Antiretrovirals Flashcards
What is a retrovirus?
A retrovirus is an RNA virus which possesses reverse transcriptase enzyme with which it produces DNA copy of its RNA genome.
What are antiretrovirals?
Antiretroviral agents are drugs for the treatment of infection caused by retroviruses.
Examples of retroviruses
- Human immune deficiency virus (HIV)
- Simian immunodeficiency virus (SIV)
- Human T-cell lymphotropic virus type 1 (HTLV-1)
Classification of Antiretroviral agents
- Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
- Non-nucleoside reverse transcriptase inhibitors
- Protease inhibitors
- Fusion inhibitors
- Entry/CCR5 inhibitors
- Integrase inhibitors
- Maturation inhibitors
Examples of Nucleoside/nucleotide reverse
transcriptase inhibitors (NRTIs)
abacavir (ABC)
didanosine (DDC)
emtricitabine (FTC)
zidovudine (AZT)
lamivudine (3TC)
stavudine (D4T)
zalcitabine
tenofovir (TDF) [nucleotide]
Mechanism of action of NTRIs
NRTIs are phosphorylated by the host cell enzymes (kinase) to their 5’-triphosphate derivatives.
These then compete with their corresponding host cellular triphosphates and act as false substrate to the viral reverse transcriptase (viral RNA-dependent DNA polymerase) enzyme in the synthesis of the proviral DNA.
The incorporation of the 5’-triphospate into the growing viral DNA chain eventually results in
chain termination.
- Gives the virus fake materials to build with.
Uses of NRTIs
- Mainly for HIV with other ARVs.
- Lamivudine &
adefovir are also used for hepatitis B.
Class adverse effects of NRTIs
Lactic acidosis: The
build up of lactic acid in the blood due to mitochondria toxicity, which results in production of lactic acid as a bye product of energy formation
Specific adverse effects of NRTIs
- Zidovudine: anaemia
- Stavudine: peripheral neuropathy & lipodystrophy
- Abacavir: allergic reaction
TDF (tenofovir disoproxil fumarate) has better effects
on bones and kidney and is preferable in
patients with underlying bone or kidney
disease than TAF (tenofovir alafenamide) .
True or False
False
TAF has better effects
on bones and kidneys.
TDF has better lipid lowering effects than TAF.
True or False
True.
TDF produce higher level of tenofovir, which lowers lipid.
Examples of Non-nucleotide Reverse Transcriptase Inhibitors
1st generation: efavirenz (EFV), nevirapine (NVP), and delavirdine
D-E-N
2nd generation: etravirine and rilpivirine
E-R
Uses of NNRTIs
- HIV in combination with other ARVs
- Etravirine: resistant case in tmt exp pt only
- Rilpivirine: tmt naïve pt
Mechanism of action of NNRTIs
NNRTIs bind to the reverse transcriptase enzyme near its catalytic site and denature it.
- They spoil the virus’ toools
Class adverse effects of NNRTIs
Rash
Specific adverse effects of NNRTIs
- Efavirenz: CNS toxicity (headache, fatigue, sleep disturbances, dizziness and depression).
- Nevirapine: hepatoxicity
- Etravirine: allergic reaction
- Delavirdine: allergic reaction, fever, blurred vision,
stuffy nose.
Examples of Protease Inhibitors
– 1st generation: LINDRAFTS
lopinavir (LPV)
indinavir
nelfinavir
droxinavir
ritonavir (r/RTV)
amprenavir
fosamprenavir
telinavir
saquinavir (SQV)
– 2nd generation: TAD
Tipranavir
Atazanavir (ATV)
Darunavir
Mechanism of action of protease inhibitors
Protease inhibitors bind to the site where cleavage normally occurs on the two biochemically inactive polyproteins translated from mRNA that was transcribed from the provirus.
This prevents the viral specific protease from breaking down the inert polyproteins at the appropriate cleavage positions into various viral structural and functional proteins.
Mechanism of action of protease inhibitors
Treatment of HIV infection in combination with other antiretroviral drugs of different classes.
Class adverse effects of protease inhibitors
paraesthesia
rhabdomyolysis
myalgia
lipodystrophy
hyperglycemia
Specific adverse effects of protease inhibitors
Atazanavir causes raised
bilirubin levels but has less effects on lipodystrophy and hyperglycemia
Examples of HIV fusion inhibitors
Enfuvirtide
Mechanism of HIV fusion inhibitors
Inhibition of the fusion of
HIV with the host cells.
Uses of HIV fusion inhibitors
They are used in treatment of HIV in combination with other antiretroviral drugs when resistance becomes a problem or when there is intolerance to other antiretroviral drugs.
Adverse effects of HIV fusion inhibitors
flu-like symptoms
hypersensitivity reactions
Examples of HIV Integrase inhibitors
– 1st generation: raltegravir and elvitegravir
– 2nd generation: dolutegravir and bictegravir
Mechanism of action of HIV integrase inhibitors
They inhibit the viral integrase enzyme which is responsible for integration of the viral DNA with the infected cell DNA.
Side effects of raltegravir
– Common: headache, nausea, diarrhoea, weakness, insomnia
– Rare: hepatitis, thrombocytopenia, rhabdomyolysis, pyrexia, diaphoresis, rashes, renal failure, nephrolithiasis, depression, suicidal behaviours, anxiety and paranoia.
Examples of Entry Inhibitors or CCR5 antagonists
maraviroc
aplaviroc
vicriviroc
Mechanism of action of Maraviroc
MSaraviroc binds to CCR5 and blocks its association with the HIV gp120, thereby preventing entry into the host cell.
However, some HIV can also enter the host cell through CXCR4, so HIV tropism test is essential for efficacy.
Side effects of Entry Inhibitors
fever, insomnia and cough
Examples of maturation inhibitors
vivecon and bevirimat
Mechanism of action of maturation inhibitors
They inhibit the conversion of viral polyprotein to mature capsid leading to formation of non-infective virions with defective cores.
Principles of pharmacotherapy with antiretroviral drugs
– start treatment as soon as HIV is diagnosed
– use combination of at least three different antiretroviral drugs (HAART)
– monitoring of plasma viral load and cd4+ cells count
– change treatment regimen if viral plasma concentration persists or increases.
HAART eradicates HIV from the body.
True or False
False
HAART reduces the virus to undetectable levels.
Guideline for ART treatment in naïve patients (patients with no previous therapeutic exposure to originator)
- Tenofovir + emtricitabine + efavirenz
- Tenofovir/emtricitabine + atazanavir/ritonavir
- Tenofovir/emtricitabine + darunavir/ritonavir
- Tenofovir/emtricitabine + raltegravir
- Tenofovir/emtricitabine + Elvitegravir/cobicistat
- Tenofovir/emtricitabine + dolutegravir
- Abacavir/lamivudine + dolutegravir in (HLA*B-5701 negative)
- Lamivudine could be used to replace emtricitabine in all the
regimen.
Prevention of mother to child transmission
of HIV (PMTCT)
- MOTHER: continue HAART therapy in mother, but avoid efavirenz since it ssis teratogenic
- INFANT: start nevirapine within 6-72hrs of birth till one week after stoppage of breastfeeding.
- For non-breastfeeding infants, nevirapine can be stopped after 6 weeks.
Post -exposure prophylaxis of HIV
(a) TENOVOFIR/EMTRICITABINE + LOPINAVIR/RITONAVIR for 28
days
(b) TENOFOVIR/EMTRICITABINE + ATAZANAVIR/RITONAVIR for
28 days
- Lamivudine could replace emtricitabine in either case.
- And patient should avoid unprotected sex during this period.
