Pharm for HIV

Question 1

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

Answer 1

Abacavir (ABC)
Emtricitabine (FTC)
Lamivudine (3TC)
Tenofovir DF (TDF)

Question 2

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Answer 2

Efavirenz (EFV)

Question 3

Protease Inhibitors (PIs)

Answer 3

Atazanavir (ATV)
Darunavir (DRV)
Lopinavir/Ritonavir (LPV/RTV)

Question 4

Integrase Strand Transfer Inhibitors (INSTIs)

Answer 4

Raltegravir (RAL)

Question 5

HIV Life Cycle

Answer 5

Attachment/Fusion
Uncoating
Reverse Transcription
Integration
Transcription
Translation
Assembly
Budding
Maturation

Question 6

HIV Genome & Virion Structure

Answer 6

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

Question 7

Goals of Drug Therapy

Answer 7

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

Question 8

Monitoring HIV-infected patients

Answer 8

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

Question 9

CD4+ T-Cell Count

Answer 9

Marker of immune function
Predictor of disease progression/survival
Determines urgency of ART and need for opportunistic infection prophylaxis
Helps assess immunologic response

Question 10

Plasma HIV RNA

Answer 10

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

Question 11

Drug Resistance

Answer 11

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

Question 12

Antiretroviral Therapy (ART)

Answer 12

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

Question 13

Preferred Regimens in Drug-Naïve

Answer 13

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

Question 14

what do you have to test for with abacavir/ lamivudine?

Answer 14

HLA-B*5701 must be negative

Question 15

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs) MOA, PK, ADRs

Answer 15

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)

Question 16

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Answer 16

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)

Question 17

efavirenz significant side effects

Answer 17

CNS issues, vivid dreams, etc.

Question 18

Protease inhibitors agents, MOA, PK, ADRs

Answer 18

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

Question 19

Entry Inhibitors: fusion

Answer 19

Fusion Inhibitor: enfuvirtide

MOA: binds gp41, prevents conformational change necessary for fusion

PK: only administered subcutaneously

ADRs: local injection site reactions, insomnia, headache, hypersensitivity

Question 20

Entry Inhibitors: CCR5 Antagonist

Answer 20

maraviroc

MOA: bind CCR5 preventing viral entry into host cell

PK: substrate of CYP3A4

ADRs: cough, upper respiratory tract infections, muscle and joint pain

Question 21

Integrase Strand Transfer Inhibitors (INSTIs) MOA, PK, ADRs

Answer 21

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

Question 22

Preexposure Prophylaxis (PrEP)

Answer 22

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

Question 23

Postexposure Prophylaxis (PEP)

Answer 23

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