Lec 35 HIV Treatment Flashcards
What is mech of NRTI action?
NRTI = nucleoside reverse transcriptase inhibitors
- compete with native nucleotides as substrates for RT
What are side effects common to NRTIs?
- mitochondrial toxicity: muscle weakness, mental state change, pancreatitis, lactic acidosis
- dyslipidemia
What is a side effect specific to AZT [zidovudine]?
anemia
What is a side effect specific to 3TC [lamivudine]?
minimal toxicity
What is a side effect specific to FTC [emtricitabine]?
minimal toxicity
Which two NRTIs are preferred in ARV-naive patients?
- FTC [emtricitabine]
- TDF [tenofovir]
What is a side effect specific to ABC [abacavir]?
- hypersensitivity reaction in HLA B-5701 [can be fatal]
What is a side effect specific to tenofovir [TDF]?
- renal toxicity [major one]
- also osteopenia
What sides effects of didanosine [ddI]?
- higher risk mitochondrial toxicity
- peripheral neuropathy
- insulin resistance
What side effects of stavudine [d4T]?
- higher risk of mitochondrial toxicity
- lipoatrophy
- insulin resistance
What were early principles of HIV treatment?
first: treat early and treat hard
then: treat based on CD4/VL/symptoms
What are the downside of NNRTIs?
- resistance develops easily
- all have interactions with CP450
What are side effects specific to nevirapine [NVP]?
- hypersensitivity rxn [hepatitis, rash, mucoal alteration]
- rxn more common in women and pts with relatively high CD4
What are side effects specific to efavirenz [EFV]?
- neuropsychiatric symptoms
- potential teratogen
- lipid elevation
- rash
What are the 2 NNRTIs?
- nevirapine [NVP]
- efavirenz [EFV]
What is mech of action of NNRTIs?
NNRTIs = non-nucleoside reverse transcriptase inhibitors
- act as allosteric inhibitor to bind RT
What is mech of action of PIs?
PIs - protease inhibitors
- block viral proteases involved of cleavage of viruses from non-infectious to mature infectious form
What are class side effects of PIs?
- dyslipidemia
- lipohypertrophy [accumulate fat around waste]
- CP450 interactions
What are side effects specific to atazanavir [ATV]?
- indirect hyperbilirubinemia [main effect]
- nephrolithiasis
What are side effects specific to darunavir [DRV]?
rash
What are side effects specific to fosamprenavir [FPV]?
rash
What are side effects specific to lopinavir/ritonavir [LPV/r]?
GI intolerance
What are side effects specific to tipranavir [TPV]?
hepatotoxicity
What are side effects specific to rotonavir [RTV}?
- potent CP450 inhibitor
- use only as PK booster at low dose –> no longer used for antiretroviral effect
What are the 6 PIs?
- atazanvir [ATV]
- darunavir [DRV]
- fosamprenavir [RPV]
- lopinavir/ritonavir [LPV/r]
- tipranavir [TPV]
- ritonavir [RTV]
What are the first line PIs for ARV-naive?
- atazanvir [ATV]
- darunavir [DRV]
What is mech of integrase inhibitors?
- inhibit integration of HIV DNA with host DNA
What are INSTIs?
INSTI = integrase strand transfer inhibitor
What are the 3 INSTIs?
- raltegravir [RAL]
- elvitegravir [EVG]
- Dolutegravir
How is elvitagravir [EVG] administered?
- only as combination pill with:
- – NRTIs tenofovir and emtricitabine
- – CP450 inhibitor cobicistat
What is cobicistat?
A CP450 inhibitor given in combination pill with elvitegravir, tenofovir, emtricitabine
What is the first line INSTI in ARV-naive?
raltegravir [RAL]
What is mech of action maraviroc [MVC]? Who does it work for?
MVC = a CCR5 antagonist
only works if patient has CCR5 viral tropism –> need to do viral tropism assay
- prevents HIV from attaching to host cell by CCR5 co-receptor
What is enfuviritide [T20]? mech? downsides?
enfuviritide [T20] = fusion inhibitor
- inhibits fusion of HIV with host cell membrane [so HIV can’t enter host cell]
downsides: injectable, no serious side effects but can have local inject side reaction
What are current treatment indications for HIV?
- ART recommended for all HIV infected to reduce risk of disease progression and prevent further transmission
What are the current 4 preferred regimens for ARV naive?
- tenofovir/emtricitabine, atazanavir, ritonavir
- tenofovir/emtricitabine, darunavir, ritonavir
- tenofovir/emtricitabine/efavirenz [single pill]
- tenofovir/emtricitabine, raltegravir
all use tenofovir/emtricitabine as backbone [except the 3rd which has a single pill with those 2 + efavirenz]
use of ritonavir is as for PK
each is once a day
Why do you use genotypic assay for ARV resistance early on in infection but not so much later on?
- later on in infection have lots and lots of mutations that may interact with each other or cancel each other out so much harder to interpret
What are ways you can test for resistance?
- genotypic assay for ARV resistance
- phenotypic resistance testing
What does phenotypic resistance testing do?
- look at inhibition of viral replication over different drug conc, compare patient to wild type lab strain
compare based on IC50 = conc of drug at which inhibit 50% of viral replication and decide if its resistant or not based on the difference in IC50 [the “fold change”]
What is downside of resistance assay?
resistance assays cannot detect minority resistance population –> what might be a minority without treatment will become a majority with treatment when the non-resistant dies off and you are only left with the resistant
What is primary prophylaxis?
give prophylactic treatment for disease pt has never had
What is prophylactic treatment for pneumocystis jiroveci with HIV? When do you give it?
- trimethoprim-sulfamethoxazole
- give at CD4 < 200
What is prophylactic treatment for mycobacterium avium-complex with HIV? When do you give it?
- azithromycin
- give at CD4 < 50
How do you prevent with ARV
- give treatment as prevention
- post-exposure prophylaxis [PEP]
- prevention of mother to infant transmission of HIV
- pre exposure prophylaxis
What drugs do you give in pre-exposure prophylaxis [PrEP]?
TDF [tenofovir] or TDF/FTC [tenofovir/emtricitabine]
What are the 5 NRTIs? mnemonic? KNOW THIS!
ZELAT
- zidovudine
- emtricitabine
- lamivudine
- abacavir
- tenofovir
