HIV/AIDS - Regal Flashcards
What are some general concepts to keep in mind with HIV treatment?
Goal is fully undetectable levels of virus
The lower the viral RNA can be driven, the lower the rate of accumulation of drug resistant mutants will be & the longer the therapeutic effect will last
Maximally inhibit viral replication
To achieve maximal and durable suppression of viral RNA, drug combinations and patient compliance are required
Resistance testing recommended before starting therapy
Monitor HIV RNA levels (viral load) and CD4+ cell count
increased viral load may indicate development of drug resistance
Use drug combinations
but avoid contraindicated drug combinations (lists available)
Think about drug interactions
Encourage compliance
What is the MOA of Nucleoside Reverse Transcriptase Inhibitors (NRTIs)?
Competitively inhibit reverse transcriptase
in cytosol
Can be incorporated into viral DNA chain
the inhibitor binds to the DNA chain and terminates the production of DNA
What do NRTIs require to become active?
Phosphorylation by cellular enzymes to the triphosphate form
What are the four NRTI drugs that we need to know?
Zidovudine (Azidothymidine or AZT)
Lamivudine
Emtricitabine
Abacavir
What are the general adverse effects of NRTIs?
Potentially fatal syndrome of lactic acidosis with hepatic steatosis
probably due to mitochondrial toxicity
Associated with fat redistribution and hyperlipidemia
skinny arms and a fat trunk
What is unique about Zidovudine compared to the other NRTI drugs?
granulocytopenia and anemia in up to 45% of treated patients
hematological monitoring at 2 week intervals
CNS disturbances:
severe headache
nausea
insomnia
malaise
What is unique about Lamivudine & Emtricitabine compared to the other NRTI drugs?
Probably best tolerated of the NRTIs
Also active against Hepatitis B
What is unique about Abacavir compared to the other NRTI drugs?
hypersensitivity reactions can be a problem
What is the MOA of Nucleotide Reverse Transcriptase Inhibitors (NRTI)?
Same as Nucleoside Reverse Transcriptase Inhibitors:
Competitively inhibit reverse transcriptase
in cytosol
Can be incorporated into viral DNA chain
the inhibitor binds to the DNA chain and terminates the production of DNA
What is the difference between a nucleotide and a nucleoside?
Nucleotides are phosphorylated nucleosides.
What is the one Nucleotide Reverse Transcriptase Inhibitor drug that we need to know?
Tenofovir
What are adverse side effects of Tenofovir?
Most common: N/V Diarrhea potential for renal failure Potentially fatal syndrome of lactic acidosis with hepatic steatosis probably due to mitochondrila toxicity
What is the MOA of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)?
Bind directly to the reverse transcriptase at a site distinct from that of the NRTI
enzyme cannot produce viral DNA
Does not require phosphorylation for activity
What are the two Non-Nucleoside Reverse Transcriptase Inhibitor drugs that we need to know?
Efavirenz
Etravirine
Is there cross resistance with NNRTIs and NRTIs and protease inhibitors?
NO
What are adverse side effects of NNRTIs?
Varying levels of GI intolerance
Skin rash
Drug interactions
metabolized by and can affect hepatic cyp450
can be inducers, inhibitors, or mixed inducers/inhibitors of enzyme
What is unique about Efavirenz compared to the other NNRTIs?
Once daily dosing CNS effects vivid dreams nightmares hallucinations
What is unique about Etravirine compared to the other NNRTIs?
Rash
Nausea
Peripheral neuropathy
What is the MOA of Protease Inhibitors?
Prevent protease action required for maturation of the fully assembled virus
prevent post-translational cleavage of the Gag-Pol polyprotein
prevent the processing of viral proteins into functional conformations
without cleavage, virus is not infectious
inhibit HIV protease activity and prevent HIV replication in vitro
Active against viral strains resistant to reverse transcriptase inhibitors
What are the three Protease Inhibitor drugs that we need to know?
Atazanavir
Ritonavir
Darunavir
What are the potential adverse side effects of Protease Inhibitors?
GI disturbances
Hepatotoxicity
Hyperglycemia and insulin resistance
Dyslipidemia
Cardiac conduction abnormalities
Peripheral lipoatrophy and central fat accumulation
Metabolized by and inhibit hepatic CYP3A4
What is Ritonavir boosting?
Giving low doses of Ritonavir (a protease inhibitor) in addition to other PIs
Why?
it is a potent inhibitor of CYP3A4
with CYP3A4 inhibited by Ritonavir, it increases the serum concentrations of other protease inhibitors
decreases the dosage and frequency of other PIs
What is the name of the pharmacokinetic enhancer that inhibits CYP3A4 as well as certain intestinal transport proteins and can also act as a booster of protease inhibitors (but is not a protease inhibitor itself)?
Cobicistat
What is the MOA of Fusion Inhibitors?
binds to gp41 and prevents the conformational change required to facilitate fusion of the viral and host cell membranes
What is the one Fusion Inhibitor drug that we need to know?
Enfuvirtide (T-20)
What are potential adverse side effects of Enfuvirtide?
High incidence of local reactions with pain, erythema, induration, nodules, & cysts
SubQ administration x2 daily
Systemic hypersensitivity rare
Maybe a higher incidence of bacterial pneumonia
What is the MOA of Integrase Inhibitors?
By binding integrase, it inhibits strand transfer
stops final step of provirus integration
What is the one Integrase Inhibitor drug that we need to know?
Raltegravir
What are the potential adverse side effects of Raltegravir?
Fewer drug-drug interactions that PI or NNRTI based regimens.
What is the MOA of CCR5 Antagonist?
Binds specifically and selectively to host CCR5
prevents HIV-1 binding to receptor
virus is not able to gain entry into the host cell
What is the one CCR5 Antagonist drug that we need to know?
Maraviroc
What are adverse side effects of Maraviroc?
Pyrexia (fever)
Rash
Postural dizziness
No evidence yet of increased risk of malignancy or infection.
What is HAART treatment?
Highly Active Antiretroviral Therapy
therapy with reverse transcriptase inhibitors (RTIs) in combination with protease inhibitors (PIs)
What is the major adverse side affect associated with HAART?
HAART associated lipodystrophy
wasting of subcutaneous fat
central adiposity
hyperlipidemia, insulin resistance, and diabetes mellitus
How common is HAART associated lipodystrophy?
Estimated to affect 25-50% of patients
Most often seen with use of NRTIs + PI
but also see with single NRTI treatment
Why is compliance with antiretroviral therapy a challenge?
High number of pills
Adverse side effects of therapy
Fixed dose combinations are becoming available, but are less flexible in terms of dosage requirement.
Why are most antiretroviral drugs used in combination or as “drug cocktails”?
High mutation rate of reverse transcriptase
(HIV loves to mutate)
***Best way to avoid drug resistance.
