Viral Infection and HIV Flashcards
1
Q
What are the 3 viral enzymes involved in HIV viral replication
A
Reverse transcriptase, integrase, protease
2
Q
Describe the stages of HIV replication
A
- Surface proteins on HIV recognise specific receptor proteins on the surface of target cells, bind
- Fusion: HIV envelope and cell membrane fuse, allows HIV to enter the cell
- HIV replicates within the cell via translation and transcription, using reverse transcriptase
- Maturation of HIV cell - protease
- Budding of HIV cell - formation of the capsid and new HIV pushes out of host cell
3
Q
What does protease do?
A
Protease is toxic to cells, chops us viral precursor proteins which go on the make viral proteins
4
Q
What does intergrase do?
A
It is a critical enzyme, which takes viral DNA and inserts it into the Host DNA, leading to irreversible infection
5
Q
What does reverse transcriptase do/which function does it not have?
A
Reverse transcriptase is used to produce complimentary DNA strands to produce viral proteins. It does not have a proof reading function
6
Q
Discuss the structure-activity relationship of RNA
A
RNA’s sugar has 3 chiral centres, The 2’ and 3’ OH groups in RNA make it less stable. The sugar part of the nucleotide is responsible for orientating the base and triphosphate into the correct position.
7
Q
What is the purpose of the sugar in a nucleotide and can it be changed?
A
The sugar is the scaffold, it holds the triphosphate in the correct orientation. You can change this configuration, as do chain terminators which stops rRNA polymerisation
8
Q
What is the purpose of the base in a nucleic acid and can it be changed?
A
The base allows the nucleotide to make the complementary strand and bonds via hydrogen bonding, Changing this would lead to the wrong tautomer
9
Q
what is the purpose of the triphosphate in a nucleic acid and can it be changed?
A
The triphosphate lacks an active site an cannot be changed as it is important for molecule recognition.
10
Q
What changes can be made to sugars on nucelotides?
A
Remove the hydroxyl group, opportunities at the 2’ and 3’. Changing the sugar element is how nucleoside inhibitors work
11
Q
Describe the process of HIV replication with reference to reverse transcriptase
A
- Reverse transcriptase reads RNA and makes complementary DNA strand.
- RT cuts RNA out and leaves a single strand of viral DNA
3) integrase inserts this viral DNA into the host cell DNA
4) Host cell replicates this viral DNA as part of it’s Genome
5) protease translates viral proteins
12
Q
Describe the structure/function relationship of reverse transcriptase
A
Reverse transcriptase’s structure can be described as a right hand with palm, fingers and thumb. The active site sits in the crease between the fingers and thumb. This active site has aspartic acid residues, holding Mg2+ ions, which are lewis acids and would pair with lewis bases. Reverse transcriptase also has an allosteric binding site.
13
Q
How are NRTIs able to bind to the active site of reverse transcriptase
A
o2 on the phosphate group of NRTIs are strong lewis bases and therefore can bind to the strong lewis acid Mg2+ in the active site of reverse transcriptase
14
Q
Do NRTIs need to be phosphorylated to be active? Why?
A
Yes, to gain the phosphate groups in order to appear like the Nucleotides and prevent chain elongation
15
Q
How do NRTIs work?
A
The 3 hydroxyl group on the sugar is replaced with an azido group, to prevent chain elongation. NRTIs are transported into the cell via soluble carrier transporters, are phosphorylated by kindases but it is not the correct sugar, and chain elongation is terminated, as there is no proof reading function
16
Q
How can NRTIs have toxicity?
A
The phosphorylation inside cells can have toxic effects due to it’s effect on mitochondria
17
Q
How are NRTIs used?
A
As part of Highly Actrive Antiretroviral Therapy (HAART).
2 nucleoside reverse transcriptase inhibitors are given with an NNRTI
2X NRTIs + boosted protease inhibitor
18
Q
When is therapy with 2x rt inhibitors + protease inhibitors saved for?
A
Resistance to 1st line regimens and for patients that wish to become pregnant or have psychiatric illness
19
Q
What are some key points to remember about tenofovir?
A
It doesnt inhibit mitochondrial DNA polymerases but there is no way to administer it orally
20
Q
What does NNRTI stand for?
A
Non nucleoside reverse transcriptase inhibitor
21
Q
Discuss common physiochemical propertires of NNRTIs
A
High logP in order to enable binding, high chemical diversity
22
Q
Where do NNRTI’s bind?
A
At the allosteric binding site
23
Q
How do NNRTIs work?
A
They bind to the allosteric binding site on reverse transcriptase, into the hydrophobic binding pocket. This binding leads to a conformational change in the aspartic acid residues in the active site, binding is inhibited. There is a change in the thumb position, which leads to decreased thumb mobility, and slowing or prevention of the primer strand
24
Q
Discuss the key chemical aspects of NNRTI therapy
A
Resistance - as they bind to non-essential site on RT
Used as part of the HAART regimen to reduce risk of resistance
Very long t1/2
High logP:2.3 which gives it just the right amount of water solubility and hydrophobicity
25
Examples of NRTIs
Abacavir
Emtricitabine
Tenofovir
26
Discuss the pharmacodynamic and physiochemical properties of Nevirapine (NRTI)
```
pKa 2.8
strong base
poor water solubility
High CSF/CNS penetration
Efavirenz preffered NNRTI in pregnant women
```
27
Discuss the pharmacodynamic and physiochemical properties of delvaridine (NRTI)
```
pKa 4.5, weak base
poorly water soluble at physiological pH
low CNS penetration
Teratogenic in rats
hepatic metabolism
```
28
Discuss the pharmacodynamic and physiochemical properties of etravine (NRTI)
pKa 3.5, weak base
insoluble in water
highly lipid soluble
taken with food to increase gastric residence time
elimination in faeces
limited cross-resistance with other NNRTIs
29
Discuss the pharmacodynamic and physiochemical properties of Efavirenz (NRTI)
```
practically insoluble
high membrane permeability (40-50% bioavailability)
hepatic metabolism
Induces CYP enzymes
Effects in CNS
```
30
Discuss the pharmacodynamic and physiochemical properties of doravine (NRTI)
Pka 3.5
quickly absorbed after oral administration
pharmacodynamics not affected by age/gender/ethnicity
metabolised by cyp3a4
31
Discuss the pharmacodynamic and physiochemical properties of ripilvirine (NRTI)
```
pka 5.6 - weak base
poorly water soluble
administered with food
metabolised by cyp3a4
lower incidence of cns effects
not recommended in breast feeding women
```
32
Discuss the pharmacodynamic and physiochemical properties of elsufarazine (NRTI)
oral formulation
t 1/2 9 days, once weekly dosing?
active against isolates from NNRTI experienced patients
higher barrier to genetic resistance
33
In simple terms, what do NRTIs do?
Chain Terminators
34
In simple terms, what do NNRTIs do?
Bind to reverse transcriptase and denatures it
35
Which drugs block entry of HIV?
Fusion inhibitors - block gp41 (fuzeon)
Post attachment inhibitors - (ibalizumab, temsavir)
Entry inhibitors CCR5 co recepotor antagonists (maraviroc)
36
What is membrane fusion?
The fusion of enveloped vriuses and host cell membranes. It is mediated by viral glycopeptides.
37
How does membrane fusion occur?
1. Binding of gp120 to target cell surface on CD4 changes the confirmation of GP120, enabling the protein to bind to another receptor on the cell surface (CCR5/CXCR4)
2. binding of GP120 leads to a confirmational change in GP120 which exposes GP41 and allows it to insert itself into the membrane, which leads to fusion of the two membranes
38
What is the function of gp41?
Gp41 drives final fusion step - a transmembrane protein
39
What is the function of gp120?
It is a surface protein responsible for host cell recognition. Gets the HIV particle into the correct place
40
What does fuzeon do?
Binds to gp41 and blocks the fusion of membranes
41
Discuss the clinical use of fuzeon
- fuzeon is a polypeptide not orally absorbed
- salvage therapy
- administered s/c
- hypersensitivity reactions are common
42
What is albivuirtide?
- fusion inhibitor
- links to serum albumin which increases t 1/2 whilst maintaining activity
- chemically modified peptide derived from HIV-1 protein GP41
43
How do drugs inhibit HIV entry?
Virus attaches to the cell via very few, specific high affinity molecular interactions, mediated by viral glycoproteins, blocking these (gp120, gp41)
Inhibit co-receptors CXCR4 and ccr5
44
Which drugs act on post-attachment?
Idalizumab
45
What is idalizumab used for?
For treatment of heavily experienced patients with multi-drug resistance. Antibody binds to CD4 receptor. Requires loading dose
46
Which drug acts on the CCR5 co-receptor? How does it work?
Maravirol. The only drug in it's class. Binds to allosteric binding site on CCR5 receptor, causes a conformational change and disrupts binding of the virus
47
What is integrase?
An essential viral enzyme. Binds to doubled stranded viral DNA generated by reverse transcriptase and mediates it's integration into the cellular genome
48
What is integration?
The final step before irreversible and productive HIV infection of the target cell
49
What is an active reservoir?
Untreated person
50
What is a latent reservoir?
Virus lies dormant
51
Describe the structure of integrase
It has 3 functional domains: N-terminal, catalytic core and the c-terminal
52
Why is LEDGF-p75 Significant?
It manages chromatin. If you disrupt this, defective viral proteins are produced
53
How does intergrase interact with LEDGF-P75?
Intergrased and LEDGF P75 bind and form a tetramer intasome.
54
What is the N-terminal domain and what is its purpose?
Domain that is part of integrase structure, contains a zinc ion which stabilises the enzyme and is critical for it's function
55
What is the catalytic core domain and what is its purpose?
Part of the structure of integrase and binds to DNA non-specifically
56
What is the C-terminal domain and what is its purpose?
Part of integrase's structure. Contains 3 negatively charged amino acids, which coordinate the mg2+ divalent metal ions, which is essential for catalysing the reactions that lead to 3' strand transfer of DNA
57
Describe the process of strand transfer and integrase’s involvement
3' processing occurs in the cytoplasm. Integrase cuts DNA and produces sticky ends, preparing DNA to be inserted into the nucleus of the host cell. Integrase cuts cellular DNA and inserts viral DNA, leading to permanent infection
58
What is the stable synaptic complex?
A tetramer of intasome engages two viral dna forming the stable synaptic complex
59
What happens to form the CDC?
3' processing of the intasome and 2 vdna. Liable phosphodiester bond is cleaved, mg2+ is key for activity
60
What is the cleaved donor complex?
It is partly in the cytpolasm and the nucleus of the host cell
61
What happens after the CDC is formed?
tDNA binding to the CDC forms the TARGET CAPTURE COMPLEX
62
What happens and is formed after the TCC?
Cleavage of the phosphodiester bond, 3' processing and the joining of v DNA of to cellular DNA
63
What is the strand transfer complex?
Where bonds form between vDNA and cellular DNA
64
How does inhibition of strand transfer occur?
All integrase inhibitors work by blocking this reaction. They all chelate to MG2+ ions on integrase via a lewis acid and base reaction
65
Describe 1st and 2nd generation intergrase inhibitors and give examples
1st generation - have oxygen atoms which are lewis basic centres, mg2+ in the integrase active site are lewis acid centres, chelation occurs and strand transfer is shut down.
2nd generation - are core planar with locked arrangement. They have an aromatic ring with halogens and are hydrophobic. They have high residence times in the active site, leads to high barrier to resistance
66
What interaction should be rememebred for integrase inhibitors?
they are metal chelators and so careful caution should be taken when they are co-administered with antacids and milk
67
What is dual inhibitor therapy?
A co-formulation of dolutegravir (integrase inhibitor) and rilpivirine (NNRTI) Juluca brand
68
Discuss the pros and cons of dual inhibitor therapy
Pros: decreased cost, decreased drug interactions, increased adherence, decreased toxicity
cons: increased virological failure, increased reisstance, viral escape at compartments
69
Give an example of a dual inhibitor
Dual inhibitor example - Juluca dolutegravir and riplivirine
| Cabuneva - carbotegravir and rilpivirine. 12 doses/year
70
What is protease?
An enzyme that plays a crucial role in the viral replicative cycle and is essential for the generation of mature virus
71
How does protease play a part in viral replication?
Acts as chemical scissers to cleave polypeptides into functional proteins within the process of maturation
72
What is maturation? Describe the stages of replication that lead to maturation
The creation of new viral particles
Upstream, Reverse transcriptase has read RNA and created double stranded DNA, which has been inserted into the host cell where transcription of the new mRNA has occurred and translation into new viral proteins. Protease cleaves GagPol fusion proteins to produce new functional proteins
73
What are the two types of proteases?
Peptidases and proteinases
74
What do peptidases do?
Cleave single amino acid from the end of the peptide chain
75
What do proteinases do?
Cleave peptide bonds within a substrate
76
What is the structure of HIV protease?
A homodimer (2 identical polypeptide chains with one active site, formed by 2 key amino acids from each peptide)
77
Describe the quaternary structure of HIV protease
The quaternary structure is made up of 3 separate domains: dimerisation, core, flap
78
What is the core domain?
A highly conserved sequence of amino acids. Aspartate 25 is the key enzyme for the function. This domain is useful in dimer stabilisation as well as catalytic site stability
79
What is the flap domain?
Flexible flaps that enclose the active site and provide important ligand binding interactions. Closes the active site
80
What is the dimerization domain
site crucial for dimer formation
81
How does protease work?
Aspartate 25 on each dimer and a water molecule induce acid-base hydrolysis. Water molecule is activated and generates OH-.
Nucleophile attacks the carbonyl group on the peptide which has natural polarity.
O- electrophile removes proton, bond is cleaved and produces an amine and a caboxylic acid
82
How do isosteres inhibit the action of protease
Isosteres fit into the active site of HIV protease but are non cleavable, so cannot be released. They do not have a leaving group
83
What are the key features of drugs to inhibit protease
NO OH group
| OH on different carbons
84
What are the key features of drugs to inhibit protease
NO OH group
| OH on different carbons
85
How does Tipranavir work?
Used for highly resistant patients with resistance to protease inhibitors.
Contains a dihydropyrone ring, which fits into the active site and mirrors the transition state in order to prevent water from entering the active site
86
Give examples of protease inhibitors
ritinovir
| saquinavir
87
Discuss resistance with relation to protease inhibitors
Cross resistance between protease inhibitors is observed, so it would be pointless to switch.
88
What are key interactions with protease inhibitors?
Interaction with CYP450 metabolism - can increase plasma conc of drugs metabolised in this way. Caution with ketoconazol, rifabutin, warfarin, st john's wort
89
What is ‘boosting?
Co administering protease inhibitors with ritonnavir as it reduces the metabolism of the protease inhibitor
90
Which drug Is usually used for boosting?
Ritonavir
91
How does boosting work?
Ritonavir inhibits CYP450 which leads to increased bioavailability of other protease inhibitors
92
Discuss metabolism, absorption and distribution with relation to boosting
M - main metabolic pathways involve CYP450, with the exception of indinavir
Food - important effect on the absorption of agents eg high fat meal can increase absorption of saquinavir and rifinavir, but reduces absorption of indinavir and amprenavir
93
How is cobicistat used for boosting?
It is a booster with no antiviral activity and is highly selective for CYP13A4.
94
Are there any interactions with cobocistat
ca2+ channel blockers. beta blockers, drugs for erectile dysfunction, statins
95
What are the 3 main routes of transmission for HIV?
sex, needle stick injury, via foetus, contaminated blood products. Purely sexual fluids and blood
96
How have needle exchanges impacted the transmission of HIV?
decreased transmission by lowering risk of sharing contaminated products
97
What is POCT? Describe
Point of care testing. Highly accurate test for HIV 6 weeks after expsure. It is a HIV antibody test, and can be taken 4-8 weeks after exposure. it is a finger prick/mouth swab and results are received within 20-30 minutes
98
What is the 4th generation assay? Describe
HIv antibody test, a blood sample and can take up to 7 days
99
How is HIV diagnosed?
POCT/4th generation assay test.
| POCT is less sensitive and positive results are sent away for a 4th gen test
100
Which markers are used to detect HIV?
CD4 Count, viral load
101
What is the CD4 count?
The number of CD4+ T cells in 1mm3 of blood. Represents the how well the immune system is functioning
102
What does CD4% represent?
The proportion of CD4+ cells in relation to other white blood cells
103
What is the treatment aim with regards to CD4?
Increase CD4 count
104
What level of CD4 cells is considered to put the patient at risk of opportunistic infection?
below 350/200
105
What is viral load?
The number of copies of HIV in the blood
106
What is the treatment aim with regards to viral load?
Decrease viral load to less than 20/ml
107
Why should treatment not be stopped even when the viral load is decreased?
Because the viral load may decrease but the virus can remain latent in the body, so do not stop treatment
108
Describe the course of HIV infections
The primary infection occurs and the CD4 count decreases rapidly, as HIV copies increase. after 6 weeks or so, HIV copies decrease and the patient enters a period of clinical latency which can last between 6-8 years, as the cd4 count slowly declines. As cd4 declines, the patient becomes increasingly at risk of opportunistic infections. CD4 count full decline, patient dies
109
What is a common symptom noticed in the first 1-6 weeks of HIV?
weight loss
110
what is clinical latency?
When the patient has a detectable viral load but is well and not presenting with any symptoms. These patients can still transmit HIV
111
What is acute infection/seroconversion and when does it usually occur? Describe the symptoms
An infection that occurs 1-6 weeks after infection. Patient has a high viral load and unaware of HIV infection. Non specific, flu like symptoms that clear in 1-4 weeks
112
What is AIDS? How is it diagnosed?
Advanced, immunodeficiency syndrome. Diagnosed in people with a low CD4 count and aids definiing illness. AIDS defining illness - opportunistic infections
113
What is the most common aids defining illness?
Pneumocystis jirovecci infection
114
How do you prevent pcp? When do you withdraw it?
Co-trimoxazole prophylaxis until CD4 count has risen and remains high
115
How do you treat severe pcp?
Co trimoxazole IV/PO
116
How do you treat mild to moderate pcp?
Oral co-trimoxazole
117
What is MAC? How do you prevent it?
Mycobacterium avium complex. Presents as fever, night sweats, fatigue, weight loss, anorexia and diarrhoea
118
What is mycobacterial TB? Why do you have to be cautious when treating it with regards to HIV medication?
HIV patients are 20-40x more likely to get TB infection.
| There is drug-drug interactions with rifampicin as it is an enzyme inducer so may impact the plasma levels of HIV drugs
119
What malignancies are associated with HIV?
- unusual skin cancers
- non hodgkins lymphoma
- cerebral lymphoma
- cervical cancer
120
What are the drug targets for HIV therapy?
Attachment - CCR5 inhibitors
Reverse transcriptase - NRTI/NNRTI
Integration - integrase inhibitors
Budding, release and maturation - protease inhibitors
121
How do attachment inhibitors work? Give examples
They attach to surface glycoproteins on HIV cells, to prevent attachment to host cells. EXAMPLE: temsavir CCR5 co receptor antagonist
fusion inhibitors - bind to gp41
122
How do reverse transcriptase inhibitors work? Describe the two sub types
NRTI - binds to the active site on RT, blocks binding of DNA, prevents chain elongation as the incorrect sugar is present. They are chain terminators.
NNRTI - binds to allosteric binding site which cause a conformational change in the active site and prevents binding
123
Give NRTIs example
Tenofovir (TDF/TAF) emtricitabine, abacavir, lemividine
124
Give examples of NNRTIs
Rilpivirine, nevirapine, efavirenz, etravine
125
How do integration inhibitors work?
Integrase inhibitors block the strand transfer reaction. They chelate to Mg2+ ions on integrase enzymes which leads to an acid bace reaction and strand transfer is shut down
126
Give examples of integrase inhibitors
dolutegravir, elvitegravir, cotegravir, raltegravir
127
How do budding and maturation inhibitors work?
Protease inhibitors, fit into the active site of HIV protease and mimic the transition state betwen HIV protease and DNA peptide chains. Unlike peptide chains they have no leaving group, therefore the reaction is locked in the transition state and the two functional proteins cannot be produced
128
Give examples of protease inhibitors
Atazanavir/ darunavir + cobicistat or ritonavir
129
What are the goals of HIV treatment? Clinical/immunological/viral/epidemiological goals
Clinical - extend life expectancy and improve quality of life
Immunological - preserve and restore CD4 cell count
virological - viral load undetectable within 4-6 months
epedemiological - prevent transmission
130
When should treatment be started for HIV? Describe the four main scenarios
Primary infection, chronic infection, presentation of AIDs or a major infection, prevention of transmission
131
How should HIV treatment be initiated following primary infection?
Offer treatment early in infection, treatment should only be started when the patient is ready, but should be recommended ASAP if:
- patient has neurological symptoms, any AIDS defining illness, CD4 count persistently less than 350 cells
132
How should HIV treatment be initiated following chronic infection?
- Start when the patient is ready
133
How should HIV treatment be initiated following aids/major infection presentation?
Start treatment within 2 weeks of antimicrobials if patient presents with AIDS defining illness/serious bacterial infection with CD4 less than 200
134
What are the main factors to consider before starting HIV treatment?
```
CD4 cell count
viral load
pregnant
patients likely adherence
partners where one partner has high viral load
transmission risk
comorbidities
CVD risk
```
135
Discuss the pros and cons of early treatment for HIV
PROS: increased immunological recovery, reduced transmission, reduced disease progression/morbidity, reassurance to patient
CONS: poor preparedness leading to poor adherence and drug resistance, cost, long term side effects/renal impairments
136
What is IRIS?
Immune reconstitution inflammatory syndrome. Patients with dampened immune syndrome and chronic infection can cause large antiinflammatory response if you start antbacterial/antiretrovirals together. Start antimicrobials first then add ART and steroids
137
Discuss CVD risk with relation to HIV
HIV is a CV risk in itself and adding drug therapy can also increase the risk. An extra medication to manage this wouldnt make much difference. Be aware of drug interactions
138
What are the 5 classes of antiretroviral drugs? Give examples of each
NRTI - tenofovir, emtricitabine, abacavir, lamivudine
NNRTI - efavrienz, riplivirine, nevirapine
Protease inhibitors - atazanavir, darunavir, ritonavir
Integrase inhibitors - dolutegravir, elvitegravir, raltegravir
entry inhibitos - CCR5 inhibitors, GP41 inhibitors. Maraviroc
139
What is the NRTI backbone? What does it do?
2 NRTIs. Block addition of nucleosides to DNA chain during retrotranscription, they structurally resemble nucleosides but act to terminate the building of the chain
140
What drugs is Truvada made up of? Discusss the pros and cons
Tenofovir TDF and emtricitabine
Pros: preferred first line, good viral end points
Cons: cautioned in stage 3-5 CKD. Have long term effects on bone density
141
What drugs is descovy made up of? Discuss the pros and cons
Tenofovir TAF and emtricitabine.
PROS: preferred line, equivalent to truvada. Has some benefit in renal/bone disease
CONS: expensive, so only given in confirmed renal disease, lack of experience
142
What drugs is kivexa made up of? Discuss the pros and cons
Abacavir and lamuvidine
PROS: alternative drug which can be used ig the viral load is less than 100,000. Has favourable mineral bone density, cost
CONS: cautioned in CVD
143
What are key points for abacavir?
- 8% people are allergic
| - caution in patients with significant CVD risk
144
What are the 2 tenofovir salts?
TDF and TAF
145
What is TDF?
A salt of tenofovir, activated in the plasma
146
What is TAF?
A salt of tenofovir, which is activated intracellularly, lower plasma concentration and fewer side effects
147
List the 3 third agents for HIV treatment
Protease inhibitors, integrase inhibitors, NNRTIs
148
discuss the pros and cons of protease inhibitors
PROS - high barrier to resistance, high efficacy. Can be so effective in some patients that they can be used alone
CONS - drug interactions, cost, side effects, redistribute fat from stomach to the back
149
discuss the pros and cons of integrase inhibitors
PROS: Fewer side effects, fewer drug-drug interactions, rapid virological response
CONS: cost, low barrier to resistance
150
discuss the pros and cons of NNRTIS
PROS: previous efficacy as first line, relatively few side effects
CONS: efavirenz C/I in psychiatric illness. Ripilivirine can only be used in lower viral loads
drug-drug interactions and resistance can occur
151
What drug factors influence ARV choice?
side effects/toxicity, drug resistance, previous treatments and pill burden, storage, potential for drug-drug interactions
152
Which patient factors influence ARV choice?
renal function, liver function, CV risk, pregnancy, pill burden, psychiatric/mental illness, experienced or naive, adherence, choice, viral load
153
What causes treatment failure?
resistance, poor adherence, drug-drug interactions. Presents as sustained viral load rebound that has been detectable for a while
154
Discuss adherence and resistance related to HIV infection
Very high levels of adherence correlates to succesful treatment. Poor adherence leads to failure, disease progression, transmission of resistant virus, increased healthcare costs. Patients should miss less than one dose per month. Reverse transcriptase is prone to errors which leads to drug resistant mutations
155
What is wild type HIV?
HIV without genetic mutations that confer resistance and will always outgrow other types of HIV.
156
Discuss Drug-drug interactions with ARV (metabolism, transporter proteins, absorption, renal clearance?
Absorption - chelation of integrase with calcium/iron supplements
Changes to gastric PH can reduce absorption, Alanzavir and ripilivirne contraindicated with PPI
Transporter proteins - shunt drugs in and out
Metabolism - inhibition or induction of enzymes. CYP450 problem with protease inhibitors or NNRTIs
Renal clearance - drugs causing renal insufficiency. Protease inhibitors reduce the cleaners of TAD
157
List Potential comorbidities with potential interactions with HIV
diabetes, hyperlipidaemia, neuro-psychiatric illness, malignancies, hypertension, hepatitis, transplants, TB, opioid dependance, other infections
158
Why are some HIV drugs taken with food?
To reduce the side effects or to increase absorption of lipid soluble drugs by lowering gastric pH and causing delayed stomach emptying e.g ripilivirine absorption is lower on fasted stomach, efavirenz is taken on an empty stomach, truvada take with food
