Pharmacology - HIV antiretroviral drugs (classes, mechanism of action and side effects)

Summary

This video covers the treatment of HIV using antiretroviral therapy (ART). It explains the HIV life cycle and how various antiretroviral drugs target different stages, such as attachment, fusion, reverse transcription, integration, and protease activity. Key drug classes include reverse transcriptase inhibitors, integrase inhibitors, and protease inhibitors. The video also touches on side effects, combination therapy, and managing opportunistic infections in HIV patients, as well as important considerations like immune reconstitution syndrome (IRIS) when starting ART.

Takeaways

• 🧬 Antiretrovirals are crucial for treating HIV by targeting various stages of the viral life cycle.
• 💊 All patients with HIV should start antiretroviral therapy as soon as they're ready, regardless of their CD4 T cell count.
• 🔗 HIV attaches to CD4 T cells via gp120 and co-receptors CCR5 and CXCR4, allowing viral fusion and entry into the cell.
• 🧪 Reverse transcription is the process by which HIV converts its RNA into DNA using reverse transcriptase.
• 🧬 Integrase allows the integration of HIV DNA into the host's DNA, making the virus part of the host cell.
• 🧫 Nucleoside and nucleotide reverse transcriptase inhibitors block the creation of viral DNA by mimicking nucleotides.
• 💉 Protease inhibitors prevent the maturation of new HIV viruses, leading to non-infectious viral particles.
• 🦠 Fusion inhibitors, like enfuvirtide, prevent the fusion of the HIV envelope with the host cell membrane.
• 🧬 Non-nucleoside reverse transcriptase inhibitors directly inhibit reverse transcriptase by binding to it.
• 💉 Immune reconstitution syndrome (IRIS) can occur after starting antiretroviral therapy, as the immune system rebounds and attacks latent infections.

Q & A

What is the role of antiretroviral therapy in treating HIV patients?

Antiretroviral therapy (ART) is essential in treating HIV patients by targeting different stages of the viral life cycle, preventing the virus from replicating and thus slowing the progression of HIV.

Why should all HIV patients begin antiretroviral therapy, regardless of CD4 T cell count?

All HIV patients should start antiretroviral therapy as soon as they are ready because it helps control the virus, prevents disease progression, and reduces the risk of transmission, regardless of their CD4 T cell count.

How does HIV infect CD4 T cells?

HIV targets CD4 T cells by binding its glycoprotein gp120 to CD4 receptors, along with co-receptors CCR5 and CXCR4, allowing the virus to fuse with the cell membrane and release its viral contents into the host cell.

What is the significance of reverse transcription in the HIV life cycle?

Reverse transcription is crucial because it allows the virus to convert its RNA into DNA using the enzyme reverse transcriptase, enabling integration into the host cell's DNA and initiating viral replication.

How do reverse transcriptase inhibitors block HIV replication?

Reverse transcriptase inhibitors block HIV replication by preventing the enzyme reverse transcriptase from creating viral DNA. They either mimic nucleotides or bind directly to the enzyme, terminating the DNA chain and stopping viral replication.

What is the function of integrase in the HIV life cycle, and how do integrase inhibitors work?

Integrase is an enzyme that helps integrate viral DNA into the host cell's DNA. Integrase inhibitors prevent this process, stopping the virus from using the host's genetic machinery to replicate itself.

What are some adverse effects of the protease inhibitors used in HIV treatment?

Protease inhibitors can cause side effects such as nausea, diarrhea, hyperlipidemia, and insulin resistance. Some specific inhibitors, like atazanavir, may also cause hyperlipidemia and issues with absorption if the patient is using proton pump inhibitors (PPI).

Why is prophylaxis important for HIV patients, and what are common prophylactic treatments?

Prophylaxis is important for preventing opportunistic infections in HIV patients, especially when their CD4 T cell count is low. Common prophylactics include Bactrim for preventing PJP and toxoplasmosis, and azithromycin (historically) for preventing Mycobacterium avium complex.

What is immune reconstitution syndrome (IRIS) in the context of HIV treatment?

Immune reconstitution syndrome (IRIS) occurs when a patient starts antiretroviral therapy, and their recovering immune system begins to attack existing infections in the body, leading to an inflammatory response and worsening symptoms of those infections.

Why are live vaccines generally not recommended for HIV patients with low CD4 counts?

Live vaccines are usually avoided in HIV patients with CD4 counts below 200 cells/mm³ because their weakened immune systems may not handle the live virus in the vaccine, potentially leading to infections.

Outlines

00:00

🦠 Antiretroviral Therapy and the HIV Life Cycle

This paragraph introduces antiretroviral therapy (ART) as a vital treatment for HIV. It explains that ART targets different stages of the HIV life cycle and should be started as soon as a patient is ready, regardless of CD4 T cell count. It provides an overview of how HIV infects CD4 T cells, beginning with the virus binding to CD4 receptors and co-receptors (CCR5 and CXCR4), and continuing through the fusion of the viral envelope with the host cell. The virus uses enzymes like reverse transcriptase and integrase to integrate into the host's DNA and replicate, ultimately reducing the host's CD4 T cell count.

05:02

💉 Blocking HIV Entry with CD4 and CCR5 Inhibitors

This section details antiretroviral drugs that block the entry of HIV into cells. It introduces CD4 binding inhibitors, such as ibalizumab, and CCR5 inhibitors like maraviroc, which prevent HIV from binding to the co-receptor CCR5, thereby stopping the infection process. The paragraph also covers the adverse effects of maraviroc, including hepatotoxicity and rash. Fusion inhibitors like enfuvirtide, which prevents the fusion of HIV with the host cell by binding to gp41, are also discussed, along with their potential side effects like localized skin reactions.

10:02

🔄 Reverse Transcriptase Inhibitors: Stopping HIV Replication

This paragraph focuses on reverse transcriptase inhibitors (RTIs), which block the reverse transcription step of HIV replication. There are two main types: nucleoside reverse transcriptase inhibitors (NRTIs) and nucleotide reverse transcriptase inhibitors (NtRTIs), both of which prevent the creation of viral DNA. Examples include abacavir and tenofovir. NRTIs act as thymine analogs, while NtRTIs like tenofovir are adenosine analogs. Side effects of these drugs, such as hypersensitivity reactions, nephrotoxicity, and bone toxicity, are also highlighted. Non-nucleoside reverse transcriptase inhibitors (NNRTIs), like efavirenz, which directly inhibit reverse transcriptase, are briefly mentioned with their distinct side effects, such as neuropsychiatric symptoms.

🔗 Integrase Inhibitors: Preventing Viral DNA Integration

This section explains the function of integrase inhibitors, which block the integration of viral DNA into the host's genome. These drugs, like raltegravir and dolutegravir, inhibit the HIV enzyme integrase, preventing the virus from hijacking the host cell's DNA to replicate. The paragraph also discusses side effects, such as myopathy and elevated creatinine levels, associated with these drugs.

⚙️ Protease Inhibitors: Halting Viral Maturation

Protease inhibitors (PIs), which block the HIV protease enzyme, are the focus of this paragraph. By inhibiting protease, PIs prevent the virus from cleaving and activating essential proteins, resulting in the production of immature and non-infectious viral particles. Commonly used PIs include atazanavir and darunavir, with side effects such as nausea, diarrhea, hyperlipidemia, and insulin resistance. The paragraph also notes the need for PIs to be taken with a booster like ritonavir or cobicistat, and warns about drug interactions, such as the need to avoid proton pump inhibitors (PPIs) when taking atazanavir.

💉 Prophylaxis and Other Treatments for HIV Patients

This final paragraph discusses additional treatments for HIV patients, such as prophylaxis for opportunistic infections and vaccinations. Patients with a CD4 count below 200 are at risk for infections like Pneumocystis jirovecii pneumonia (PJP) and toxoplasmosis, for which prophylactic treatment with medications like Bactrim is common. It also touches on the use of azithromycin for preventing Mycobacterium avium complex in the past and the importance of treating latent tuberculosis in HIV-positive patients. Lastly, it highlights the risk of immune reconstitution inflammatory syndrome (IRIS) when starting antiretroviral therapy, as the immune system begins to recover and attack existing infections.

Keywords

💡Antiretrovirals

Antiretrovirals are medications that are central to the treatment of patients with HIV. These drugs target various stages of the HIV life cycle, preventing the virus from replicating. The script highlights that all HIV-infected individuals should start antiretroviral therapy regardless of their CD4 T cell count.

💡CD4 T cells

CD4 T cells are a type of immune cell targeted by HIV. The virus binds to CD4 receptors on the cell surface, initiating the infection process. The script emphasizes the role of these cells in the immune system and how their gradual destruction leads to immunodeficiency.

💡Reverse Transcriptase

Reverse transcriptase is an enzyme used by HIV to convert its RNA into DNA, allowing it to integrate into the host's genome. The video explains that certain antiretroviral drugs, like reverse transcriptase inhibitors, block this enzyme, preventing the virus from replicating.

💡Fusion

Fusion refers to the process where HIV merges with the CD4 T cell membrane, allowing the virus to enter the cell. Antiretroviral drugs like enfuvirtide inhibit this process by blocking the viral protein gp41, thereby preventing the virus from infecting the cell.

💡Integrase

Integrase is an enzyme used by HIV to integrate its viral DNA into the host's DNA, allowing the virus to hijack the cell’s machinery for replication. Integrase inhibitors, such as dolutegravir, prevent this integration, which is crucial for the virus to multiply.

💡Protease

Protease is another HIV enzyme that helps in the maturation of new viruses. Protease inhibitors block this enzyme, leading to the formation of immature and non-infectious viral particles. The script mentions drugs like darunavir as examples of protease inhibitors.

💡CCR5 Co-receptor

The CCR5 co-receptor is found on the surface of CD4 T cells and is required for certain strains of HIV to enter these cells. The script discusses CCR5 inhibitors, such as maraviroc, which block this receptor and prevent the virus from attaching and entering the cell.

💡Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

NRTIs, such as abacavir, are a class of antiretroviral drugs that mimic the building blocks of viral DNA. By incorporating themselves into the viral DNA, they terminate its synthesis. The script highlights their role in halting the viral replication process.

💡Immune Reconstitution Inflammatory Syndrome (IRIS)

IRIS is a condition that occurs after starting antiretroviral therapy, where the recovering immune system begins to attack infections already present in the body. The video warns about IRIS as a potential complication of treatment, particularly as CD4 T cell counts recover.

💡Prophylaxis

Prophylaxis refers to preventive treatments given to HIV patients to protect them from opportunistic infections. The script mentions the importance of using prophylactic treatments like Bactrim to prevent infections such as PJP (Pneumocystis jirovecii pneumonia) when CD4 counts are low.

Highlights

Antiretrovirals are the cornerstone of treatment for HIV patients, regardless of CD4 T cell count.

HIV targets CD4 T cells by binding to CD4 receptors and co-receptors (CCR5, CXCR4), facilitating viral entry.

Fusion inhibitors, like enfuvirtide, block the fusion of the viral envelope with the cell membrane by targeting gp41.

Reverse transcription is a crucial process where HIV converts its RNA into DNA using the enzyme reverse transcriptase.

Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs and NtRTIs) prevent the formation of viral DNA.

Abacavir, a nucleoside reverse transcriptase inhibitor, requires genetic testing for HLA-B*5701 due to hypersensitivity risks.

Tenofovir comes in two forms: TDF and TAF. TDF is associated with higher risks of nephrotoxicity and bone toxicity.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs), like efavirenz, directly inhibit reverse transcriptase and may cause neuropsychiatric effects.

Integrase inhibitors, such as raltegravir and dolutegravir, block the insertion of viral DNA into host cell DNA.

Protease inhibitors prevent the maturation of HIV by blocking the protease enzyme, leading to non-infectious viruses.

Protease inhibitors, like atazanavir and darunavir, often require boosting agents and are associated with metabolic side effects.

HIV patients with low CD4 counts (<200) require prophylaxis against opportunistic infections, such as PJP and toxoplasmosis.

Live vaccines are typically safe for HIV patients with CD4 counts over 200 cells/mm³, but not below.

Immune reconstitution inflammatory syndrome (IRIS) may occur after starting antiretroviral therapy, as the immune system rebounds.

Combination antiretroviral therapy, such as using reverse transcriptase and integrase inhibitors together, is essential for effective HIV treatment.

Transcripts

antiretrovirals are the Cornerstone to

treat patients with human

immunodeficiency virus or HIV

anti-retrovirals work on different parts

of the viral life cycle all patients

with a HIV infection should begin

anti-retroviral therapy as soon as they

are ready regardless of CD4 T cell count

so let's recap their HIV life cycle to

understand the pharmacotherapy the drugs

used to treat HIV

HIV targets the CD4 T cells such as this

cell here the CD4 T cell are the human

immune cells

the glycoproteins on the envelope of the

HIV gp120 binds to CD4 receptors

together with the co-receptors

ccr5 and cxcr4 on the surface of T cells

this allows Fusion of the viral envelope

with the cell membrane which is

facilitated by the glycoprotein gp41

Fusion releases the capsid with the

viral content including the enzymes

necessary for viral survival

the third step reverse transcription

involves the virus reading its own

genetic RNA material and then making a

DNA copy of it with its enzyme reverse

transcriptase

from a single stranded viral RNA the

virus produces double-stranded viral DNA

which will be transported to the nucleus

of the host cell via integrase

this allows integration of the viral DNA

with the host DNA which is the fourth

step in the HIV life cycle

the HIV virus is now part of the cell

essentially the CD4 T cell and can use

this cell's own Machinery to create more

of its genetic material and more of its

structures in order to make more HIV

viruses

transcription is where the host's own

RNA polymerase reads the viral DNA and

with that information it creates viral

RNA which is a genetic material as well

as mRNA which will be used to create

important proteins for the virus

translation is where the MRNA that was

just made is read by the host's

ribosomes to create proteins that will

essentially create the enzymes and other

proteins required to make a new HIV

virus

all these enzymes proteins and the viral

RNA that is created gets assembled

packaged up and released by The CD4 T

cell

once released there is a final process

of maturation where the HIV virus uses

its enzyme again to form its final

infective form

while the virus replicates within the

city for T Cell it actually injures the

cell itself and thus causes a slow

reduction in the CD4 T cell count

antiretrovirals are the Cornerstone to

treat patients with HIV

these antiretrovirals work on different

parts of the viral life cycle we just

learned

all patients should be started on

antiretroviral therapy

let's learn about these anti-retrovirals

by looking at each step of the HIV life

cycle

now there are several antiretrovirals

which block different stages of the

process of attachment and entry

the CD4 binding Inhibitors such as

ebalizumab the monoclonal antibody it

binds to CD4 T cells inhibiting the HIV

virus from entering the cell

you also have ccr5 inhibitors

maravi Rock which mechanisms of action

is as the name suggests it blocks the

ccr5 co-receptor that is essential to

cell infection for some HIV genotypes

common adverse effects of this drug

include hepatotoxicity and rash

there are also antiretrovirals which

inhibit Fusion such as enthubertide

which mechanism of action

is it competitively binds to the viral

protein gp41 and thereby prevents Fusion

of the virus envelope with the cell

this is an injection and so common

adverse effects include localized skin

reaction

then you have the antiretrovirals that

Target reverse transcription

most of these drugs end in i and e iron

except two very important reverse

transcriptase Inhibitors abacavia and

tenophobia which you have to know

now the two main types of reverse

transcriptase inhibitors

are the nucleoside reverse transcriptase

Inhibitors and the nucleotide reverse

transcriptase inhibitors

and both work to essentially stop the

enzyme reverse transcriptase

and so stop the creation of DNA the

viral DNA

nucleoside reverse transcriptase

Inhibitors include a back of ear

lamivudine

and zidovidine

essentially these drug work as a thymine

analog

they incorporate into the viral DNA via

reverse transcriptase essentially

disrupting the creation of the viral DNA

and thus terminates the DNA chain

here you have the single viral RNA the

reverse transcriptase helps create the

viral DNA

nucleoside reverse transcriptase

Inhibitors such as a back of ear acts as

a thymine analog disrupting this whole

process terminating The Strand early

a backup is specifically is important to

know because it is commonly used side

effects of a bacteria include

hypersensitivity reaction and so

patients with abacavia are normally

undergo genetic testing to exclude

hlab5701 a bacteria also increases the

risk of cardiovascular disease and so

patients with pre-existing heart

conditions you must be careful

now the nucleotide reverse transcriptase

Inhibitors the most important to know is

tenophobia now the mechanism of action

is that it is a adenosine nucleotide

analog and acts again as a chain

Terminator when incorporated into the

viral DNA

tenophobia comes in two forms tenofavir

disoproxylfumerate tdf and tenofavir

Allah finnamide TAF

tdf and TAF are oral tablets they differ

in Half-Life and effects on the kidneys

and the bones

both tdf and TAF are taken up from the

gut when you swallow the tablet and act

inside the cells to inhibit reverse

transcriptase as mentioned

however tdf has a shorter Half-Life and

is taken up by the kidneys more readily

tdf is more present in plasma and

because of this it's taken up by the

kidneys and increases the risk of

nephrotoxicity as well as bone toxicity

leading to osteoporosis

those are the two main types of reverse

transcriptase Inhibitors the nucleotide

and nucleoside reverse transcriptase

inhibitors

however there is another version that

non-nucleoside reverse transcriptase

inhibitors and an example of this is

effeverance the mechanism of action of

effeverens is that it binds directly to

reverse transcriptase inhibiting its

function rather than being an analog of

some nucleotide nucleoside

the adverse effects of this drug include

Neuropsychiatric effects being hungover

having a hungover feeling bizarre and

vivid dreams

the reverse transcriptase Inhibitors all

of them block this step here thus

preventing viral DNA creation and

therefore disrupts the viral life cycle

another class of antiretrovirals are the

integrase Inhibitors which block the

enzyme here

HIV integrates Inhibitors usually end

with gravier

and have been developed to inhibit the

HIV enzyme integrase preventing the

transfer and insertion of viral DNA to

the host cell DNA

examples of integrase Inhibitors include

Rel tegravir and doltegravir

the main side effect of reltigravir is

myopathy as well as an elevation in

creatinine and Dot tegravir It causes

elevation creatinine

the next antiretroviral class are the

HIV protease Inhibitors the protease

Inhibitors usually end with navir and

are designed to block the activity of

the protease enzyme inhibition of the

vile protease here causes the inability

of the virus to cleave certain proteins

to activate certain proteins and thus

results in the generation of an immature

non-infectious HIV virus

the protease Inhibitors usually require

a booster another agent such as

retonovir or kobisistat

examples of protease Inhibitors include

atasanavir and darunavir

all protease Inhibitors have the side

effects of nausea diarrhea

hyperlipidemia and insulin resistance

you can think of metabolic syndrome for

protease inhibitors

however specifically

a tesanavir causes hyperlipidemia and

also requires gastric juices for its

absorption so patients that use PPI

should not

darunavir causes GI upset lipodystrophy

hyperlipidemia and increases myocardial

infarction risk

so those are some major classes of

antiretroviral drugs other treatments

that patients with HIV are required

include possibly prophylaxis for

opportunistic infections

so vaccination is very important

HIV patients can have live vaccines

usually only if the CD4 cell count is

greater than 200 cells per millimeter

cubed

if the CD4 cell count is less than 200

really their risk of a lot of

opportunistic infections and so bactrim

is usually used as prophylaxis against

PJP and toxoplasmosis infections

previously if the CD4 cell count was

less than 50

azithromycin is used was used for

myobacterium avium complex however my

understanding is this is not used

anymore

finally

patients with latent TB who also have

HIV require TB treatment

when starting patients with HIV

treatment the antiretrovirals it is

important to look out for immune

reconstitution syndrome or Iris for

short this occurs within a few months of

starting antiretroviral therapy because

what happens is when you treat

patients with antiretroviral therapy the

CD4 cell count returns it gets

replenished basically and so as a result

you get this inflammatory State as the

immune system begins to regain its

function it attacks any infection it has

in the body and so Iris with Iris you

develop bad infective symptoms as a

result

to conclude the anti-retrovirals used

for HIV are used in combination so for

example a reverse transcriptase

inhibitor with an integrase inhibitor

and that concludes the video on HIV

pharmacology in this video we looked at

the HIV lifecycle and we looked at how

the anti-retrovirals target different

parts of the HIV life cycle

the important ones to remember include

the reverse transcriptase inhibitors

into Graves Inhibitors and the protease

Inhibitors thank you for watching

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