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.

You can get a downloadable (and printer friendly) PDF of the entire series here.

Part VII: Entry Inhibitors & Attachment Inhibitors

Well, we're coming full circle here. Our epic series on HIV is nearing its coda. We've only got two "classes" of HIV meds left to talk about.

The Entry Inhibitors and Attachment 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.

We also have two newer arrivals: Trogarzo, which binds to CD4 receptors, and Rukobia, which is an attachment inhibitor. Like entry inhibitors, these stop HIV from invading CD4+ cells—but through entirely different mechanisms.

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.

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).

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.

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 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)

Trogarzo

Trogarzo (ibalizumab) is a humanized monoclonal antibody (remember, the ‘zu’ part of the name ibalizumab tells you it’s humanized) that binds to your CD4 receptor. It is indicated for salvage therapy (and not monotherapy). So think of Trogarzo for your heavily “treatment-experienced” HIV patient that has failed multiple regiments and/or has a high mutational burden.

Specifically, Trograzo binds to domain 2 of CD4. Why does that matter? Because your macrophages (and other MHC Class II cells) bind to domain 1. By binding specifically to domain 2, Trogarzo allows other immune cells to bind to domain 1 and do their thing.

Interestingly, HIV can also still bind to your CD4 receptors. So Trogarzo doesn’t actually stop HIV from binding to your T-cells. It stops the step that happens after binding (where CD4 goes through a conformational change so that HIV can bind to its CCR5 co-receptor).

All in all, Trogarzo seems very well tolerated with the most commonly reported adverse effects of diarrhea, dizziness, nausea, and rash. It is a monoclonal antibody so there is always a risk of infusion reaction—but, severe rash was only reported in 1 patient.

In terms of dosing, you give a 2000 mg load followed by 800 mg IV every 2 weeks. So automatically, when you sign on for Trogarzo, you’re signing on for a visit to the infusion center every two weeks for life or until treatment failure. In addition to the time of infusion, you’re also going to need to be monitored after the infusion (because of the risk of infusion reaction). That’s an additional 1 hour of waiting for your first dose, but it reduces to 15 min for your subsequent doses.

Lastly, holy crap is ibalizumab expensive. The Wholesale Acquisition Cost (WAC) is right around $118,000 annually. To their credit, Thera Technologies has said that "the majority of patients will pay less than $25 per infusion in out-of-pocket costs for Trogarzo."

Of course, even if the patient isn't paying all of that extra money, someone is. And through increased healthcare costs, we all are paying for it eventually. That money doesn't just come from a magical pot of gold.

But that's a conversation for another day and another post.

For now, if you're one of the ~25,000 people with multi-drug resistant HIV, you've got a new treatment option in ibalizumab (as long as you're an adult, Trogarzo hasn't been studied in peds yet). This was deemed important enough by the FDA to give Trogarzo Fast Track, Priority Review and Breakthrough Therapy designations. It also got an Orphan Drug designation.

Rukobia

Lastly we have Rukobia (fostemavir) which is a gp-120 directed attachment inhibitor. Rukobia is only indicated for patients who are heavily treatment resistant.

In order to enter CD4+ cells, HIV uses a protein-based envelope spike and attaches to the cell membrane. This envelope spike is made of glycoproteins 120 and 41.

By inhibiting gp-120, Rukobia prevents the initial viral attachment to the cell membrane. It’s similar to entry inhibitors…only slightly different. Like drug cousins.

In terms of dosing, Rukobia is administered as an extended release 600 mg tablet twice daily, with or without food. Yay for no needles!

We do have to be mindful for CYP450 interactions as Rukobia is a CYP inhibitor. Other adverse effects include:

Immune reconstitution syndrome
QTc prolongation
Increased hepatic transaminases in patients with hepatitis B or C

On top of monitoring, we have to consider how much this medication costs. A quick google search shows that a 30 day supply of Rukobia costs $7, 650—or, $91, 800 annually. Keep on mind that this is add-on therapy, so the patient is already paying for their current regimen.

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?

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.

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.

HIV Boot Camp: Entry Inhibitors & Attachment Inhibitors