Antiviral Agents

Question 1

Process of HIV infection of CD4 T Cell

Answer 1

HIV binds to receptors and enter the cell to get conversation of viral RNA to DNA via reverse transcriptase and this involves integrase, but after transcription and translation you get viral polyproteins and then broken down with protease in HIV and then the completed virus is released

Drugs for entry blockage (entry inhibitors) and then reverse transcriptase inhibitors, and have protease inhibitors, and integrase inhibitors

Question 2

Reverse Transcriptase Inhibitors (RTIs)

Answer 2

Zidovudine: also known as AZT; look like endogenous nucleotides (A, G, T, and C), but do not have phosphate groups (require 3 phosphates to be involved in DNA synthesis)

In order to have chain elongation, need 3’ hydroxyl group; so reverse transcriptase inhibitors can compete because looks alike, but must have hydroxyl group for DNA synthesis to continue so it stops the DNA synthesis of the virus

Question 3

Zidovudine Mechanism of Action

Answer 3

Undergoes three phosphorylations by cellular (host cell) kinases

The triphosphate acts as a competitive inhibitor of reverse transcriptase (RNA-dependent DNA polymerase)

Functions as a DNA chain terminator after incorporation into DNA

AZT must be converted to triphosphate to have good inhibition

Question 4

Zidovudine Pharmacokinetics

Answer 4

Rapidly absorbed after oral administration (oral bioavailability approx. 65%)

Well distributed throughout body (CSF levels approx. 60% of those in serum)

Undergoes liver metabolism (glucuronidation); some unchanged drug & the glucuronide eliminated renally (glomerular filtration & tubular secretion)

Question 5

Zidovudine Clinical Uses

Answer 5

Used in combination regimens for initial treatment of HIV (human immunodeficiency virus) infections for many years (has given way to less toxic agents); monotherapy leads to rapid resistance

Included in some regimens for prevention of maternal-fetal HIV transmission

Included in some alternative combination regimens for post-exposure prophylaxis (PEP) in health care workers

Question 6

Zidovudine Adverse Effects

Answer 6

Bone marrow suppression (anemia; neutropenia)
Gastrointestinal intolerance (nausea & vomiting)
Headaches, insomnia, and muscle pain

Question 7

Nucleoside RTIs

Answer 7

Nucleoside RTIs (same mechanism of action as zidovudine); called NRTIs

Lamivudine (& its fluorinated analog emtricitabine) & abacavir

Question 8

Nucleotide RTIs

Answer 8

Nucleotide RTIs (same mechanism of action as zidovudine, but fewer phosphorylations required for activation); a NTRTI

Tenofovir

Question 9

Non-Nucleoside RTIs

Answer 9

Nonnucleoside RTIs (inhibit reverse transcriptase by binding directly to the enzyme & inducing a conformational change; called NNRTIs)

Efavirenz, nevirapine & delavirdine

Does not resemble DNA, and binds outside of catalytic site
Not meant for monotherapy because virus will develop resistance eventually

Question 10

Adverse Effects – Other RTIs (NRTIs & NTRTIs)

Answer 10

Abacavir - possible severe hypersensitivity reactions

Lamivudine (& Emtricitabine) – nausea, diarrhea, headache & rash

Tenofovir (an NTRTI) – nausea, diarrhea, vomiting & flatulence; possible renal insufficiency (damage to proximal renal tubules)

Question 11

Adverse Effects-NNRTIs

Answer 11

Delavirdine & nevirapine - skin rash

Nevirapine – hepatotoxicity

Efavirenz - CNS toxicity (dizziness/headache/insomnia & nightmares) & skin rash

All 3 are substrates for cytochrome P450 enzymes & modify the metabolism of other drugs by these enzymes

Nevirapine & efavirenz induce the system (including CYP3A4) and delavirdine inhibits it.
If you induce it, then it can degrade the drugs to make them less useful
If you inhibit it, then it can increase drug toxicity

Question 12

Other Adverse Effects Associated with NRTIs

Answer 12

Severe hepatomegaly, lactic acidosis, fatty liver

Lipodystrophy (especially lipoatrophy in limbs; fat redistribution to abdomen & other areas); also metabolic changes including:
Elevations of plasma triglycerides & total cholesterol
Hyperglycemia & hyperinsulinemia

*may be related to inhibition of DNA polymerase gamma in mitochondria; some newer RTIs have low affinity for this enzyme & thus are less toxic by this mechanism: lamivudine, emtricitabine, abacavir (also, the NTRTI tenofovir)

Question 13

Protease Inhibitors

Answer 13

Ritonavir

Structure: active site of HIV protease = based off of that site

Mechanism of Action: prevents maturation of virus protein by competitively inhibiting HIV protease, an enzyme essential for viral protein cleavage (to dissect the proteins into their active components)

Question 14

Ritonavir Pharmacokinetics

Answer 14

Well absorbed orally (bioavailability of 60 to 80%)
Undergoes metabolism by the hepatic cytochrome P450 enzymes
Concern: drug to drug interactions with metabolism by the liver
May have TB infection at the same time as HIV for example

Question 15

Ritonavir Clinical Use

Answer 15

Treatment of HIV infection (in combination with other antiretroviral drugs)

Current primary use is as a ‘booster’ agent to increase the bioavailability of other protease inhibitors
ritonavir is a potent inhibitor of CYP3A4 and thus reduces the metabolism of other co-administered protease inhibitors

By inhibiting P450 enzyme it protects the more potent protease inhibitor it is combined with so not metabolized as much

Question 16

Ritonavir Adverse Effects

Answer 16

G.I. Intolerance - nausea, vomiting, diarrhea
Paresthesias - circumoral and peripheral
Elevated serum triglycerides & cholesterol
Drug interactions - ritonavir is an inhibitor as well as a substrate for cytochrome P450 enzymes

Round mouth circumoral (like seen in CMV and scarlet fever)

Question 17

Ritonavir Drug-Interactions

Answer 17

Inducers of one cytochrome P450 enzyme isoform (CYP3A4) will accelerate the metabolism of ritonavir & may result in treatment failure
Examples: rifampin & rifabutin

By inhibiting certain other cytochrome P450 enzyme isoforms (CYP3A4 & 2D6), ritonavir will inhibit the metabolism of other drugs, thus increasing their toxicity
Examples: lovastatin, simvastatin, clarithromycin, diazepam, & desipramine

Question 18

Other HIV Protease Inhibitors

Answer 18

Fosamprenavir
Atazanavir
Darunavir
Tipranavir

As you go down the list you have decreased toxicities and longer half lives
Bottom two are newest – more popular because less toxicity

Question 19

Adverse Effects of Selected Protease Inhibitors

Answer 19

Fosamprenavir – rash (skin eruptions)

Atazanavir – headache, peripheral neuropathy, EKG changes (PR interval prolongation), hyperbilirubinemia, jaundice and skin rash

Darunavir – headache & skin rash; possible liver toxicity

Tripranavir – rash; severe liver toxicity; possible intracranial hemorrhage

Question 20

Adverse Effects Common to Most HIV Protease Inhibitors

Answer 20

Lipodystrophy - altered body fat distribution consisting of central fat accumulation called hyperadiposity (buffalo hump & truncal obesity) & peripheral fat wasting called lipoatrophy (face, buttocks & limbs)

Insulin resistance & hyperglycemia (along with increased triglyceride and cholesterol levels)

Note: The above effects do not appear to be associated with atazanavir & the magnitude of these effects may be less with darunavir than other ‘boosted’ PIs.

Question 21

Examples of Antiretroviral Drug Regimens Recommended (or Alternative) for Initial Treatment

Answer 21

NNRTI-based regimen (1 NNRTI + 2 RTIs)

PI-based regimen (1 PI + 2 RTIs)

INSTI-based (integrase inhibitor) regimen (1 INSTI + 2 RTIs)

Example of 1st regimen above = efavirenz + tenofovir + emtricitabine (EFV/TDF/FTC) **

Example of 2nd regimen above = darunavir/ritonavir (i.e. ritonavir-boosted darunavir) + tenofovir + emtricitabine (DRV/r + TDF/FTC) *

Example of 3rd regimen given on previous slide = raltegravir (an INSTI) + tenofovir + emtricitabine (RAL + TDF/FTC) *
Note: INSTI = integrase strand transfer inhibitor

• Recommended regimen
• • Alternative regimen