HIV Boot Camp: Integrase Inhibitors

HIV Boot Camp: Integrase 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 IV, Part V

Part VI: Integrase Inhibitors

Alright, so let's jump in with a quick review.

We've learned that NRTIs are the "backbone" of most HAART regimens. There is often 2 of them paired with a "non-NRTI" drug to make up the triple therapy of HAART that we know and love. 

We also discussed how NRTIs work. Using the "Frodo and Sam Analogy," we learned that NRTIs mimic natural nucleosides. They bind to the active site of HIV Reverse Transcriptase, which snatches up these fake nucleosides and tries to build DNA out of them.

This fails catastrophically, and middle earth is saved. 

NNRTIs also shut down HIV Reverse Transcriptase. But not at the active site. They bind to an allosteric site and change the shape of Reverse Transcriptase. This newer version can't bind to nucleosides as well, and so HIV genome replication shuts down.

Once again, middle earth is saved.

Protease Inhibitors work on a different step in the process of HIV replication. They work on the translation process (RNA to protein). NRTIs and NNRTIs both work on the transcription process (in HIV's case, RNA to DNA). Protease inhibitors act on one of the last steps of HIV replication.

Anyway, when HIV proteins are first getting translated by the host cell machinery, they are non-functional and jumbled. They're like a very rough first draft (complete with typos and seplling erorrs). HIV Protease transforms them into mature, functioning proteins.

By inhibiting protease, we save middle earth. 

And that brings us to Integrase Inhibitors

Integrase Inhibitors (also known as IN Strand Transfer Inhibitors...or commonly abbreviated as INSTIs) first appeared on the market in 2007. This may come as a surprise to you, but their job is to inhibit the HIV enzyme Integrase.

What does Integrase do?

It takes the DNA made by Reverse Transcriptase and inserts it into the host cell genome. Integrase literally cuts, splices, and inserts HIV DNA into the middle of your own DNA strands.

You might say that it "integrates" it. 

Remembering that HIV is a virus, it needs your cell to complete its own replication cycle. If it can't incorporate its genome into yours, it cannot replicate.

If you'd like visual assistance to help understand the full process, here is a short (but dry and narrated by a robot) video

All of this is to say... 

If you inhibit integrase, you save middle earth.

An interesting fact worth remembering is that Mg2+ is a critical co-factor for the strand transfer (i.e. the integration) process to occur with integrase. If there isn't a supply of Mg2+ available, the integration process shuts down. 

All of our current INSTIs go to the active site of integrase and bind to (chelate) Mg2+. So they basically suck up the supply and leave integrase with none. 

This becomes an important counseling point for your patients taking INSTIs. Because the drugs are designed to bind to divalent cations, their dosing must be separated from anything with a +2 charge. 

The biggest players are calcium and magnesium here. You'll commonly find them in antacids, dairy products, and multivitamins. 

In general, if you give the INSTI 2 hours before the antacid, you will be safe. There are more specific recommendations here (or in the handy charts at the bottom of this post). 

 

Integrase Inhibitor Clinical Pearls

Compared to everything else we've talked about, INSTIs are very well tolerated. That tolerability combined with a convenient dosing schedule, puts INSTIs at the top of the DHHS preferred list. Remembering that they just entered the game in 2007, this rise to the top happened quickly. 

The biggest clinical pearl is the aforementioned separation from divalent cations when dosing. That has a big impact on therapy and it's guaranteed to show up on tests. 

Otherwise, there are few "class" side effects. 

There is a small chance of rash/hypersensitivity for all agents. But the risk is very low (hovering at or below 1%). 

In general, INSTIs have improved over time. Raltegravir was the original. It's dosed BID, and it has the potential to increase CPK and LFTs. 

Next came elvitegravir, as part of the combination Stribild (and later Genvoya). It got down to once daily dosing, because it was combined with cobicistat (a pharmacokinetic enhancer used to "boost" elvitegravir concentrations). It also got rid of some of the CPK and liver effects of raltegravir. 

The biggest issue with elvitegravir is the drug interactions. The interactions aren't due to elvitegravir specifically, but to the cobicistat it's always combined with. It's contraindicated with every NOAC (except dabigatran), and causes problems everywhere else there's a CYP enzyme. 

The newest INSTI is dolutegravir. It has a few benefits over raltegravir and elvitegravir. It's dosed once daily, and doesn't need to be boosted. It doesn't have the untoward CPK/liver effects. 

But most importantly, it binds tighter and more selectively to the Integrase active site. This gives it a higher barrier to resistance than raltegravir and elvitegravir. Not only that, it has shown efficacy against HIV strains resistant to the other INSTIs

This has really catapulted dolutegravir to the forefront of INSTI regimens (and therefore HIV therapy in general). It's also included in the once daily combination pill Triumeq. 

Anyway, you can find more specifics on the INSTIs in the handy charts we below. 

 

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.  

Dolutegravir (Tivicay)

DTG

Standard Dosing
INSTI-Naïve 50mg QDaily
INSTI Mutations/Resistance 50mg BID
Strong UGT1A/CYP3A Inducers 50mg BID
Preg: B
Renal Dosing Severe Renal Impairment: Use with caution.
Hepatic Dosing Child-Pugh Class C: Not evaluated
Notes ADRs of Note:
  • Headache
  • Insomnia
  • Hypersensitivity
Drug Interactions
  • NVP: Contraindicated
  • ETV: Only if with boosted ARV (ATV/r, DRV/r, or LPV/r)

Take >2 hours before or 6 hours after polyvalent cations (Al/Mg/Ca/Zn), including multivitamins

Alternatively, may take with calcium or iron supplements if taken with food.

Elvitegravir (Vitekta)

EVG

Standard Dosing ARV-Treatment Experienced Patients, In Combination With These RTV-Boosted PIs:
PI Dose EVG Dose
ATV/r (300/100 QDaily) 85mg QDaily
LPV/r (400/100 BID) 85mg QDaily
DRV/r (600/100 BID) 150mg Qdaily
FPV/r (700/100 BID) 150mg Qdaily
TPV/r (500/200 BID) 150mg Qdaily
Preg: B
Renal Dosing No Adjustment
Hepatic Dosing Child-Pugh Class C: Not evaluated
Notes ADRs of Note:
  • Diarrhea
  • Nausea
  • Headache

Take >2 hours before or 6 hours after polyvalent cations (Al/Mg/Ca/Zn), including multivitamins

Take with food

Coadministration with COBI-boosted PIs is NOT recommended due to lack of dosing recommendations.

 

Raltegravir (Isentress)

RAL

Standard Dosing 400mg BID Preg: C
Renal Dosing No Adjustment
Hepatic Dosing Severe Impairment: Not evaluated
Notes ADRs of Note:
  • Insomnia
  • Headache
  • Elevated AST/ALT/CPK
  • Myopathy/Rhabdomyolysis

Take >2 hours before or 6 hours after polyvalent cations (Al/Mg/Ca/Zn), including multivitamins

 

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