Antivirals

Question 1

**Antiviral nucleosides **- mechanism of action

Answer 1

• Mimic natural nucleosides - deoxy derivatives of Adenosine, Cysteine, Thymidine and Guanine
• Need to be phosphorylated to be substrate for DNA polymerase enzymes
• Virion polymerase is less specific and doesn’t recognise the false nucleotides –> they are incorporated into viral DNA –> nonsense genes
• Also act as competitive inhibitors and DNA chain terminators
• Thus antiviral is targeted to affected cells and is not incorporated into human DNA

Question 2

**Aciclovir **- mechanism of action

Answer 2

• Nucleoside analogue of guanosine
• Competitive inhibitor of Viral DNA polymerase - an obligate DNA chain terminator
• Requires initial monophosphorylation with viral thymidine kinase
• Incorporated as aciclovir triphosphate into viral DNA by viral DNA polymerase
• Resistance associated with both thymidine kinase deficient and DNA polymerase mutants

Question 3

**Aciclovir **- pharmacokinetics

Answer 3

• Limited oral bioavailability –> 5-10%
  
  • Must be given 5x daily for 5-7 days
  • Treatment must start within 24-72 hours
• IV therapy substatially better at disaese control in all compartments
  
  • Given 8 hourly
• Topical therapy (creams) of limited value except eye drops used in opthalmic herpes and opthalmic zoster
• Very safe. Reduced dose used in patients with renal dysfunction as accumulation can –> encephalopathy

Question 4

**Aciclovir **- indications

Answer 4

• Effective against: HSV types 1 and 2, VZV
• Inhibits CMV and EBV but not clinically useful
• Main indications are:
  
  • Severe primary bilabial and genital herpes
  • Opthalmic HSV and VZV
  • Eczema herpeticum
  • Herpes zoster
  • Chickenpox
  • Herpes encephalitis
  • Prevention/treatment of disseminated herpetic disease in the immunocompromised

Question 5

**Valaciclovir **- anti-herpes prodrug

Answer 5

• Valine ester of acyclovir
• Improved bioavailability of 55%
• Orally absorped - delivers aciclovir after deamination in the liver
• Used as an alternative to aciclovir for similar indications - reduced dosing schedule of 2/3 times day vs. 5
• Similar safety profile to aciclovir
• Used for better blood levels of aciclovir after GI disturbance seen in immunocompromised patients or when better antiviral control is required

Question 6

**Famciclovir **- anti-herpes prodrug

Answer 6

• Di-acetyl ester of penciclovir
• Penciclovir = a short chain terminator allowing limited incorporation before DNA chain dissociation
• 77% bioavailability
• Delivers penciclovir after deacetylation in the liver
• Used in patients >50 years with herpes zoster to significantly reduce the duration of acute and chronic pain including post-herpetic neuralgia
• Once daily dosing of 750mgs for 7 days
• Similar activity and safety profile to aciclovir

Question 7

Ganciclovir - anti-CMV drug

Answer 7

• Available as IV oral and prodrug formulation (valganciclovir)
• Nucleoside analogue (guanosine)
  
  • Competitor for guanosine and DNA polymerase inhibitor
  • Short chain terminator allowing limited incorporation before DNA chain dissociation
• Activated by monophosphorylation by viral kinase UL97
• Resistance (UL97 and polymerase mutants) produced after polonged therapy of >3 months in the immunocompromised
• Usefulness often limited by tendancy to induce neutropaenia

Question 8

**Foscarnet **- anti-CMV drug

Answer 8

• Available in IV formation
• Doesn’t require phosphorylation and therefore useful in UL97 resistance after ganciclovir therapy
• DNA polymerase blocker - not nucleoside competitor
• Limited usefullness due to SEs of renal toxicity and biochemical disturbances

Question 9

**Anti-CMV antivirals **- indications

Answer 9

• Ganciclovir and foscarnet used in similar situations
• Very potent
• Renally excreted - dose must be reduced in renal failure
• Indications
  
  • CMV infection and disease in immunocompromised
    
    • haemato-oncology
    • HIV
  • CMV pneumonitis, retinitis, colitis, hepatitis, encephalitis
  • Used in neonates with congenital infection to stop progression of hearing loss and other associated neurology

Question 10

Nucleoside reverse transcriptase inhibitors (NRTIs) + Nucleotide reverse transciptase inhibitors (phosphorylated NRTIs) - HIV antivirals

Answer 10

• Reverse transcriptase inhibitors and obligate chain terminators
• In HAART used as the backbone supplemented with other antivirals e.g. NNRTIs, PI or integrase/entry inhibitors
• Drugs:
  
  • Zidovudine (AZT)
  • Lamivudine (3TC)
  • Emtricitabine (FTC)
  • Abacavir (ABC)
  • Tenofovir (TDF)
  • Stavudine (d4T)
  • Didanosine (ddI)

Question 11

Non-reverse transcriptase inhibitors (NNRTIs) - HIV antivirals

Answer 11

• Act as reverse transcriptase blocking agents but not as competitors
• Less potent than NRTIs
• Resistance more likely over time (1-3 years)
• Always used in combination with a NRTI/pNRTI agent
• Examples:
  
  • Nevirapine (NVP)
  • Efavirenz (EFV)
  • Delaviridine (DLV)
  • Relpivirine (RPV)
  • Etravirine (ETV)

Question 12

Protease Inhibitors (PIs) - HIV antivirals

Answer 12

• Act as protease blockers thereby preventing maturation of the HIV virion following release from the cell
• Very potent when virus is susceptible but resistance common when unprotected
• Therefore always used with a NRTI/pNRTI agent
• Metabolised by the cytochrome p450 pathway
  
  • p450 inducer/inhibitor drug interactions must be avoided
  • Dual PI’s use low dose ritonavir to inhibit cytochrome p450 –< higher leverls of main PI
• Examples:
  
  • Ritonavir (RTV)
  • Nelfinavir (NFV)
  • Tipranavir (TPV)
  • Lopinavir (LPV)
  • Darunavir (DRV)
  • Atazanavir (ATV)
  • Dual PI - lopinavir/rionavir (rLPV)

Question 13

**HAART **- Highly active anti-retroviral therapy

Answer 13

• Combination therapy of 2-5 classes of HIV antivirals
  
  • NRTI e.g. tenfovir/entricitabine
  • Phosphorylated NRTIS
  • Non-nucloside reverse transcriptase inhibitor (NNRTI) e.g. nefirapine/efavirenz
  • Protease inhibitor e.g. nelfinavir
  • Fusion inhibitor e.g. enfuvirtide
  • Co-receptor (CCR5) inhibitor e.g. maravir
• For starting therapy usually:​
  
  • Tenfovir/entricitabine (NRTIs) plus efavirenz (NNRTI) or atazanavir/ritonavir (PIs) or raltegravir (Integrase inhibitor)
• To overcome primary resistance:
  
  • Switch NNRTI to a PI
  • Switch current PI for newer one e.g. darunavir/ritonavir

Question 14

HAART - Goals

Answer 14

• Goal is not cure but to suppress HIV viral load and improve CD4 count to improve quality of life, avoid opportunistic infections and lower transmission.
• Initiation of therapy is delayed until the CD4 cell count is <350/ml blood
• For most patients with wild-type naiive HIV - Viral load will decrease from >500,000 copies to undetectable (<50 copies) with a signifcant rise in CD4 count within 6 weeks of beginning therapy
• Maintenance of an undetectable viral load requires >80% of the dose with >80% adherence >80% of the time.
• Adherence issues are usually caused be adverse effects and the tolerability of the drug combination

Question 15

**HAART **- Failure and resistance

Answer 15

• Failure occurs in 10% at one year for those on current 1st line treatments
• Treatment failure is defined as not maintaining an undetectable viral load of <50 copies/ml of blood
• Viral resistance - revealed by a fall in CD4 count and an significant (>1 log) increase in VL whilst on therapy
• Choice of second line drug combination determined by:
  
  • Review of drug adherence
  • Drug therapeutic monitoring to measure absorbance
  • Sequencing of reverse transcriptase and protease genes to determine genotypic resistance
• _​_More than one drug is changed at once, often the entire regimen

Question 16

**HAART **- Adverse events

Answer 16

• NRTIs are limited by serious toxicities:
  
  • Anaemia and neutropenia (ZDV)
  • Peripheral neuropathies (d4T)
  • Mitochondrial toxicity (less specific enzymes)
  • Lactic acidosis
  • Abacavir hypersensitivity (4%) = life-threatening on readministration
  • **Lamivudine (3TC) **has no significant toxicities
• NNRTIS can cause:
  
  • Rash
  • Fever
  • Myalgia
  • Hepatitis
  • Diarrhoea (NVP)
  • Depression (EFV)
• PIs cause
  
  • Wide range of GI symptoms
  • Lipodystrophy
    
    • Increasing stroke/MI risk
    • Altering body shape

Question 17

Hepatitis B Antivirals

Answer 17

• Drug regimens:
  
  • Interferon alpha 5mu tiw x 24 weeks
  • Lamuvidine 100mg od x 48 weeks
  • Adefovir 10mg od X 48 weeks
• All equally effective as monotherapies for chronic Hep B infection in pts with deranged LFTs and histological liver damage
• Adefovir is effective against the YMDD lamivudine induced mutation

Question 18

Hepatitis C Antivirals

Answer 18

• Drug regimens
  
  • Interferon alpha 3Mu tiw x 24 weeks
  • Oral ribavirin 1-1.2g o.d. x 24 weeks
• Sustained virological response (SVR) with combination chemotherapy (55% undetectable viral load/ALT normalisation)
• Response dependant on genotype:
  
  • Good for types 2 and 3
  • Worse for types 1, 4, 5 and 6
• Viral load measured at baseline and at 12 weeks for early virological response (EVR)
• Treatment for genotype 1 with newer PIs boceprevir and telaprevir

Question 19

Interferon alpha (2a or 2b) - Adverse effects

Answer 19

• Common
  
  • Fever
  • Lethargy
  • Insomnia
  • Diarrhoea
• Rare but serious
  
  • Depression
  • Bone marrow suppression –> anaemia and neutropenia
• Minor
  
  • Hypothyroidism
  • Hyperthyroidism
• Contraindications
  
  • Severe cardiac disease
  • Decompensated liver disease
  • Renal failure
  • Epilepsy, depression and other serious psychiatric disorders
  • Autoimmune liver disease
  • Uncontrolled thyroid disease
  • Pregnancy and breastfeeding

Question 20

**PEGylated interferon alpha **- prodrug

Answer 20

• Attatchment of non-toxic polymers of polyethylene glycol to the IFN alpha molecule –> improved pharmacokinetics/dynamic
• Once weekly s.c. dose –> better IFNa blood levels than 3x weekly dose of the conventional IFNa
• Commercially available for HCV infection - improves endpoint efficacy combined with oral ribavirinz
  
  • 40KD IFNalpha-2a
  • 12KD IFNalpha-2b
• PEG-IFNa now recommended for HCV genotype 1 infections
  
  • Conventional IFNa sufficient for 2 and 3

Question 21

Amantadine and Rimantidine - Influenza A antivirals (specific)

Answer 21

• *Amantadine *and Rimantidine
  
  • ​Non-nucleosides
  • Act on early phase of virus uncoating - block the function of the matrix protein
  • Ion-channel blockers
  • Taken as 100 or 200mg OD for up to 2 weeks
  • Used preferentially as a prophylactic or post-exposure agent rather than treatment
  • Amantadine - not well tolerated in the elderly (Rimantidine fewer SEs):
    
    • Nausea and dizziness often
    • Parkinsonian/extra-pyramidal side effects sometimes

Question 22

**Zamamivir and Oseltamivir **- Influenza A and B antivirals

Answer 22

• Neuramidase inhibitors - inhibit virus maturation and release at the cell membran
• Relenza (Zanamivir)
  
  • Delivered as an aerosol of powder from blister pack inhaled as 10mg BD for 5 days
  • Must be taken within 48 hours of first symptoms
• Tamiflu (**Oseltamivir)
  
  • ​Oral formulation (75mg capsule or suspension) BD for 5 days
• Both drugs effective in reducing duration and severity of influenza A and B
• Efficacy in most ‘at risk’ populations not yet fully evaluated

Question 23

**Ribavarin **- Anti-RNA broad spectrum antiviral

Answer 23

• Effective against RSV, parainfluenza and influenza viruses in the management of viral bronchiolitis and pneumonitis
• Difficult to administer in ventilated patients
  
  • In bronchiolitis delivered by nebulised aerosol 5 micron particles in an enriched O₂ humidification tent

Question 24

**Cidofovir **- Anti-DNA broad spectrum antiviral

Answer 24

• Active against:
  
  • BK
  • HHV6
  • CMV
  • aciclovir resistant HSV and VZV
  • UL97 resistant CMV
• Given IV once weekly then fortnightly for four doses
• Limited by:
  
  • Some renal dysfunction
  • Increasing serum creatinine
  • Some bone marrow toxicity