November 22, 2022 • 47 mins
Dr. Rupeena Purewal invites special guest Dr. Jason Brophy, Infectious Diseases Pediatrician at the Children's Hospital of Eastern Ontario, to review Dolutegravir, an antiretroviral agent for the treatment of HIV.
Canadian Dolutegravir Product Monograph: tivicay.pdf (viivexchange.com)
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Episode Transcript
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(00:00):
Thanks for joining us again at the Canadian Breakpoint, a Canadian infectious diseases
(00:12):
podcast by Canadian infectious diseases physicians.
I'm Summer Stewart, here with Dr. Rupeena Purewal, pediatric infectious diseases specialist
from Saskatoon.
In this episode, we welcome infectious diseases pediatrician Dr. Jason Brophy to review Dolutegra
Vir Disperseable Tab.
Dr. Purewal.
(00:32):
All right, welcome to another episode of our podcast the Canadian Breakpoint.
Today, we have a very special guest with us, Dr. Brophy, who is a pediatric infectious
disease specialist and researcher at the Children's Hospital of Eastern Ontario, and an associate
professor of pediatrics at the University of Ottawa.
His research interests are in pediatric and perinatal HIV and other congenital infections.
(00:58):
He is the current chair of the Canadian Pediatric and Perinatal HIV and AIDS Research Group,
CPARCH, and co-lead of the Clinical Care and Management Research Corps of the Canadian
HIV Trials Network.
He works part-time as a pediatric HIV clinical advisor with the Clinton Health Access Initiative,
(01:21):
supporting the uptake of optimal pediatric HIV care in West Central Africa and Southeast
Asia.
So welcome, Dr. Brophy.
Thanks.
Great to be here.
Perfect.
So today, we have a very exciting episode because we're talking about Dolutegra Vir.
And so for some of our listeners who manage adult HIV, they're probably quite familiar
(01:44):
with Dolutegra Vir and its mechanism of action, uses, and indications.
But we're very fortunate that there's been new formulary in pediatrics, so the disperseable
tabs that are now available.
And you have some clinical experience and research experience with Dolutegra Vir.
(02:06):
So it's really a pleasure to have you here today.
Yeah, no, I agree.
It's nice to have some new drugs for kids because for a long time, we've been without
the poor cousin to the adult HIV crowd.
So it's nice to have new modern drugs to offer our kids here in Canada.
(02:28):
Yeah, no, very fair.
Yeah.
So I think in terms of what I would like to start with today is for a lot of our listeners.
So we have listeners across the globe, definitely, you know, first, like family physicians, we
have pediatric physicians, we have infectious disease physicians across the globe.
(02:50):
And so it would be nice to kind of maybe not everybody is aware of Dolutegra Vir.
So can we just kind of introduce maybe what Dolutegra Vir is and its common uses and mechanism
of action?
Sure, happy to do that.
Thanks.
So Dolutegra Vir is in the integrase strand inhibitor family or INSTEE family.
(03:11):
And its mechanism of action is that it prevents the HIV enzyme integrase from integrating
the viral DNA into the host CD4 cell DNA.
And so it's one of the newer families of drugs.
So back in the old, old days, we had the NRTIs first, like AZT, 3TC.
(03:37):
And we had NRTIs like nevirapine and afavron.
And then the protease inhibitors came out and they really were kind of the linchpin
that helped move us ahead.
And in 1996, we learned that using them in combination, like two NRTIs plus one NRTI
(03:59):
or PEI protease inhibitor, that was what we called highly active antiretroviral therapy
or HEART.
And so for years, we were working with those three families.
And now we're up to five families that are commercially available.
And there's other ones that are coming out, which is really nice.
(04:19):
But the integrase inhibitors or INSTEE family really have kind of taken over in terms of
being the main ones that we're using nowadays as their anchor drugs.
So two NRTI drugs plus one third drug.
And the third drug is increasingly becoming something from the INSTEE family.
(04:39):
And so dolutegra Vir is one of those.
There are five that we have available for use in Canada right now.
Rauhtegra Vir, Elvitegra Vir, Bictegra Vir, Cabotegra Vir, and dolutegra Vir.
And then we have three of those that have pediatric formulations available.
(05:02):
And so the kind of advantages of these drugs are that they tend to be really well tolerated
and that they don't have the same nasty side effects that some of the earlier ones had.
Like, Favrons caused a lot of neuropsychiatric stuff, like nightmares or made people really
(05:22):
groggy or sleepy or dizzy.
And then the protease inhibitors, the older ones at least, that we had in the liquid ones
that we used for kids, caused a lot of GI upset, diarrhea, vomiting, nausea, especially
for the little babies, like the main one that we always use, dolpenevir, ritonavir.
(05:44):
We did taste tests of it when I was a trainee many years ago.
And I'll never forget that day.
It was like taking a shot of kerosene and it really just stuck with you the whole day.
But like really bad reflux and burning.
And so every time I heard a mom come in saying how hard it was to give this medicine, I was
(06:05):
like, yeah, I know why.
Right.
So yeah, we're all hoping for newer, better drugs.
And so this family has kind of allowed that to happen, which is great.
That's awesome.
Yeah.
So definitely, as you talked about, I mean, there's not too many options in pediatrics.
So for dolpenevir specifically, when we talk about pediatric meds in general, we always
(06:30):
have weight cutoffs or age cutoffs that we can use them.
So for this new formulation of dolutegravir, how young can we be giving that or adding
it to the regimen?
Yeah, there have been a few really, really good studies that have helped inform how we
use dolutegravir.
(06:50):
So they add out tablet, which is actually pretty tiny.
It's about the size of an ibuprofen tablet, the 50 milligram one.
We know from the Odyssey trial that we can actually use that down to 20 kilos of weight,
regardless of the age.
And then with the pediatric dispersable tablet, which is strawberry flavored and you drop
(07:13):
it in water and it dissolves pretty quickly, and then the kid can just drink it.
That one is approved for age one month and up and three kilos and up.
And so that makes pretty much all the kids that we would want to be treating eligible
for it.
There's actually neonatal studies that are planned or starting up now.
(07:36):
And so hopefully we'll even be able to be using it in younger age groups.
But the metabolism is tricky in the first month, especially the first week.
And so they tend to clear things more slowly.
And so we'll learn more about that as the studies progress.
But yeah, the dispersable tablet's making her lives a lot easier here.
(08:00):
Unfortunately, the NRTIs still don't come in similar dispersable formulations in North
America.
But it's interesting, like in my global work with the chai, the chai kind of made its name
(08:21):
in the HIV game by working with generic companies to produce generic versions of the drugs that
we have in the West.
And they actually have had dispersable formulations of the NRTIs, like abacagran, limididine together,
or sadavidine, limididine together.
(08:42):
And then the other tablet, the other ones like the NRTIs, they've had them for years.
And so the pediatric dialyutegibir came out a couple of years ago as a generic product
just after it was released here in North America.
And so when I go and do my teaching in these other countries, I tell them, you're actually
(09:04):
luckier than me in that I don't have access to all of these same formulations of dispersable
tablets, which makes them feel a bit better that they have some advantages over us here.
Right.
Yeah.
No, I mean, it makes a huge difference.
And so I guess clinically, in my practice, there's definitely been indications.
(09:29):
For instance, you mentioned with some of the other medications that we commonly use, they
don't taste very good.
So the compliance gets poor and poor, especially as children are getting older and they're
actually involved in the process of taking their meds.
And they now are starting to decline them because of taste or a lot of reflux.
And so I think having a medication like dialyutegibir where it's disperable, and ideally only in
(09:54):
very small amount of MLs of fluid, like clear fluid that you can disperse it in.
And so it's not a huge volume that they're taking.
Yeah.
So that's probably where I've used it clinically.
So are there other indications?
Is it something like you would...
Are the studies showing that it's something that we would be starting off as a primary
(10:17):
regimen as opposed to like second line?
Kind of what I was saying.
Yeah.
So the WHO actually recommended it as their first line preferred therapy, even before
there was a pediatric formulation available, just because there was a big move globally
(10:38):
to kind of embrace integrase inhibitors.
The only one that was really coming to market was dialyutegibir.
So even before the pediatric formulation was available, it was already recommended.
But in North America, we've had like raltegibir in pediatric formulations for a while.
And then the other ones like alvitegibir, which is in a fixed dose combination tablet
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called Genfoya, and triimek, which is the dialyutegibir, back of your lamedidine, comes
in a fixed dose combination.
So those were approved for kids 25 kilos and older.
But these new dispersable ones for the younger kids are the ones that are newer.
But they've really, as soon as the formulations were available and the studies showing that
(11:30):
they were effective either as new therapy or switch therapy, then they became the first
line regimens of choice.
So yeah, this is what we should be starting people on.
I guess the other benefit that is worth mentioning is dialyutegibir is once a day, whereas raltegibir,
(11:52):
which we've had for a while, is twice a day, has a lower barrier to resistance.
So if kids are missing any or their drug levels are low for missing doses or vomiting doses,
then there's a higher chance of getting resistance because there's a lower genetic barrier.
It's a developing resistance with the first generation integrates inhibitor raltegibir.
(12:16):
So dialyutegibir is well tolerated, easy to take once a day.
And we know it's really potent that this family suppresses HIV usually within a month in adults.
Kids often start with a higher viral load than adults, especially in the younger kids.
(12:37):
And so it can take a bit longer than that.
But generally it works pretty fast.
So yeah, there's not a lot of downsides except for occasional drug interactions to think
about.
Right.
Yeah.
So one of those would be like probably a contraindication.
So as you mentioned, there aren't any drawbacks.
Are there any main contraindications that where, you know, sometimes we worry about,
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is there any maybe like renal issues or liver issues if a child is having those and has
obviously like comorbidity?
Is there a strong contraindication to when not to use dialyutegibir?
So that it is contraindicated in kids or adults with severe renal impairment or severe liver
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impairment.
But mild to moderate, it's okay to use for both.
And then in terms of drug-drug interactions, we know it's metabolized mostly by the cytochrome
P450-3a as well as the UGT1A1.
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And so those are the ones that kind of get induced by things like rifampin and some of
the anti-epileptic drugs like phenyton or phenobarb.
So because rifampin is such a big drug to treat TB globally, there's been a fair amount
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of work looking at how we can overcome that interaction.
So we know if you double the dose of dialyutegibir, like give it twice a day instead of once a
day, then that should overcome that drug-drug interaction.
But for other ones like phenyton or phenobarb, those are too potent in terms of inducing.
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So it's recommended not to use those with dialyutegibir.
But there are other anti-epileptic choices.
And so that would be an option to move them to a different anti-epileptic if you wanted
to use the NHGRACE inhibitor or vice versa if you wanted to use those anti-epileptics
and pick a different antiretroviral.
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Yeah, that's fair.
Thank you.
Yeah.
I think these are important things because we, you know, if we're commonly seeing patients,
especially the, you know, some of the younger patients and then over time, if they're, let's
say on a regimen and then they're developing other conditions, then we should be probably
well aware of those.
So if I have a patient on dialyutegibir, I mean, a lot of the NHGRACE inhibitor is not
(15:13):
too much monitoring they have to do regularly.
Whereas like some of our other drugs, there's like neutropenia risks.
They definitely have a lot of bone marrow suppression.
Are there any routine labs that a child, like, I mean, outside of our normal every three
months that we would be following them?
Is there anything specific to dialyutegibir that we would need to be monitoring?
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So the NHGRACE inhibitors generally can cause myositis.
So we're recommended to monitor CK.
And then they can really cause some like biochemical hepatitis.
And so monitoring of the enzymes as well.
In my experience, I really haven't seen either of those things.
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The other main side effects that they talk about with intergastin inhibitors generally
and dialyutegibir in particular are included, I should say, is insomnia, which I'd say
the very first patient ever treated with dialyutegibir had wicked insomnia.
He came back and was saying he was like not able to sleep at night and he was falling
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asleep on the bus on the way home from school.
Oh no.
Poor guy.
But he really didn't like his twice a day regimen before that.
And so I said, well, it's supposed to resolve within a month or two.
So if you want to stick it out.
And so he stuck it out and it completely resolved within two months.
And so that was a really good learning point for me to just see that, oh yeah, these like
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uncommon side effects reported in trials can actually happen in people.
Funnily enough, he's like the only patient I've ever had get that side effect.
First one.
So I usually I usually warn people that it definitely can happen.
But if you stick it out, it should go away.
Like most side effects with antiretrovirals.
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Then GI stuff can happen.
Headache can happen.
They say that if your drug levels are really high, that it can cause neuropsychiatric side
effects, like if you had depression, it can worsen it or stuff like that.
But again, my experience has been with pediatrics.
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All the side effects that you see in adults are much less common in children.
That is true.
I usually say I think kids are just tougher than adults or maybe we as adults tend to
complain a bit more.
But that's fair.
But yeah, I usually find that it's a really well tolerated drug.
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Yeah, no, that's great.
So in terms of, I guess if we're starting to use it more in our clinical practice, what
are some of the costs or the cost to the patient in terms of the health care system, just kind
of looking at from a health care standpoint to is this something that's more affordable
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than other drugs and is the access quite easy?
So if a physician would want to start it, how do they go about ordering that in Canada
or the US?
Yeah, so Canada, our health system needs to be a bit better unified.
It's like we have 13 different countries and 13 different systems for how we do health
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care and fund it and provide it.
But generally in most provinces, ARVs are covered by provincial programs.
And then the main people I find who have difficulty with paying for ARVs are the ones who have
partial insurance.
So it's kind of like the folks in the lower middle class who have jobs and have private
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insurance, but it's not 100%.
And so all the ARVs are still pretty expensive, like running in between like $1,500, $2,000
a month.
So if you only have 80% coverage, like 20% of that is still a fair amount of money.
So the nice thing is that most of the big antiretroviral manufacturers do have support
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programs.
And so if people are, say, new to Canada and don't have their health care, like their OHIP
or the provincial coverage set up, or don't have their private insurance or their other
forms of insurance set up, then they'll usually pay for the medications for up to six months.
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And then Veev that makes pediatric dolly type of care has a program that will provide partial
coverage as well if people have coverage, but not 100% coverage through their insurance.
So I always tell people that no kid and really no adult in Canada should go without ARVs.
We have lots of options and we have good support programs in place.
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That's ideal.
In the global setting though, it's very interesting to work on both sides of the globe with HIV,
because we know that, like I said, most ARV combinations for adults cost somewhere between
$1,500 to $2,000 a month.
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So it's $24,000 a year about.
And the same medications for the most part, when they're produced generically, are significantly
cheaper.
And so the adult treatment of choice like TLD, it's not very limiting, which comes as
a single pill.
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The price for that has been brought down to about $50 to $60 per patient per year.
So pretty significant reduction, right?
And then for kids, the pediatric value tag of your tablet is a fraction of the cost of
the previous recommended regimen, which is lopinavir, ritonavir tablets.
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Those costs, I believe somewhere around 200 to 300 per patient per year.
Because on the kid, how many tablets are taking, the pediatric value tag of your is a fraction
of that.
So really part of why the WHO moved to recommend it was not only the fact that there's increasing
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NNRTI resistance to favorens and the barium pain, because it's pretty low bariatric resistance.
You only need one mutation to become resistant to those.
Whereas with value tag of your, it's a lot higher barrier to resistance.
So they're wanting to move away from NNRTI-based first line treatment, especially in countries
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that have had reached like the 10% resistance kind of threshold at baseline to NNRTI.
And so there was that, there was the cost part coming down, there was the side effects
profile.
We knew the people on a favorens, which is the main drug used before, at a higher rate
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of neuropsychiatric side effects, depression, higher risk of suicide, higher risk of people
going off medications over time.
And so really the kind of coalesced around getting behind this new drug and regimen.
And so that extended down to kids too, which is great.
Especially they're stuck on the old Kalitra or Lopinavir, which we can't complain, right?
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It's a good antiretroviral, it treats the HIV well, and it saved a lot of people's lives.
And we can't be too down on these old drugs.
They got us to where we are today and saved a lot of our patients' lives.
Long-term usage and having people be able to stay on them in the long-term, it's better
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to have drugs that are better tolerated.
Yeah, definitely.
Yeah.
And it's nice because most of these kids then can remain on that once they get into their
tablet forms and it's a really easy switch over.
It's a whole new drug for them, which is really nice because I think, especially us who are
managing pediatric patients and they grow with you, you're definitely transitioning
(23:37):
them to that adult care even or even the adolescent age group, you always want to make it as streamlined
as possible.
So if it's something that's familiar to them already, then they may feel better.
Whereas coming off of some of the older drugs and switching to a drug that they've never
heard of, they sometimes are a little bit nervous too.
So I've definitely seen that.
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Yeah.
And then the great thing that is happening is that these companies are really getting
on board with being more sensitive to kids' needs.
And so we have the disperseable Diuretegavir single tablet, but now they've come out with
a three-in-one.
I call it baby Triomec, which is like a baccalaurelamidine and Diuretegavir all in one disperseable tablet,
(24:26):
which can be used down to younger kids.
And that generic version is also coming out in our plan to be coming out for low middle
income countries.
So that's my next job to get countries to move over to that, which will make life even
easier instead of like two separate medications that need to be dispensed down to just one
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single tablet regimen or single disperseable tablet regimen, which we'll have here in North
America as well as in low middle income countries for the majority of kids with HIV or living.
Yeah.
That'll be really fantastic.
I mean, one of the most difficult parts about treating HIV is make insuring compliance,
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right?
Because if they're not on their meds, then those are when the complications start and
then their viral load is not suppressed.
And so I think that's probably one of the...
So if we can make the patient's life easier by not having to take so many meds, I think
we can probably achieve undetectable viral loads too.
(25:31):
So yeah, so that'll be...
That's great.
Nice to hear.
So when we first got in touch about Diuretegavir and we were talking about you coming on the
podcast, you mentioned your awesome work with the Clinton Health Initiative.
So I guess I wanted to touch base with you about some of the work that you're doing out
there.
(25:52):
And if you wanted to highlight for some of...
I know some of the audience members who are interested in global health for sure would
find this a very, very intriguing conversation for sure.
Yeah.
So when I was back in my training days, I was like, when I grow up, I wanted to do global
health and do global HIV work.
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And it was a bit of a rough slog to figure out how to do that.
But I'm very lucky that I get to mix my job here in Canada, looking after kids at an academic
pediatric hospital, and then also work part time abroad.
And so with CHI, Clinton Health Access Initiative, it used to be the Clinton Foundation, but
(26:35):
then they started doing a lot of different things, including environmental work and political
advocacy.
So they carved up all the health stuff and put it into this CHI, or Clinton Health Access
Initiative.
And so they made their name on HIV and getting generic products for HIV care and treatment.
(27:00):
But now they do a lot of other stuff, TB, cryptococcal meningitis, hepatitis C, maternal
newborn child health, lots of other stuff, COVID now.
And so who's not doing COVID?
But my stuff is still predominantly focused on HIV and then advanced HIV disease like
(27:25):
TB and other opportunistic infections.
So what I do is we have products like this that we're trying to get countries to take
up to modernize their approaches.
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And so we work directly with ministries of health across Sub-Saharan Africa and Southeast
Asia and Southern Asia, India, parts of the Caribbean and South America as well.
So my work is working directly with ministries of health, kind of going through with them
what are the WHO guidance recommendations, how can they make changes to their guidance
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in accordance with WHO, if it fits, right?
Like it really needs to be tailored to their needs and what they're ready to do.
And then making, ordering these products more available, negotiating pricing agreements
to get the best use for money possible.
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So it's been great that people think I go and work in hospitals abroad, but I don't
really do that.
I go and do workshops with clinicians, talk just about all the stuff I've talked about
with you, but kind of translate it into what is important for them and tell them how to
use these drugs and how you would monitor them.
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We make a knowledge translation and educational materials both for the clinicians as well
as the patients and their families.
And so really try to make life easier for them to be able to do their job well.
So it's a lot of fun.
I get to see a lot of the world and know that even this pediatric value tag of your product
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only came out.
The first countries had access to it back in the second half of last year.
And now the majority of countries with high HIV burden have transitioned or are in the
process of transitioning their patients over to pediatric value tag of your, and some countries
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are up to like over 90% of kids on this product within a year of it coming out.
So it's really, really nice.
Yeah, it's great.
It's probably nice to see that comparison and between different countries, and then
you can kind of bring that experience even back to North America, but not only that,
but to like their neighboring countries too.
(30:05):
Because I think one thing with using newer drugs and newer medications is just people
want experience.
And it's nice to have, oh yes, like this was used in this case and we saw really good,
we achieved really good undetectable viral loads, that type of thing, or this is an indication.
And so I think just kind of having that comfort in a way that it's used and is frequently
(30:32):
used kind of helps in the HIV world.
So would you say like that's kind of what your experience has been?
For sure, for sure.
When I go to countries and have workshops with clinicians, they usually bring like one
or two hard cases and want to get our advice.
And being able to say you've used this product and this is your experience with it, and you
(30:58):
had cases with wrinkles, X, Y, Z, they really appreciate hearing those experiences and knowing
that they're not alone and knowing that they have access to what are really considered
the treatments of choice and that their patients are not behind or underprivileged like they
(31:21):
definitely used to be.
But one of the things that we have tried with pediatric diet, check your rollout, is to
incorporate some operational research.
And so we negotiated for six countries across Africa to have what we called a catalytic
procurement of drugs, so they got an early shipment of this drug to roll it out, gain
(31:47):
experience in their countries to be able to kind of inform how they would roll it out
more broadly.
And in three of those countries, Uganda, Nigeria, and Benin, we incorporated a research component
to that where we interviewed the families and the clinicians and if they're old enough
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kids to ask them, like, compare to your old regimen, how does this new one compare to
the parents, did you see any side effects, to the clinicians, did you see any side effects?
And then just having really overall very, very positive results and being able to share
that with people within those countries but also across the regions.
(32:32):
Because one thing I noticed when I was working in Vietnam in particular, some years ago with
Chai, and then working across West Africa, is they really feel like their population
is distinct and they want to know that the product will work in their country with their
(32:52):
country's children.
Right.
So I always think it's like, well, children are children.
Yeah.
We're not so genetically distinct from each other, but they really sometimes become fixated
on that.
And so being able to say, no, this was research done in your region or done in your country
and we showed that it was really well tolerated and had XYZ results, then they really appreciate
(33:16):
that and it really facilitates the acceptability and uptake.
And then sometimes you learn things that maybe you weren't expecting.
One of the things that really comes up frequently with Dalu Taggiver is there's been some adult
research showing weight gain as a potential longer-term complication with integrates and
inhibitors generally.
(33:37):
But Dalu Taggiver, because it's been the most rapidly used one in low-middle income
countries, and so people are concerned about that because they don't want to have the problems
of the West.
They're concerned about obesity, epidemics, and so having some work around that with this
(34:01):
pediatric operational research has been helpful too to show that we're monitoring for this.
Generally, it doesn't seem like a big deal.
Children are supposed to gain weight because that's the job to grow.
So those are the things that really have been helpful to be able to share across countries.
(34:24):
And even coming back here to Canada, because a lot of our patients, our HIV patients in
Canada in the pediatric sphere at least, are migrants from other countries.
So being able to say, I'm actually doing the same work and providing the same advice to
people in Sub-Saharan Africa or Southeast Asia as what you're getting here in Canada,
(34:50):
that's also in reverse reassuring.
Yeah.
No, that's fair.
Yeah.
And so are there currently, so that's one of the operational trials out there.
Are there currently trials ongoing in North America with Dalu Taggiver in this disperseable
tab that we could enter patients into or anything that you're aware of in that regard?
(35:12):
I don't think there's anything going on new that there was an impact to trial looking
at pediatric Dalu Taggiver that was done that led to its licensure.
And then they're following kids out longer term.
But it's interesting, those studies were quite small compared to the volumes who are starting
(35:34):
it globally.
Right.
And as I mentioned, there is a neonatal study that is, I believe it's just started.
It's in North America and multiple international sites.
But yeah, in terms of enrolling patients, not so much.
But in our pediatric studies in Canada, we have been kind of looking at things like weight
(36:00):
gain with integrase inhibitors over time.
And also looking at the experience of integrase inhibitors in pregnancy, like if moms are
on them in pregnancy.
There's a big scare that a lot of people in HIV probably remember that when they first
started using it in Botswana, there was some concern about maybe an increased risk of neural
tube defects to find the evidence for that.
(36:23):
Which I think was just one of those like 95% confidence interval thing.
So 5% of the time things will happen by chance.
And so they found this slight increased risk.
But then over time that increased risk seemed to go away.
And it was just that they had a number of cases up front.
(36:46):
That risk certainly doesn't seem to be real at this point.
Yeah, that's fair.
Yeah, exactly.
Yeah, it makes it better for our kind of adult or adolescent use too.
Because some things you can't really predict and then you don't want to...
And then having an undetectable HIV viral load we know has a better outcome for those
(37:08):
neonates too.
So it's almost like is this risk versus benefit, right?
So yeah, that's fair.
So in terms of yeah, I think lately in my practice, I think we're slowly becoming more
and more comfortable with this dispersable tab.
And it's always nice to have newer formulation.
So do you foresee any changes to this formulation?
(37:32):
Or do we think that currently what's out there will remain?
And are there...
You talked about having a combo tab, right?
And that coming out.
So I guess is there anything else that you foresee with any changes with this Dolly Tiger
Veer Dispersable Tab in the near future?
Yeah, so the Avaka Veer Limit Veerine Dolly Tiger Veer 3M1 Dispersable Tablet is available
(37:58):
in the US just in the last six months.
Forgetting exactly when it was licensed, but it's recently out.
And so hopefully we'll have access to that here in Canada too.
And that was only licensed I think for 14 kilos and a half.
(38:20):
And then there's work going on looking at the younger or smaller kids.
But hopefully that will be available and we'll be able to use those here in Canada.
I think the next big thing is the injectables.
And so the Integress Inhibitor Cabotegravir is available for adults and adolescents as
(38:47):
an injection, but it's interesting using it for kids.
And then there's even interesting work looking at things like patch delivery.
So just like there's a contraceptive patch that you just put on your skin, but there'll
be a patch version of these injectable ARVs.
Oh wow.
(39:07):
Those are still far off in the future I think overall.
But I don't know, when patients come to you, they want to know what's coming.
They want to know what they can have hope about.
And like you said, most people are like, this works for me.
I'm happy with it.
We don't need to go messing with the formula.
(39:29):
But other people really struggle with taking a pill every day.
Even just like one pill a day.
We can talk about how like 10 years ago people were on like a handful of pills or multiple
pills twice a day.
And now we're down to one pill a day.
And it seems like that's a lot better.
But if you're the person having to take one pill a day, sometimes it's still pretty hard.
(39:50):
Yeah, exactly.
I mean, I always tell my patients, like, I can't even sometimes take vitamins in a day.
So I commend them for sticking to their regimen and taking their pills.
And it's a difficult task.
Like if you think about the pediatric patients that we see, they go through so many changes
in their life.
Even going through your teenage years, having to do all of this.
(40:14):
So I think whatever we can make, you know, anything that you can make that's easier for
them, I think always improves compliance, especially in that age group.
So yeah, but definitely.
And then I find like with adherence issues in teenagers, like sometimes it's about difficulty
with like remembering or having to take a bunch of pills and feeling like you're having
(40:39):
side effects.
But a good chunk of people just don't like being reminded of HIV.
And taking that pill every day is like a reminder that you have this problem.
And so I think for some people, like the injectables once a month, like there's even orals that
will be available in the not distant future that can be taken weekly or monthly or even
(41:02):
less frequently.
Like I think being able to just put HIV kind of on the shelf and not think about it, or
put it in the back of your mind and not think about it is going to be helpful for some people.
Yeah, no, I agree.
Yeah, definitely.
So that was, I mean, so much information definitely bringing into like my clinical practice.
(41:25):
So in terms of some take home points for some of our listeners who, you know, may be seeing
HIV patients who are on older regimens or struggling to, you know, ensure compliance.
What are some take home points for them for Dolutegravir that you would kind of highlight
today?
I mean, I think I would start by saying this is like probably the one of two or three main
(41:52):
drugs that we use in pediatrics and in adults and definitely in pediatrics nowadays.
It's one of the first line recommended products and if your patients are on older products,
it's very reasonable to offer this as a switch.
I think in the old days, we used to say, oh, we'll save this for later just in case.
(42:17):
If your current ones don't work or have issues, but we know that having people on the best
drugs from the start is going to allow them to stay on those best drugs for longer.
So don't be afraid to try something new when we know that it's a good drug.
It's very well tolerated of anything.
(42:39):
I think insomnia for the first month is the main thing to warn about, but only one in
10 adult patients will get that.
And so even less common in kids and very few drug interactions to worry about.
So yeah, hard to find a lot of problems with this medication.
(43:02):
And yeah, I think it's really helped a lot of people achieve undetectable, which is our
goal in addition to a good quality of life.
Yeah, it's there.
And I think as we use more and more drugs that are being authorized for that age group,
they become more accessible in our communities as well.
(43:24):
And then so it makes it easier to actually use these medications then as well, because
even if you have a patient that may be out in a pharmacy, they usually have the older
drugs in our regimens easily accessible.
And so sometimes we resort to use those if we can't find other drugs.
But I think everything in terms of health care has changed and we can get lots of things
(43:51):
approved and sent to different pharmacies.
And so I think as use increases that also increases our chances of getting meds like
Dalu Tegravir out in community pharmacies and that type of thing.
So I've definitely seen some of that in my clinical practice too.
Yeah, no, that's fantastic.
So is there anything else that you feel that our audience should know about Dalu Tegravir
(44:16):
before we kind of close off today's episode, which was like fantastic knowledge for myself.
And I think viewers would appreciate, you know, are going to appreciate having somebody
to not only like reach out to as a clinical expert, but also just have more information
about Dalu Tegravir today.
(44:37):
I think I just closed by saying that this is probably going to be, if not already, going
to be the most commonly used ARV globally.
The vast majority, like 90% plus of adults around the world who have HIV and are on treatment
are going to be on this for first or even second line or third line.
(45:03):
Soon enough, the majority of kids in the world will be on it.
So if you're studying for the exam, this is a good one to fold up on.
There you go.
Perfect.
Yeah.
And then I always like to give everybody a disclaimer that this was an informational
podcast and in by no means is a replacement for an infectious disease console, but definitely
(45:29):
very informative, you know, presentation today regarding Dalu Tegravir.
And I think it'll be nice to see how these, you know, if more trials come up in pediatrics
and just see, you know, even with Z parched is to see other people's experience and their
clinical experience with the use of Dalu Tegravir.
So pediatric HIV, I think is always evolving and there's like so many changes.
(45:56):
And so, and like you said, you know, a few years back even, we didn't have so many meds
and there weren't, there wasn't a lot of research and now we're seeing more of that.
And I don't know about personally, like in Saskatchewan, we've had an uptick in our vertical
transmission as well and so having access to some of these newer drugs is really helping
(46:17):
our practice out here.
Yeah.
I agree.
Caring for the little, those little ones, especially can be really difficult, especially
when they hit the terrible twos and saying no to everything.
Having a drug that doesn't taste like kerosene actually tastes like strawberry cream and
(46:39):
you only have to take once a day can be a lifesaver.
So it's a good thing.
That's great.
All right.
Well, thank you so much, Dr. Brophy.
We really appreciate you coming on the podcast and it would be nice to have you back for
future episodes.
You know, even if it's regarding HIV or with your Clinton Health Initiative work, it's
(46:59):
fantastic what you're doing out there and it's fantastic what you do out at CHEO too.
So thank you so much.
We really appreciate it.
Thanks for having me.
Thank you, Dr. Pirwal and thank you, Dr. Brophy, for joining us.
Have a topic suggestion?
Email us at thecanadianbreakpoint at gmail.com and follow us on Twitter at CABbreakpoint.
(47:22):
See you then soon at the Canadian Breakpoint.
Thanks for joining us again at the Canadian Breakpoint, a Canadian infectious diseases
(00:12):
podcast by Canadian infectious diseases physicians.
I'm Summer Stewart, here with Dr. Rupeena Purewal, pediatric infectious diseases specialist
from Saskatoon.
In this episode, we welcome infectious diseases pediatrician Dr. Jason Brophy to review Dolutegra
Vir Disperseable Tab.
Dr. Purewal.
(00:32):
All right, welcome to another episode of our podcast the Canadian Breakpoint.
Today, we have a very special guest with us, Dr. Brophy, who is a pediatric infectious
disease specialist and researcher at the Children's Hospital of Eastern Ontario, and an associate
professor of pediatrics at the University of Ottawa.
His research interests are in pediatric and perinatal HIV and other congenital infections.
(00:58):
He is the current chair of the Canadian Pediatric and Perinatal HIV and AIDS Research Group,
CPARCH, and co-lead of the Clinical Care and Management Research Corps of the Canadian
HIV Trials Network.
He works part-time as a pediatric HIV clinical advisor with the Clinton Health Access Initiative,
(01:21):
supporting the uptake of optimal pediatric HIV care in West Central Africa and Southeast
Asia.
So welcome, Dr. Brophy.
Thanks.
Great to be here.
Perfect.
So today, we have a very exciting episode because we're talking about Dolutegra Vir.
And so for some of our listeners who manage adult HIV, they're probably quite familiar
(01:44):
with Dolutegra Vir and its mechanism of action, uses, and indications.
But we're very fortunate that there's been new formulary in pediatrics, so the disperseable
tabs that are now available.
And you have some clinical experience and research experience with Dolutegra Vir.
(02:06):
So it's really a pleasure to have you here today.
Yeah, no, I agree.
It's nice to have some new drugs for kids because for a long time, we've been without
the poor cousin to the adult HIV crowd.
So it's nice to have new modern drugs to offer our kids here in Canada.
(02:28):
Yeah, no, very fair.
Yeah.
So I think in terms of what I would like to start with today is for a lot of our listeners.
So we have listeners across the globe, definitely, you know, first, like family physicians, we
have pediatric physicians, we have infectious disease physicians across the globe.
(02:50):
And so it would be nice to kind of maybe not everybody is aware of Dolutegra Vir.
So can we just kind of introduce maybe what Dolutegra Vir is and its common uses and mechanism
of action?
Sure, happy to do that.
Thanks.
So Dolutegra Vir is in the integrase strand inhibitor family or INSTEE family.
(03:11):
And its mechanism of action is that it prevents the HIV enzyme integrase from integrating
the viral DNA into the host CD4 cell DNA.
And so it's one of the newer families of drugs.
So back in the old, old days, we had the NRTIs first, like AZT, 3TC.
(03:37):
And we had NRTIs like nevirapine and afavron.
And then the protease inhibitors came out and they really were kind of the linchpin
that helped move us ahead.
And in 1996, we learned that using them in combination, like two NRTIs plus one NRTI
(03:59):
or PEI protease inhibitor, that was what we called highly active antiretroviral therapy
or HEART.
And so for years, we were working with those three families.
And now we're up to five families that are commercially available.
And there's other ones that are coming out, which is really nice.
(04:19):
But the integrase inhibitors or INSTEE family really have kind of taken over in terms of
being the main ones that we're using nowadays as their anchor drugs.
So two NRTI drugs plus one third drug.
And the third drug is increasingly becoming something from the INSTEE family.
(04:39):
And so dolutegra Vir is one of those.
There are five that we have available for use in Canada right now.
Rauhtegra Vir, Elvitegra Vir, Bictegra Vir, Cabotegra Vir, and dolutegra Vir.
And then we have three of those that have pediatric formulations available.
(05:02):
And so the kind of advantages of these drugs are that they tend to be really well tolerated
and that they don't have the same nasty side effects that some of the earlier ones had.
Like, Favrons caused a lot of neuropsychiatric stuff, like nightmares or made people really
(05:22):
groggy or sleepy or dizzy.
And then the protease inhibitors, the older ones at least, that we had in the liquid ones
that we used for kids, caused a lot of GI upset, diarrhea, vomiting, nausea, especially
for the little babies, like the main one that we always use, dolpenevir, ritonavir.
(05:44):
We did taste tests of it when I was a trainee many years ago.
And I'll never forget that day.
It was like taking a shot of kerosene and it really just stuck with you the whole day.
But like really bad reflux and burning.
And so every time I heard a mom come in saying how hard it was to give this medicine, I was
(06:05):
like, yeah, I know why.
Right.
So yeah, we're all hoping for newer, better drugs.
And so this family has kind of allowed that to happen, which is great.
That's awesome.
Yeah.
So definitely, as you talked about, I mean, there's not too many options in pediatrics.
So for dolpenevir specifically, when we talk about pediatric meds in general, we always
(06:30):
have weight cutoffs or age cutoffs that we can use them.
So for this new formulation of dolutegravir, how young can we be giving that or adding
it to the regimen?
Yeah, there have been a few really, really good studies that have helped inform how we
use dolutegravir.
(06:50):
So they add out tablet, which is actually pretty tiny.
It's about the size of an ibuprofen tablet, the 50 milligram one.
We know from the Odyssey trial that we can actually use that down to 20 kilos of weight,
regardless of the age.
And then with the pediatric dispersable tablet, which is strawberry flavored and you drop
(07:13):
it in water and it dissolves pretty quickly, and then the kid can just drink it.
That one is approved for age one month and up and three kilos and up.
And so that makes pretty much all the kids that we would want to be treating eligible
for it.
There's actually neonatal studies that are planned or starting up now.
(07:36):
And so hopefully we'll even be able to be using it in younger age groups.
But the metabolism is tricky in the first month, especially the first week.
And so they tend to clear things more slowly.
And so we'll learn more about that as the studies progress.
But yeah, the dispersable tablet's making her lives a lot easier here.
(08:00):
Unfortunately, the NRTIs still don't come in similar dispersable formulations in North
America.
But it's interesting, like in my global work with the chai, the chai kind of made its name
(08:21):
in the HIV game by working with generic companies to produce generic versions of the drugs that
we have in the West.
And they actually have had dispersable formulations of the NRTIs, like abacagran, limididine together,
or sadavidine, limididine together.
(08:42):
And then the other tablet, the other ones like the NRTIs, they've had them for years.
And so the pediatric dialyutegibir came out a couple of years ago as a generic product
just after it was released here in North America.
And so when I go and do my teaching in these other countries, I tell them, you're actually
(09:04):
luckier than me in that I don't have access to all of these same formulations of dispersable
tablets, which makes them feel a bit better that they have some advantages over us here.
Right.
Yeah.
No, I mean, it makes a huge difference.
And so I guess clinically, in my practice, there's definitely been indications.
(09:29):
For instance, you mentioned with some of the other medications that we commonly use, they
don't taste very good.
So the compliance gets poor and poor, especially as children are getting older and they're
actually involved in the process of taking their meds.
And they now are starting to decline them because of taste or a lot of reflux.
And so I think having a medication like dialyutegibir where it's disperable, and ideally only in
(09:54):
very small amount of MLs of fluid, like clear fluid that you can disperse it in.
And so it's not a huge volume that they're taking.
Yeah.
So that's probably where I've used it clinically.
So are there other indications?
Is it something like you would...
Are the studies showing that it's something that we would be starting off as a primary
(10:17):
regimen as opposed to like second line?
Kind of what I was saying.
Yeah.
So the WHO actually recommended it as their first line preferred therapy, even before
there was a pediatric formulation available, just because there was a big move globally
(10:38):
to kind of embrace integrase inhibitors.
The only one that was really coming to market was dialyutegibir.
So even before the pediatric formulation was available, it was already recommended.
But in North America, we've had like raltegibir in pediatric formulations for a while.
And then the other ones like alvitegibir, which is in a fixed dose combination tablet
(11:05):
called Genfoya, and triimek, which is the dialyutegibir, back of your lamedidine, comes
in a fixed dose combination.
So those were approved for kids 25 kilos and older.
But these new dispersable ones for the younger kids are the ones that are newer.
But they've really, as soon as the formulations were available and the studies showing that
(11:30):
they were effective either as new therapy or switch therapy, then they became the first
line regimens of choice.
So yeah, this is what we should be starting people on.
I guess the other benefit that is worth mentioning is dialyutegibir is once a day, whereas raltegibir,
(11:52):
which we've had for a while, is twice a day, has a lower barrier to resistance.
So if kids are missing any or their drug levels are low for missing doses or vomiting doses,
then there's a higher chance of getting resistance because there's a lower genetic barrier.
It's a developing resistance with the first generation integrates inhibitor raltegibir.
(12:16):
So dialyutegibir is well tolerated, easy to take once a day.
And we know it's really potent that this family suppresses HIV usually within a month in adults.
Kids often start with a higher viral load than adults, especially in the younger kids.
(12:37):
And so it can take a bit longer than that.
But generally it works pretty fast.
So yeah, there's not a lot of downsides except for occasional drug interactions to think
about.
Right.
Yeah.
So one of those would be like probably a contraindication.
So as you mentioned, there aren't any drawbacks.
Are there any main contraindications that where, you know, sometimes we worry about,
(13:00):
is there any maybe like renal issues or liver issues if a child is having those and has
obviously like comorbidity?
Is there a strong contraindication to when not to use dialyutegibir?
So that it is contraindicated in kids or adults with severe renal impairment or severe liver
(13:26):
impairment.
But mild to moderate, it's okay to use for both.
And then in terms of drug-drug interactions, we know it's metabolized mostly by the cytochrome
P450-3a as well as the UGT1A1.
(13:48):
And so those are the ones that kind of get induced by things like rifampin and some of
the anti-epileptic drugs like phenyton or phenobarb.
So because rifampin is such a big drug to treat TB globally, there's been a fair amount
(14:09):
of work looking at how we can overcome that interaction.
So we know if you double the dose of dialyutegibir, like give it twice a day instead of once a
day, then that should overcome that drug-drug interaction.
But for other ones like phenyton or phenobarb, those are too potent in terms of inducing.
(14:30):
So it's recommended not to use those with dialyutegibir.
But there are other anti-epileptic choices.
And so that would be an option to move them to a different anti-epileptic if you wanted
to use the NHGRACE inhibitor or vice versa if you wanted to use those anti-epileptics
and pick a different antiretroviral.
(14:51):
Yeah, that's fair.
Thank you.
Yeah.
I think these are important things because we, you know, if we're commonly seeing patients,
especially the, you know, some of the younger patients and then over time, if they're, let's
say on a regimen and then they're developing other conditions, then we should be probably
well aware of those.
So if I have a patient on dialyutegibir, I mean, a lot of the NHGRACE inhibitor is not
(15:13):
too much monitoring they have to do regularly.
Whereas like some of our other drugs, there's like neutropenia risks.
They definitely have a lot of bone marrow suppression.
Are there any routine labs that a child, like, I mean, outside of our normal every three
months that we would be following them?
Is there anything specific to dialyutegibir that we would need to be monitoring?
(15:37):
So the NHGRACE inhibitors generally can cause myositis.
So we're recommended to monitor CK.
And then they can really cause some like biochemical hepatitis.
And so monitoring of the enzymes as well.
In my experience, I really haven't seen either of those things.
(15:58):
The other main side effects that they talk about with intergastin inhibitors generally
and dialyutegibir in particular are included, I should say, is insomnia, which I'd say
the very first patient ever treated with dialyutegibir had wicked insomnia.
He came back and was saying he was like not able to sleep at night and he was falling
(16:22):
asleep on the bus on the way home from school.
Oh no.
Poor guy.
But he really didn't like his twice a day regimen before that.
And so I said, well, it's supposed to resolve within a month or two.
So if you want to stick it out.
And so he stuck it out and it completely resolved within two months.
And so that was a really good learning point for me to just see that, oh yeah, these like
(16:45):
uncommon side effects reported in trials can actually happen in people.
Funnily enough, he's like the only patient I've ever had get that side effect.
First one.
So I usually I usually warn people that it definitely can happen.
But if you stick it out, it should go away.
Like most side effects with antiretrovirals.
(17:05):
Then GI stuff can happen.
Headache can happen.
They say that if your drug levels are really high, that it can cause neuropsychiatric side
effects, like if you had depression, it can worsen it or stuff like that.
But again, my experience has been with pediatrics.
(17:28):
All the side effects that you see in adults are much less common in children.
That is true.
I usually say I think kids are just tougher than adults or maybe we as adults tend to
complain a bit more.
But that's fair.
But yeah, I usually find that it's a really well tolerated drug.
(17:49):
Yeah, no, that's great.
So in terms of, I guess if we're starting to use it more in our clinical practice, what
are some of the costs or the cost to the patient in terms of the health care system, just kind
of looking at from a health care standpoint to is this something that's more affordable
(18:10):
than other drugs and is the access quite easy?
So if a physician would want to start it, how do they go about ordering that in Canada
or the US?
Yeah, so Canada, our health system needs to be a bit better unified.
It's like we have 13 different countries and 13 different systems for how we do health
(18:34):
care and fund it and provide it.
But generally in most provinces, ARVs are covered by provincial programs.
And then the main people I find who have difficulty with paying for ARVs are the ones who have
partial insurance.
So it's kind of like the folks in the lower middle class who have jobs and have private
(18:58):
insurance, but it's not 100%.
And so all the ARVs are still pretty expensive, like running in between like $1,500, $2,000
a month.
So if you only have 80% coverage, like 20% of that is still a fair amount of money.
So the nice thing is that most of the big antiretroviral manufacturers do have support
(19:25):
programs.
And so if people are, say, new to Canada and don't have their health care, like their OHIP
or the provincial coverage set up, or don't have their private insurance or their other
forms of insurance set up, then they'll usually pay for the medications for up to six months.
(19:48):
And then Veev that makes pediatric dolly type of care has a program that will provide partial
coverage as well if people have coverage, but not 100% coverage through their insurance.
So I always tell people that no kid and really no adult in Canada should go without ARVs.
We have lots of options and we have good support programs in place.
(20:12):
That's ideal.
In the global setting though, it's very interesting to work on both sides of the globe with HIV,
because we know that, like I said, most ARV combinations for adults cost somewhere between
$1,500 to $2,000 a month.
(20:33):
So it's $24,000 a year about.
And the same medications for the most part, when they're produced generically, are significantly
cheaper.
And so the adult treatment of choice like TLD, it's not very limiting, which comes as
a single pill.
(20:53):
The price for that has been brought down to about $50 to $60 per patient per year.
So pretty significant reduction, right?
And then for kids, the pediatric value tag of your tablet is a fraction of the cost of
the previous recommended regimen, which is lopinavir, ritonavir tablets.
(21:17):
Those costs, I believe somewhere around 200 to 300 per patient per year.
Because on the kid, how many tablets are taking, the pediatric value tag of your is a fraction
of that.
So really part of why the WHO moved to recommend it was not only the fact that there's increasing
(21:39):
NNRTI resistance to favorens and the barium pain, because it's pretty low bariatric resistance.
You only need one mutation to become resistant to those.
Whereas with value tag of your, it's a lot higher barrier to resistance.
So they're wanting to move away from NNRTI-based first line treatment, especially in countries
(22:01):
that have had reached like the 10% resistance kind of threshold at baseline to NNRTI.
And so there was that, there was the cost part coming down, there was the side effects
profile.
We knew the people on a favorens, which is the main drug used before, at a higher rate
(22:21):
of neuropsychiatric side effects, depression, higher risk of suicide, higher risk of people
going off medications over time.
And so really the kind of coalesced around getting behind this new drug and regimen.
And so that extended down to kids too, which is great.
Especially they're stuck on the old Kalitra or Lopinavir, which we can't complain, right?
(22:49):
It's a good antiretroviral, it treats the HIV well, and it saved a lot of people's lives.
And we can't be too down on these old drugs.
They got us to where we are today and saved a lot of our patients' lives.
Long-term usage and having people be able to stay on them in the long-term, it's better
(23:11):
to have drugs that are better tolerated.
Yeah, definitely.
Yeah.
And it's nice because most of these kids then can remain on that once they get into their
tablet forms and it's a really easy switch over.
It's a whole new drug for them, which is really nice because I think, especially us who are
managing pediatric patients and they grow with you, you're definitely transitioning
(23:37):
them to that adult care even or even the adolescent age group, you always want to make it as streamlined
as possible.
So if it's something that's familiar to them already, then they may feel better.
Whereas coming off of some of the older drugs and switching to a drug that they've never
heard of, they sometimes are a little bit nervous too.
So I've definitely seen that.
(24:00):
Yeah.
And then the great thing that is happening is that these companies are really getting
on board with being more sensitive to kids' needs.
And so we have the disperseable Diuretegavir single tablet, but now they've come out with
a three-in-one.
I call it baby Triomec, which is like a baccalaurelamidine and Diuretegavir all in one disperseable tablet,
(24:26):
which can be used down to younger kids.
And that generic version is also coming out in our plan to be coming out for low middle
income countries.
So that's my next job to get countries to move over to that, which will make life even
easier instead of like two separate medications that need to be dispensed down to just one
(24:49):
single tablet regimen or single disperseable tablet regimen, which we'll have here in North
America as well as in low middle income countries for the majority of kids with HIV or living.
Yeah.
That'll be really fantastic.
I mean, one of the most difficult parts about treating HIV is make insuring compliance,
(25:10):
right?
Because if they're not on their meds, then those are when the complications start and
then their viral load is not suppressed.
And so I think that's probably one of the...
So if we can make the patient's life easier by not having to take so many meds, I think
we can probably achieve undetectable viral loads too.
(25:31):
So yeah, so that'll be...
That's great.
Nice to hear.
So when we first got in touch about Diuretegavir and we were talking about you coming on the
podcast, you mentioned your awesome work with the Clinton Health Initiative.
So I guess I wanted to touch base with you about some of the work that you're doing out
there.
(25:52):
And if you wanted to highlight for some of...
I know some of the audience members who are interested in global health for sure would
find this a very, very intriguing conversation for sure.
Yeah.
So when I was back in my training days, I was like, when I grow up, I wanted to do global
health and do global HIV work.
(26:13):
And it was a bit of a rough slog to figure out how to do that.
But I'm very lucky that I get to mix my job here in Canada, looking after kids at an academic
pediatric hospital, and then also work part time abroad.
And so with CHI, Clinton Health Access Initiative, it used to be the Clinton Foundation, but
(26:35):
then they started doing a lot of different things, including environmental work and political
advocacy.
So they carved up all the health stuff and put it into this CHI, or Clinton Health Access
Initiative.
And so they made their name on HIV and getting generic products for HIV care and treatment.
(27:00):
But now they do a lot of other stuff, TB, cryptococcal meningitis, hepatitis C, maternal
newborn child health, lots of other stuff, COVID now.
And so who's not doing COVID?
But my stuff is still predominantly focused on HIV and then advanced HIV disease like
(27:25):
TB and other opportunistic infections.
So what I do is we have products like this that we're trying to get countries to take
up to modernize their approaches.
(27:45):
And so we work directly with ministries of health across Sub-Saharan Africa and Southeast
Asia and Southern Asia, India, parts of the Caribbean and South America as well.
So my work is working directly with ministries of health, kind of going through with them
what are the WHO guidance recommendations, how can they make changes to their guidance
(28:11):
in accordance with WHO, if it fits, right?
Like it really needs to be tailored to their needs and what they're ready to do.
And then making, ordering these products more available, negotiating pricing agreements
to get the best use for money possible.
(28:34):
So it's been great that people think I go and work in hospitals abroad, but I don't
really do that.
I go and do workshops with clinicians, talk just about all the stuff I've talked about
with you, but kind of translate it into what is important for them and tell them how to
use these drugs and how you would monitor them.
(28:55):
We make a knowledge translation and educational materials both for the clinicians as well
as the patients and their families.
And so really try to make life easier for them to be able to do their job well.
So it's a lot of fun.
I get to see a lot of the world and know that even this pediatric value tag of your product
(29:18):
only came out.
The first countries had access to it back in the second half of last year.
And now the majority of countries with high HIV burden have transitioned or are in the
process of transitioning their patients over to pediatric value tag of your, and some countries
(29:43):
are up to like over 90% of kids on this product within a year of it coming out.
So it's really, really nice.
Yeah, it's great.
It's probably nice to see that comparison and between different countries, and then
you can kind of bring that experience even back to North America, but not only that,
but to like their neighboring countries too.
(30:05):
Because I think one thing with using newer drugs and newer medications is just people
want experience.
And it's nice to have, oh yes, like this was used in this case and we saw really good,
we achieved really good undetectable viral loads, that type of thing, or this is an indication.
And so I think just kind of having that comfort in a way that it's used and is frequently
(30:32):
used kind of helps in the HIV world.
So would you say like that's kind of what your experience has been?
For sure, for sure.
When I go to countries and have workshops with clinicians, they usually bring like one
or two hard cases and want to get our advice.
And being able to say you've used this product and this is your experience with it, and you
(30:58):
had cases with wrinkles, X, Y, Z, they really appreciate hearing those experiences and knowing
that they're not alone and knowing that they have access to what are really considered
the treatments of choice and that their patients are not behind or underprivileged like they
(31:21):
definitely used to be.
But one of the things that we have tried with pediatric diet, check your rollout, is to
incorporate some operational research.
And so we negotiated for six countries across Africa to have what we called a catalytic
procurement of drugs, so they got an early shipment of this drug to roll it out, gain
(31:47):
experience in their countries to be able to kind of inform how they would roll it out
more broadly.
And in three of those countries, Uganda, Nigeria, and Benin, we incorporated a research component
to that where we interviewed the families and the clinicians and if they're old enough
(32:07):
kids to ask them, like, compare to your old regimen, how does this new one compare to
the parents, did you see any side effects, to the clinicians, did you see any side effects?
And then just having really overall very, very positive results and being able to share
that with people within those countries but also across the regions.
(32:32):
Because one thing I noticed when I was working in Vietnam in particular, some years ago with
Chai, and then working across West Africa, is they really feel like their population
is distinct and they want to know that the product will work in their country with their
(32:52):
country's children.
Right.
So I always think it's like, well, children are children.
Yeah.
We're not so genetically distinct from each other, but they really sometimes become fixated
on that.
And so being able to say, no, this was research done in your region or done in your country
and we showed that it was really well tolerated and had XYZ results, then they really appreciate
(33:16):
that and it really facilitates the acceptability and uptake.
And then sometimes you learn things that maybe you weren't expecting.
One of the things that really comes up frequently with Dalu Taggiver is there's been some adult
research showing weight gain as a potential longer-term complication with integrates and
inhibitors generally.
(33:37):
But Dalu Taggiver, because it's been the most rapidly used one in low-middle income
countries, and so people are concerned about that because they don't want to have the problems
of the West.
They're concerned about obesity, epidemics, and so having some work around that with this
(34:01):
pediatric operational research has been helpful too to show that we're monitoring for this.
Generally, it doesn't seem like a big deal.
Children are supposed to gain weight because that's the job to grow.
So those are the things that really have been helpful to be able to share across countries.
(34:24):
And even coming back here to Canada, because a lot of our patients, our HIV patients in
Canada in the pediatric sphere at least, are migrants from other countries.
So being able to say, I'm actually doing the same work and providing the same advice to
people in Sub-Saharan Africa or Southeast Asia as what you're getting here in Canada,
(34:50):
that's also in reverse reassuring.
Yeah.
No, that's fair.
Yeah.
And so are there currently, so that's one of the operational trials out there.
Are there currently trials ongoing in North America with Dalu Taggiver in this disperseable
tab that we could enter patients into or anything that you're aware of in that regard?
(35:12):
I don't think there's anything going on new that there was an impact to trial looking
at pediatric Dalu Taggiver that was done that led to its licensure.
And then they're following kids out longer term.
But it's interesting, those studies were quite small compared to the volumes who are starting
(35:34):
it globally.
Right.
And as I mentioned, there is a neonatal study that is, I believe it's just started.
It's in North America and multiple international sites.
But yeah, in terms of enrolling patients, not so much.
But in our pediatric studies in Canada, we have been kind of looking at things like weight
(36:00):
gain with integrase inhibitors over time.
And also looking at the experience of integrase inhibitors in pregnancy, like if moms are
on them in pregnancy.
There's a big scare that a lot of people in HIV probably remember that when they first
started using it in Botswana, there was some concern about maybe an increased risk of neural
tube defects to find the evidence for that.
(36:23):
Which I think was just one of those like 95% confidence interval thing.
So 5% of the time things will happen by chance.
And so they found this slight increased risk.
But then over time that increased risk seemed to go away.
And it was just that they had a number of cases up front.
(36:46):
That risk certainly doesn't seem to be real at this point.
Yeah, that's fair.
Yeah, exactly.
Yeah, it makes it better for our kind of adult or adolescent use too.
Because some things you can't really predict and then you don't want to...
And then having an undetectable HIV viral load we know has a better outcome for those
(37:08):
neonates too.
So it's almost like is this risk versus benefit, right?
So yeah, that's fair.
So in terms of yeah, I think lately in my practice, I think we're slowly becoming more
and more comfortable with this dispersable tab.
And it's always nice to have newer formulation.
So do you foresee any changes to this formulation?
(37:32):
Or do we think that currently what's out there will remain?
And are there...
You talked about having a combo tab, right?
And that coming out.
So I guess is there anything else that you foresee with any changes with this Dolly Tiger
Veer Dispersable Tab in the near future?
Yeah, so the Avaka Veer Limit Veerine Dolly Tiger Veer 3M1 Dispersable Tablet is available
(37:58):
in the US just in the last six months.
Forgetting exactly when it was licensed, but it's recently out.
And so hopefully we'll have access to that here in Canada too.
And that was only licensed I think for 14 kilos and a half.
(38:20):
And then there's work going on looking at the younger or smaller kids.
But hopefully that will be available and we'll be able to use those here in Canada.
I think the next big thing is the injectables.
And so the Integress Inhibitor Cabotegravir is available for adults and adolescents as
(38:47):
an injection, but it's interesting using it for kids.
And then there's even interesting work looking at things like patch delivery.
So just like there's a contraceptive patch that you just put on your skin, but there'll
be a patch version of these injectable ARVs.
Oh wow.
(39:07):
Those are still far off in the future I think overall.
But I don't know, when patients come to you, they want to know what's coming.
They want to know what they can have hope about.
And like you said, most people are like, this works for me.
I'm happy with it.
We don't need to go messing with the formula.
(39:29):
But other people really struggle with taking a pill every day.
Even just like one pill a day.
We can talk about how like 10 years ago people were on like a handful of pills or multiple
pills twice a day.
And now we're down to one pill a day.
And it seems like that's a lot better.
But if you're the person having to take one pill a day, sometimes it's still pretty hard.
(39:50):
Yeah, exactly.
I mean, I always tell my patients, like, I can't even sometimes take vitamins in a day.
So I commend them for sticking to their regimen and taking their pills.
And it's a difficult task.
Like if you think about the pediatric patients that we see, they go through so many changes
in their life.
Even going through your teenage years, having to do all of this.
(40:14):
So I think whatever we can make, you know, anything that you can make that's easier for
them, I think always improves compliance, especially in that age group.
So yeah, but definitely.
And then I find like with adherence issues in teenagers, like sometimes it's about difficulty
with like remembering or having to take a bunch of pills and feeling like you're having
(40:39):
side effects.
But a good chunk of people just don't like being reminded of HIV.
And taking that pill every day is like a reminder that you have this problem.
And so I think for some people, like the injectables once a month, like there's even orals that
will be available in the not distant future that can be taken weekly or monthly or even
(41:02):
less frequently.
Like I think being able to just put HIV kind of on the shelf and not think about it, or
put it in the back of your mind and not think about it is going to be helpful for some people.
Yeah, no, I agree.
Yeah, definitely.
So that was, I mean, so much information definitely bringing into like my clinical practice.
(41:25):
So in terms of some take home points for some of our listeners who, you know, may be seeing
HIV patients who are on older regimens or struggling to, you know, ensure compliance.
What are some take home points for them for Dolutegravir that you would kind of highlight
today?
I mean, I think I would start by saying this is like probably the one of two or three main
(41:52):
drugs that we use in pediatrics and in adults and definitely in pediatrics nowadays.
It's one of the first line recommended products and if your patients are on older products,
it's very reasonable to offer this as a switch.
I think in the old days, we used to say, oh, we'll save this for later just in case.
(42:17):
If your current ones don't work or have issues, but we know that having people on the best
drugs from the start is going to allow them to stay on those best drugs for longer.
So don't be afraid to try something new when we know that it's a good drug.
It's very well tolerated of anything.
(42:39):
I think insomnia for the first month is the main thing to warn about, but only one in
10 adult patients will get that.
And so even less common in kids and very few drug interactions to worry about.
So yeah, hard to find a lot of problems with this medication.
(43:02):
And yeah, I think it's really helped a lot of people achieve undetectable, which is our
goal in addition to a good quality of life.
Yeah, it's there.
And I think as we use more and more drugs that are being authorized for that age group,
they become more accessible in our communities as well.
(43:24):
And then so it makes it easier to actually use these medications then as well, because
even if you have a patient that may be out in a pharmacy, they usually have the older
drugs in our regimens easily accessible.
And so sometimes we resort to use those if we can't find other drugs.
But I think everything in terms of health care has changed and we can get lots of things
(43:51):
approved and sent to different pharmacies.
And so I think as use increases that also increases our chances of getting meds like
Dalu Tegravir out in community pharmacies and that type of thing.
So I've definitely seen some of that in my clinical practice too.
Yeah, no, that's fantastic.
So is there anything else that you feel that our audience should know about Dalu Tegravir
(44:16):
before we kind of close off today's episode, which was like fantastic knowledge for myself.
And I think viewers would appreciate, you know, are going to appreciate having somebody
to not only like reach out to as a clinical expert, but also just have more information
about Dalu Tegravir today.
(44:37):
I think I just closed by saying that this is probably going to be, if not already, going
to be the most commonly used ARV globally.
The vast majority, like 90% plus of adults around the world who have HIV and are on treatment
are going to be on this for first or even second line or third line.
(45:03):
Soon enough, the majority of kids in the world will be on it.
So if you're studying for the exam, this is a good one to fold up on.
There you go.
Perfect.
Yeah.
And then I always like to give everybody a disclaimer that this was an informational
podcast and in by no means is a replacement for an infectious disease console, but definitely
(45:29):
very informative, you know, presentation today regarding Dalu Tegravir.
And I think it'll be nice to see how these, you know, if more trials come up in pediatrics
and just see, you know, even with Z parched is to see other people's experience and their
clinical experience with the use of Dalu Tegravir.
So pediatric HIV, I think is always evolving and there's like so many changes.
(45:56):
And so, and like you said, you know, a few years back even, we didn't have so many meds
and there weren't, there wasn't a lot of research and now we're seeing more of that.
And I don't know about personally, like in Saskatchewan, we've had an uptick in our vertical
transmission as well and so having access to some of these newer drugs is really helping
(46:17):
our practice out here.
Yeah.
I agree.
Caring for the little, those little ones, especially can be really difficult, especially
when they hit the terrible twos and saying no to everything.
Having a drug that doesn't taste like kerosene actually tastes like strawberry cream and
(46:39):
you only have to take once a day can be a lifesaver.
So it's a good thing.
That's great.
All right.
Well, thank you so much, Dr. Brophy.
We really appreciate you coming on the podcast and it would be nice to have you back for
future episodes.
You know, even if it's regarding HIV or with your Clinton Health Initiative work, it's
(46:59):
fantastic what you're doing out there and it's fantastic what you do out at CHEO too.
So thank you so much.
We really appreciate it.
Thanks for having me.
Thank you, Dr. Pirwal and thank you, Dr. Brophy, for joining us.
Have a topic suggestion?
Email us at thecanadianbreakpoint at gmail.com and follow us on Twitter at CABbreakpoint.
(47:22):
See you then soon at the Canadian Breakpoint.
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