Anti-viral drugs

Question 1

What does a HIV antiretroviral regimen generally comprise of?

Answer 1

**2 nucleoside reverse transcriptase inhibitors and either a(n)
**integrase strand transfer inhibitor OR
protease inhibitor OR
non-nucleoside reverse transcriptase inhibitor.

**Newer regimen includes Dolutegravir (ISTI) and Lamivudine (NRTI)

Question 2

When can lamivudine & dolutegravir be used?

Answer 2

most HIV tx naive pts

except those w 1) hep B/ 2) initiating ART before testing for RT genotype/HBV testing are out/ 3) RNA titres > 500,000 copies/mL

Question 3

Name the nucleoside reverse transcriptase inhibitors (NRTIs) and state which riboside’s analogue they each are

Answer 3

1. Emtricitabine - cytosine
2. Lamivudine - cytosine
3. Abacavir - guanosine
4. Tenofovir - adenosine
5. Zidovudine - thymidine

Question 4

What is the mechanism of action of nucleoside reverse transcriptase inhibitors?

Answer 4

NRTIs are analogs of native ribosides.
Upon cell entry, they are phosphorylated to the corresponding triphosphate analog, which is *preferentially incorporated into the viral DNA by reverse transcriptases. Because the 3′-OH group is not present, a 3′,5′-phosphodiester bond between an incoming nucleoside triphosphate and the growing DNA chain cannot be formed, and DNA chain elongation is terminated.

Question 5

Which 2 NRTIs should not be co-administered?

Answer 5

Emtricitabine and lamivudine as they are both cytosine analogues

Question 6

Which NRTIs can also be used in the management of Hepatitis B?

Answer 6

1. Emtricitabine
2. Tenofovir
3. Lamivudine
   (An ART regimen for patients with both HIV and HBV should include (TAF or TDF) plus (3TC or FTC))

• if discontinued - severe acute exacerbation of hepatitis

Question 7

How are most NRTI cleared?

Answer 7

Renal clearance
except Zidovudine (thymidine) - hepatic clearance

Question 8

How can all NRTI usually be taken?

Answer 8

Oral

Question 9

What are the 2 types of Tenofovir (NRTI)?

Answer 9

Tenofovir alafenamide

Tenofovir disoproxil fumarate

Question 10

Which is the tenofovir preferred?

Answer 10

Tenofovir alafenamide has more favorable effects on renal and bone markers

Question 11

Which NRTI can only be used in HLA-B*5701–negative individuals?

Answer 11

Abacavir - guanosine

A test that detects the presence of HLA-B5701. HLA-B5701 is a genetic variation that is linked to hypersensitivity to the antiretroviral (ARV) drug abacavir. A person who tests positive for HLA-B*5701 should not use abacavir or any other abacavir-containing medicine.

Question 12

Name 2 examples of long-term toxicities associated with HIV antiretroviral treatment

Answer 12

1. metabolic syndrome

2. lipodystrophy syndrome

Question 13

What is the mechanism of action of integrase inhibitors?

Answer 13

The inhibitor binds and inhibits the catalytic site of the HIV integrase, which terminates integration of HIV DNA into the host genome.

Question 14

Name 3 examples of integrase inhibitors

Answer 14

1. Dolutegravir
2. Raltegravir
3. Elvitegravir

Question 15

What should not be taken tgt with integrase inhibitors?

Answer 15

Oral bioavailability affected by
Polyvalent cations
avoid antacids 2 hours before or 6 hours after

Question 16

What is taken tgt with Elvitegravir (ISTI)?

Answer 16

Cobicistat - PK enhancer to inhibit CYP450

*usually avoid elvitegravir as+ cobicistat increase risk DDI

Question 17

Name one adverse effects of integrase inhibitor

Answer 17

weight gain

Question 18

Can integrase inhibitor be used in pregnancy?

Answer 18

DTG preferred throughout pregnancy
Alternative ART if trying to conceive

All pregnant pt take at least 400mcg folic acid daily

Question 19

What is the mechanism of action of protease inhibitors?

Answer 19

Protease inhibitors bind to the site where polyprotein cutting occurs, and prevent the viral enzyme protease from releasing the individual core proteins.

*resistance less common as higher genetic barrier (req stepwise mutation)

Question 20

Name 2 examples of protease inhibitors

Answer 20

1. Darunavir

2. Lopinavir

Question 21

What is the mechanism of action via which the pharmacokinetic enhancer such as ritonavir works?

Answer 21

Low doses of ritonavir used have no significant anti-protease activity, but sufficient CYP450- inhibitory activity that interferes with the metabolism of protease inhibitors.

• note that ritnoavir is a str analogue of cobicistat but has additional AR effect (ritonavir booster better for HIV-2)

Question 22

Name at least 3 adverse effects associated with protease inhibitors

Answer 22

1. GI disturbances: Nausea, vomiting, and diarrhea.
2. Hyperglycaemia
3. Hyperlipidaemia
4. Hepatic injury
5. Lipodystrophy

Question 23

Drug-drug interactions are a common problem associated with which class of HIV anti-viral drugs?

Answer 23

Protease inhibitors
(Drug interactions are a common problem for all protease inhibitors as they are not only *substrates but also potent *inhibitors of CYP450 isoenzymes.)

CYP450 inhibitors like macrolides, azoles, rifampicin, isoniazid, fluoroquinolones(?)

Question 24

Drawbacks of HIV protease inhibitors?

Answer 24

1. poor pt compliance as high no of pills

2. drug resistance if used alone - used w 2 RTI

Question 25

Name the NNRTI non-nucleoside reverse transcriptase inhibitor.

Answer 25

Efavirenz

Question 26

What is the mechanism of action of non-nucleoside reverse transcriptase inhibitors (NNRTI)?

Answer 26

NNRTIs bind *HIV-1 reverse transcriptase at an allosteric hydrophobic site to induce a conformational change resulting in enzyme inhibition.

Question 27

Name one adverse effect of efavirenz (NNRTI).

Answer 27

CNS associated effects eg vivid dreams, headache, dizziness

Question 28

Both NRTI & ISTI & PI work against?

Answer 28

HIV-1 (more common) & HIV-2 except NNRTI only HIV-1

Question 29

Which drugs cannot be used in HIV-2 infections?

Answer 29

NNRTI (efavirenz)-- as high rates of resistance Enfuvirtide

Question 30

Name the 2 entry inhibitors.

Answer 30

Enfuvirtide | Maraviroc

Question 31

All of the ART drugs are given orally except ____

Answer 31

Enfurbvitide (Entry inhibitor)-- subcutaneous injection | can have injection related AR

Question 32

How does the entry inhibitor enfuvirtide work?

Answer 32

Enfuvirtide is a polypeptide that binds to HIV fusion protein gp41, preventing the conformational change, and interfering with HIV-1 entry by inhibiting the fusion of viral and cellular membranes.

Question 33

What is the mechanism of action of maraviroc?

Answer 33

Maraviroc blocks the binding of the HIV outer envelope protein gp120 to the CCR5 chemokine receptor * only effective in HIV preferentially expressing CCR5 over CXCR4 coreceptor

Question 34

How may HIV acquire resistance to maraviroc?

Answer 34

They may preferentially express CXCR4 co-receptor, which would then limit the ability of maraviroc to block HIV entry.

Question 35

Who is pre-exposure prophylaxis used for?

Answer 35

It is useful when people are at a high risk of getting infected with HIV. (e.g. sex workers)

Question 36

Name an anti-viral combination that is used as PrEP.

Answer 36

Tenofovir disoproxil fumarate and emtricitabine (Truvada®)

Question 37

How long after the last possible exposure to HIV should an individual taking PrEP continue the medication before he/she stops?

Answer 37

He/she should continue for at least 4 weeks after the last significant exposure.

Question 38

How soon after an exposure to HIV should an individual initiate Post-Exposure Prophylaxis?

Answer 38

He should initiate PEP within the first 72 hours.

Question 39

How long must an individual take PEP following an exposure?

Answer 39

28 days

Question 40

Is PEP and PrEP treatment regimen the same?

Answer 40

No. PEP treatment is similar to the treatment used for an established HIV infection. It will use the recommended 3 anti retrovirals regimen for 28 days. PrEP is a combination of Emtricitabine and Tenofovir taken daily

Question 41

Name a drug that is used in the management of conditions related to Herpes simplex virus type 1 and 2 and TYPE 3: varicella-zoster virus such as cold sores, oral and genital herpes, and chicken pox.

Answer 41

Acyclovir | Valacyclovir - prodrug of acyclovir but greater oral bioavailability hence less frequent dose

Question 42

What is the mechanism of action of acyclovir?

Answer 42

Acyclovir is a nucleoside analogue that is phosphorylated by viral thymidine kinase to acyclovir monophosphate, and host cell enzymes to acyclovir triphosphate form. It 1. Competitively inhibits viral DNA polymerase 2. Incorporates into and terminates the growing viral DNA chain, and 3. Inactivates the viral DNA polymerase. (More effective against HSV than VZV as HSV more efficient thymidine kinase)

Question 43

Name one other use of acyclovir

Answer 43

prophylaxis for seropositive pt before bone marrow transplant

Question 44

Which antiviral has a better oral bioavailability, acyclovir or valacyclovir?

Answer 44

Valacyclovir

Question 45

Which anti-viral is commonly used as a prophylaxis in immunocompromised patients against cytomegaloviral infections (opportunistic infections)?

Answer 45

Ganciclovir (pro drug- oral) Valganciclovir *

Question 46

What is the mechanism of action of ganciclovir?

Answer 46

It is monophosphorylated intracellularly by viral thymidine kinase and viral phosphotransferase during HSV and CMV infections respectively before being phosphorylated to diphosphate and triphosphates by cellular enzymes. The triphosphate is a competitive inhibitor of the native deoxyguanosine triphosphate for incorporation into DNA and preferentially inhibits viral rather than host cellular DNA polymerases. Incorporation into viral DNA causes termination of DNA chain elongation. *cmv can become resistance by phsophotransferase mutation