Pharm for HIV Flashcards
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
Abacavir (ABC)
Emtricitabine (FTC)
Lamivudine (3TC)
Tenofovir DF (TDF)
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz (EFV)
Protease Inhibitors (PIs)
Atazanavir (ATV)
Darunavir (DRV)
Lopinavir/Ritonavir (LPV/RTV)
Integrase Strand Transfer Inhibitors (INSTIs)
Raltegravir (RAL)
HIV Life Cycle
Attachment/Fusion Uncoating Reverse Transcription Integration Transcription Translation Assembly Budding Maturation
HIV Genome & Virion Structure
gag: capsid, matrix, and nucleocapsid proteins
pol: reverse transcriptase, protease, integrase
vif: required for maturation
vpr: required for viral replication
env: envelope glycoproteins gp120 and gp41
Goals of Drug Therapy
Antiretrovirals will not eradicate HIV infection
Pool of latently infected CD4 T-cells
Primary Goals: Decrease morbidity and prolong duration/quality of survival Restore/preserve immunologic function Suppress viral load Prevent transmission
Initial Patient Evaluation
HIV antibody testing, CD4 count, plasma HIV RNA, CBC, chemistry profile, LFTs, BUN, SCr, urinalysis, blood glucose, serum lipids, resistance testing, hepatitis screening
Monitoring HIV-infected patients
HIV-related testing: HIV serology, CD4 cell count (every 3-6 months0, HIV viral load, genotypic resistance testing, HLA-B+5701 testing, tropism testing
medication toxicity testing: CBC with differential, BUN and SCr, ALT, AST and total bilirubin, urinalysis
CD4+ T-Cell Count
Marker of immune function
Predictor of disease progression/survival
Determines urgency of ART and need for opportunistic infection prophylaxis
Helps assess immunologic response
Plasma HIV RNA
Marker of response to ART
Impacts choice of drug regimen
Reductions result in decreased risk of AIDS progression and death
Surveillance to maintain undetectable levels
Drug Resistance
Assessed at:
Baseline, initiation of therapy, drug failure, adjusting drug regimens
Resistance:
High rates of HIV replication (109 virions/daily)
HIV transcriptase error prone (frequent mutations)
Mutations in key enzymes render them resistant to drugs
Drug therapy itself does not cause mutations provides selective pressure to promote growth of resistant viruses
Potential for cross-resistance among drugs of same class
*** Combination drug regimens minimize development of resistance
Seek expert consultation resistance testing interpretation
Antiretroviral Therapy (ART)
Older terminology: Highly Active AntiRetroviral Therapy = HAART
Basic strategy:
Combination of 3 or more medications from different classes
Two nucleoside reverse transcriptase inhibitors (NRTIs) +
Integrase strand transfer inhibitor (INSTI) –or–
Non-nucleoside reverse transcriptase inhibitor (NNRTI) –or–
Protease inhibitor (PI)
Regimens chosen:
Virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance testing, comorbid conditions, and cost
Preferred Regimens in Drug-Naïve
basic strategy: 2 nucleoside reverse transcriptase inhibitors
one is either emtricitabine OR llamivudine
as part of the backbone
combined with an integrase strand inhibitor like raltegravir
what do you have to test for with abacavir/ lamivudine?
HLA-B*5701 must be negative
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs) MOA, PK, ADRs
Agents: abacavir (ABC), emtricitabine (FTC), lamivudine (3TC), tenofovir disoproxil fumarate (TDF), zidovudine (ZDV)
MOA: inhibit reverse transcriptase; cause premature chain termination
PK: not metabolized via CYP450 system
ADRs: mitochondrial toxicity – anemia, granulocytopenia, myopathy, peripheral neuropathy; lipoatrophy; lactic acidosis with hepatic steatosis
Tenofovir DF + emtricitabine preferred NRTI backbone (Truvada)
Abacavir + lamivudine another recommended combo (Epzicom)
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Agents: efavirenz (EFV),
MOA: allosterically inhibit RNA- & DNA dependent DNA polymerase
PK: CYP450 drug metabolism
CYP inhibitors, inducers, or mixed inducer/inhibitor
ADRs: varying GI intolerance; skin rash
Efavirenz combined with emtricitabine/tenofovir (Atripla)
efavirenz significant side effects
CNS issues, vivid dreams, etc.
Protease inhibitors agents, MOA, PK, ADRs
Agents: atazanavir (ATV), darunavir (DRV), lopinavir/ritonavir (LPV/RTV)
MOA: competitively inhibit viral protease; prevents post-translational protein processing; results in immature, noninfectious viral particle production
PK: extensive CYP450 metabolism, primarily 3A4
ADRs: nausea, diarrhea, dyslipidemia, altered fat distribution
Darunavir/ritonavir plus tenofovir/emtricitabine one of recommended initial combinations
Entry Inhibitors: fusion
Fusion Inhibitor: enfuvirtide
MOA: binds gp41, prevents conformational change necessary for fusion
PK: only administered subcutaneously
ADRs: local injection site reactions, insomnia, headache, hypersensitivity
Entry Inhibitors: CCR5 Antagonist
maraviroc
MOA: bind CCR5 preventing viral entry into host cell
PK: substrate of CYP3A4
ADRs: cough, upper respiratory tract infections, muscle and joint pain
Integrase Strand Transfer Inhibitors (INSTIs) MOA, PK, ADRs
MOA: binds integrase; prevents integration of reverse-transcribed HIV DNA into host chromosomes
PK: metabolized primarily by hepatic glucuronidation (UGT1A1)
Substrate of CYP3A4
ADRs: well tolerated; headache and GI effects; elevations in serum aminotransferases and creatine kinase; some CNS effects
raltegravir, tenofovir/emtricitabine
Preexposure Prophylaxis (PrEP)
Goal: reduce risk of acquiring HIV infection in high risk patients
PrEP Recommended in High Risk:
Sexually-active, adult MSM
Heterosexually-active, men and women
Injection drug users
***Must have documented, negative HIV test before PrEP
Daily, tenofovir DF/emtricitabine with follow-up every 3 months
Postexposure Prophylaxis (PEP)
Goal: reduce likelihood of HIV transmission
Percutaneous, mucous membrane, or non-intact skin exposure to body fluids of concern (blood, semen, vaginal secretions, other body fluids contaminated with visible blood)
Fluids not considered infectious (unless contain blood): urine, nasal secretions, saliva, gastric secretions, sputum, sweat, tears, etc.
***PEP less effective if > 72 hours have passed since exposure.
Three-drug regimen including two NRTIs + integrase inhibitor x 4 weeks
