HIV/AIDS drugs

Question 1

Conditions for a two-drug regimen

Answer 1

Two drug treatments always include drugs of different classes. Also, they have at least one drug with a high barrier of resistance and usually an NNRTI or NRTI.

Question 2

Mechanism for enfuvirtide

Answer 2

Enfuvirtide is a synthetic 36-amino-acid peptide fusion inhibitor that blocks HIV entry into the cell. Enfuvirtide binds to the gp41 subunit of the viral envelope glycoprotein, preventing the conformational changes required for the fusion of the viral and cellular membranes.

Question 3

Advserse effects of enfuvirtide

Answer 3

• Injection site reactions (painful erythematous nodules)
• Eiosinophilia

Question 4

When is maraviroc used

Answer 4

Maraviroc is approved for use in combination with other antiretroviral agents in treatment-experienced adult patients infected with only CCR5-tropic HIV-1 who are resistant to other antiretroviral agents

Question 5

Adverse effects of maraviroc

Answer 5

• Upper respiratory infections
• Hepatotoxicity
• Increased risk for MI

Question 6

Initial treatment of HIV is with 1-2 drugs from ___ and one drug from ____ or _____ or _____.

Answer 6

NRTI

INSTI

PI

NNRTI

Question 7

PEP regimen

Answer 7

It is a 3-drug regimen that is taken for 28 days, and should be started as soon as possible after exposure, and always started within 72 hours of exposure.

Question 8

Nucleotide reverse transcriptase inhibitor (NRTI) mechanism

Answer 8

The NRTIs act by competitive inhibition of HIV-1 reverse transcriptase and replace nucleotides usually used by that enzyme; incorporation into the growing viral DNA chain causes premature chain termination due to inhibition of chain elongation.

Question 9

Class-wide toxicity for NRTIs

Answer 9

• Mitochondrial dysfunction (mainly ddI (didanosine), 4dT (stavudine), and ZDV (zidovudine))
• Lactic acidosis, presents as anion-gap acidosis and elevations in AST/ALT on bloodwork. Rare but fatal
• Hepatic steatosis
• Lipodystrophy
• GI Intolerance

Question 10

Abacavir (ABC) class and toxicities

Answer 10

NRTI - guanosine analog

Hypersensitivity reactions, occasionally fatal, have been reported in up to 8% of patients receiving abacavir and may be more severe in association with once-daily dosing. This reaction manifests with rash and nonspecific GI symptoms initially is more common in patients with the HLA-B*5701 genotype. So, determination of HLA-B*5701 status before initiation of abacavir therapy is recommended

Question 11

Didanosine (ddi) class and toxicities

Answer 11

NRTI - adenosine analog

dose-dependent pancreatitis

Peripheral neuropathy and retinal changes

Question 12

Lamivudine (3TC) class and toxicities

Answer 12

NRTI - cytosine analog

Mild GI discomfort

Often an initial treatment

Question 13

Emtricitabine (FTC) class and toxicities

Answer 13

NRTI - cytosine analog

Some hyperpigmentation of hands and soles of feet

Can be used with tenofovir in PrEP

Both emcitrabine and its analog lamivudine will quickly select for the same resistant mutants and so they are not used together

Question 14

Stavudine (d4T) class and toxicities

Answer 14

NRTI - thymidine analog

he major toxicity is a dose-related peripheral sensory neuropathy

This drug has the highest incidence of pancreatitis, arthralgias, and elevation in serum aminotransferases, and lactic acidosis with hepatic steatosis, as well as lipodystrophy of any of the NRTIs

Dyslipidemia and increased insulin resistance

Question 15

TENOFOVIR DISOPROXIL FUMARATE (TDF) class and toxicities

Answer 15

NRTI - adenosine analog

GI complaints, and the cumulative loss of renal function has been observed, so tenofovir should be used with caution in patients at risk for renal dysfunction. Monitoring of bone mineral density should be considered with long-term use in those with risk factors for (or known) osteoporosis, as well as in children.

Can also treat HBV

Question 16

TENOFOVIR ALAFENAMIDE FUMARATE (TAF) class and toxicity

Answer 16

NRTI - adenosine analog

More stable than TDF so serum concentrations are lower, leading to less nephrotoxicity and decrease in bone density

Question 17

Zidovudine (ZDV, AZT) class and toxicities

Answer 17

NRTI - thymidine analog

The most common adverse effect of zidovudine is bone marrow suppression-myelosuppression, resulting in macrocytic anemia (1-4%) or neutropenia (2-8%) and requiring monitoring of blood counts during therapy.

Lipodystrophy, hyperlipidemia, insulin resistance

Most common HIV drug

Question 18

Methods of prevention for maternal transmission

Answer 18

• performing a C-section (with the consent of the mother, obviously) if viral loads are not suppressed <1,000
• Formula instead of breast feeding
• providing the correct medications during pregnancy as well as delivery to mother and to mother and baby after delivery to decrease the risk of transmission
• Infant on antivirals for 6 weeks

Question 19

Risk of maternal HIV transmission without and with guidelines

Answer 19

Without: 25%

With: <1%

Question 20

NNRTIs mechanism

Answer 20

The NNRTIs bind directly to HIV-1 reverse transcriptase, resulting in allosteric inhibition of RNA- and DNA-dependent DNA polymerase activity. The binding site of NNRTIs is near to but distinct from that of NRTIs. Unlike the NRTI agents, NNRTIs neither compete with nucleoside triphosphates nor require phosphorylation to be active.

Question 21

NNRTIs class toxicities

Answer 21

NNRTI agents cause varying levels of gastrointestinal intolerance, hepatotoxicity, and skin rash

Metabolized by CYP3A4, leading to problems with drug and food interactions.

Question 22

Delavirdine class and toxicities

Answer 22

NNRTI

Skin rash, can be teratogenic (so not in pregnancy)

Question 23

Efavirenz class and toxicities

Answer 23

NNRTI

CNS toxicities (some psychiatric), GI, teratogenic, some cardiac problems

Question 24

Nevirapine class and toxicity

Answer 24

NNRTI

Skin rash, sometimes severe, and some hepatotoxicity

Question 25

Rilpivirine class and toxicity

Answer 25

NNRTI

Lesser CNS effects, heart effects

Question 26

INSTIs mechanism

Answer 26

INTEGRASE STRAND TRANSFER INHIBITORS

This class of agents binds integrase, a viral enzyme essential to the replication of both HIV-1 and HIV-2. By doing so, it inhibits strand transfer, the third and final step of provirus integration, thus interfering with the integration of reverse-transcribed HIV DNA into the chromosomes of host cells.

Question 27

INSTIs class toxicities

Answer 27

GI intolerance, insomnia, increased serum creatinine

Question 28

Dolutegravir class and toxicities

Answer 28

INSTI

Well tolerated

Rare and severe events include systemic hypersensitivity reactions, and can cause some liver dysfunction

Question 29

Elvitegravir class and toxicities

Answer 29

INSTI

Elvitegravir requires boosting with cobicistat (a pharmacokinetic enhancer that inhibits CYP3A4 as well as certain intestinal transport proteins) or ritonavir.

Question 30

Raltegravir class and toxicity

Answer 30

INSTI

Rare and severe events include life threatening systemic hypersensitivity reactions and rhabdomyolysis (muscle breakdown)

Question 31

Protease Inhibitors (PI) mechanism

Answer 31

By preventing post-translational cleavage of the Gag-Pol polyprotein, protease inhibitors (PIs) prevent the processing of viral proteins into functional conformations, resulting in the production of immature, noninfectious viral particles. Unlike the NRTIs, PIs do not need intracellular activation.

Question 32

PI class toxicities

Answer 32

PIs are associated with mild-to-moderate nausea, diarrhea, dyslipidemia, and insulin resistance.

Lipodystrophy, cardiac conduction abnomalies, some hepatotoxicity

Question 33

Atazanavir class and toxicities

Answer 33

PI

Good for pregnancy

Peripheral neuropathy and indirect hyperbilirubinemia with visible jaundice

Kidney stones, renal toxicity

Question 34

Darunavir class and toxicities

Answer 34

PI

liver toxicity, including severe life threatening hepatitis

Skin rash, especially if sulfa allergy

Question 35

Fosamprenavir class and toxicities

Answer 35

PI

perioral paresthesias (numb, tingling around the mouth), depression, may cause a rash in up to 3% of patients, sometimes severe enough to warrant drug discontinuation.

Question 36

Indinavir PI and toxicities

Answer 36

PI

indirect hyperbilirubinemia and nephrolithiasis due to urinary crystallization of the drug (have to drink 48 oz water daily)

Question 37

Lopinavir class and toxicities

Answer 37

PI

pancreatitis and prolonged boosted use is associated with cumulative loss of renal function

Has to be given with itonavir, which inhibits the CYP3A-mediated metabolism of lopinavir

Question 38

Nelfinavir class and toxicities

Answer 38

PI
Diarrhea, flatulance

Question 39

Ritonavir class and toxicities

Answer 39

PI

Used at lower concentrations to boost other protease inhibitors by inhibiting CYP3A4.

Specific adverse effects include paresthesias, altered taste, and elevations in serum creatine kinase, but are not common at the lower concentration used for boosting

Question 40

Saquinavir class and toxicities

Answer 40

PI

increases the risk for serious cardiac arrhythmias.

Question 41

Tipranavir class and toxicities

Answer 41

PI

hive-like or maculopapular rash is more common in women and may be accompanied by systemic symptoms or diffuse sloughing of skin. Tipranavir has a sulfonamide moiety, use with caution in people with sulfa allergies.

Hepatotoxicity, increased risk for intracranial hemorrhage