Antiretrovirals Flashcards
List two NRTIs
zidovudine, abacavir
List an NNRTI
efavirenz
List two protease inhibitors
ritonavir, atazanavir
List a membrane fusion inhibitor
enfuvirtide
List an entry inhibitor
maraviroc
List an integrase inhibitor
raltegravir
Fusion between HIV-1 envelope and the host cell membrane, mediated by viral surface ____ and ____ is essential for entry of HIV into the cell
gp120 and gp41
HIV must bind to CD4 as well as _____ in order to enter a cell
co-receptor, either CCR5 or CXCR4
Cleavage of HIV polyproteins by _____ is essential for mature virus formation
protease
Enfuvirtide is a peptide that was developed to inhibit a specific region of _____ ap
gp41
Enfuvitide is typically considered _________, meaning it is given to treatment experienced patients who have developed extensive resistance to other agents
salvage therapy
Describe how resistance to enfuvirtide can arise
Mutation in gp41 envelope gene
Describe the normal function of gp41
Envelope protein; two regions fold upon each other to form a six helix bundle that brings the virus closer to the host cell and is required for membrane fusion
What is the major adverse effect of enfuvirtide?
Must be injected 2x daily, leads to injection site reactions
Describe the mechanism of action of maraviroc
Inhibits attachment of viral gp120 to the CCR5 co-receptor on host cells
Describe appropriate use of maraviroc
Approved for treatment experienced patients with R5 tropic virus
Will not be effective in patients with X4 or mixed tropism
How does resistance to maraviroc arise?
Possible to have mutations in gp120 but more likely to have emergence of mixed tropic or X4 tropic virus
What is unique about maraviroc compared to all other HAART drugs?
Something from the host is inhibited instead of something from the virus
List the constituents of common combination drugs: Combivir Trizivir Epzicom Truvada
Combivir= Lamivudine + Zidovudine Trizivir= Lamivudine + Zidovudine + Abacavir Epzicom= Abacavir + Lamivudine Truvada= Tenofovir + Emtricitabine
NRTIs are _____ analogues that lack ____ on the ribose sugar, so when they are incorporated by reverse transcriptase they cause termination of chain elongation
nucleoside analogues
3’OH
For NRTIs to become active, they must be _______ by host enzymes
phosphorylated
List three main functions of reverse transcriptase
- synthesizes the - strand of DNA with the viral RNA genome as the template
- hydrolyzes viral + RNA
- synthesizes the + strand of DNA
List a negative drug interaction that occurs between zidovudine and stavudine
Because thymidine kinase (TK) has a higher affinity for zidovudine than stavudine, zidovudine antagonizes the effects of stavudine.
Describe two main mechanisms of NRTI drug resistance
- mutations in RT allow the enzyme to discriminate between NRTIs and dTNPs
- mutations in RT that promote the hydrolytic removal of chain termination NRTIs to allow for continued DNA synthesis
True or false: significant cross resistance exists for NRTI drugs
True
What is one common, class wide adverse effect seen with NRTIs
Mitochondrial toxicity and lactic acidosis, hepatic steatosis
Describe the mechanism of mitochondrial toxicity caused by NRTIs
inhibition of DNA polymerase gamma
leads to a depletion of certain key mitochondrial proteins essential for the electron transport chain leading to a buildup of lactic acid and triglycerides.
What specific toxicity is associated with zidovudine?
bone marrow suppression
What specific toxicity is associated with didanosine?
pancreatitis, peripheral neuropathy
What specific toxicity is associated with stavudine?
peripheral neuropathy
What specific toxicity is associated with abacavir?
abacavir hypersensitivity syndrome
Describe abacavir hypersensitivity syndrome
fever, rash, headache, nausea, abdominal pain, cough and shortness of breath
abacavir gets linked onto a protein (ex EtOH dehydrogenase) in APCs, peptide with abacavir on it is bound by HLA-B5701. When this interaction occurs, there is activation of T cells and upregulation of interferon
NNRTIs block reverse transcriptase by binding an _________ site on the RT enzyme, inducing a conformational change.
allosteric site
True or false: Like NRTIs, NNRTIs must be phosphorylized in vivo in order to be active
False
Describe how resistance to NNRTIs can emerge
Mutation in NNRTI binding site, leads to high level resistance against first generation NNRTIs but can usually still use second generation agents
Resistance arises very quickly if NNRTIs are used as monotherapy
Describe the positive drug interaction that occurs between NNRTIs and NRTIs
some point mutations in RT that confer resistance to NNRTIs may sensitize RT to NRTIs by inhibiting phosphorolysis
What class-wide toxicities are seen with NNRTIs?
Rash and hepatotoxicity
What specific toxicity is associated with efavirenz?
CNS effects and teratogenicity
Describe the mechanism of raltegravir
Integrase inhibitor, docks in the acceptor DNA binding site and interferes with strand transfer
Describe the mechanism of action of protease inhibitors
Bind to active site o protease and prevent cleavage of gag-pol and blocks viral maturation
Why are lopinavir and ritonavir always formulated together?
A small dose of ritonavir is used in Kaletra to inhibit Cytochrome P450 CYP3A4 metabolism of Lopinavir and make it a viable drug
Describe class wide toxicity seen with protease inhibitors
Hepatotoxicity, GI upset, lipodystrophy, insulin resistance highly associated with protease inhibitors
What specific adverse reactions are seen with atazanavir?
hyperbilirubinemia and QT prolongation
Describe the difference between genotypic and phenotypic testing for drug resistance
Phenotypic: rate of growth of sample virus compared to wild virus in the presence of drug
Genotypic: sequence of sample compared to wild type virus
