HIV Boot Camp: PIs

HIV Boot Camp: PIs

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 III, Part IV

Part V: Protease Inhibitors

PIs. Ahhh the ever-so-important private investigators.

Err...I mean protease inhibitors.

You may recall that we've already discussed protease inhibitors in our post on Hepatitis C.

For those who haven't read that post yet (you should!), here's a quick breakdown of how protease inhibitors work. We'll also delve into adverse effects. And of course we'll have some handy drug-by-drug charts to cap it all off. 

 

Protease Inhibitor Mechanism of Action

Remember from Part I of this series, that HIV is a retrovirus. Instead of following the central dogma of molecular genetics (DNA to RNA to Protein), it starts with RNA. 

And it goes from RNA to DNA to RNA to Protein.

When HIV translates its viral genome (which it does by hijacking and enslaving your own cells), the proteins that initially come out are not fully mature. 

In fact, they're completely non-functional. 

They actually look a lot like the first draft of that paper you wrote in your college english composition class. They're loaded with unnecessary "junk." 

There's woefully inarticulate adverbs. "Passive voice" was used to much during the creation. You used the word "very" at least 2 dozen times. There's difficult to understand complex and run-on sentences that attempt to fit too many ideas into a single phrase as a way of either demonstrating complexity or just because your thoughts were poorly organized before you began writing. 

The initial viral proteins look kind of like that. 

So HIV protease comes in, and makes them look more like this:

There's adverbs. You relied too heavily on passive voice. You overused the word "very." Your thoughts were unorganized when you started writing. This led to complex, run-on sentences that are difficult to follow. 

Ahh. Much better. 

In a sense, HIV protease is the copy editor of the viral translation process. When its job is done, what's left is a protein that's ready to go to publication.

And if we were to inhibit protease?

We're left with the first draft. An immature, non-infective virus. No one's gonna read that. No one's gonna buy that on the news stands.  

Dino DNA! (Source)

Dino DNA! (Source)

Do your remember Jurassic Park? And their version of Microsoft Clippy? 

That's right. The talking DNA strand. 

The one with the syrupy Savannah, Georgia accent. "Dinosawr!"

Got it? Good.

He taught us that DNA is just a blueprint. And that "engineers" were needed to convert that blueprint into living, breathing dinosawrs. He compared the process to constructing a building. The blueprint doesn't actually create a building with plumbing and electricity. Engineers are required to build those, based off the design of the blueprint.

Protease is an engineer. It builds functional proteins from the blueprint provided by the HIV genome. 

Or, to use another analogy, I present: bagels. This mountain of dough is similar to a massive string of amino acids that the bagelmaker (protease) can cut into strands. These strands give us delicious, nourishing bagels (proteins).

Editor's note: Bagels are comprised mostly of carbs. Do not eat them if you're doing Paleo. 

Inhibiting protease means no dinosawrs and no bagels...I mean HIV.

 

Protease Inhibitor Adverse Effects

Our last post mentioned the cross-resistance to NNRTIs. If HIV becomes resistant to one of the NNRTIs, it often becomes resistant to the entire class. 

Luckily, the same cannot be said for protease inhibitors. Yes, there are certain mutations that will knock several PIs out of contention. But in general, if resistance develops to one PI you can still use another.

So that's good. Now that we've got the good of the PIs, what about the bad and the ugly?

For the bad, there is an atrocious amount of drug interactions. Every PI goes through the CYP pathway (usually 3A4). And many of the PIs induce or inhibit CYP enzymes themselves. 

CYP interactions are particularly irksome if the patient happens to need anticoagulation. Every single one of the NOACs is contraindicated with PIs. Warfarin can be monitored, but you've gotta keep it on a tight leash. 

You'll also need to watch out for anticonvulsants. Lamotrigine and levetiracetam are usually OK, but you're just asking for a headache if the patient is on phenytoin, carbamazepine, or valproic acid.

You're basically having a contest to see which drug "wins" on having the biggest impact on the CYP pathway.

Then you've got the ugly...

PIs can really screw with a person's metabolism. They can induce metabolic syndrome. They increase blood sugar. They increase serum lipids.

They can cause lipodystrophy. That's right. PIs can literally move fat from one part of your body to another. This is where you'll see buffalo humps and moon face

Add in some hepatitis (PIs can increase LFTs) and an increased risk of bleeding in hemophiliacs and you've got a recipe for fun.

If you're thinking "I'll just give the patient a statin to counteract the lipid increase," think again. Or at least choose carefully. Simvastatin and lovastatin are contraindicated with every PI. There are specific recommendations for the rest of the statins, but the general rule is "start low, go slow."

Darunavir and atazanavir seem to have the lowest risk for metabolic complications. This has led to these two being the most common PIs used today. 

 

Clinical Pearls for Common Protease Inhibitors

Darunavir

Darunavir is the only PI that is considered "preferred" therapy. You'll find it loftily sitting at the top of the DHHS guidelines along side of Integrase Inhibitors. 

That's because for a PI, it's pretty darn well tolerated. Sure, there's about a 10% risk of rash. And there's a sulfa moiety, so you have to be cautious with sulfa allergies (although cross-sensitivity is very rare and darunavir is not contraindicated). 

But in terms of metabolic profile, darunavir is the bees knees. There is considerably less glucose/lipid issues compared to most other PIs. 

Darunavir needs to be taken with a meal, or its AUC is decreased by about 40%. You'll find that this "take with meal" rule holds true for most PIs. Speaking of AUC...

There is an interaction specifically between darunavir and pravastatin. Pravastatin completely avoids the CYP pathway. So it is often considered our "go to" statin when there are CYP interactions. Darunavir, being a PI and all, has plenty of CYP interactions.

It turns out, however, that darunavir can increase pravastatin levels by 81%. And the interaction is not CYP mediated. This can, obviously, lead to myalgias, increased LFTs, and other fun side effects of statins. 

It doesn't happen in every patient. And there isn't a specific contraindication between the two drugs. But caution is advised if you're gonna use darunavir and pravastatin together. Remember, "start low, and go slow."

For a final clinical pearl, darunavir must always be boosted. It can be given either twice a day (600mg BID), or once per day (800mg QDay). No matter how it's given, it must be taken with ritonavir each time.

So ritonavir is either going to be 100mg BID or 100mg daily in patients taking darunavir.

Or...

There is a handy new formulation of darunavir called Prezcobix. It is co-formulated with cobicistat (which acts as the booster instead of ritonavir). Prezcobix only exists at the once daily dosing (800mg darunavir with 150mg cobicistat daily). 

More on cobicistat versus ritonavir in a couple of paragraphs...


Atazanavir

Atazanavir doesn't have the coveted distinction of "preferred" like darunavir has, but it's still a very common PI. It's also well tolerated on the glucose/lipids front. 

There's a few things that knock atazanavir down to the "alternative therapy" designation on the DHHS guidelines. For starters, it can increase your bilirubin. This can lead to jaundice, itching, and every other complication of increased bili you're thinking about.

It's also contraindicated with proton pump inhibitors. Atazanavir needs the acidity of the stomach to be absorbed. There is a technical loophole with treatment naive patients where boosted atazanavir can be allowable...but in practice we just avoid PPIs altogether (at least in my experience). 

You can give atazanavir with H2 antagonists, but you have to separate the dose (atazanavir goes 2 hours before or 10 hours after the H2RA). 

Atazanavir can also decrease the efficacy of oral contraceptives. Keep this in mind for your patients that are of child-bearing age...it's recommended to use another form of contraception.

And, like darunavir, atazanavir also has a new formulation with cobicistat. This one is called Evotaz, and it's given once per day. 

 

Ritonavir

I'm including ritonavir here to make an important point...

Ritonavir is never the sole PI in a HAART regimen. 

Ritonavir is not given by itself. The doses required to be effective against HIV would toxic and intolerable to the patient.

So be on the lookout for that. If you see an HIV regimen that contains ritonavir as the only PI, then something is missing...

If it's on a test, that answer choice is wrong...

If you see it in practice, you need to do a med rec.

Alright. With that out of the way, let's move on. We use ritonavir only as a "pharmacokinetic enhancer." This is just a fancy word for "booster." 

Remember all of those class side effects for PIs we mentioned above? The lipids, the glucose, the buffalo humps, and especially the drug interactions?

Ritonavir is the poster child for all of those side effects. If we give it at lower doses, we mitigate some of the metabolic risks. But we still have the CYP inhibition. And we use that to our advantage.

We use ritonavir to "boost" the concentration of other PIs. The powerful CYP inhibition by ritonavir increases the AUC and helps ensure therapeutic concentrations. It may also let us decrease the dosing frequency of the other PI. 

Ritonavir follows the dosing schedule of the drug it's boosting. And it's dose is almost always 100 mg. So if the other PI is taken twice daily, ritonavir will be given 100 mg BID. If the other PI is taken once daily, ritonavir is 100 mg once daily (we saw this with darunavir above).  

Cobicistat is the new pharmacokinetic enhancer on the block. But it's used for the same reason. It only exists to increase the concentration of other HIV meds. Cobicistat has no efficacy against the virus itself. 

Cobicistat's dose is 150 mg once daily. 

Overall, it's better tolerated than ritonavir, so we're seeing more drugs co-formulated with cobicistat. Cobicistat can increase serum creatinine, though it's not believed to cause kidney injury.

Whether you're using ritonavir or cobicistat, just remember that inhibiting the CYP pathway to boost PIs is also going to lead to drug interactions with other drugs going through the CYP pathway.

 

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

 

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.  

Atazanavir (Reyataz)

ATV

Standard Dosing 400mg QDaily
300mg + 150mg COBI QDaily
300mg + 100mg RTV QDaily
Preg: B
Renal Dosing
Hemodialysis Patients Dose
ARV-Naïve 300mg + 150mg COBI QDaily
300mg + 100mg RTV QDaily
ARV-Experienced Not Recommended
Hepatic Dosing Child-Pugh Class C: Not Recommended
Notes Take With Meals

ADRs of Note:

  • Hyperbilirubinemia
  • Prolonged PR Interval
  • Nephrolithiasis/Cholelithiasis (Stones!)
Acid reducing agents:
  • PPIs: Unboosted Not Recommended, Space PPI (Omeprazole 20mg Equivalent) by 12 Hours
  • H2RAs: 10 Hours Before or 2 Hours After Unboosted ATV, 10 Hours Before or Simultaneously for Boosted ATV
  • Antacids (Al/Mg/Ca): 2 hours before or after ATV

Oral Contraceptives:

  • MINIMUM 35 mcg Ethinyl Estradiol w/ ATV/r
  • MAXIMUM 30mcg Ethinyl Estradial w/ Unboosted ATV

Darunavir (Prezista)

DRV

Standard Dosing 800mg + COBI 150mg Qdaily
800mg + RTV 100mg Qdaily
600mg + RTV 100mg BID
Preg: C
Renal Dosing No Adjustment
Hepatic Dosing Severe Impairment: Not Recommended
Notes

Take With Meals

ADRs of Note:

  • Rash
  • Abdominal Pain
  • Sulfa Allergy (Not A Contraindication)

Lopinavir/Ritonavir (Kaletra)

LPV/r

Standard Dosing 400/100mg BID
800/200mg QDaily (Only PI-naïve, non-pregnant or <3 mutations)
Preg: B
Renal Dosing No Adjustment
Hepatic Dosing Caution, Hepatically Metabolized
Notes ADRs of Note:
  • N/V/D
  • Asthenia
  • Prolonged PR/QT Intervals

Solution: Take With Food

Oral Solution Contains 42% Alcohol

Hold Until Menstrual Age >42 Weeks / Postnatal >14 Days

Fosamprenavir (Lexiva)

FPV

Standard Dosing 1400mg BID
1400mg + RTV 100-200mg QDaily (ARV-Naïve Only)
700mg + RTV 100mg BID
Preg: C
Renal Dosing No Adjustment
Hepatic Dosing Child-Pugh 5-6: 700mg BID + 100mg RTV QDaily or BID
Child-Pugh 7-9: 700mg BID (ARV-Naïve) or 450mg BID + RTV 100mg QDaily
Child-Pugh 10-15: 350mg BID or 300mg BID + RTV 100mg Qdaily
Notes ADRs of Note:
  • Rash
  • N/V/D
  • Sulfa Allergy (Not A Contraindication)
Acid reducing agents:
  • PPIs: Okay to Use
  • H2RAs: Use With Caution, Separate Dosing

Suspension: Take On Empty Stomach

Indinavir (Crixivan)

IDV

Standard Dosing 800mg Q8H
800mg + RTV 100mg BID
Preg: C
Renal Dosing Minimally renally cleared
Hepatic Dosing Mild-Moderate w/ Cirrhosis: 600mg Q8H
Notes ADRs of Note:
  • Nephro/Urolithiasis (hydrate!)
  • Hyperbilirubinemia
  • N/V/D

Pregnancy: Not studied, varying dosing recommendations

Take with water 1 hour before or 2 hours after meals

Saquinavir (Invirase)

SQV

Standard Dosing Treatment Naïve: 500mg + RTV 100mg BID x 7 Days, then 1000mg + RTV 100mg BID
Treatment-Experienced: 1000mg + RTV 100mg BID
Preg: B
Renal Dosing No adjustment necessary
Hepatic Dosing Mild-Moderate: No adjustment necessary
Notes ADRs of Note:
  • PR/QT Prolongation
  • Pneumonia
  • N/V/D

Contraindicated in patients with AV block or QT prolongation

May open capsules and mix with 15 mL simple syrup, sorbital syrup or jam

Tipranavir (Aptivus)

TPV

Standard Dosing 500mg + RTV 200mg BID Preg: C
Renal Dosing No adjustment necessary
Hepatic Dosing Child-Pugh Class B or C: Contraindicated
Notes ADRs of Note:
  • Intracranial Hemorrhage
  • Rash
  • N/V/D
  • Impaired platelet aggregation

Store unopened bottles of capsules in refrigerator (but not oral solution)

Use with caution in patients with sulfa allergy

Do not use in treatment-naïve patients

Vitamin E: Oral solution contains 116 IU/mL Vitamin E, avoid supplementation

Nelfinavir (Viracept)

NFV

Standard Dosing 1250mg BID
750mg TID (not in pregnancy)
Preg: B
Renal Dosing No data
Hepatic Dosing Moderate-Severe: Avoid
Notes ADRs of Note:
  • Flatulence
  • Rash
  • N/V/D

May dissolve tablets in small amount of water

Take with meals

Phenylketonuria: Oral powder contains 11.2mg phenylalanine/gm of powder

Ritonavir (Norvir)

RTV

Standard Dosing 100mg/Dose as booster only Preg: B
Renal Dosing Minimally renally cleared
Hepatic Dosing Primarily metabolized by liver, use caution
Notes ADRs of Note:
  • N/V/D
  • Neurological disturbances
  • Rash

600mg QDaily was used for treatment dose, DO NOT USE AS TREATMENT

Oral solution contains 43.2% alcohol

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