The Ultimate Guide to HIV for Pharmacists

The Ultimate Guide to HIV for Pharmacists

Editor's Note: Over a period of several months, we wrote a 7 part series on tl;dr pharmacy called "HIV Boot Camp." However, we don't like clicking around several different posts to find specific information, so we thought we'd make it easier for you. 

The following is an organized (and slightly condensed) summary of the entire HIV Boot Camp series. This Ultimate Guide will shore up your HIV fundamentals, then go through each drug class piece by piece to highlight what you need to know (including dosing tables!).

We've also made an HIV Cheat Sheet that covers most clinically relevant (i.e. testable) facts about current HAART meds. Be sure to check that out. It's a handy companion that will get you through your ID module, an APPE rotation or the NAPLEX with ease. 

 

Background and Pathophysiology

 

Background

HIV is a bastard. Let's just start right out with that. Although it's thought to have been around for decades, it didn't really "arrive" on the US scene until the early 1980s. It made it's first splash with strings of case reports involving healthy gay men getting a rare lung infection called Pneumocystis carinii pneumonia (PCP). 

After about a year, with more cases of PCP mounting up, it was decided that something sexual must be transmitting this immune deficiency. It was considered an immune deficiency because PCP does not typically cause disease in healthy people. 

So the super awesome and totally PC move was made to call this new syndrome "GRID." Gay-Related Immune Deficiency. Yep. That's what science decided. 

Anyway, then some other stuff happened. We eventually started calling it Acquired Immunodeficiency Syndrome (AIDS). We learned that it was caused by a retrovirus named Human Immunodeficiency Virus (HIV). Getting diagnosed with the HIV was basically considered a death sentence. Tom Hanks won an Oscar. The Broadway musical "Rent" was made. Magic Johnson defeated the virus with cash. And eventually treatment advanced to present day where (if managed properly) HIV can almost be considered a chronic disease. Not too dissimilar from heart disease or diabetes. 

As an interesting (to me) side note, HIV is one of the earliest retroviruses ever discovered. Our central dogma of biology clearly stated that the order of operations went from DNA to RNA to Protein. We had a hard time figuring out what HIV was because it went from RNA to DNA to RNA to Protein. More on that in a bit...

 

Pathophysiology

So what exactly does HIV do to the body?

Like other viruses, it hijacks your body's cells and turns them into virus factories. From the patient's perspective, it goes like this. You're exposed and nothing happens for about 10 days. The virus exposure most likely came from either unprotected sex or IV needle sharing. But it can also be transmitted vertically (mother to baby).

Anyway, you're feeling fine and then all of a sudden you're not. You have to leave work early because you've got a fever of 102 and you're all achy. Your head hurts. You're exhausted. Your face is flushed. There's a rash on your back and abdomen. Every time you swallow it feels like you're trying to get down a golf ball. You take Advil. It does nothing. You take Tylenol. It does nothing. You lay down on the couch and try to binge watch the new season of Unbreakable Kimmy Schmidt. But you can't focus. You throw up into the small bathroom trash can you placed by the couch. You have a hard time keeping down even gatorade and sprite. 

Then you keep doing this for a full week or two. 

You try going to a doctor. They run an influenza test (if it's in season) and find that it's negative. They tell you that you probably have the flu anyway. They say to keep up your fluid intake and to try to eat a soft diet of soups and broths. 

Finally (thank God) it gets better. You start to feel normal again. You're exhausted and dehydrated, but your appetite comes back. You go back to work. And after another few days or so you start to feel like your old self again. You finally resume your social life and everything is right in the world again. You go on about your life for a few years with no real restrictions.

Then things start getting weird. You feel like you're constantly getting colds. You've been losing weight gradually for a few months. You've had bronchitis 3 times this year. Last month, you had an ear infection. A friggin' ear infection! What are you, 5 years old?! Finally on what feels like your 14th trip to the doctor, they take some blood and run some tests.

A day or two later, they call you and ask you to come into the office.

They sit you down on the exam chair with the disposable rolled out paper. And they tell you that you have HIV. Your CD4 count is 160. They want to send you to a specialty clinic to do some more tests and discuss treatment options.

So what's happening in the story above?

Once in the body, HIV burrows its little way into the cells of your immune system. Primarily, it goes into T lymphocytes (specifically, CD4+ T-lymphocytes), but it also can infect macrophages, dendritic cells and more. When it first causes infection, it spends some time under the radar replicating in these immune cells. 

Eventually, the immune system catches on and gets pissed. It goes ape shit for a few weeks launching every countermeasure it can think of. Think "Independence Day" where we ineffectively send planes and even atom bombs up against the aliens to try to beat their superior technology.

The body develops antibodies to HIV. This is called seroconversion, and it's what the poor patient above was going through for 2 or 3 weeks feeling like he had the flu. 

Then it enters a "clinical latency" phase that can last for years. Patient's are asymptomatic, but behind the scenes their CD4 counts are steadily dropping at a rate of about 200 cells/ml per year. Meanwhile, the number of HIV copies in the body is steadily increasing. On a graph, it looks like this:

HIV Time Course. Image Source: Wikimedia Commons

HIV Time Course. Image Source: Wikimedia Commons

 

Eventually, CD4 counts get so low that "weird diseases that don't infect healthy people" start showing up. These are the opportunistics such as PCP and MAC. Untreated, HIV is indeed a death sentence....but indirectly. It's normally a respiratory infection or similar that technically ends up "killing" the patient. 

 

About that retrovirus bit from earlier...

We'll go into more specifics of the virus life cycle when we talk about the actual treatments for HIV. That way we can see what each drug class does to affect each stage of viral replication. But, we'd be remiss to not mention this one bit about retroviruses in general.

They mutate all the damn time.

Most known retroviruses (HIV included) use an enzyme called reverse transcriptase to break the central dogma of DNA to RNA to Protein. Reverse transcriptase is what converts RNA into DNA. It's also extremely error prone. It's like that friend you have that never has her shit together. She's always late. She's forgets to bring her pencil to class. She locks her keys inside her car. She's clutzy. She just spilled coffee on herself (again). 

That's what reverse transcriptase is. Like your friend, reverse transcriptase means well. It tries to faithfully convert RNA to DNA with no mistakes and no hassle. But inevitably it always makes a mistake. 

Why does this matter?

Because a virus that mutates all the damn time is a pain in the ass to treat. It quickly gains resistance to a given drug or a regimen. Meaning that even stable patients will periodically need to check their viral loads and CD4 counts. If either starts going in the wrong direction, then it's time to run another genotype to see if there's new resistance. 

 

Treatment Goals and Considerations

Alright. So now we've got the background and patho under our belts. We've also looked at a small glimpse of what a patient might experience in the early days of an HIV infection.

As practitioners, we have to ask ourselves "Now what?" Is it time to just give the patient an Atripla and go on about our day?

Ummm...No. 

Baseline Labs

First things first, we're gonna need to get some information. Some more intel. Some deets.

At a minimum, we need to check the baseline CD4 count, HIV viral load, a Basic Metabolic Profile (BMP), and a Complete Blood Count with differential (CBC w/ diff). However, while we're at it, we should also grab the viral genotype. And the patient's fasting lipid profile andliver panel. Finally, for an added bonus, we're going to throw in theHLA test too. There's a lot deeper we can dig as far as lab work goes. But this is a good "Start Here" list that will get you through most scenarios. 

That's a lot of information. What do we need all of that for?

CD4 - Remember that CD4 is a receptor on the T-helper cells of your immune system. And that HIV specifically targets these CD4(+) T cells. So we measure and monitor CD4 counts for for a couple of reasons. For starters, some practitioners don't believe in starting Highly Active Antiretroviral Therapy (HAART) until the CD4 count drops below a certain number (this number is usually 500). There isn't a consensus on this though. Many other practitioners recommend in starting HAART as soon as possible. There's not necessarily a right or wrong answer here....

It's kind of like debating which way to load a toilet paper roll (but withslightly more at stake). You'll get strong proponents from each side. And each will have a list of reasons why they are right. But if you don't have small children/cats and you load toilet paper "bottom up," then you and I have nothing in common and could never develop any kind of meaningful relationship. 

For what it's worth, some of the most recent guidelines recommend initiating HAART in every HIV patient....regardless of CD4 count. If you read that link, you'll see it's a pretty strong recommendation. So it's probably "more right" (much like loading the toilet paper "top down" is more right). Just be aware that you could see differing recommendations and practices. 

Anyway, we also need a baseline CD4 count because certain drugs (I'm looking at you, nevirapine) cannot be initiated if the CD4 count is too high. We'll get more in why that is as we delve deeper into each drug class. Spoiler alert: For nevirapine, it's because of liver toxicity. 

We'll also continue to monitor CD4 count throughout treatment as a way to determine the effectiveness of the regimen. In general, you're looking for an increase in CD4 count...or at least for it to hold steady. If you notice that the CD4 count is decreasing, it's time to re-evaluate the patient's therapy. Most likely you're either dealing with resistance from HIV or a lack of compliance from the patient. 

Just for a quick review, HAART is basically considered synonymous with "HIV Treatment." It's the drugs that we give. HAART used to specifically mean 'triple therapy.' Prior to HAART, we treated HIV with zidovudine or another drug as monotherapy, so the name HAART carried some weight. But when we started moving to triple therapy as the standard of care, the name HAART became slightly less relevant. Either way, it's a term that is still used by basically everyone so now you're at least familiar with it. 
Young Anakin's viral load is even higher than Master Yoda's (Image)

Young Anakin's viral load is even higher than Master Yoda's (Image)

HIV Viral Load - Next up, we need the viral load (ie. How many copies of HIV exist per ml of blood). Think of viral load as the opposite of CD4 count.

  • Low viral load = Good
  • High viral load = Bad

So we use viral load as another marker (along with CD4 counts) to measure how therapy is progressing. If the viral load is decreasing, and CD4 count is increasing....then our treatment is working. 

If the viral load starts to rise (which will typically correlate with a decrease in CD4), however, then it's time to reassess therapy. 

We also check the viral load because if it's too high then it excludes certain drugs from being used. Specifically, rilpivirine is prone to treatment failures if the viral load is > 100,000 when initiating. 

BMP - Primarily, this is all about renal function. As you'll soon see, NRTIs form the backbone of most HAART regimens. And every NRTI (except abacavir) requires a renal adjustment. Well how are we going know what renal function is without a BMP? Yes we could do a 24 hour urine collection and get an even more accurate picture of CrCl...but who has the time? The BMP will also let you assess if electrolytes are out of whack and need correcting. 

CBC w/ diff - You can get a pretty decent picture of what the immune system is doing by looking at a CBC w/ diff. It won't tell you anything specifically pertaining to HIV, but remember that HIV's calling card is making people sick with other infections. The CBC w/ diff helps to evaluate that by breaking down white blood cell (WBC) counts. It also gives a good baseline on where your patient stands in terms of anemia (via hemoglobin) and if they are a bleeding risk (via platelets).   

Viral Genotype - Also known as the "resistance panel," you have to check this to see which HIV medications will be effective against the actual virus you're fighting. As we mentioned in Part I of this series, retroviruses mutate all the damn time. This leads to resistance to medications and treatment failures. Just like bacteria have genes that make them resistant to methicillin, there are genes on the HIV genome that cause resistance to the entire class of NNRTIs. 

Checking the viral genotype will make sure we're selecting an appropriate combination of drugs. 

Lipid Profile - We'll check this at baseline especially if the patient will be using protease inhibitors as part of their HAART regimen. Many of the protease inhibitors can do wacky things to your lipid panel, so we can use this as a way to monitor that. Please note that this test must be done in a fasted state. One of the most common causes for crazy numbers on a lipid profile test is the patient eating a Denny's Grand Slam before coming to their appointment.

That "fasted" bit has a habit of showing up on tests as well. I've seen more than one patient case study question that snuck in a patient eating before taking a lipid test.

Liver Panel - First of all, it is unfortunately very common for HIV patients to be co-infected with hepatitis. So we should really check out what's going on with the liver. But secondly, many of the potential HAART drugs a patient may take can cause liver problems. Getting a baseline LFT helps us monitor and prevent liver complications. 

HLA Test - HLA stands for Human Leukocyte Antigen. It's a protein that's on the surface of your macrophages. As pharmacogenomics has become more of a thing, HLA tests have played an increasing role in drug therapy. There are thousands of known variations (polymorphisms) of HLA.

We've found that certain drugs do bad things to people if they have the "wrong" HLA type. Specifically in HIV, if your patient has the type HLA-B*5701, you cannot give them abacavir. This is kind of a big deal, as you'll see one of our preferred HAART regimens contains abacavir. 

What happens if you give abacavir to a person with HLA-B*5701 on their macrophages? Basically their immune system goes apeshit. They have a pretty decent chance of developing a huge hypersensitivity reaction. They may go into shock and die. They may develop SJS or TEN. Either way, it's just something to avoid. 

HLA-B*5701 is a very important HLA to remember. It is one of the few HLA tests that are required before treatment. This will show up on the NAPLEX and other tests. If your patient has not had an HLA test, they cannot receive abacavir. The HLA type doesn't change, so it's just nice to grab an HLA test in the very beginning when you're initially working up the patient. Then you'll know from the get go if abacavir is ever an option. 

 

Treatment Goals

What is our end game here? What are we actually trying to accomplish with HAART therapy? Unfortunately, we cannot eradicate HIV at this time. Once contracted, you're pretty much a lifer. 

That being said....properly managed, HIV is not the death sentence it once was. Patients can live normal lives for decades with the treatment advances that have been made. So what are our treatment goals?

  • To suppress the HIV viral load. 
  • To preserve and restore immune function
  • To reduce morbidity and prolong survival
  • And to prevent the transmission of HIV

With regular monitoring and adherence to HAART, these goals can be met pretty much indefinitely. 

 

Treatment Considerations

In the interest of time and space, what follows is far from an exhaustive list. There are phenomenal resources here and here if you really want some handy info. What follows is more of a tl;dr summary. These are the biggest points you need to orient yourself with HAART therapy. And again, we'll be drilling down into a lot more drug-specific information when we go through each of the respective drug classes. 

 

1. Never use monotherapy

Back in the day, one drug may have been enough. Zidovudine monotherapy was pretty much our treatment strategy for much of the '80s (AZT Break). But much like the NBA, you generally need a big 3 to succeed now (Lebron/Wade/Bosh, any three Spurs, Green/Curry/Thompson, Kobe's left hand/Kobe's right hand/Fisher...you get the idea). So the standard of care is triple therapy. There are always exceptions, of course. But start by assuming that everyone gets triple therapy.

What makes up that triple therapy? The "backbone" of any HAART regimen is two NRTIs + "something else." That something else is usually an integrase inhibitor, a protease inhibitor, or an NNRTI. 

Lucky for us (and patients), there are plenty of single tablet regimens out there to make things easy. Atripla, Complera, Stribild, Triumeq, Genvoya, Odefsey. There's a growing list of options to choose from. These all contain an NRTI backbone and the "something else" in a convenient once daily tablet. 

 

2. Preferred HAART Regimens

There are several HAART regimens that are considered "preferred." They're preferred because they have a solid efficacy and safety profile. They work, and they are tolerated with minimal side effects.

Assuming your patient doesn't have resistance to one of the components (which we check through the viral genotype), or some other baseline lab abnormality, you'd start them with one of the following regimens. The brand name has been included if the regimen exists as a single-tablet combination pill. 

  • dolutegravir + abacavir + lamivudine [Triumeq] 
  • dolutegravir + emtricitabine + tenofovir
  • elvitegravir/c + emtricitabine + tenofovir [Stribild]
  • elvitegravir/c + emtricitabine + tenofovir alafenamide [Genvoya]
  • raltegravir + emtricitabine + tenofovir
  • darunavir + emtricitabine + tenofovir

These are the preferred regimens. You'll notice that all of them contain an integrase inhibitor, except darunavir (a protease inhibitor). You'll also see that the preferred list does not include an NNRTI. You'll find these under "alternative" regimens. They're still good choices. In fact, NNRTIs combinations like Atripla and Complera were the preferred regimens just a few years ago. But the new integrase inhibitors (and their wonderful tolerability) have moved them to the forefront.

You may also be confused by tenofovir alafenamide. You can read more about this new formulation of tenofovir on our post here

 

3. Opportunistic Infection Prophylaxis

Remember from Part I, that we discovered HIV from otherwise healthy males becoming infected with a rare pneumonia. Opportunistic infections are things that don't normally cause disease in healthy patients. But when you lack a functioning immune system (ala HIV, leukemia, etc) then they can start showing up. 

With HIV specifically, we've been able to correlate when these infections start causing problems to a CD4 count. There are 3 main bugs to worry about here. Pneumocystis jirovecii pneumonia (PCP),Toxoplasma gondii encephalitis, and Mycobacterium avium complex (MAC). What you need to memorize are the CD4 counts where you'd need to begin prophylaxis. And the drugs we actually use for prophylaxis. 

For PCP, we begin prophylaxis when the CD4 count dips below 200. For toxo, the count is 100. And for MAC, the CD4 count is 50. Conveniently, sulfamethoxazole-trimethoprim (SMZ/TMP) covers both PCP and toxoplasma. So when you start a patient on PCP prophylaxis, you're also covering toxo. MAC is covered with either azithromycin (preferred) or clarithromycin. To summarize:

  • CD4 < 200 = PCP (SMZ/TMP)
  • CD4 < 100 = Toxo (also SMZ/TMP)
  • CD4 < 50 = MAC (azithromycin or clarithromycin)

That's all for now. In Part III, we start breaking down each drug class. We'll start with NRTIs, as they make up the backbone of most regimens. Stay tuned!


Simplify Your Studying with The 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

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Nucleoside Reverse Transcriptase Inhibitors make up what's called the "backbone" of every traditional HAART regimen. It is also an awfully long phrase to type, so I will refer to them only as "NRTIs" from here on out. 

But before I go on, there's another distinction I have to make. There are actually both nucleoside and nucelotide reverse transcriptase inhibitors. We lump them into the same "NRTI" bucket because they work in exactly the same way. But they are technically different from each other. 

I never thought my bachelors degree in Molecular Genetics would come in handy, but here goes. Let's time travel back to the stuff you learned about in your own genetics pre-pharm classes. All the way back to DNA base pairs. A DNA base pair is the A, T, G, and C that make up a DNA sequence. They also form the title of a charming movie called "GATTACA." 

In a technical sense, nucleoside is one of those DNA base pairs (A,T,G, or C) attached to a sugar.

A nucleotide is the same thing. But with a a phosphate attached to it. So you might have something like 5'-Adenosine monophosphate.

Chemically, what you have is this:

Nucleoside: Base + Sugar
Nucleotide: Base + Sugar + Phosphate

When a nucleotide loses it's phosphate through hydrolysis (or any other means), it becomes a nucleoside.

Back to our NRTIs. All of them are nucelosides....except for tenofovir. Tenofovir is the only nucelotide of the bunch. As far as I know, there is no active research into getting more NRTIs (nucleoside or nucleotide), so this is going to be the landscape for a while. 

Does any of this really matter much to you in terms of pharmacy school? No, not really. But you're here to learn right? You might win something on HIV drug trivia now. Or you can be like one of those smug people that go around correcting everyone on their english. 

Get it? Cause it's an owl. Owls say "who" (Image)

Get it? Cause it's an owl. Owls say "who" (Image)

Anyway, that's enough "science" for now. Let's get on with it. 

How do NRTIs work?

NRTIs are designed to mimic natural nucleotides in structure, but not in function.

To try and describe how this works: imagine you run an evil corporation that makes knock-off cell phones. You go out to get some source material to make these cellphones, and some guy in a suit sell you what looks like gold and feels like gold for your circuits.

When you go and try to make your phones, the "gold" basically mucks up your systems. Your factory shuts down and you die of dysentery (for some reason) like you were on the Oregon Trail.

In the same way, NRTIs muck up reverse transcriptase by inserting themselves into the genome, but then shutting down transcription . No reverse transcription? No viral replication.

Or, to put it another way, think of when you were asked to recreate a drawing as a kid. You get that 4 crayon box with four colors (AGTC). What NRTIs essentially do is come in (like a bully) and replace the Crayola crayons you had with some plastic colored sticks that don't color at all. Now you can't recreate the drawing. You become sad, and you no longer function.

The nucleotides of art. (Source)

The nucleotides of art. (Source)

Because crayons are life.

Or, for yet another example (because sometimes you need 3), we once made an analogy comparing NRTIs to Frodo and Sam marching undetected through Mordor to throw the One Ring into Mt. Doom and ruin Sauron's shit.

Moving on...

The downside of NRTIs is that since they mimic actual nucleotides, they can also screw up human genome replication (by screwing with DNA polymerase).

Luckily, beautiful human creatures like ourselves have built in redundancy to correct mistakes made by DNA polymerase. HIV's Reverse Transcriptase does not have said redundancy. Unfortunately, our redundancy process is not perfect and adverse effects still happen.

Let's talk about those adverse effects.

We'll start with class side effects. These are things that can occur with any NRTI.

Damage to DNA, particularly in the mitochondria (the power house of the cell!) leads to most adverse effects attributed to NRTIs. Lactic acidosislipoatrophy (if you don't know what this is, Google it and you will never forget), and peripheral neuropathy.

A mantra that fellow HU (#youknow) alumni will recognize is "lactic acidosis and hepatic steatosis." It was drilled in our heads by our wonderful IT2B professor. It rhymes. And it's a black box warning for every single NRTI. Remember this, and you will appreciate it when it shows up on the NAPLEX.

Moving on to individual agents, we're going to do something a little different. There are several NRTIs, and each has its own quirks. There's a lot of great resources available for HAART information. AETC (our personal fave), AidsmapWHO, and CDC to name a few. 

Well....we're going to give you more drug-specific information. The tl;dr way.

For starters, tenofovir is worthy of a special mention. It is included in a lot of combination regiments, it's also used to treat HBV, and it's recently been getting a formulation makeover from Gilead. In large part, the salt tenofovir disoproxyl fumerate (TDF) is being converted to tenofovir alafenamide (TAF). TAF has better cell penetration, so it can be given at a lower dose and maintain the same efficacy. There's solid data showing that it has lower toxicity in the two main "problem" areas for tenofovir (renal failure and osteoporosis). We've been writing about a lot of the new agents as they've been approved by the FDA. 

Anyway, for your convenience, here's a handy list of the "cousins" that currently exist. The TAF brand is on the left, and the TDF brand is on the right:

  • Vemlidy = Viread
  • Genvoya = Stribild
  • Odefsey = Complera
  • Descovy = Truvada

As for the other individual NRTIs, we've got some dosing tables for you. What you'll see in the tables below includes the pertinent dosing (and dose adjustments) you need for each agent. The tables will also highlight some important characteristics worth noting about each drug (ex. tenofovir is associated with both renal failure and osteoporosis). 

We tried to make it nice and easy by breaking things down in tables. It's not an exhaustive resource on each drug. But it's more than what you'd need for the NAPLEX (and for most practice situations). 

 

NRTI Dosing Charts

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 this post. 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

Tenofovir Disoproxil Fumarate (Viread)

TDF

Standard Dosing 300mg QDaily Preg: B
Renal Dosing
CrCl (mL/min) Dose
30 – 49 300mg Q48
10 – 29 300mg Q72 or Q96
Dialysis 300mg Q7D or 12H Post-Dialysis
Hepatic Dosing N/A
Notes ADRs of Note:
  • Fanconi syndrome (TDF will F' up kidneys)
  • Acute renal failure (again, F' up kidneys)
  • Decreases bone mineral density (osteopenia/osteoporosis)
ART Interactions:
  • ddI levels increased
  • ATV levels decreased (must boost ATV)
  • ATV/r DRV/r LPV/r all increase tenofovir concentrations

As noted earlier, TDF is the only nucleotide of the bunch.

TDF is also used for Hepatitis B (HBV) treatment so avoid abrupt withdrawal if treating HBV or HIV/HBV-infected.

A newer formulation, Tenofovir alefenamide (TAF) is available as part of combinations (Descovy, Genvoya), but not as single agent as of this post. TAF seems to be less nephrotoxic and safer for the bones.

Emtricitabine (Emtriva)

FTC

Standard Dosing 200mg Capsule QDaily
240mg Solution QDaily
Preg: B
Renal Dosing
CrCl (mL/min) Capsule Solution
30 – 49 200mg Q48 120mg QDaily
15 – 29 200mg Q72 80mg QDaily
<15 or Dialysis 200mg Q96 60mg QDaily
Hepatic Dosing N/A
Notes

ADR of Note:

  • Hyperpigmentation of palms/soles (aka: palmar/solar rash) (aka: hand and foot syndrome)
  • Hypersensitivity reaction

FTC also covers Hepatitis B, so avoid abrupt withdrawal in patients with (HBV) due to possible flares.

Structurally similar to Lamivudine (Epivir, 3TC). They're like cousins. So avoid the combination. Cause that's just weird. This also means that if HIV gets resistant to FTC, then it is also resistant to 3TC.

Lamivudine (Epivir)

3TC

Standard Dosing 300mg QDaily
148mg BID
Preg: C
Renal Dosing
CrCl (mL/min) Dose
30 – 49 148mg BID
300mg QDaily
15 – 29 148mg Once, 100mg QDaily
5 – 14 148mg Once, 100mg QDaily
<5 48mg Once, 25mg QDaily
Hepatic Dosing N/A
Notes

Avoid abrupt withdrawal in patients with Hepatitis B infection (HBV) due to possible HBV flares (that's right, it also covers HBV).

Goes to the same family reunion as Emtricitabine (Emtriva, FTC). In fact, they ran into each other at an Easter gather up this past year. So again, don't use them together in your HAART regimen.

Abacavir (Ziagen)

ABC

Standard Dosing 300mg BID
600mg QDaily
Preg: C
Renal Dosing

No renal adjustments here. This is the only NRTI that does not require a renal adjustment

But do note: Alcohol dehydrogenase is the mechanism of choice, so if anything no drinky and abacaviry. Alcohol can raise levels by 41%.

Hepatic Dosing Child-Pugh Class A: 200mg BID
Notes

HLA-B*5701 testing is required. This is one of the very few HLA tests required by the FDA prior to treatment (For the love of everything Holy, please remember this on the NAPLEX). If the test comes back positive, DO NOT GIVE ABACAVIR.

Abacavir can cause hypersensitivity reactions that lead to organ failure and death. Being HLA-B*5701 positive predisposes a patient to the reaction.
If someone develops a reaction, stop and DO NOT RECHALLENGE.

HIV RNA >100,000 copies? Don’t use ABC unless with dolutegravir. Dolutegravir is Abacavir’s bathroom buddy. You'll find them together (along with lamivudine) in the combination product Triumeq.

Didanosine (Videx EC)

ddI

Standard Dosing
Body Weight (BW) Dose
<60 kg 248mg QDaily
125mg BID
>60 kg 400mg QDaily
200 mg BID
Preg: B
Renal Dosing Capsules
CrCl (mL/min) BW <60 kg BW >60kg
30 – 59 125mg QDaily 200mg QDaily
10 – 29 125mg QDaily 125mg QDaily
<10 or Dialysis POWDER 125mg QDaily

Powder
CrCl (mL/min) BW <60 kg BW >60kg
30 – 59 148mg QDaily
75mg BID
200mg QDaily
100mg BID
10 – 29 100mg QDaily 148mg QDaily
<10 or Dialysis 75mg QDaily 100mg QDaily
Hepatic Dosing N/A
Notes

Not commonly used today, because it's side effect profile sucks. It has a similar side effect profile as Stavudine (Zerit, d4T) . Both have documented neuropathy, fatal hepatic events and pancreatitis. So don't use them together. Also note that Didanosine and Stavudine are the only HAART medication with a weight-based dosing. That's just begging to show up on a test somewhere...

Save the pancreas.

Stavudine (Zerit)

d4T

Standard Dosing
Body Weight (BW) Dose
<60 kg 30mg BID
>60 kg 40mg BID
Preg: B
Renal Dosing
CrCl (mL/min) BW <60 kg BW >60kg
26 – 48 15mg BID 20mg BID
10 – 25 or Dialysis 15mg QDaily 20mg QDaily
Hepatic Dosing N/A
Notes

There's that weight-based dosing again. Similar ADR profile as Didanosine (Videx EC, ddI) and again, documented neuropathy, fatal hepatic events and pancreatitis.

Avoid concurrent use, and avoid using this one with Zidovudine (Retrovir, AZT/ZDV).

Zidovudine (Retrovir)

AZT, ZDV

Standard Dosing 300mg BID
200mg TID
Preg: C
Renal Dosing Dialysis: 100mg Q6-8
Hepatic Dosing N/A
Notes

ADRs of Note:

  • Hyperpigmentation of skin/nails
  • Myelosuppresion (anemia, neutropenia)
  • Myopathy

This one is a doozy. It's also known as azidothymidine (hence the AZT shorthand...don't get this mixed up with azathioprine). It was the first HAART medication approved in the US (this is what they're talking about in the musical "Rent" when they say "AZT Break"). Of note, it has an IV formulation available. This makes it one of only two HIV medications available parenterally (the other being enfuvirtide, which is administered subcutaneously).

Avoid with Stavudine (Zerit, d4T).

Brand

Shorthand

Ingredients

Note

Combivir (3TC + AZT/ZDV) Lamivudine
Zidovudine
Renal:
<48mL/min – Avoid
Epzicom (ABC + 3TC) Abacavir
Lamivudine
Renal:
<48mL/min – Avoid
HLA-B*5701 testing required
Trizivir (ABC + 3TC + AZT/ZDV) Abacavir
Lamivudine
Zidovudine
Renal:
<48mL/min – Avoid
HLA-B*5701 testing required
Truvada (FTC + TDF) Emtricitabine
Tenofovir Disoproxil Fumarate
Renal:
30-49 mL/min – 1T Q48
<30 mL/min – Split Components
Descovy (FTC + TAF) Emtricitabine
Tenofovir Alefenamide
Renal: <30mL/min – Avoid

 

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

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 fashionednucleoside 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 imageit 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. Hepatitiselevated 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

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.

 

NNRTI Dosing Charts

Delavirdine (Rescriptor)

DLV

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)

EFV

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)

ETR

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)

NVP

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)

RPV

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).

 

This is a lot to memorize. Make it easier on yourself with an HIV Cheat Sheet. 

It's yours for only $4

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 way up at the top of this page, 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 canincrease 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.

 

Protease Inhibitor Dosing Charts

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

 

 

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. 

Integrase Inhibitor Dosing Tables

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

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. 

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 theonly 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'srequired (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. 

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.

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

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

But, there may be another option: the Biojector 2000.

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. 

 

Entry Inhibitor Drug Tables

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.

 

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

New FDA Approval: Amjevita

New FDA Approval: Amjevita

HIV Boot Camp: Entry Inhibitors

HIV Boot Camp: Entry Inhibitors

0