Antiretrovirals

Question 1

Goals of ARV treatment

Answer 1

• Suppress viral replication - immune recovery
• Decrease morbidity and mortality
• improve QoL

Question 2

3 classes of ARVs

Answer 2

Reverse Transcriptase inhibitors (RTI)
Integrase inhibitors
Protease inhibitors

Question 3

Reverse transcriptase inhibitors MoA

Answer 3

1. Nucleoside and nucleotide RTI: These mimic nucleotides and terminate the DNA chain therefore stopping the reverse transcription process [Zidovudine; Lamivudine; Emtricitabine; Tenofovir; Abacavir]
2. Non-nucleoside RTI: These bind at non-active sites and alter conformation of the reverse transcriptase enzyme structure [Nevirapine; Efavirenz; Etravirine]

Question 4

Name these drugs from their dumb abbreviations (just for fun):
AZT
3TC
FTC
TDF
ABC
NVP
EFV
DTG

Answer 4

AZT - Zidovudine
3TC - Lamivudine (bro how even)
FTC - Emtricitabine
TDF - Tenofovir
ABC - Abacavir
NVP - Nevirapine
EFV - Efavirenz
DTG - Dolutegravir

Question 5

Integrase Inhibitors (Dolutegravir) MoA

Answer 5

Bind to the central catalytic domain of integrase enzyme stopping the viral DNA from entering the cell DNA

Question 6

Protease inhibitors MoA [Ritonavir, Lopinavir, Atazanavir, Darunavir]

Answer 6

These bind to the active site where the newly formed HIV proteins are created into a viral droplet thing so that it cannot infect new cells

Question 7

CD4 counts for stages and a few symptoms
Stage 1
Stage 2
Stage 3
Stage 4

Answer 7

Stage 1: >500 cells/uL; [Asymptomatic + generalized LN enlargement]
Stage 2: <500 cells; [LOW <10 %; Mucocutaneous manifestations + recurrent URTIs]
Stage 3: <350 cells; [LOW >10%; Unexplained chronic diarrhoea > 1/12; severe bacterial infection]
Stage 4: <200 cells; [severe Symptoms; toxoplasmosis; candidiasis of esophagus and shiii]

Question 8

ART drug interactions: all act on CYP450

Answer 8

There inducers of CYP450: Nevirapine, Efavirenz, Rifampicin
Inhibitors: Pls (Ritonavir)
Substrates (these are broken down by CYP450 therefore these drugs are affected by inducers and inhibitors): NNRTis (NVP, EFV); PIs; (DTG); Benzodiazepines, oral contraceptive, statins

Question 9

Who do we start ARTs in

Answer 9

All adults and children with confirmed HIV, Prioritize pregnant woman, advanced disease, <5 years

Question 10

When to delay initiation of ARTs:

Answer 10

Meningitis [cryptococcal and TB meningitis]
- due to increased risk of death due to immune reconstitution inflammatory syndrome (IRIS)
- TB meningitis: 8 weeks after starting TB treatment
- Cryptococcal meningitis: 4-6 weeks after starting antifungal therapy

TB at non-neurological site
- CD4 < 50 cells, start ARVs 2 weeks after TB Rx initiation (need to treat it sooner)
- CD4 > 50 cells, start ARVs 8 weeks after TB Rx initiation

Question 11

NRTI (nucleotide RTI) Side effects

Answer 11

Tenofovir - Renal dysfunction, osteopaenia
Zidovudine - Anaemia, neutropaenia
Class effects - lactic acidosis

Question 12

NNRTIs (non nucleotide RTIs) Side effects

Answer 12

Efavirenz and nevirapine - rash, hepatotoxicity
Efavirenz only - neuropsychiatric SE

Question 13

Integrase inhibitors Side effects

Answer 13

Dolutegravir: insomnia, CNS SE, ?Weight gain
Increased neural tube defects if taken with first 4 weeks after conception

Question 14

Protease inhibitors Side effects

Answer 14

Lopinavir and ritonavir: Diarrhoea, hypertriglyceridaemia
Atazanavir - unconj. hyperbilirubinaemia (aka. gilberts)

Question 15

Diagnosis of a treatment failure

Answer 15

May be virological/immunological/clinical (progression in that order)
Virological= unsuppressed viral load
VL > 1000 copies/mL on 2 occasions!

Immunological = low CD4 count

Clinical = clinical progression

Question 16

Steps in changing to 2nd line ART regimen

Answer 16

1. If VL >1000 copies then:
   - Check adherence and address adherence issues
   - repeat viral load in 3 months
2. If there is still an elevated VL load and pt. is on a efavirenz (NNRTI) regimen:
   - SWITCH to 2nd line therapy
   - this is because this therapy has a lower barrier to resistance so it is more likely the pt. has developed resistance
3. However, if there is a elevated VL load and pt. is on a DTG (InSTI) regimen:
   - DTG has a much higher barrier against resistance so it is much less likely therefore not as quick to change to 2nd line therapy
   - only will switch if there is a high VL on 3 occasions over course of 2 year (a long time) and signs of immunological or clinical failure

Question 17

The first line regimens:
NNRTI-based
InSTI-based

Answer 17

NNRTI-based: TDF + 3TC/FTC + EFV/NVP
Tenofovir, lamivudine/Emtricitabine, Efavirenz/nevirapine
InSTI-based: TDF + 3TC/FTC + DTG
Tenofovir, Lamivudine/Emtricitabine, Dolutegravir

Question 18

The second line regimens:

Answer 18

AZT + 3TC/FTC + DTG
Zidovudine, lamivudine/Emtricitabine, Dolutegravir