HIV Boot Camp: Entry Inhibitors

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 IPart IIPart IIIPart IVPart 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. 

Maraviroc

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. 

Maraviroc: the chastity belt of T cells (source).

Maraviroc: the chastity belt of T cells (source).

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. 

Sorry Captain America: trofile, not profile (source).

Sorry Captain America: trofile, not profile (source).

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

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.

"Convenience Kit" (source).

"Convenience Kit" (source).

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... sort of looks like a spaceship (source).

The Biojector 2000... sort of looks like a spaceship (source).

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

Visual representation of maraviroc's MOA (Image)

Visual representation of maraviroc's MOA (Image)

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. 

 

Do You Want an HIV Cheat Sheet?

This well-designed sheet gives you the deets and clinical pearls you need to you through your ID module, your APPE rotation, the NAPLEX, or your practice career.  

It packs a ton of useful (read: testable) information in a single page. Pre-treatment requirements, CrCl cutoffs, notable adverse effects, which PIs must be boosted, which drugs are safe in pregnancy, drug interactions, and much more. You could basically call this sheet “HIV drug trivia likely to show up on the NAPLEX.”

It's yours for only $4

 

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.  

Enfuvirtide (Fuzeon)

ENF

Standard Dosing 90mg SC BID Preg: B
Renal Dosing No adjustment recommended.
Hepatic Dosing Not studied.
Notes ADRs of Note:
  • Injection Site Reaction (98%!!!)
  • Neuralgia/Parasthesia (Biojector 2000)
  • Pneumonia

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.

Maraviroc (Selzentry)

MVC

Standard Dosing CYP3A Inhibitors (except TPV/r): 150mg BID
CYP3A Inducers: 600mg BID
All Other Meds: 300mg BID
Preg: B
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:
  • Cough
  • Fever
  • URTIs
  • Rash
  • Musculoskeletal Symptoms
  • Abdominal Pain
  • Dizziness

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.

The Ultimate Guide to HIV for Pharmacists

The Ultimate Guide to HIV for Pharmacists

The Complete (but Practical) Guide to Aminoglycosides

The Complete (but Practical) Guide to Aminoglycosides

0