Pharmacology - HIV antiretroviral drugs (classes, mechanism of action and side effects)
Summary
TLDRThis 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
🦠 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.
💉 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.
🔄 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.
Mindmap
Keywords
💡Antiretrovirals
💡CD4 T cells
💡Reverse Transcriptase
💡Fusion
💡Integrase
💡Protease
💡CCR5 Co-receptor
💡Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
💡Immune Reconstitution Inflammatory Syndrome (IRIS)
💡Prophylaxis
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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