Antiretroviral therapy

Question 1

How many patients undergo rapid HIV progression?

Answer 1

<5%

Question 2

What iss the percetnage of patinets who are long-term non-progressors?

Answer 2

5%

Question 3

What is the typical HIV progression?

Answer 3

7-10 years

Question 4

What is seen with primary HIV disease in terms of viral count and CD4?

Answer 4

during primary, there is very high viraemia with rapid decrease in CD4, then with seroconversion, CD4 count rises

Question 5

What did the SMART study look at?

Answer 5

continuous ART vs drug conservation strategy

Question 6

What is the drug conservation strategy with ART?

Answer 6

defer use of ART til CD4 <250 then episodic ART based on CD4 count to increase counts to >350

Question 7

What were the results of the SMART study?

Answer 7

opportunistic disease and all-cause death were both considerably lower in the virologic suppression cohort– first evidence that HIV doesn’t just affect immune system but also results in inflammatory disease eg MIs; strokes which can be reduced with ART

Question 8

What was the START study looking at?

Answer 8

immediate vs deferred ART for asymptomatic, ART-naive patients

Question 9

What was the result of the START study?

Answer 9

60% reduction in serious events or death with immediate ART vs deferred—everyone with HIV gets ART

Question 10

What are the 2 types of entry inhibitor?

Answer 10

CCR5 inhibitor- maraviroc and fusion gp41- T20

Question 11

What is the problem with CCR5 inhibitors?

Answer 11

have to ensure that the patietns has an R5 tropic virus

Question 12

How can you determine if a patients virus is R5 or X4 tropic?

Answer 12

viral culture to look at characteristcs- phenotypic test ; genotypic test- sequence the envelope of the virus

Question 13

How does T20 work?

Answer 13

big peptide which stops the receptor changing shape therefore prevents entry

Question 14

What is the problem with T20?

Answer 14

has to be injected as it is a large peptide but is exogenous so there are injection site reactions

Question 15

What are the 3 types of reverse transcriptase inhibitor?

Answer 15

NRTI (nucleoside RTI); NTRTI (nucleotide RTI) and NNRTI (non-nucleoside)

Question 16

How do the NNRTIs work?

Answer 16

enzmye inhibitors- bind to RT

Question 17

How do the NRTIs and NTRTIs work?

Answer 17

chain terminators

Question 18

Why are integrase inhibitors now first line?

Answer 18

massively reduced SE profile

Question 19

What is the MOA of AZT?

Answer 19

acts as an analogue for thymidine in growing pro-viral DNA chain

Question 20

How many HIV viral particles are produced each day?

Answer 20

10^11

Question 21

How does HIV resistance develop?

Answer 21

error prone reproduction, drug resistant mutatns have no advantage (are less fit) but drug pressure selects out and creates mutants

Question 22

How long does AZT work for?

Answer 22

6 months (resistance)

Question 23

Which drugs were the first developed using rationale drug design

Answer 23

protease inhibitors (after protease enzyme structure established)

Question 24

What is the best HAART combination?

Answer 24

2 nucleoside RTIs and another drug- usually integrase

Question 25

Which NRTIs are recommended first line?

Answer 25

tenofovir; emtricitabine

Question 26

What was the prupose of the ESPIRIT study?

Answer 26

look at whether you can boost a patietns immune system to fight HIV by giving IL-2

Question 27

What were the results of the ESPIRIT study?

Answer 27

got massive CD4 response to IL-2 but there was not difference in OI or death between arms

Question 28

What is the minimum adherence required to prevetn resistance?

Answer 28

a dose every 6 months

Question 29

What were the main side effects with the historical NRTIs?

Answer 29

mitochondrial toxicity; lipoatrophy; individual drug toxicities

Question 30

What is the mechanism behind the SE of historical NRTIs?

Answer 30

some cross-reactivity between RT and DNA polymerase, lots of DNA polymerase in mitochondria--drugs tend to hit a specific organs mitochondria

Question 31

What is a problem with abacavir?

Answer 31

4% of caucasians have a genetic hypersensitivity to abacavir; increased risk of MI

Question 32

How can the hypersensitivity to abacavir be avoided?

Answer 32

screen patietns for HLA-B27 01 before using; only give to patients with a low risk of MI- QRISK score

Question 33

What organs does tenofovir affect?

Answer 33

renal and bone

Question 34

What is the difference bewteen the 2 forms of tenofovir (DF and AF)?

Answer 34

different prodrugs- AF gives v. high concentrations in lymphocytes vs kidneys and bones so has less SE than DF version

Question 35

What are the general SE of NNRTIs?

Answer 35

rash; hepatotoxicity; CNS effects

Question 36

What are the specific SEs of nevirapine?

Answer 36

allergic rash and hepatitis/ SJS

Question 37

What are the specific SE of efavirenz?

Answer 37

insomnia; vivd dreams; pychosis; rash

Question 38

What are hte main SE with protease drugs?

Answer 38

metabolic syndrome- hyperlipidaemia; hyperglycaemia; body fat accumulation

Question 39

What is a specific SE of indinavir?

Answer 39

renal stones

Question 40

What is a specific SE of atazanavir?

Answer 40

scleral icterus

Question 41

When would the TAF version of tenofovir be used instead of TDF?

Answer 41

if decreased GFR and abnormal BMD or young patient (bones still growing)

Question 42

What metabolises the protease inhibitors?

Answer 42

CYP 3A4

Question 43

Why are CYP 3A4 inhibitors given with protease inhibitors?

Answer 43

as without there are a lot of peaks and troughs in drug levels so reduces doses needed

Question 44

What is a major problem with protease inhibitors?

Answer 44

lots of drug interactions

Question 45

When is T20 used?

Answer 45

in patietns resistance to all other classes

Question 46

What adverse effect is more common in integrase inhibitors?

Answer 46

insomnia- CNS toxicity?

Question 47

What comorbdities are more common in HIV persons?

Answer 47

hypertension; angina; MI ; liver disease; renal failure and cancer

Question 48

What are the future challenges with HIV treatment?

Answer 48

less drug-drug interactions; less imapct on comorbidities and easier adherence