Antiretroviral Drugs Flashcards
What are the different stages of the HIV lifecycle where drugs can be used?
- Binding of the virus to the host cell membrane- blocked by CCR5 receptor antagonists
- Fusion and uncoating of the virus- blocked by fusion inhibitors
- Reverse transcription- blocked by NRTIs and NNRTIs inhibitors
- Viral DNA integration- blocked by integrase inhibitors
- Budding and maturation of the virus- blocked by protease and maturation inhibitors
Maximally suppressive antiretroviral therapy
Requires combo of at least 3 drugs
What does a typical treatment regimen for HIV look like?
“Backbone” – typically 2 NRTIs
“Base” – NNRTI, protease inhibitor, integrase strand transfer inhibitor, CCR5 antagonist
Selection Criteria for Drugs within a Class
Results of resistance testing (treatment-naïve vs -experienced)
Allergy history (screening for presence of HLA*5701)
Hypersensitivity to abacavir
Pregnancy status (efavirenz pregnancy category D)
Patient convenience (once-daily dosing and combo products reduce “pill burden”)
Comorbidities: hepatitis B, tuberculosis, cardiovascular disease, osteoporosis, psychiatric disorders, kidney disease
Side effect profiles
Potential drug interactions: many HAART drugs are CYP450 substrates and/or inducers- inhibitors
Specific drug combos used
Backbone: 2 NRTIs
Tenofovir-Emtricitabine preferred
Base: plus
An integrase inhibitor (Dolutegravir)
or a boosted (+ ritonavir) PI combination (Atazanavir or Darunavir preferred)
or an NNRTI (Efavirenz preferred
or a CCR5 antagonist (Maraviroc)
NRTIs- Mechanism of action
Nucleoside–tide Reverse Transcriptase Inhibitors (Tenofovir disoproxil fumarate, Emtricitabine)
Activation by intracellular kinases to active triphosphate (REQUIRES ACTIVATION)
Phosphorylated analogs competitively inhibit viral RT and when incorporated into viral DNA causes chain termination
Prevents genome replication and establishment of provirus
How does HIV develop resistance to NRTIs?
Associated with mutations at various AA positions on RT
Cross resistance within class is common and is basis for avoiding certain NRTI combinations
What’s important when considering NRTI plasma concentration?
plasma levels falling too low: risk of resistance
too high- risk of toxicity
Which NRTIs are hepatically metabolized and which are renally excreted?
Know organ of elimination: avoid DDIs – dosage changes
Hepatic glucuronidation: Abacavir and Zidovudine
Renal excretion: All Others
Adverse Drug Reactions of NRTIs
Class Effects:
Related to varying levels of NRTI activity against mitochondrial DNA polymerase γ: anemia, myopathy, granulocytopenia, neuropathy
Lactic acidosis – hepatic steatosis, potentially fatal
Renal impairment potential with tenofovir
What are the two best-tolerated NRTIs?
Lamivudine (3TC) and emtricitabine (FTC)
Both agents are also active against HBV in co-infected patients
What are the pros and cons of dual NRTI therapy?
Advantages:
Established backbone of combination therapy
Minimal drug interactions
Disadvantages:
Lactic acidosis and hepatic steatosis: highest with d4T, then ddI and ZDV, lower with TDF, ABC, 3TC, and FTC (rarely used now)
Lipodystrophy: highest with d4T
NNRTIs- Mechanism of action
Non-Nucleoside Reverse Transcriptase Inhibitors (Efavirenz)
Possess variety of dissimilar structures
Do NOT require activation by intracellular kinases
Bind to NON-CATALYTIC hydrophobic region and non-competitively inhibit HIV Reverse Transcriptase
Prevents genome replication - establishment of provirus
How does HIV develop resistance to NNRTIs?
Associated with single AA substitutions at various positions on RT
Developing resistance to one NNRTI confers cross-resistance to remaining class members
Newer member etravirine appears to have higher barrier to resistance
DDIs of NNRTIs
All are substrates of CYP450: innumerable DDIs due to induction-inhibition of CYP450 and potential for altered levels of co-administered PIs
Efavirenz: induces CYP3A4 (decreased methadone levels)
Etravirine: induces CYP3A4 – inhibits CYP2C9-19
Nevirapine: induces CYP3A4
Efavirenz (what is it and side effects)
NNRTI
Most common are rash, dizziness, headache, insomnia, impaired concentration; more severe CNS effects possible
Only anti-retroviral agent in pregnancy category D
Emtricitabine
NRTI
Tenofovir disoproxil fumarate
NRTI
Hard on pts with kidney disease
Pros and cons of NNRTIs
Advantages:
Long half-lives
Less metabolic toxicity than PIs
PIs and INSTIs preserved for future use
Disadvantages:
Low genetic barrier to resistance - single mutation
Cross resistance among most NNRTIs
Rash, hepatotoxicity (esp. nevirapine)
Potential CYP450 drug interactions
Transmitted resistance to NNRTIs more common than resistance to PIs
PIs- Mechanism of action
Protease Inhibitors (Atazanavir, Darunavir)
Noncleavable peptidomimetic agents that selectively target retroviral aspartyl proteases (not host proteases)
HIV protease cleaves and processes HIV gag and pol proteins necessary for survival and replication, thus inhibition prevents viral maturation
How does HIV develop resistance to protease inhibitors?
Drug resistance to most PIs requires multiple mutations - seldom develops “boosted” PI-based regimens
Relatively high barrier to resistance compared with NNRTIs and integrase inhibitor
Atazanavir
PI
dosed once daily
less adverse effects on lipid profiles; reversible jaundice; mild-moderate rash (20%)
Darunavir
PI
dosed once daily
incidence of side effects similar to other PIs, but rash can be severe (S-J Syndrome)
DDIs of PIs
Metabolized by CYP3A4 and innumerable DDIs occur due to inhibition of CYP3A4
Side effects of PIs
Many PIs can cause GI distress, hyperglycemia, insulin resistance, hyperilipidemia and increased risk of CAD
Can see peripheral lipoatrophy - central fat accumulation
Hepatotoxicity more common in patients with HBV-HCV
Pros and Cons of PIs as part of initial therapy
Advantages:
Higher genetic barrier to resistance
PI resistance uncommon even with sub-optimal adherence (boosted PI)
NNRTIs and INSTIs preserved for future use
Disadvantages:
Metabolic complications (fat maldistribution, insulin resistance, dyslipidemia) GI intolerance Potential for CYP450 drug interactions (esp. ritonavir)
INSTIs- mechanism of action
Integrase Strand Transfer Inhibitors (Raltegravir, Dolutegravir)
Viral integrase involved in processing of DNA strands and catalyzing direct insertion of viral DNA into host cell DNA
Raltegravir inhibits integrase activity preventing HIV-1 replication
No effect on human DNA polymerases α, β, or γ
Dolutegravir
INSTI
unlikely to develop resistance mutations
Eliminated via phase 2 glucuronidation – levels decreased by inducers (e.g., rifampin)
once daily
Raltegravir
INSTI
eliminated via phase 2 glucuronidation – levels decreased by inducers (e.g., rifampin)
Twice daily
HIV resistance to INSTIs?
Raltegravir and elvitegravir have low genetic barrier
Dolutegravir unlikely to develop resistance mutations: high barrier
Adverse Drug Reactions of INSTIs
Generally well tolerated
Diarrhea, nausea, headache
Pros and cons of INSTIs as part of initial HIV therapy
Advantages:
Neutral effects on triglycerides and cholesterol
High barrier for resistance with dolutegravir
Fewer adverse events than efavirenz
Fewer drug interactions than with NNRTIs or PIs
NNRTIs and PIs preserved for future use
Disadvantages:
Twice daily dosing (once a day for dolutegravir)
Lower genetic barrier to resistance than PIs (RAL-EVG)
Myopathy, rhabdomyolysis, and skin reactions reported but rare
Maraviroc
Entry Inhibitor
HIV-1 virions using CCR5 called “R5 tropic”, present during initial and chronic phases
HIV-1 virions using CXCR4 called “X4 tropic”, associated with later stages and disease progression
Maraviroc is small molecule antagonist of CCR5 receptor that inhibits its interaction with viral gp120
Indicated for treatment experienced adults with R5-tropic virus (assay to determine R5, X4, or dual tropism)
Dosed twice daily
Substrate of CYP3A4 – DDIs possible with strong CYP3A4 inducers or inhibitors (e.g., NNRTIs or DDIs)
Resistance to maraviroc
Has been observed, esp. when X4 strains are present; also associated with mutations in viral gp120
Adverse rxn to maraviroc
Generally well tolerated, mild effects include cough, fever, URI, dizziness, abdominal pain
Hepatotoxicity possible with higher doses
Pros and cons of maraviroc in initial HIV therapy
Advantages:
Virologic response noninferior to efavirenz
Fewer adverse events than efavirenz
NNRTIs, PIs, and IIs preserved for future use
Disadvantages:
Requires tropism testing before use (CCR5 vs CXCR4)
Twice daily dosing
Less experience than with PI- or NNRTI-based ART - limited data with NRTIs other than ZDV-3TC
CYP3A4 substrate - dosage adjustment required with concomitant inducers or inhibitors
Enfuvirtide
Fusion Inhibitor
Enfuvirtide is a synthetic peptidomimetic of the viral gp41 HR2 sequences
Binds to HR1 sequences - unavailable for hemiperfusion stalk
Prevention of viral entry into cell and infection
MUST BE ADMINISTERED SUBCUTANEOUSLY
Resistance to enfuvirtide
Reported to result from mutations in gp41 binding regions
DDIs with enfuvirtide
Eliminated by proteolytic hydrolysis – no CYP involvement, thus NO potential for DDIs
Adverse Drug Reactions of Enfuvirtide
Injection site reactions occur in almost all patients
Eosinophilia
Hypersensitivity reactions
Increase in bacterial pneumonia
“FOVIR”
nucleotides
