HIV Boot Camp:  NNRTIs

HIV Boot Camp: NNRTIs

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 II, Part III


Non-Nucleoside Reverse Transcriptase Inhibitors, or NNRTIs (pronounced like NRTIs, but with a stutter), are the next class of HIV drugs we'll be covering.

What makes a NON-nucleoside as opposed to a regular old fashioned nucleoside reverse transcriptase inhibitor?

As we learned in our previous post, NRTIs look just like the nucleosides used by reverse transcriptase to replicate the HIV genome.

NRTIs bind to the active site of reverse transcriptase and shut down replication.

 I'm HIV. And I'm sad. 

I'm HIV. And I'm sad. 

So, being NON-nucleosides and all, NNRTIs must do something else. 

They bind to a different place (an allosteric site) on reverse transcriptase. And when they bind, the shape of the reverse transcriptase enzyme is altered enough that it can no longer bind to real nucleosides.

So once again, HIV genome replication shuts down and everyone is happy. Except for HIV. HIV isn't happy.

The cool thing about NNRTIs is that because they don't look like nucleosides, they don't have the mitochondrial toxicities of the NRTIs.

No need to worry about lactic acidosis here.

The downside is that NNRTIs have their own problems. And many of those problems occur on the regular. 

As a result, NNRTIs have moved down a rung in terms of when to use them. Just a few short years ago, the preferred triple therapy HAART regimen was an NNRTI + 2 NRTIs.

That's why you saw the once daily combination pills Atripla and Complera. 

Things have changed since then. Now the preferred regimen is an Integrase Inhibitor (II) + 2 NRTIs. The Protease Inhibitor (PI) darunavir + 2 NRTIs is also a first line regimen.

NNRTI therapy is still used (and used a lot). But they're now "less preferred" after II or PI-based regimens. 

Let's talk about the NNRTI issues that caused this shift...


NNRTI Adverse Effects

For starters, the class side effects. The big one is hypersensitivity. It's a weird type of hypersensitivity that can manifest in several ways...

Most commonly, it's rash. Not too different than the rash you'd expect from a sulfa allergy (though not at all related). 

But it can be much worse than that. 

The rash can progress to SJS/TEN. As is our standard practice at tl;dr pharmacy, if you don't know what SJS or TEN is, you can google image it and never forget (warning: awful images that you will never un-see are in the preceding link). 

The hypersensitivity can also jam up your liver. Hepatitis, elevated LFTs, and outright liver failure are potential side effects of NNRTIs.

This is of particular concern because many HIV patients end up co-infected with HepB or HepC (which mucks the liver up even more). 

There's also the cross-resistance. Some classes of HIV meds (for example, Protease Inhibitors) do well in the face of resistant strains of HIV. So if you get resistance to one PI, you can usually switch to another PI without too much risk of treatment failure. 

In other words, the viral gene that causes resistance to darunavir probably doesn't also cause resistance to atazanavir. 

That's not the case with NNRTIs.

Of course, it depends on the exact genotype of the HIV strain you're working with, but frequently resistance to one NNRTI is resistance to all NNRTIs. So once resistance develops to efavirenz (for example), your patient just lost the entire NNRTI class as a treatment option.

And finally, there's the drug interactions

Lot's and lots o' drug interactions

 No. Not  that  Big 3. ( Image )

No. Not that Big 3. (Image)

Take a quick scan through the chart in the above link. There's extensive CYP metabolism throughout the NNRTIs. But depending on the agent, you'll see a lot of oddball stuff too (e.g. acid suppressing agents and rilpivirine).

In practice, only a few of the NNRTIs are used regularly in. So in addition to the charts below, we'll first cover the important points for The Big 3.  


Efavirenz [Sustiva]

Probably the most common NNRTI in use. It's part of the combination pill Atripla, which is a complete HAART regimen in a single tablet (dosed daily).

In terms of hypersensitivity and liver toxicity, efavirenz is one of the safest NNRTIs. The risk for rash or hepatitis is pretty low compared to the rest of the class. 

It's got 2 main things going against it... 

  • It's pregnancy category D in the first trimester (more on this in the charts below)
  • CNS side effects (somnolence, vivid dreams, hallucinations, suicidal ideation, depression).

Those CNS effects are legit too. I once spoke with a patient who stopped taking Atripla because he had a dream that he rose out of his own body and killed himself.

How meta. 

We try to mitigate the CNS effects by dosing efavirenz QHS. That does the trick for most patients. 


Rilpivirine [Edurant]

Another common NNRTI is rilpivirine. It's also part of a complete regimen combination pill called Complera.

And like efavirenz, it's pretty well tolerated...with a relatively low risk of rash or hepatitis.

The "issues" with rilpivirine?

First and foremost, the potential for treatment failures. Specifically, treatment failures based off of baseline viral load and CD4 count. If your patient's baseline viral load is > 100,000 or if their CD4 is < 200, rilpirivine is not your drug. There's a high risk of treatment failure

And even worse, it's a treatment failure that can lead to broad NNRTI resistance. 

And for another strike, rilpivirine requires an acidic environment to be absorbed. It can't be be given with proton pump inhibitors, and you must separate the dose (4 hours before or 12 hours after) with H2RAs (so good luck if your patient needs BID famotidine...).


Nevirapine [Viramune] 

Remember all of that hepatitis and rash talk earlier? Nevirapine is the poster child for it.

It's got a very high risk of hypersensitivity reactions that normally show up within the first month or two of treatment (remember from earlier, NNRTI sensitivity has a tendency to show up as rash and hepatitis). 

The hepatitis risk is worse if the patient is co-infected with HepB or HepC.

There's also a couple of NAPLEX-worthy testing points...

Nevirapine has pre-treatment CD4 recommendations. Specifically, we try to avoid nevirapine if your patient's baseline CD4 count is > 400 (males) or > 250 (females). The reason? Once again, it's because of an increased risk of hypersensitivity and hepatitis. 

In practical terms, this means that we don't use nevirapine as first line therapy (unless there is an incredibly compelling reason to). 

And secondly, nevirapine is an auto-inducer. You learned about this before with carbamazepine. Basically, nevirapine speeds up the metabolism of...nevirapine.

So we have to escalate the dosing when first initiating. And just like with carbamazepine, we double the dose after 2 weeks. With nevirapine, we give 200 mg daily x 14 days, then escalate to 200 mg BID thereafter. 

Alright. Those are the "Big 3" NNRTIs. Let's look at all of them in convenient chart form.


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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.”

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The Drugs

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 the rest of 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.  

Delavirdine (Rescriptor)


Standard Dosing 400mg TID Preg: C
Renal Dosing Not evaluated, primarily metabolized in liver.
Hepatic Dosing Not evaluated, primarily metabolized in liver. Exercise caution.
Notes ADRs of Note:
  • Severe, life-threatening skin reactions (SJS, erythema multiforme)
  • Nausea

RARELY used. Who wants to take something TID when there are so many other options?

Efavirenz (Sustiva)


Standard Dosing 600mg QDaily HS Preg: D
Renal Dosing N/A
Hepatic Dosing Use with caution in patients with hepatic impairment.
Notes ADRs of Note:
  • CNS: drowsiness, dizziness, insomnia, vivid dreams, agitation
  • Teratogenic risk in first 5-6 weeks of pregnancy, consider alternative if childbearing potential. Can continue treatment if already pregnant and patient virologically suppressed.
ART Interactions:
  • Do not use with ATV/c or DRV/c

May cause false positive for cannabinoids or BZPs on screening, confirmatory negative.

EFV may also be a drug of abuse. Seriously, not kidding. (it's that aforementioned hallucination/vivid dream stuff).

Use with caution in patients with unstable psychiatric disorders (for obvious reasons if you look above).

You can find me in the club single tablet regimen Atripla (EFV/FTC/TDF). (Keep an eye out for a TAF version)

Etravirine (Intelence)


Standard Dosing 200mg BID Preg: B
Renal Dosing N/A
Hepatic Dosing Child-Pugh Class C: Not evaluated
Notes ADRs of Note:
  • Nausea
  • Hypersensitivity with rash
ART Interactions (do not combine with):
  • All unboosted PIs
  • ATV/r, ATV/c, DRV/c, FPV/r, TPV/r
  • (Standard dosing with DRV/r, LPV/r, SQV/r)

Should be taken after meals.

For patients having trouble swallowing, may dissolve with a teaspoonful of water and mix with a non-carbonated drink and take immediately (look out for this factoid on tests!). No sparkling ETR drinks here.

Nevirapine (Viramune, Viramune XR)


Standard Dosing 200mg QDaily for 14 days, then:
  • 200mg BID or
  • 400mg XR QDaily
Preg: B
Renal Dosing

No adjustments with CrCl >20 mL/min.

Hemodialysis: Give additional 200mg following hemodialysis.

Hepatic Dosing Child-Pugh Class B/C: Contraindicated
Notes ADRs of Note:
  • Increased LFTs
  • CD4 count >250 (females) or >400 (males) at greater risk for increased LFTs
ART Interactions (do not combine with):
  • ATV/r, ATV/c, DRV/c

If discontinued for >7 days, restart dosing at lower dose.

May switch between 200mg BID and 400mg QDaily XR.

Rilpivirine (Edurant)


Standard Dosing 25mg QDaily Preg: B
Renal Dosing Severe renal impairment/hemodialysis: Use with caution and monitor for side effects.
Hepatic Dosing Child-Pugh Class C: Not evaluated
Notes ADRs of Note:
  • Depression
  • Insomnia
Acid reducing agents with RPV:
  • PPIs: Contraindicated
  • H2RAs: 12 hours before or 4 hours after RPV
  • Antacids (Al/Mg/Ca): 2 hours before or 4 hours after RPV

Should be taken with meals.

Caution with drugs that cause QT prolongation

NOT RECOMMENDED if pretreatment HIV RNA >100,000 copies/mL or CD4 count <200 due to risk of virologic failure.

Part of a complete breakfast regimen in Complera (RPV/FTC/TDF) or Odefsey (RPV/FTC/TAF).

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