08 Anti-Viral Agents Louie

Question 1

What are the Viral Entry Inhibitors currently available?

Answer 1

EnFuvirtide (CD4 blocker). Maraviroc (CCR5 Antagonist)

Question 2

What is the problem with monotherapy of EnFuvirtide for HIV?

Answer 2

Very quick resistance occurs

Question 3

How does Maraviroc (Selzentry) work?

Answer 3

Competitively binds to CCR5, preventing an interaction with GP120. It is a “chemokine receptor antagonist”

Question 4

What is Maraviroc (Selzentry) indicated for?

Answer 4

Indicated for treatment-experienced adult patients infected with only CCR5-tropic HIV-1 detectable, who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents

Question 5

What is Ibalizumab?

Answer 5

A novel humanized monoclonal antibody (Mab) binding to a conformational epitope on CD4, blocking entry to HIV-1. In Phase II right now

Question 6

What did the IV Ibalizumab Phase 2b study results show?

Answer 6

Favorable data indicating efficacy and drug will continue in development

Question 7

What are the NRTIs that are Dideoxynucleoside Analogs?

Answer 7

Stavudine. Lamivudine. Didanosine. Zidovudine. Emtricitabine. Abacavir. On all of these, the 3’ Hydroxyl group is important for elongation

Question 8

What are the steps in Intracellular Transport of Nucleosides?

Answer 8

Dideoxy Nucleoside (ddN) is brought in through a channel (ENT2). Once inside, it interacts with kinase to become ddN-TP. This can then either bind to RT (termination of vDNA), go into the mitochondria (causes toxicity, Lactic Acidemia), or go into the Nucleus

Question 9

How do cells get ride of ddN?

Answer 9

Once converted to ddN-MP it can actually get pumped out by the MRP-2, -4, or -5 pumps

Question 10

Why is Nucleoside therapy for Men and Women different?

Answer 10

The ENT2 transporter is also used for folic acid, so there are more of them in women. This causes women to have more ADRs, but also better remission rates

Question 11

What is the benefit of Acyclic Nucleoside Analogs?

Answer 11

No ribose ring, avoids enzymes that cleave them, longer T1/2

Question 12

What are some of the Acyclic Nucleoside Analogs?

Answer 12

Acyclovir. Ganciclovir. Penciclovir. Cidovovir, Adefovir, Tenofovir

Question 13

Which Acyclic Nucleoside Analogs come with a phosphate group already attached?

Answer 13

Cidofovir. Adefovir. Tenofovir. This phosphate group causes them to be highly renally toxic, can also lead to osteoporosis (since calcium will be excreted along with the phosphate group)

Question 14

What is Ganciclovir used for?

Answer 14

CMV. Active against herpes viruses but especially cytomegalovirus (CMV) infections, which typically cause retinitis, and may cause pneumonia, colitis, esophagitis, and hepatitis in immunocompromised patients

Question 15

What is Cidofovir used for?

Answer 15

Synthetic acyclic purine nucleotide analog of cytosine nucleoside when phosphorylated to the diphosphate, inhibits CMV DNA polymerase and blocking viral replication. Disphosphate has 2-3d T1/2. Indicated for treatment of CMV retinitis

Question 16

What are the NNRTIs used?

Answer 16

Delavirdine. Efavirenz. Etravine. Nevirapine

Question 17

Which NNRTI is a potent CYP3A INHIBITOR?

Answer 17

Delavirdine. All others are inducers

Question 18

What is a common ADR with all NNRTIs?

Answer 18

Rash

Question 19

Which NNRTIs cause Hepatotoxicity?

Answer 19

Efavirenz. Etravine. Nevirapine. The only one that doesn’t is Delavirdine

Question 20

What is the 2nd Gen NNRTI?

Answer 20

Etravirine. Resistance to other NNRTIs does not seem to confer resistance to Etravirine. Etravirine, in combination therapy, is indicated for the treatment of HIV Type 1

Question 21

Rilpivirine is a new NNRTI being looked at, why is it dosed 25mg in study results?

Answer 21

At 100mg/day it started showing signs of QT Prolongation

Question 22

What are the Protease Inhibitors used?

Answer 22

Indinavir. Sawuinavir. Ritonavir. Nelfinavir. Indinavir. Atazanavir

Question 23

What does the inhibition of Integrase cause?

Answer 23

Strand Transfer Shifts the fate of HIV-1 DNA resulting in an irreversible block to infection. Dead-end products = cell death

Question 24

What are the Integrase Inhibitors in advanced clinical developed?

Answer 24

Raltegravir. Elvitegravir

Question 25

What did a trial conclude when looking at the effect of Dolutegravir on actual GFR and CrCl in healthy subjects?

Answer 25

DTG has no effect on actual GFR. DTG decreases eGFR and CrCl via effect on proximal renal tubular excretion of creatinine, similar to cobicistat

Question 26

What is the goal of Zinc Finger Gene Therapy?

Answer 26

Create a modification to CCR5 co-receptor. Persons with the delta 32 deletion of CCR5 are highly resistant to HIV infection. Zinc Finger Nucleases (ZFNs) are “designer restriction endonucleases” which cleave an area between two CCR5 binding domains. This in turn introduces a DNA break that causes permanent CCR5 co-receptor modification in target cells

Question 27

What is Amantadine (Symmetrel)?

Answer 27

Prevention/treatment of Influenza A Virus (not B). Prevention has efficacy of ~70%. CNS effects limit wide use

Question 28

What is the MOA of Amantadine?

Answer 28

It appears to be VIRUSTATIC by preventing uncoating of virus particles, leading to no viral replication and no infection (ideally). It affects maturation of Influenza HA Glycoprotein in trans-Golgi network

Question 29

What is Rimantadine?

Answer 29

Same as Amantadine, but with fewer ADRs

Question 30

What do Neuraminidase Inhibitors do?

Answer 30

Neurominidase breaks the bond that holds new virus particles to the outside of an infected cell by cleaving sialic acid from the cell surface. This releases new viruses that can infect other cells and spread infection. Neuraminidase inhibitors prevent viral cleavage of sialic acid preventing new virus particles from being released, thereby limiting the spread of infection

Question 31

What are the Neuraminidase inhibitors used?

Answer 31

Oseltamivir and Zanamivir

Question 32

What are the common drugs used for HCV?

Answer 32

PegIFN and RBV

Question 33

How is PegIFN dosed for HCV?

Answer 33

1.5ug/kg weekly

Question 34

What is the range that RBV is dosed for HCV?

Answer 34

800-1400mg daily

Question 35

What are the difference classes of Interferons?

Answer 35

a, B, and y. Each distinct. Different producer cells, inducers, and biologic effects. IFN-a and -B are produced by nearly all cells in response to invasion. Only INF-a has been approved for viral treatment. IFN-y only produced by T cells and NK cells

Question 36

What is the MOA of IFN?

Answer 36

Induces changes in the infected or exposed cell to promote resistance to the virus. Induces several enzyme activities that promote an antiviral state

Question 37

Peginterferons vs. Interferons, what is the rationale for pegylation?

Answer 37

Reduces rate of absorption and clearance. Lower immunogenicity. Maintains higher steady state –> increased viral response

Question 38

What is Ribavirin?

Answer 38

Active against many DNA/RNA viruses and highly active against influenza A and B, but is only approved for treating RSV in infants and young children by aerosol and Hep C together with interferon

Question 39

What are the characteristics of the new target: NS3 Protease?

Answer 39

Hepatitis C RNA encodes for a polyprotein that is 3,000 AA long. This is cleaved by viral and host proteases to form structural and nonstructural proteins. The Nonstructural (NS) proteins are further processed by two viral proteases, NS2/3 and NS3

Question 40

What are the two types of NS3 Protease Inhibitors?

Answer 40

a-Ketoamides (form a reversible covalent bond with serine in the active site). Competitive, noncovalent inhibitors (aim to bind more strongly to active site than substrate through noncovalent interactions)

Question 41

What is needed for NS3 Protease to be active?

Answer 41

In order to be activated it must be bound to an NS4a cofactor