HIV Boot Camp: Entry Inhibitors
Editor's note: To date, our most reader requested topic has been HIV. We've written a guest post at MedEd101 to cover the most NAPLEX-worthy testing points. But we thought we'd dig in a little further here. Over the next few weeks, we're posting a series called HIV Boot Camp. We'll shore up your HIV fundamentals. Then we'll breakdown each drug class piece by piece to highlight what you need to know. For convenience, we'll link each part of the series here. Part I, Part II, Part III, Part IV, Part V, Part VI
Part VII: Entry Inhibitors
Well, we're coming full circle here. Our epic series on HIV is nearing its coda. We've only got one "class" of HIV meds left to talk about.
The Entry Inhibitors.
I say "class" (I'm totally doing air quotes with my fingers right now) because there are only 2 entry inhibitors currently on the market. And they have nothing to do with each other.
Their only common feature is that they both stop HIV from getting inside of CD4(+) cells. They accomplish it by different mechanisms (working on different steps of the process). But they both inhibit entry into the cell.
So we're going to cover them together.
I've always loved the brand name of maraviroc. [Selzentry] just makes your mind think "cells entry" which is exactly what maraviroc is stopping HIV from doing.
Specifically, maraviroc binds to and blocks the CCR5 co-receptor on human T cells and macrophages. Notice the italics I conveniently placed for you. Maraviroc binds to a human receptor (making it the only HIV drug that has a human target).
CCR5 is a co-receptor used by HIV to enter the human cell. If HIV can't bind to CCR5; no infection.
There's a big caveat though. Maraviroc only blocks CCR5. There are actually other co-receptors that a patient may or may not have (e.g. CXCR4). HIV can just as easily use those to gain access to the cell.
So before giving maraviroc, you have to check which receptor is on your patient's cells. This is called a trofile test, and it's required (which means you'll be tested on it). Maraviroc can only be used for patients who only have CCR5 receptors.
If they have "dual" or "mixed" tropism (meaning they have other co-receptors like CXCR4), then maraviroc is a no go.
Let's cover some other clinical pearls for maraviroc.
Like (seemingly everything else we've covered), there is a potential for hepatotoxicity and rash. Notably, there is also a potential for MI or other ischemic events.
It's got a scaled dosing depending on CYP3A4 inhibitors/inducers. It's "standard" dosing is 300mg BID. However, if there is a strong 3A4 inhibitor, you'll knock it back to 150mg BID. Likewise, if there's a strong inducer, you'll increase it to 600mg BID.
At the end of the day, maraviroc's style is cramped by the tropism thing. This limits the usefulness of the drug, which limits how often you'll come across it in practice.
Enfuvirtide is another entry inhibitor. But more specifically, this one is a fusion inhibitor. Similar to maraviroc, its brand name [Fuzeon] kind of tells you how the drug works.
Basically, enfuvirtide is a protein that mimics one of the components of the HIV-1 (read: not HIV-2) fusion mechanism, throwing a wrench into the whole process. To get a bit granular, it binds gp41 to prevent the entry pore formation that lets the virus capsid into the CD4+ cell.
Unless you specialize in HIV, you will probably never see this drug. Even if you specialize in HIV, there's a good chance you'll never come across this.
It's not that enfuvirtide is bad. It's just...not that good. It's a peptide-based drug, so it's only given as an injection (and twice daily, no less).
As a quick side note, this means that enfuvirtide and zidovudine are the only 2 injectable HIV meds...file that away for test fodder.
It can cause pneumonia (always a hassle in immunocompromised patients). Injection site reactions are practically a guarantee. Throw in neuralgia and parasthesia and you've got a winning combination for some sweet adherence.
There's another issue: the product itself. Since it's an injection that's given subcutaneously, you're looking at syringes, alcohol pads, diluent, sharps waste, and having to stick yourself twice daily. I mean, look at the "convenience kit".
No lie: this is what the convenience kit contains:
60 vials of FUZEON (2 cartons of 30)
60 vials of sterile water (2 cartons of 30)
Reconstitution syringes (60 total)
3 mL safety syringe with a 23-gauge, 1" needle
Injection syringes (60 total)
1 mL safety syringe with a 27-gauge, 1/2" needle
Yes, that defines convenience. Welcome to luxury.
But, there may be another option: the Biojector 2000.
The Biojector 2000 is basically a needle-free injection system that uses CO2 to deliver a stream straight into the skin. It can deliver about 1 mL, has a single-use tip, and uses little CO2 cartridges like the ones you see in BB guns.
The idea is basically the same as Chigurh's captive bolt pistol in No Country for Old Men. Except, instead of a bolt, you've got Enfuvirtide. And instead of death you get a slightly painful, twice daily treatment.
Still, you have disposable parts to deal with, along with the fact that you're shooting liquid into your skin. And the possible neuralgia and parasthesia if used near large nerves; bruising and hematomas; and the spaceship you crash into your belly twice a day.
To be honest, the idea behind Enfuvirtide is fantastic. What better way to treat something that is invasive than to stop it from invading at all? Home Alone would have been a very different movie if Kevin McCallister were to build a big wall or a massive moat around his house to keep out The Wet Bandits.
Actually, let's run with this Home Alone analogy...
Enfuvirtide is a fictional situation in which Kevin builds a moat....
Maraviroc is kind of like when Kevin puts the charcoal lighter on the front door to prevent Marv's entry. #MarvMustBeCCR5
And basically every other HIV drug is the rest of Home Alone. The Wet Bandits (HIV) get inside the cell (house)...but they are assaulted by electrocution, paint buckets, spiders, an iron, staplers, tar, a battering ram, gasoline, bricks, a tool chest, a tool bag, toys, broken Christmas ornaments, bird seed or a shovel.
Actually, come to think about it...Kevin McCallister is kind of an ass and should probably be charged with attempted homicide. You can't throw bricks at somebody's head from the 4th story of a building and claim self defense (I realize we're blurring the lines between Home Alone and Home Alone 2, but humor me here).
Anyway, it may have taken us seven posts to get there, but I think Home Alone is a useful analogy to simplify HAART.
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It’s hard to even call this a cheat “sheet,” as this sucker weighs in at 16 pages. But you could call these 16 pages “Basically everything you need to know about HIV pharmacotherapy.” It’s got renal/hepatic dosing adjustments, adverse effects and clinical pearls, brand/generic/abbreviation for every drug and combination product, preferred regimens for healthy adults, pediatrics, and pregnancy, opportunistic infection prophylaxis and treatment, adult and pediatric dosing tables, drug-drug interactions, drug-food interactions, and (seriously) a lot more.
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Entry Inhibitor Drug Tables
Editor's Note: You'll notice as you go through these tables that the three-letter abbreviations are used for each drug. While it's not absolutely necessary to know the three-letter abbreviation, it is incredibly helpful. You'll find that most literature and HAART resources use the abbreviations.
Most abbreviations make sense and follow some sort of rhyme/reason. Others (3TC, FTC and d4T I'm looking at you), unfortunately don't seem to have much of a naming scheme. You'll just have to memorize those.
Anyway, we're using the abbreviations throughout HIV Boot Camp. So consider this a heads up. Again, they're not completely necessary to commit to memory...but they will make your life easier if you do.
|Standard Dosing||90mg SC BID||Preg: B|
|Renal Dosing||No adjustment recommended.|
|Hepatic Dosing||Not studied.|
|Notes||ADRs of Note:
Also known as T-20.
Must be reconstituted prior to use.
Reconstituted drug must be used immediately or refrigerated and used within 24 hours.
Injections should be subcutaneously given in the upper arm, anterior thigh or abdomen with rotated injection sites.
|Standard Dosing||CYP3A Inhibitors (except TPV/r): 150mg BID
CYP3A Inducers: 600mg BID
All Other Meds: 300mg BID
|Renal Dosing||<50 mL/min w/ CYP3A inhibitors: Only if benefit outweighs risk of increased ADRs|
|Hepatic Dosing||Not studied, undergoes hepatic metabolism.|
|Notes||ADRs of Note:
Only for CCR-5 Tropic HIV-1 infected, treatment-experienced patients.
Use with caution in patients with pre-existing liver conditions or HBV or HCV.
Use with caution in patients with increased CV risk.