Antiretroviral therapy Flashcards
How many patients undergo rapid HIV progression?
<5%
What iss the percetnage of patinets who are long-term non-progressors?
5%
What is the typical HIV progression?
7-10 years
What is seen with primary HIV disease in terms of viral count and CD4?
during primary, there is very high viraemia with rapid decrease in CD4, then with seroconversion, CD4 count rises
What did the SMART study look at?
continuous ART vs drug conservation strategy
What is the drug conservation strategy with ART?
defer use of ART til CD4 <250 then episodic ART based on CD4 count to increase counts to >350
What were the results of the SMART study?
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
What was the START study looking at?
immediate vs deferred ART for asymptomatic, ART-naive patients
What was the result of the START study?
60% reduction in serious events or death with immediate ART vs deferred—everyone with HIV gets ART
What are the 2 types of entry inhibitor?
CCR5 inhibitor- maraviroc and fusion gp41- T20
What is the problem with CCR5 inhibitors?
have to ensure that the patietns has an R5 tropic virus
How can you determine if a patients virus is R5 or X4 tropic?
viral culture to look at characteristcs- phenotypic test ; genotypic test- sequence the envelope of the virus
How does T20 work?
big peptide which stops the receptor changing shape therefore prevents entry
What is the problem with T20?
has to be injected as it is a large peptide but is exogenous so there are injection site reactions
What are the 3 types of reverse transcriptase inhibitor?
NRTI (nucleoside RTI); NTRTI (nucleotide RTI) and NNRTI (non-nucleoside)
How do the NNRTIs work?
enzmye inhibitors- bind to RT
How do the NRTIs and NTRTIs work?
chain terminators
Why are integrase inhibitors now first line?
massively reduced SE profile
What is the MOA of AZT?
acts as an analogue for thymidine in growing pro-viral DNA chain
How many HIV viral particles are produced each day?
10^11
How does HIV resistance develop?
error prone reproduction, drug resistant mutatns have no advantage (are less fit) but drug pressure selects out and creates mutants
How long does AZT work for?
6 months (resistance)
Which drugs were the first developed using rationale drug design
protease inhibitors (after protease enzyme structure established)
What is the best HAART combination?
2 nucleoside RTIs and another drug- usually integrase
Which NRTIs are recommended first line?
tenofovir; emtricitabine
What was the prupose of the ESPIRIT study?
look at whether you can boost a patietns immune system to fight HIV by giving IL-2
What were the results of the ESPIRIT study?
got massive CD4 response to IL-2 but there was not difference in OI or death between arms
What is the minimum adherence required to prevetn resistance?
a dose every 6 months
What were the main side effects with the historical NRTIs?
mitochondrial toxicity; lipoatrophy; individual drug toxicities
What is the mechanism behind the SE of historical NRTIs?
some cross-reactivity between RT and DNA polymerase, lots of DNA polymerase in mitochondria–drugs tend to hit a specific organs mitochondria
What is a problem with abacavir?
4% of caucasians have a genetic hypersensitivity to abacavir; increased risk of MI
How can the hypersensitivity to abacavir be avoided?
screen patietns for HLA-B27 01 before using; only give to patients with a low risk of MI- QRISK score
What organs does tenofovir affect?
renal and bone
What is the difference bewteen the 2 forms of tenofovir (DF and AF)?
different prodrugs- AF gives v. high concentrations in lymphocytes vs kidneys and bones so has less SE than DF version
What are the general SE of NNRTIs?
rash; hepatotoxicity; CNS effects
What are the specific SEs of nevirapine?
allergic rash and hepatitis/ SJS
What are the specific SE of efavirenz?
insomnia; vivd dreams; pychosis; rash
What are hte main SE with protease drugs?
metabolic syndrome- hyperlipidaemia; hyperglycaemia; body fat accumulation
What is a specific SE of indinavir?
renal stones
What is a specific SE of atazanavir?
scleral icterus
When would the TAF version of tenofovir be used instead of TDF?
if decreased GFR and abnormal BMD or young patient (bones still growing)
What metabolises the protease inhibitors?
CYP 3A4
Why are CYP 3A4 inhibitors given with protease inhibitors?
as without there are a lot of peaks and troughs in drug levels so reduces doses needed
What is a major problem with protease inhibitors?
lots of drug interactions
When is T20 used?
in patietns resistance to all other classes
What adverse effect is more common in integrase inhibitors?
insomnia- CNS toxicity?
What comorbdities are more common in HIV persons?
hypertension; angina; MI ; liver disease; renal failure and cancer
What are the future challenges with HIV treatment?
less drug-drug interactions; less imapct on comorbidities and easier adherence
