Antiviral Drugs

Question 1

What are the major sites of antiviral Drug action?

Answer 1

1. Viral attachment and entry
Blocked by:
Enfuvirtide (HIV)
Maraviroc (HIV)
Docosanol (HSV)
Palivizumab (RSV)

2. Viral Penetration
Blocked by:
Interferon-a (HBV, HCV)

3. Uncoating of viral proteins
Blocked by:
Amantadine, Rimantadine (Influenza)

4. Nucleic acid synthesis
Blocked by:
NRTIs (HIV, HBV)
NNRTIs (HIV)
Acyclovir (HSV)
Foscarnet (CMV)

5. Late Protein synthesis and processing
Blocked by:
Protease Inhibitors (HIV)

6. Viral release
Blocked by:
Neuraminidase inhibitors (Influenza)

Question 2

Amantadine

Answer 2

Used for prophylaxis of Influenza A

• *Inhibits M2 proton channel** (unique to viruses)
• -> prevents acidification necessary for uncoating
• Toxicities are those expected from a dopamine agonist
  (originally deeloped as an anti-parkinson drug)

Rimantidine is an alpha-mehtyl derivative of Amantadine with similar mode of action

• May shorten duration of illness if taken after symptoms present

Question 3

Maraviroc

Answer 3

Inhibits HIV attachment

Inhibits bindign of gp120 to CCR5

Question 4

Enfuvirtide

Answer 4

Inhibits HIV attachment
Synthetic peptide

• Locks gp41 in extended conformation

–> No fusion of viral envelop and cell membrane

Question 5

Docosanol

Answer 5

Topical treatment against HSV
(abreva)

–> prevents attachment and penetration of virus

Question 6

Palivizumab

Answer 6

Humanized mAb against coat protein of RSV for high-risk patients

• Prevents attachment and penetration

Question 7

Triflundine

Answer 7

Treatment for herpes keratitis treatment

Inhibits thymidylate synthase

(very toxic)

Question 8

Ribavirin

Answer 8

Inhibits purine biosynthesis

Interferes with RNA metabolism needed for viral replication; widely active with DNA and RNA viruses

Aerosolized delivery for RSV (especially infants)

Hepatitis C (in combination with IFN-alpha)

Question 9

Acyclovir

Answer 9

Acyclovir is a pro-drug that is phosphorylated by viral Thymidine Kinase

Then cellular kinases convert it to acycloguanosine triphosphate (acyclo GTP) which is incorporated into infected DNA

–> acyclo GTP doesn’t have the hydroxyl group required to make phosphodiester bonds

Question 10

Ganciclovir

Answer 10

Another nucleoside analog (like acyclovir) that is most useful against CMV

Question 11

What are the types of Nucleoside Reverse Transcriptase Inhibitors (NRTIs) for HIV?

Answer 11

Azidothymidine/Zidovudine

Stavudine

Lamivudine - used with IFN-a to treat HBV and pregnant women (lower side effects)

Zalcitabine

Didanosine

Abacavir

Emtricitabine - fluorinated analog of lamivudine

Question 12

Azidothymidine (AZT, zidovudine)

Answer 12

Prodrug converted by cellular kinases into AZT-TP in which Reverse Transcriptase has and increased affinity for, making it more specific to infected cells

• -> many Side Effects:
  i. e. Anemia, granulocytopenia

Short 1/2 life

–> frequent dosing required

Question 13

Didanosine

Answer 13

Nucleoside RT inhibitor

Side effect: pancreatitis

Question 14

Abacavir side effects

Answer 14

Nucleoside RT inhibitor for HIV

Hypersensitivty rxns

hepatosplenomegaly

–> especially in HLA-B*5701 patients

–> used only after genotyping

Question 15

What are the nucleoside RT inhibitors for HBV only?

Answer 15

Entecavir (guanosine analog)

Telbivudine (thymidine analog)

–> not effective against HIV

–> effective against HBV RT/DNA polymerase

Question 16

What are the available Nucleotide Reverse Transcriptase Inhibitors?

Answer 16

Tenofovir

Cidofovir

Adefovir

Question 17

Tenofovir

Answer 17

Nuceotide analog

Nucleoside phosphonate that is converted to the di- and tri-phosphate in resting cells

–> this gets around the problem of initial phosphorylation

Competitively inhibits HIV RT, causes chain termination
(approved for HBV as well)

reduced renal function over time

Question 18

Cidofovir

Answer 18

Nucleotide RTI

** Inhibitory effect on viral DNA polymerase**

used for ganciclovir/foscarnet-resistant CMV and acyclovir-resistant HSV

Doesn’t require virally coded enzymes for phosphorylation

Question 19

Adefovir

Answer 19

Nucleotide RTI

Used against HBV

Potential for lactic acidosis

Question 20

What are the available Non-nucleoside RT inhibitors?

Answer 20

Nevirapine - recommended against pregnant patients, Stevens Johnson syndrome possible, risk fo hepatotoxicity

Rilpivirine

Etravirine

Delavirdine

Efavirenz

Question 21

Efavirenz

Answer 21

NNRTI for HIV

Once a day dosing

Fewer serious toxic side effects (nightmares)

NOT to be used during pregnancy

Question 22

Foscarnet

Answer 22

Inorganic pyrophosphate analog

Inhibits HSV and CMV DNA polymerase

Used for treatment of ganciclovir-resistant CMV retinitis

IV only

Side effects:
Nephrotoxicity
Hypocalcemia

Question 23

What are the available integrase inhibitors?

Answer 23

Raltegravir

Elvitagravir - newer inhibitor; only used in combination therapy

Question 24

What are the available protease inhibitors?

Answer 24

Fosamprenavir
atanazavir
darunavir
indinavir
Lopinavir*
Nelfinavir
Ritonavir*
Saquinavir
Tipranavir
Telaprevir** (inhibits HCV serine protease)
Boceprevir** (inhibits HCV serine protease)

*Recommended for pregnant patients
**Beware drug interactions!

Question 25

Does resistance to one protease inhibitor mean resistance to all?

Answer 25

**Not necessarily** protease inhibitors each have different sites of action, thus making them variable in resistance --\> sequencing of viral protease can help predict resistance to various inhibitors

Question 26

Side effects of protease inhibitors

Answer 26

Increased LDL Decreased HDL Increased Triglycerides **--\> Lipodystrophies** Hyperglycemia (insulin resistance) \*Atanazavir has lower incidence of lipodystrophies

Question 27

Why are Interferons used for antiviral treatment?

Answer 27

**IFN-alfa** has antiviral activity (hepatitis B and C) **Transcription inhibition Translation Inhibition Protein Processing Inhibition Virus Maturation Inhibition** --\> most effective against C when used in combination with: Ribavirin (Nucleoside RTI) and Protease Inhibitors --\> pegylated forms have improved pharmacokinetics

Question 28

What are available neuraminidase inhibitors?

Question 29

How is use of Anti-Retroviral Therapy determined for HIV patients?

Answer 29

CD4 Count is the major indicator ( --\> best predictor of disease progression Regardless of CD4 Count: History of AIDS-defining illness Pregnant women HIV-associated nephropathy Hepatitis B coinfection, when HBV treatment is indicated Acute opportunistic infections Age \>50yrs HIV Viral load is not a determinant in ART

Question 30

When would deferral of ART be considered for HIV?

Answer 30

Clinical or personal factors may support deferral - When there are significant barriers to adherence - if co-morbidities complicate or prohibit ART - "Elite controllers" and long-term nonprogressors

Question 31

What are potential risks of early ART for HIV?

Answer 31

ARV-related side effects and toxicities Drug resistance (attributable to ART failure) Inadequate time to learn about HIV, treatment, and adherence Increase in total time on ART; greater chance of treatment fatigue Current ART may be less effective or more toxic than future therapies Transmission of ARV-resistant virus, if incomplete virologic suppression Pill Fatigue --\> increases risk of developing resistance

Question 32

What are the benefits of early ART for HIV?

Answer 32

Maintain higher CD4 count; prevent irreversible immune system damage Decrease risk of HIV-associated complications Decrease risk of nonopportunistic conditions and non-AIDS associated conditions Decrease risk of HIV transmission

Question 33

What are the ART options for HIV?

Answer 33

2 NRTIs + a Protease Inhibitor\* 2 NRTIs and a NNRTI\* (PI sparing regimen) 2 NRTIs + and Integrase Strand Inhibitor\* \*Denotes backbone agent of regimen; most powerful