00:00
So let’s talk HIV agents now and
let’s focus on the entry inhibitors.
00:05
So you can see why me talking about the
molecules is important because we classify
our drugs based on the
molecules that they attached to.
00:14
So let’s talk first about
the Gp41 inhibitors.
00:17
Now the Gp41 inhibitors
are a very effective drugs.
00:21
The prototypical one in this
drug class is Enfuvirtide.
00:25
Now, the downside and I’ll say it
right up front incredibly expensive.
00:30
So very few of patients in the United
States can afford to get this medication.
00:35
Fortunately,
if you’re in Canada or in Europe
and you have a socialized
health care system,
you can actually get this
medication for your illness.
00:43
Now it is little used in the
United States due to its prize.
00:48
The other downside of this particular
medication is that it’s injectable.
00:52
However, this is a favorite
topic for exam questions
and I want you to know this
drug particularly well.
00:58
This is one of the reasons why I
put it at the top of your list.
01:02
The mechanism of action is that
it binds to the Gp41 molecule
and it interferes with the
ability to create an entry pore
for that virus or
for the capsid.
01:14
Now, I want to point out that this
is going to be an exam question.
01:19
It’s active against HIV-1 only.
01:23
Now one of the adverse events that
you have to be particularly aware of
are injection site reactions.
01:29
From a clinical point of view almost
all of these drugs that are injectable
have some kind of element of
injection site reactions to them.
01:37
Now, that’s not going to
be on the exam question,
what will be on
the exam questions
is cough, dyspnea,
and arthralgia.
01:43
So think about that triumvirate when
you’re talking about Enfuvirtide.
01:48
This is something that’s a
common, common question.
01:51
The next category of drugs
are the CCR5 inhibitors.
01:55
Remember what CCR5 is,
I just spoke about it in the last section.
02:01
CCR5 is a transmembrane receptor
that’s involved in the fusion
or binding of the HIV envelope
to the mammalian cell membrane.
02:12
Now these drugs like maraviroc,
vicriviroc, cenicriviroc, bind to CCR5,
it targets that
particular molecule.
02:22
Now if you have a cell that binds with
Gp120 and is unable to bind with CCR5,
you can’t get entry of
the virus into the cell.
02:32
Now one of these drugs,
Cenicriviroc also targets
another receptor complex
called the CCR2 complex.
02:41
That’s a little complicated but if you
just remember that C comes before M and V
so CCR2 comes before CCR5 alphabetically,
that’s how I remember which one does what.
02:54
Now, if the HIV particle
uses the CXCR4 receptor,
remember the CXCR4 receptor looks
just like the CCR5 receptor,
these agents don’t work.
03:05
So the CCR5 antagonists, like their
names, are only active against CCR5.
03:11
If a virus has CXCR4, this drug won’t
work so we have to do a Trofile assay
on particles on the patient’s blood to
see if these particular agents will work.
03:25
Now in terms of resistance,
the nice thing about these agents
is that there’s not really
a lot of cross-resistance
between these agents and others.
03:34
We will sometime see
resistance of the virus
through a mutation in the
env gene in the virus itself.
03:42
Now in terms of Maraviroc,
there are side effects.
03:45
It can cause some serious life-threatening
side effects which include hepatitis
and can include
allergic reactions.
03:53
Now I just want to give you a little
clue or a little help on your exams.
03:59
Generally speaking, almost all drugs can
cause a hepatitis or an allergic reaction.
04:06
So if you’re not sure how to
pick the answer in a question,
sometimes you can actually put these down
and play the odds and still get it right.
04:16
Let’s move on to
the Gp120 binders.
04:19
Remember that
Gp120 is a molecule
or a protein that’s on the
surface of the HIV particle.
04:26
Now, one of the most commonly known of these
drugs is fostemsavir. It targets a highly conserved
protein and the resistance it should be low.
Initial studies indicate that that is the case.
04:41
Now this is a prodrug of another drug that
is commonly being used in practice today. So
remember that this drug does have to be
converted from the original to the active
component. Finally, we have the CD4 binders.
This is the last category in our Entry Inhibitors
on my list, but I do want to point out that
as many molecules there are on the surface of
the HIV particle, there are probably going
to be drug categories coming up in the future.
05:09
So, even though this is being made in the early
21st century, this lecture, it still may be
relevant, you know, 50 years from now because
every single particle is probably going to
have a drug attached to it. So just keep
that in mind. Now moving back to the CD4
antagonists, this is an exciting area because
as I've told you probably 100 times in these
lectures, the new era of pharmacology is upon
us and it's not really pharmacology, it's
immunology. And we're using these monoclonal
antibodies to target very specific receptors
either on the HIV particle or on the million cell.
Now, this drug is called ibalizumab. Mab refers
to monoclonal antibody so you know that it's
a) going to be very expensive and b) probably
pretty effective. This was approved in 2019
for multidrug-resistant HIV. It is a monoclonal
antibody and it's a fully humanized monoclonal
antibody. How do you know that just by
looking at the drug name? If you look at the name,
it ends with umab. The mab stands for
monoclonal antibody. The u or said u stands
for fully humanized. So we know right away just
looking at this drug that it's a fully
humanized monoclonal antibody. This monoclonal antibody
binds to the CD4 receptor on the surface of
the CD4 cell. Now, there is a study that had
come out in 2019 which showed that at 48 weeks,
59% of patients achieved viral
suppression which was shocking. You know none
of us expected these kinds of numbers.
06:55
So it's a very exciting time to see that high
level of viral suppression in our patients. This
drug has to be administered by healthcare
professionals every 14 days. So in our HIV clinics
in Ottawa, we have patients getting it
through nurse-administered injections.