Chapter 47: HIV – Antiretroviral Therapy

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Welcome back to The Deep Dive.

Today we're tackling a really significant topic, the complex world of HIV pharmacotherapeutics.

That's right.

We're aiming to distill this down into the practical clinical knowledge that you, as advanced practitioners or students, really need.

We're zeroing in on antiretroviral therapy, RT, you know, those combination strategies that have just fundamentally changed everything for people living with HIV.

Exactly.

And this isn't just about memorizing drug names.

For those of you in primary care or even specialty settings, this dive is about understanding the rules of the regimen.

Rules like mechanisms of action.

Mechanisms, yeah, but also the crucial safety checks,

the clinical limitations,

all the things that actually guide which drugs a specific patient ends up taking every single day.

Okay, so let's set the stage really quickly.

Foundational context, untreated HIV we know eventually leads to AIDS.

Right, and clinically that means either having an AIDS -defining condition or seeing that CD4 plus T cell count drop below 200 cells per cubic millimeter.

And historically without any treatment, that progression took what, about 10 years on average?

Roughly, yeah, which really highlights why the modern standard is immediate aggressive treatment right from diagnosis.

And you said immediate.

That seems key.

But managing HIV isn't straightforward, is it?

Not at all.

It's incredibly challenging because there's no single recipe that works for everyone.

It has to be personalized.

Completely individualized.

You're looking at resistance testing results, the patient's other health issues, comorbidities, what other meds they're on, and honestly a big one is how well you think they'll stick to the regimen.

Adherence is huge.

Okay, let's unpack the pathophysiology then because understanding how the virus works gives us that roadmap for how the drugs fight back.

It really does.

So HIV is a retrovirus, its main target.

The immune system's key defenders, the CD4 plus T lymphocytes, it destroys them leading to that severe immune deficiency.

But the virus has a life cycle, a sequence of steps it needs to follow to replicate.

Exactly.

And each step is a potential target for our drugs.

Think of it like a multi -step assembly line.

And we have drugs designed to throw a wrench in the works at each station.

Precisely.

Station one, attachment and entry.

The virus needs to latch onto the host cell.

It uses its own proteins to grab onto the CD4 receptor and also a co -receptor, usually CCR5 or CXCR4.

Like a key fitting into specific locks.

Right.

And that's where our first set of drugs comes in the entry inhibitors.

Things like CCR5 antagonists or fusion inhibitors, they physically block the virus from even getting inside.

Okay, station two, this seems like a really big target area.

Reverse transcription.

Oh, it's huge.

This is where the virus converts its RNA genetic material into double -stranded DNA.

It uses a special enzyme called reverse transcriptase.

If we stop this step, the virus hits a dead end.

And this is where two major drug classes work.

Yes.

Two very important distinct classes.

The nucleoside reverse transcriptase inhibitors or NRTIs and the non -nucleoside reverse transcriptase inhibitors and NRTIs.

They both mess with that conversion, but different ways we'll get into.

Got it.

Onto station three, integration.

So now the virus has made its DNA copy.

It needs to permanently splice that DNA into the host cell's own genetic material inside the nucleus.

It uses another enzyme for this called integrase.

And we have drugs for that too.

We do.

The integrase strand transfer inhibitors, the NSTIs.

These are incredibly effective, often a preferred part of modern regimens.

They stop that splicing process cold.

No integration, no long -term infection of that cell.

Makes sense.

And the final step, station four.

Assembly and cleavage.

The infected cell, now following viruses instructions, starts producing long chains of viral proteins, poly proteins.

These need to be precisely cut up by another enzyme, protease, to form the components of new functional viruses.

So like cutting raw materials into finished parts.

Exactly.

And our protease inhibitors, or PIs, block that cutting enzyme.

The result.

The cell might release new viral particles, but they're immature, defective, and can't infect other cells.

Understanding those four points really shows why combination therapy is essential, hitting the virus from multiple angles.

Absolutely critical.

Monotherapy just doesn't work long -term due to resistance.

Okay, before we dive deeper into the drugs, let's quickly cover the labs.

What's the standard diagnostic test now?

We use a fourth generation assay.

It's great because it detects not just the antibodies the body makes against HIV, but also a viral protein called the P24 antigen.

Which means earlier detection?

Much earlier, yes.

It closes that window period significantly compared to older tests.

And for monitoring therapy, the CD4 count tells us about the immune system's health.

Right.

It shows the extent of the damage.

A normal count is somewhere between 500 and 1600 cells per cubic millimeter,

below 200.

That's when the risk of serious opportunistic infections and cancers really skyrockets.

That defines AIDS immunologically.

And the other key monitoring tool, viral load, the HIV RNA level, that's our measure of treatment success, isn't it?

It's the ultimate measure.

The goal is to get the viral load down to undetectable levels, which typically means less than 20 to 75 copies per milliliter, depending on the lab tests used.

Undetectable.

That's the aim.

Absolutely.

Sustained viral suppression is directly linked to better health outcomes for the patient.

And, very importantly, it prevents transmission to others.

Which leads us to something you mentioned earlier, resistance testing.

This is mandatory at the start.

Non -negotiable.

We need baseline genotypic resistance testing for every patient diagnosed with HIV before they start therapy, if possible.

Genotypic, not phenotypic.

Genotypic is generally preferred initially.

It's faster, less expensive, and tells us about specific mutations in the virus's genes that could make certain drugs ineffective.

We need to know what we're up against.

Even if treatment needs to start urgently.

Yes.

You might start a recommended standard regimen while waiting for the results, but you absolutely need that test done to guide therapy long term, or make adjustments if needed.

Okay, so let's talk treatment strategy.

What are the main goals of ARTTA, beyond just keeping people alive?

Well, there are about five key goals.

Number one is achieving that maximal and durable viral suppression we just talked about.

Undetectable.

Undetectable.

Second, restore and preserve immune function.

Get that CD4 count up.

Third,

enhance overall quality and duration of life.

Fourth, reduce HIV -related morbidity and mortality.

And the fifth links back to transmission.

Exactly.

The fifth goal is preventing HIV transmission.

This is the whole concept of TASP treatment as prevention.

Or UU.

UU.

Undetectable equals untransmittable.

It's a powerful message for patients, reduces stigma, encourages adherence.

It's a public health win.

When we structure that initial therapy, you mentioned a backbone.

Right.

The standard approach, the foundation for most recommended initial regimens, is a combination of two NRTIs.

That's the dual NRTI backbone.

And then you add something else.

Plus a third potent drug from a different class.

Nowadays, that third drug is most often an NSTI, an ingress inhibitor.

That triple combination hits the virus hard from different angles right away.

Now, here's a really practical point, a clinical pearl.

What if the patient also has hepatitis B?

Does that change the backbone choice?

It absolutely does.

If someone is

the preferred NRTI backbone is specifically tenofovir, either the TDF or the TIF formulation, paired with intracidabine, or sometimes lamivudine, which is similar.

Why that specific combo?

Because both tenofovir and intracidabine are active against both HIV and hepatitis B virus.

Using this backbone treats both infections simultaneously and prevents a dangerous flare -up of hepatitis B when you start suppressing the HIV.

That's efficient.

Okay, let's really get into these drug classes now, starting with those workhorses, the backbone drugs,

NRTIs.

How do they actually work?

You said they interfere with reverse transcription?

They do.

They're kind of like molecular mimics or imposters.

First, they need to get inside the host cell and be activated through phosphorylation.

Basically, the cell adds phosphate groups to them.

So they're prodrugs?

Essentially, yes.

Once activated, they stop the reverse transcriptase enzyme in two main ways.

First, they cause chain termination.

When the enzyme mistakenly incorporates an activated NRTI into the growing viral DNA chain, the chain can't be extended any further.

It's like adding a faulty link.

Dead end for the DNA chain.

What's the second way?

Competitive inhibition.

The activated NRTIs also directly compete with the cell's natural building blocks, the real nucleosides, for the active site on the reverse transcriptase enzyme.

So they crowd out the real components.

Both ways effectively stop viral DNA production.

NRTIs aren't without issues.

Dosing considerations.

A big one is kidney function.

Pretty much all NRTIs require dose adjustments if the patient has renal impairment.

You need to check kidney function baseline and monitor it.

Is there an exception?

Yes.

The main exception is abacavir.

It doesn't need renal adjustment, but abacavir has its own major issue.

The hypersensitivity reaction.

This requires a genetic screening.

Absolutely mandatory.

Before any patient starts abacavir, you must test them for the HLA B507 -01

It's a genetic marker.

And if they test positive?

Abacavir is completely contraindicated.

Forever.

If a positive patient takes abacavir, they have a very high risk of a severe, potentially life -threatening hypersensitivity reaction fever, rash, GI upset, respiratory symptoms.

It can be fatal if the drug is stopped and then restarted.

Wow.

So that test is critical for safety.

Absolutely critical.

And there's also some caution advised with abacavir in patients who already have significant cardiovascular risk factors due to some debated data about a possible link to heart attacks.

What about zetavudine or AZT?

It was one of the first HIV drugs.

Is it still used much?

Not really for initial treatment anymore.

Its main drawback is significant bone marrow suppression.

It can cause bad anemia and neutropenia, which limits its use compared to newer, better tolerated NRTIs.

You mainly see it in specific situations now, sometimes during pregnancy or for PP.

And as a whole class, NRTIs carry a risk, albeit rare, of a serious side effect involving lactic acid.

Yes.

Lactic acidosis with hepatic steatosis, which is fat buildup in the liver.

It's linked to mitochondrial toxicity, the drugs interfering with the cell's energy production.

It's rare, but can be fatal.

How would that present?

Often with vague symptoms initially, like persistent nausea, vomiting, abdominal pain, fatigue, weakness.

It's why we generally prefer NRTIs with lower known mitochondrial toxicity for long -term use,

like tenofovir, especially TAF, intracidabine, lamivudine, and abacavir.

Good to know.

Okay, let's move to the other class targeting reverse transcriptase, the NNRTIs.

How do they differ from NRTIs?

Their mechanism is simpler in a way.

They don't need to be activated inside the cell.

They bind directly to a different site on the transcriptase enzyme, not the active site, but another pocket.

So non -competitive binding.

Exactly.

This binding changes the enzyme shape, making it unable to do its job of converting RNA to DNA.

Got it.

Now, specific NNRTIs have some well -known side effects, effaverins and CNS issues.

Yeah.

Effaverins is famous or infamous for causing CNS side effects, especially when starting.

Dizziness, trouble concentrating, sometimes really vivid or strange dreams.

Does that get better?

Usually, yes.

For most people, these effects lessen or resolve within the first two to four weeks.

That's why the classic advice is to take effaverins at bedtime, maybe on an empty stomach, to sleep through the worst of it initially.

Okay.

What about navirapin?

It has a specific warning.

Navirapin carries a black box warning for potentially severe liver toxicity,

hepatotoxicity.

The risk is higher in certain patients specifically, women starting it with a CD4 count above 250 and men starting it with a CD4 count above 400.

So you have to be careful based on their immune status at initiation.

Absolutely.

Careful patient selection and monitoring are crucial if you use navirapin.

A general issue with NNRTIs seems to be drug interactions, right?

They interact with a lot of other medications.

That's a major challenge.

They are often metabolized by and can induce or inhibit the CYP450 enzyme system in the liver, particularly CYP3A4.

This leads to many potential interactions.

Like with common supplements.

Definitely.

St.

John's wort is a big one.

Yeah.

It's absolutely contraindicated with NNRTIs because it speeds up their breakdown, potentially leading to treatment failure.

And rilpivirin has a specific restriction based on how much virus the patient has initially.

It does.

Rilpivirin works well, but studies showed it was less effective in people starting treatment with a high viral load.

So its use is generally restricted to patients who have a baseline HIV RNA level below 100 ,000 copy as ml and a CD4 count above 200.

So if the viral load is really high, rilpivirin might not be the best choice for that third agent.

Correct.

Higher risk of virologic failure in that scenario.

Also, rilpivirin needs an acidic stomach for absorption.

So taking it with proton pump inhibitors, the PPIs, is contraindicated.

Reduce absorption, treatment failure risk again.

Lots of nuances there.

Okay.

Moving along the life cycle.

Protease inhibitors, the PIs, they target that final assembly step.

Right.

They block the protease enzyme, which is essential for cutting those long viral polyproteins into functional pieces.

Without proper cleavage, the virus particles that get released are immature and can't infect new cells.

PIs have a reputation for being potent and durable, right?

High barrier to resistance.

Generally, yes.

Resistance develops more slowly compared to, say, NNRTIs.

But their clinical use is almost always tied to the concept of boosting.

Ah, yes.

The pharmacokinetic enhancers.

Why do we need those?

PIs themselves are often rapidly metabolized by the liver, mainly by CYP3A4.

So we give them alongside a small dose of either rotonavir or covesistat.

These are potent inhibitors of CYP3A4.

So they slow down the breakdown of the main PI.

Exactly.

Boosting increases the drug levels and prolongs the half -life of the active PI, making it more effective and often allowing for less frequent dosing, like once or twice daily instead of multiple times.

But boosting complicates things with drug interactions, doesn't it?

Immensely.

Because rotonavir and covesistat inhibit CYP3A4 so strongly, they create a minefield of potential interactions with many other common medications.

Managing PI -based regimens requires careful review of all concomitant meds.

What about the characteristic side effects of the PI class itself?

Two big categories stand out.

First, lipodystrophy, which is abnormal fat distribution.

This can mean fat loss in the face and limbs, but more commonly, fat accumulation in the abdomen or the back of the neck, that classic buffalo hump.

And the second category?

Metabolic abnormalities.

PIs are notorious for causing dyslipidemia, high cholesterol and triglycerides, and hyperglycemia, or high blood sugar, which can even lead to new onset diabetes or worsen existing diabetes.

So if a patient on a PI needs a statin for high cholesterol, you have to choose carefully.

Very carefully.

Because of those CYP interactions again, statins like simvastatin, lavastatin are generally contraindicated.

Provastatin, or sometimes atorvastatin, at low doses, are often preferred because they have fewer interactions with the common boosting agents.

If you're choosing an initial PI -based regimen today, which one is usually recommended?

Darunavir, boosted with either ritonavir or cobucistat, darunavir or darunavirc, is generally the preferred PI for initial therapy.

It's highly effective and durable.

Are there alternatives?

Adaxanavir, also boosted, adaxanavir or adaxanavirc, is another option.

It tends to have less impact on lipids compared to darunavir, which is an advantage.

But adaxanavir has its own issue, right, with stomach acid?

Yes, that's its main drawback.

Adaxanavir needs an acidic environment in the stomach to dissolve and be absorbed properly.

This makes taking it with acid -reducing medications, like PPIs or even H2 blockers and antacids, very problematic.

It requires careful timing or avoidance altogether.

Okay, that brings us to the class that's often the star of initial regimens now, the integrase strand transfer inhibitors in STIs.

They really are central to modern RT.

As we said, they block the integrase enzyme, stopping the viral DNA from being inserted into the host cell's genome.

It's a critical step, and blocking it is very effective.

Why are they so often preferred as that third agent alongside the NRTI backbone?

Several reasons.

They are generally very potent, rapidly reducing viral load.

They tend to be very well tolerated compared to older classes like PIs or NNRTIs.

And crucially, they typically have fewer significant druggy interactions.

Sounds almost ideal.

Are there any major catches?

The biggest one is their interaction with polyvalent cations.

Things like calcium, iron, magnesium, aluminum found in supplements, antacids, multivitamins.

They interfere with absorption.

Yes.

These expectations can bind to the NSTI molecule in the gut, preventing it from being absorbed properly.

This is particularly an issue for dilutagravir and bictagravir.

So patients need specific instructions.

Absolutely.

They need to take the NSTI either two hours before or six hours after taking any containing these cations.

It requires careful scheduling and patient education.

And there was a concern, particularly with dilutagravir, regarding pregnancy.

Yes.

There was an initial safety signal suggesting a potential small, increased risk of neural tube defects in infants born to women who are taking dilutagravir around the time of conception.

How has that influenced practice?

While more recent data have been somewhat reassuring and guidelines have evolved, it remains a critical counseling point.

For women of childbearing potential who are not on reliable contraception, the potential risks versus benefits must be discussed thoroughly.

Often this leads clinicians to prefer other options, like bictagravir, or ensure effective contraception is in place if dilutagravir is used.

Important considerations.

Okay.

Let's shift gears slightly to prophylaxis and special populations.

First, PP post -exposure prophylaxis.

Someone gets exposed, needle stick, or unprotected sex.

What happens?

PP is an emergency intervention.

Time is critical.

It needs to be started as soon as possible after exposure, ideally within one, two hours, definitely within 72 hours.

And what's the regimen?

The preferred regimen is typically a 28 -day course of three drugs.

The NRTI backbone TD -femtristabine, Truvado or it's generic, plus an NSTI, usually raltagravir or dilutagravir.

28 days.

Okay.

Now what about pre -P, pre -exposure prophylaxis?

This is for prevention before any exposure happens.

Right.

Pre -P is for individuals who are HIV negative, but at high ongoing risk of acquiring HIV.

The strategy is daily use of an antiretroviral medication to prevent infection if an exposure occurs.

And the medications used?

The most common options are daily oral tablets containing tenofovir and emtristabine,

either TD -femtristabine, Truvado and generics, or tufemtristabine, uh, Discovy.

FFTC is approved for men and transgender women, but not yet for cisgender women for vaginal sex exposure risk due to lack of specific trial data.

There's also a long -acting injectable option now, cabotagravir.

What's the most critical thing to remember with pre -P?

Monitoring.

The person must be confirmed HIV negative before starting pre -P, usually within the week prior.

And then they need regular HIV testing typically every three months while on pre -P.

Why the frequent testing?

To ensure they haven't acquired HIV despite PEP.

If someone becomes infected while taking PEP, which is rare but possible, Continuing PVP as just one or two drugs constitutes inadequate therapy and can rapidly lead to drug resistance.

So, confirming they remain negative is key.

Prescriptions are usually limited to 90 days at a time to enforce this check -in.

Makes sense.

Finally, pregnancy.

Treating HIV in pregnancy has two main objectives, right?

Exactly.

First, treat the mother's HIV infection for her own health.

Second, prevent perinatal transmission passing the virus to the infant during pregnancy, labor, or delivery.

Is there a specific intervention during labor?

Yes.

For mothers who have a detectable viral load, particularly if it's over 1 ,000 -copy -as -a -mil near delivery,

intravenous Zitovudene, AZT, is often recommended during labor and delivery as an extra measure to reduce transmission risk.

And after birth?

The infant receives antiretroviral medication for a period as prophylaxis.

And a really important point, at least in the U .S.

and other high -resource settings, is that breastfeeding is generally not recommended for women living with HIV even if their viral load is undetectable, because there's still a small potential risk of transmission through breast milk.

Okay.

We've covered a lot of ground on the drugs and specific situations, but none of this works without adherence.

Right.

Adherence is everything.

Non -adherence patients not taking their medications consistently as prescribed is the single biggest reason for treatment failure and the development of drug resistance.

What makes adherence difficult?

What are the risk factors?

Many things.

Active substance abuse, untreated mental health conditions like depression, unstable housing, stigma associated with HIV,

complex regimens with high pill burdens or frequent dosing,

even just forgetting doses.

Side effects are also a major barrier if not managed well.

So what can we do as practitioners to support adherence?

It's multifaceted.

Education is key.

Making sure the patient understands why every dose matters.

Building a strong, trusting relationship with the patient and the whole care team is vital.

Practical strategies.

Helping them integrate the medication into their daily routine using pill boxes, setting phone alarms,

preparing them for potential side effects, and having a plan to manage them.

Simplifying the regimen as much as possible, aiming for those single tablet options if appropriate.

It's really about partnership.

And we track success with that monitoring schedule we touched on earlier.

Can you recap the typical frequency for viral load checks?

Sure.

When starting or changing therapy, you check the viral load after about two to eight weeks.

Then usually every four to eight weeks until it becomes undetectable.

And once it's undetectable?

Then you check it every three to four months, typically.

If someone has been stably suppressed for a good while, say over two years, you might extend that interval to every six months.

What about the CD4 count?

Do we monitor that as closely long -term?

Initially, yes.

You check it at baseline, then usually run three months after starting therapy, and then every three to six months for the first couple of years.

But does that continue indefinitely?

Not necessarily.

If the patient is virally suppressed consistently, and their CD4 count has recovered well, say, it's consistently above 500 cells a meter three for at least two years.

Guidelines suggest that continued CD4 monitoring might actually be optional.

The viral load becomes the main focus.

Okay, let's try to pull this all together with a quick clinical application.

Imagine Anna.

She's 36, newly diagnosed, treatment naive.

Her baseline CD4 is 400, so not AIDS yet.

But her viral load is pretty high at 110 ,000 copy as a mil.

Two key details.

She occasionally uses over -the -counter antacids for heartburn, and she's not currently using reliable birth control.

How do we choose her initial regimen?

Okay, great case.

So current guidelines strongly favor starting with an NCDI -based regimen.

That means a dual NRTI backbone plus an NCDI.

Right.

But now we apply Anna's specific details as constraints.

First, she's not using reliable contraception.

That immediately raises a flag for delugravir.

Because of that potential, though small, risk of neural tube defects if conception occurs while taking it, we'd likely avoid delugravir as the ENSTI for Anna right now, unless she starts reliable contraception.

It's a necessary discussion.

Okay, delugravir is likely out.

Second constraint.

Her occasional antacid use.

That points us away from certain other drugs.

Remember, adaxanavir, the PI, needs stomach acid for absorption.

Antacids would interfere with that, increasing her risk of treatment failure.

So an adaxanavir -based regimen is probably not ideal either.

And what about the NNRTIs, like rilpivirine?

We need to check her baseline numbers.

Her viral load is 110 ,000 copy -ASML.

That's above the 100 ,000 threshold for rilpivirine.

So rilpivirine is also not a recommended option due to the higher risk of failure at this viral load.

So we've ruled out delugravir due to pregnancy potential, adaxanavir due to antacid use, and rilpivirine due to high viral load.

What's left that's potent, well -tolerated, and convenient?

Well, considering those factors, an excellent choice, often available as a single -tablet regimen, would be biktravir tefemtricidigine.

Why does that fit?

Biktravir is a potent NSTI without the same level of concern as delugravir regarding neural tube defects.

Tefemtricidigine is a highly effective and generally well -tolerated NRTI backbone with a good safety profile, especially regarding bones and kidneys compared to the older TDF.

It avoids the adaxanavir acid issue and the rilpivirine viral load restriction.

And the single tablet really helps with adherence.

She still needs counseling about the antacid timing with biktravir, right?

Absolutely.

She still needs that two -hour before or six -hour after separation for polyvalent cations like the magnesium or aluminum in our antacids.

But overall, it addresses her specific clinical picture effectively.

That's a perfect illustration of how you take the drug pharmacology, the safety data, the patient's individual factors, and synthesize it into a specific treatment decision.

Exactly.

It's about matching the right tools to the right person.

So to wrap up, we've seen the importance of that initial regimen, usually the dual NRTI backbone plus an NSTI.

We've reviewed the mechanisms, the key side effects, the critical safety checks like HLA screening for abicavir, and the web of drug interactions, especially with PIs and NNRTIs.

Individualized care is paramount.

It really is.

And it's amazing how effective these therapies are.

We can get viral loads undetectable, restore immune systems.

It's transformed HIV from a death sentence to a manageable chronic condition.

Which leads us perfectly into our final provocative thought for you, our listeners.

We have these incredibly powerful drugs, RTI, that can suppress HIV so effectively that it's undetectable in the blood for decades.

Yeah, we still can't cure HIV.

If someone stops taking their art, even after years of undetectable viral load, the virus comes back.

So the question to ponder is, why?

If the virus is undetectable, where is it hiding?

What prevents us from achieving complete eradication with these potent therapies?

The answer lies in the latent HIV reservoirs.

Very early in the infection, the virus integrates its DNA into the genetic material of long -lived resting CD4 plus T cells.

These cells essentially go dormant, hiding the virus from both the immune system and our current drugs,

which mostly target actively replicating virus.

So these silent reservoirs persist indefinitely.

Pretty much.

They could reactivate later if treatment stops.

Tackling this latent reservoir is the major barrier to an HIV cure and the focus of intense ongoing research.

That's the challenge that remains.