extrapolate beyond what we do know. The challenge is going to be, particularly with the new drugs coming through, of getting the data quickly, which will enable us to understand better and CNS penetration is one major issue. I think that is an issue which for CNS penetration is: is that one drug going to penetrate into the CNS, and it’s not just the CNS, it is to all sites where there potentially is virus. For example, there is a recent study looking at GALT biopsies, where apparently atazanavir didn’t seem to penetrate into the GALT tissue. So, there is ongoing studies where I think, as long as we can look at the virology and the pharmacology together, we will get a greater understanding of tissue penetration and tissue localization of drugs.

Articolo presente in – HAART and correlated pathologies n. 15

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