APPLICATIONS OF RALTEGRAVIR
We are getting our first in-depth look at some of the
research behind raltegravir, a powerful therapy for multidrug-resistant HIV
infection already approved by the FDA. How is this raltegravir data impacting
current clinical strategies for attacking the virus in multidrug-resistant
patients. You are listening to ReachMD XM-157, The Channel for Medical
Professionals. Welcome to the Clinician's Round Table. I am your host, Dr.
Mark Nolan Hill, Professor of Surgery and practicing general surgeon and our
guest is Dr. Roy Steigbigel, Professor of Medicine and Pathology, Molecular
Genetics, Microbiology, and Pharmacologic Sciences and the founding director of
the comprehensive AIDS Center at the State University of New York at Stony
Brook. Dr. Steigbigel is the lead author of research on raltegravir published
in the New England Journal of Medicine.
Welcome Dr. Steigbigel.
Well thank you.
We are discussing this clinical applications of
raltegravir. Doctor for full disclosure you have served as an investigator for
Tell us a little bit about your background. How did you get
involved with this research, with this drug in particular?
Well I have been involved in HIV research before HIV was
discovered to be the cause of AIDS back in the early 80s when I was at the
University of Rochester, so I have been involved in numerous studies fairly
basic level and also at the clinical investigation level for new therapies and
this is a compound that I have been involved with since it was first used in
clinical trials, in fact, our center put the first patient in the world on this
And how specifically did you think to use this medication an
Well the advantage of this medication is as you state, it
inhibits the integration step in the virus' replication cycle and we have not
ever had a drug for that step in replication. That's an important point
because the incidence of resistant to HIV in individuals who have been on
therapy for years continues to increase. People do develop a resistant virus,
especially if they are not taking their medications regularly. Additionally
people who are newly acquiring virus, that is people who have never had therapy
before are acquiring virus from other people that is resistant to current
medications. So getting medications in a new class that is in a new step in
replication is really quite a breakthrough and this drug raltegravir does
represent that particular point.
In a very simplistic fashion and not thinking about the
resistant patients, is this a better way to approach HIV as opposed to the
standard antiretroviral treatment?
Well it is not necessarily better. It is not necessarily
better, it is better for those people who have resistant virus because the
chance of ever having virus resistant to it is very close to zero as there has
been no integrase inhibitor out there ever. So viruses have not developed
capacity to be resistant to raltegravir to this point. Of course, that does
not mean that viruses will not become resistant to it and in fact, in the
studies, a small number of people have already developed resistance to
Now you have studied for 48 weeks, I believe, the 2 clinical
markers of HIV infection, correct?
And not the clinical efficacy.
That's right, the studies that were published in New England
Journal of Medicine were not designed to look at clinical efficacy as the
length of time, i.e. 48 weeks, would not likely be able to detect any clinical
efficacy, so the design of the study, the proscribed design was to look at 2
aspects of HIV therapy which are clearly and unequivocally predictive of
clinical outcome, i.e. the drop in the viral load, the amount of virus people
have in their body and the increase in the CD4 cells, the cells that are
normally damaged and eliminated and become dysfunctional because of HIV. So in
the field of HIV research for new therapies, these 2 so-called surrogate
markers are accepted as predictive efficacy by the research community and more
importantly perhaps by the FDA.
To continue on this point, I am sure a lot of listeners are
thinking, the FDA certainly is a very particular organization and how a drug
can be approved without clinical studies is surprising, but I suppose it has to
do with what you just said, right?
Yes, it is because of study after study after study and just
basic information and knowledge about HIV indicates that the primary utility of
a drug will depend on its ability to stop the virus from replicating.
Unfortunately, none of the drugs we have cure. None eliminate virus, but they
bring the viral load down to very low levels, levels that are often referred to
How do you think this is affecting clinical practice at this
Well I think this is a breakthrough, in that for people with
highly resistant virus which was what this study was looking at, it offers an
opportunity for people who had very few options who are really going to have
major problems in the future, this offers a real turn for them to have periods
of time, how long we don’t know, but periods of time where their HIV can be
well controlled. Many people think it is analogous to what happened around 95
when we had the new class of drugs, i.e. the protease inhibitors.
If you have just joined us, you are listening to The
Clinician's Round Table on ReachMD XM-157. I am your host, Dr. Mark Nolan Hill
and our guest is Dr. Roy Steigbigel, Professor of Medicine and Pathology,
Molecular Genetics, Microbiology, and Pharmacologic Sciences and the Founding
Director of the Comprehensive AIDS Center at the State University of New York
at Stony Brook.
We are discussing the clinical applications of raltegravir.
Doctor, are we seeing a significant group of patients that develop resistance
directly to raltegravir?
There was a small group of people who on the raltegravir,
the study began just, was looking at people who received raltegravir plus
optimized treatment background versus placebo plus optimized treatment
background and in some there were a small number of people in the raltegravir
group who did develop resistant virus. They were people who had very few other
active drugs, so that as a single agent raltegravir and as any other single
agent will not be working very well. It needs to be taken in combination with
some other medications that have effect on the virus.
Now when we speak about only 1 genetic mutation is needed to
develop the resistance, what does that exactly mean?
Well, with raltegravir actually, its one major one plus
minor ones. So it is more than 1, what that means is in the enzyme which is
blocked by raltegravir, in this case integrase, the change in amino acids in
that enzyme can lead to the inability of the drug to block the integrase
function. For some medications, there is a requirement of virus to have
multiple amino acid changes and for others fewer. So raltegravir it seems at
this point a single mutation, a major mutation plus some other mutations along
with it can lead to resistance.
Is this problem of continuing resistance, is this going to affect
raltegravir and just continue on and also require more medications, different
medications in the future?
Most likely, while this is a breakthrough, it is not a
panacea for the resistance problem with HIV and that is why continuing look for
additional medications that act at other steps of viral replication inhibition
are needed. In fact, there are another class of drugs also recently approved
which operate in another step in the virus' replication cycle and they block
what is called CCR5 which is one of the places that the virus heads to latch on
to the host cell. So we do have these 2 truly new medications that have come
out in the last 6 to 8 months which represents really a breakthrough.
A general question, is there any way to combat the problem
Well the most important thing clinically is for us to
encourage our patients to take their medications very regularly, unlikely other
medications for infectious diseases, a skipped dose can lead to resistance
Why is that?
Probably because the virus has the great ability to mutate
and additionally because we haven’t cured the infection, the virus levels can
come up quite quickly and then resistance will occur. So HIV is a difficult
virus for many, many reasons, but among those reasons is the necessity for
keeping the viral load very, very, very low in which case the chance for
resistance is diminished, but never totally eliminated.
You have mentioned several times about being able to cure
the disease with this treatment. Will we be able to cure the disease at all in
Currently there is no way that we understand that this can
be cured, because in addition to the replicating virus, at a high level there
is virus replicating at a very low level or not replicating at all in resting
cells and none of the medications can get at that group of viruses or cells
currently. There have been methods that have been attempted to rid the body of
all virus, but so far they have all failed. So in the near future and may be
unfortunate longer term future, cure of HIV is not on the horizon.
Are there any patients who must stay away from raltegravir?
Well currently there is no identification of people who have
had any side effects or allergic reactions, but whether that will occur when it
gets to use in thousands of patients is unknown, but so far that has not been
Do you think that we eventually will see this as a first
line HIV therapy in nonresistant patients?
That's definitely something that is going to be looked at.
In fact, there are ongoing studies comparing it to other so-called first line
therapies to see if it as good or better than other first line therapies. So
those studies are ongoing.
Finally doctor, if you could look into your crystal ball, 5
to 10 to 15 years down the way, tell us what you see in terms of therapy for
Well I think what we have seen is a continuum of more
medications and better medications and simplified regimens. So while I have
been in this field since the early 80s, people were taking 15 to 20 to 25
medicine pills a day. We now have some regimens where people are taking 1 pill
a day which is combination therapy of several medicines. So I think we
continue to simplify and fortunately developing new medications for people who
have resistant virus. Hopefully that will continue, but at the same time, it
is likely that the virus will also continue to find ways to become resistant,
so we have to develop new medicines and of course the most important thing we
would all like to see is prevention with either vaccine which does not seem to
be in the near horizon, but also remembering that we do know how this virus is
transmitted and so methods to educate the human race about preventing
transmission is also very important.
I want to thank our guests Dr. Roy Steigbigel. We have
been discussing the clinical applications of raltegravir. I am Dr. Mark Nolan
Hill and you have been listening to The Clinician's Round Table on ReachMD
XM-157, the Channel for Medical Professionals. Be sure to visit our website at
www.reachmd.com featuring on-demand pod casts of our entire library. For
comments and questions, please call us toll-free at 888-MD-XM157 and thank you
This is Dr. Aron Karol, Director of the Center of Health
Policy and Professionalism Research in Indianapolis, Indiana and you are listening
to ReachMD XM-157, The Channel for Medical Professionals.