Treatment of HIV Flashcards
1
Q
Structure of HIV virion
A
- A retrovirus
- Single stranded RNA, that becomes Double stranded DNA once in cell via reverse transcriptase
2
Q
DNA synthesis mechanism
A
3
Q
Azidothymidine/NRTIs mechanism
A
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.
4
Q
Reasons for HIV drugs resistance
A
- High number of in vitro mutations in HIV
- 1012 every 24 hours
5
Q
Other NRTIs
A
- 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
6
Q
Charateristics of NRTIs
A
- 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.
7
Q
NRTIs and theri native nucleoside analouges
A
Thymidine-Zidovudine
Cytosine-Lamivudine
Guanosine-Abacavir
Adenosine-Didanosine
8
Q
Name the only nuceloTIDE RT inhibitor
A
Tenofovir DF
9
Q
Currently used NRTIs
A
- Zidovudine (AZT) - Thymidine
- Stavudine (D4T) - Thymidine
- Lamivudine (3TC) - Cytosine
- Emtricitabine (FTC) - Cytosine
- Abacavir (ABC) - Guanosine
- Didanosine (DDI) - Adenosine
- Tenofovir DF (TDF) - Adenosine
10
Q
Adverse effects of NRTIS
A
- 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
11
Q
Charateristics of NNRTIs
A
- 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
12
Q
Adverse effects of NNRTIs
A
- Substrates of the CYP enzymes (high potential for drug-drug interactions). Liver issues
- Efavirenz: CNS (vivid dreams, insomnia, hallucinations, depression) and teratogenicity
13
Q
Pol gene.. transcribes
A
- Reverse transcriptase
- Protease, differs from cellular protease
- Integrase
14
Q
Protease inhibitors MOA
A
- 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)
15
Q
How does resistance towards PIs occur
A
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
19
Q
Possible sites of action
A
