Antiretrovirals

Question 1

What is a retrovirus?

Answer 1

A retrovirus is an RNA virus which possesses reverse transcriptase enzyme with which it produces DNA copy of its RNA genome.

Question 2

What are antiretrovirals?

Answer 2

Antiretroviral agents are drugs for the treatment of infection caused by retroviruses.

Question 3

Examples of retroviruses

Answer 3

1. Human immune deficiency virus (HIV)
2. Simian immunodeficiency virus (SIV)
3. Human T-cell lymphotropic virus type 1 (HTLV-1)

Question 4

Classification of Antiretroviral agents

Answer 4

1. Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
2. Non-nucleoside reverse transcriptase inhibitors
3. Protease inhibitors
4. Fusion inhibitors
5. Entry/CCR5 inhibitors
6. Integrase inhibitors
7. Maturation inhibitors

Question 5

Examples of Nucleoside/nucleotide reverse
transcriptase inhibitors (NRTIs)

Answer 5

abacavir (ABC)
didanosine (DDC)
emtricitabine (FTC)
zidovudine (AZT)
lamivudine (3TC)
stavudine (D4T)
zalcitabine
tenofovir (TDF) [nucleotide]

Question 6

Mechanism of action of NTRIs

Answer 6

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.

Question 7

Uses of NRTIs

Answer 7

1. Mainly for HIV with other ARVs.
2. Lamivudine &
   adefovir are also used for hepatitis B.

Question 8

Class adverse effects of NRTIs

Answer 8

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

Question 9

Specific adverse effects of NRTIs

Answer 9

1. Zidovudine: anaemia
2. Stavudine: peripheral neuropathy & lipodystrophy
3. Abacavir: allergic reaction

Question 10

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

Answer 10

False

TAF has better effects
on bones and kidneys.

Question 11

TDF has better lipid lowering effects than TAF.

True or False

Answer 11

True.

TDF produce higher level of tenofovir, which lowers lipid.

Question 12

Examples of Non-nucleotide Reverse Transcriptase Inhibitors

Answer 12

1st generation: efavirenz (EFV), nevirapine (NVP), and delavirdine
D-E-N

2nd generation: etravirine and rilpivirine
E-R

Question 13

Uses of NNRTIs

Answer 13

1. HIV in combination with other ARVs
2. Etravirine: resistant case in tmt exp pt only
3. Rilpivirine: tmt naïve pt

Question 14

Mechanism of action of NNRTIs

Answer 14

NNRTIs bind to the reverse transcriptase enzyme near its catalytic site and denature it.

• They spoil the virus’ toools

Question 15

Class adverse effects of NNRTIs

Answer 15

Rash

Question 16

Specific adverse effects of NNRTIs

Answer 16

1. Efavirenz: CNS toxicity (headache, fatigue, sleep disturbances, dizziness and depression).
2. Nevirapine: hepatoxicity
3. Etravirine: allergic reaction
4. Delavirdine: allergic reaction, fever, blurred vision,
   stuffy nose.

Question 17

Examples of Protease Inhibitors

Answer 17

– 1st generation: LINDRAFTS
lopinavir (LPV)
indinavir
nelfinavir
droxinavir
ritonavir (r/RTV)
amprenavir
fosamprenavir
telinavir
saquinavir (SQV)

– 2nd generation: TAD
Tipranavir
Atazanavir (ATV)
Darunavir

Question 18

Mechanism of action of protease inhibitors

Answer 18

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.

Question 19

Mechanism of action of protease inhibitors

Answer 19

Treatment of HIV infection in combination with other antiretroviral drugs of different classes.

Question 20

Class adverse effects of protease inhibitors

Answer 20

paraesthesia
rhabdomyolysis
myalgia
lipodystrophy
hyperglycemia

Question 21

Specific adverse effects of protease inhibitors

Answer 21

Atazanavir causes raised
bilirubin levels but has less effects on lipodystrophy and hyperglycemia

Question 22

Examples of HIV fusion inhibitors

Answer 22

Enfuvirtide

Question 23

Mechanism of HIV fusion inhibitors

Answer 23

Inhibition of the fusion of
HIV with the host cells.

Question 24

Uses of HIV fusion inhibitors

Answer 24

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.

Question 25

Adverse effects of HIV fusion inhibitors

Answer 25

flu-like symptoms hypersensitivity reactions

Question 26

Examples of HIV Integrase inhibitors

Answer 26

– 1st generation: raltegravir and elvitegravir – 2nd generation: dolutegravir and bictegravir

Question 27

Mechanism of action of HIV integrase inhibitors

Answer 27

They inhibit the viral integrase enzyme which is responsible for integration of the viral DNA with the infected cell DNA.

Question 28

Side effects of raltegravir

Answer 28

– Common: headache, nausea, diarrhoea, weakness, insomnia – Rare: hepatitis, thrombocytopenia, rhabdomyolysis, pyrexia, diaphoresis, rashes, renal failure, nephrolithiasis, depression, suicidal behaviours, anxiety and paranoia.

Question 29

Examples of Entry Inhibitors or CCR5 antagonists

Answer 29

maraviroc aplaviroc vicriviroc

Question 30

Mechanism of action of Maraviroc

Answer 30

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.

Question 31

Side effects of Entry Inhibitors

Answer 31

fever, insomnia and cough

Question 32

Examples of maturation inhibitors

Answer 32

vivecon and bevirimat

Question 33

Mechanism of action of maturation inhibitors

Answer 33

They inhibit the conversion of viral polyprotein to mature capsid leading to formation of non-infective virions with defective cores.

Question 34

Principles of pharmacotherapy with antiretroviral drugs

Answer 34

– 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.

Question 35

HAART eradicates HIV from the body. True or False

Answer 35

False HAART reduces the virus to undetectable levels.

Question 36

Guideline for ART treatment in naïve patients (patients with no previous therapeutic exposure to originator)

Answer 36

1. Tenofovir + emtricitabine + efavirenz 2. Tenofovir/emtricitabine + atazanavir/ritonavir 3. Tenofovir/emtricitabine + darunavir/ritonavir 4. Tenofovir/emtricitabine + raltegravir 5. Tenofovir/emtricitabine + Elvitegravir/cobicistat 6. Tenofovir/emtricitabine + dolutegravir 7. Abacavir/lamivudine + dolutegravir in (HLA*B-5701 negative) * Lamivudine could be used to replace emtricitabine in all the regimen.

Question 37

Prevention of mother to child transmission of HIV (PMTCT)

Answer 37

1. MOTHER: continue HAART therapy in mother, but avoid efavirenz since it ssis teratogenic 2. 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.

Question 38

Post -exposure prophylaxis of HIV

Answer 38

(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.