Treatment of HIV

Question 1

Structure of HIV virion

Answer 1

• A retrovirus
• Single stranded RNA, that becomes Double stranded DNA once in cell via reverse transcriptase

Question 2

DNA synthesis mechanism

Answer 2

Question 3

Azidothymidine/NRTIs mechanism

Answer 3

A Nucleoside analogue Reverse Transcriptase Inhibitor (NRTI)

• 2’3’ dideoxy nucleoside analogue
• Phosphorylated by host cells, different to acyclovir
• AZT-triphosphate acts as DNA chain terminator and reverse transcriptase inhibitor as there is no oxygen on the end for further DNA binding
• Azidothymedine: Late disease 19 deaths in trial, 18 of which in placebo.
  • Early disease trial: Initial CD4 rise, but then decrease. Useful therapeutic life of about 6 months independent of time of initiation due to development of HIV resistance in vitro.

Question 4

Reasons for HIV drugs resistance

Answer 4

• High number of in vitro mutations in HIV
• 10¹² every 24 hours

Question 5

Other NRTIs

Answer 5

• ddC and ddI
• The next 2’3’dideoxy NAs developed
• Same led to more sustained CD4 responsmechanism of action. Less anaemia
• Different toxicity profiles (peripheral neuropathy, pancreatitis
• AZT +ddI or ddC gives slight improvement on single drug therapy. no overlap in gene positions for reverse transcriptase mutations that confer resistance between AZT and dd

Question 6

Charateristics of NRTIs

Answer 6

• All are analogues of native nucleotides sharing the common motif of a lack of ‘3-OH group on their ribose ring.
• Must be phosphorylated by cellular kinases before they can effectively exert their actions.

Question 7

NRTIs and theri native nucleoside analouges

Answer 7

Thymidine-Zidovudine

Cytosine-Lamivudine

Guanosine-Abacavir

Adenosine-Didanosine

Question 8

Name the only nuceloTIDE RT inhibitor

Answer 8

Tenofovir DF

Question 9

Currently used NRTIs

Answer 9

• Zidovudine (AZT) - Thymidine
• Stavudine (D4T) - Thymidine
• Lamivudine (3TC) - Cytosine
• Emtricitabine (FTC) - Cytosine
• Abacavir (ABC) - Guanosine
• Didanosine (DDI) - Adenosine
• Tenofovir DF (TDF) - Adenosine

Question 10

Adverse effects of NRTIS

Answer 10

• NRTIs block “RT”; They may inhibit the activity of normal cellular DNA polymerases (e.g. mitochondrial DNA pol-ү)
  
  • S/E: Lactic acidosis, hepatic steatosis, peripheral neuropathy, myopathy and lipoatrophy
• They may interfere with CyP450 enzymes; drug-drug interactions

Question 11

Charateristics of NNRTIs

Answer 11

• Non-Nucleoside analogue Reverse transcriptase Inhibitors
• Structurally unrelated, act at different site within RT
  
  • Non-competitive RT inhibitors, induce conformational changes within RT
• Combination therapy (NRTI + NNRTI) achieves greater loss of viral load, sustained for longer
• Nevirapine, efavirenz, etravirine

Question 12

Adverse effects of NNRTIs

Answer 12

• Substrates of the CYP enzymes (high potential for drug-drug interactions). Liver issues
• Efavirenz: CNS (vivid dreams, insomnia, hallucinations, depression) and teratogenicity

Question 13

Pol gene.. transcribes

Answer 13

• Reverse transcriptase
• Protease, differs from cellular protease
• Integrase

Question 14

Protease inhibitors MOA

Answer 14

• HIV aspartyl protease cleaves gag and gag-pol polyproteins into their essential structural and enzymatic (RT and IN) components. (Pol codes viral protease which is not same as cellular)
  
  • PIs inhibit HIV protease-mediated cleavage of HIV polyprotein precursors
  • Virus particles can still be made but they are rendered non-infectious.
  • Metabolised by CYP enzymes (use of ritonavir as CYP inhibitor to boost PIs)

Question 15

How does resistance towards PIs occur

Answer 15

Mechanism of resistance: mutations (a.a changes) modify the number and nature of points of contact between the PI and the protease molecule.

• Multiple mutations accumulate and increase reistance
• Many mutations are common for PIs, so a virus thats resistant to one is likely to be resistant to all

Question 16

Adverse effects of PIs

Answer 16

• Dyslipidaemia can be a problem with some PIs
• Implicated in causing insulin resistance.
• Lower GI symptoms are the main S/E.
• All antiretrovirals, but particularly the PIs may interere with P450 in liver: DRUG-DRUG

Question 17

Ritonavir

Answer 17

FIrst generation PI.

• Now used as booster.
• Potent P450 inhibitor
  
  • Used in combination with better PI
  • E.g. used with Lopinavir, which is P450 metabolised. So with inhibitor a lower dose can be used, less side effects

Question 18

Current PIs

Answer 18

Lopinavir

Atazanivir

Darunavir

All can be used in conjuntion with Ritonavir

Question 19

Possible sites of action

Answer 19

Question 20

Targets for new line of antiretrovirals

Answer 20

Entry inhibitors,

• block chemokine co-receptors Maraviroc
• Block fusion enfuvirtide

Integrase inhibitors

• Eukaryotic cells dont have integrase

Others

• Ibalizumab: antibody to CD4 receptor that blocks HIV entry into CD4+ T-cells; FDA approved in March 2018
• Fostemsavir: prodrug that binds HIV-1 gp120 and prevents viral attachment and entry into CD4+ cells
• PRO 140: antibody to CCR5

Question 21

Integrase strand transfer inhibitors MOA

Answer 21

• HIV integrase catalyses both cDNA processing and strand transfer.
• The drugs block strand transfer reaction: inhibit both HIV-1 and HIV-2
• Raltegravir is the 1st approved “INSTI”
• Potent, but low genetic barrier to resistance. Resistance only requires two mutations (Q148H and N155H confer resistance)

Question 22

ARV drugs classes

Answer 22

• Entry inhibitors
• Reverse transcriptase inhibitors
• Integrase inhibitors
• Protease inhibitors

Question 23

Princicbles for current anti-HIV therapy

Answer 23

• Must use cART, combination antiretroviral therapy
• Monitor by ultrasensitive viral load assays
• cART blocks the selection of mutants because:
  
  • Multiple mutations are required simultaneously for resistance to occur to all drugs in the regimen
  • If virus is not replicating, then resistance cannot happen

Question 24

criteria for starting ART

Answer 24

• When patient is diagnosed with HIV infection (current BHIVA guidance)
• Not based on CD4 count etc as previously
• Important not to miss doses; mutations

Question 25

Current preffered regiments

Answer 25

* Two NRTIs plus either an NNRTI or a ritonavir boosted PI or an INSTI * Adapt combination to ones that work for patient. **Emphasis on compliance**. use polyformulated tablets * e.g. Truvada, Kivexa, **Atripla,** Eviplera