Antivirals Flashcards
Which parts of the viral replication cycle do antivirals target?
Reverse transcription (retroviruses only)
Transcription and translation
Release (cell lysis)
What are examples of viral encoded proteins?
Nucleic acid polymerases
Proteases
Integrase
CCR5
Terminase
What are limiting factors of antiviral therapies?
Host immune response is critical to achieve suppression of viral replication.
Adherence to treatment/antiviral drug resistance.
Drug toxicity
Drug interactions
Which human herpesviruses are classified as alpha-type?
HSV1 + HSV2
VZV
What are the characteristics of alpha-type human herpesviruses?
Rapid growth, latency in sensory ganglia
Which human herpesviruses are classified as beta-type?
CMV
HHV-6
HHV-7
What are the characteristics of beta-type human herpesviruses?
Slow growth, restricted host range
Which human herpesviruses are classified as gamma-type?
EBV
HHV-8 (KSHV)
What are the characteristics of gamma-type human herpesviruses?
Oncogenic
What is chickenpox?
Caused by primary infection with varicella-zoster virus (VZV).
Majority uncomplicated in healthy children.
Adults at risk of complications including pneumonitis.
Severe disease in the immunocompromised.
What is shingles?
Reactivation of latent infection (dorsal root ganglia).
Immunocompetent:
- Dermatomal distribution
- Complication: Post-herpetic neuralgia
Immunocompromised: Can experience multidermatomal or disseminated infection with severe complications.
What is 1st line treatment for HSV and VZV?
Acyclovir
Varicyclovir (prodrug of acyclovir)
What is second line treatment for HSV and VZV and why is it used?
Famciclovir
Used for ACV-resistant strains
What is the mode of action of acyclovir?
Further elongation of the chain is impossible because acyclovir lacks the 3’ hydroxyl group necessary for the insertion of an additional nucleotide.
What is the pharmacological activity of guanosine analogues?
Monophosphorylated by viral thymidine kinase (TK) and then further phosphorylation by cellular kinases to ACV-PPP (active form).
Affinity for herpesvirus DNA polymerase is 10- to 30- fold higher than for cellular (host) DNA polymerase for ACV-PPP.
Selective activity means reduced drug toxicity.
What is the efficacy of guanosine analogues against the alpha-type human herpesviruses?
Susceptibility: HSV-1 > HSV-2 >> VZV
VZV 10x less sensitive so higher doses required
What is the management for HSV encephalitis?
On clinical suspicion:
Start empiric treatment immediately with iv ACV 10mg/kg tds without waiting for test results.
If confirmed, treat for 14 - 21 days.
When is treatment indicated for VZV?
Chickenpox in adults (risk of complication: pneumonitis)
Zoster in adults >50 (risk of complication: post-herpetic neuralgia)
1o infection or reactivation in the immunocompromised
Neonatal chickenpox
If there is an increased risk of complications
What is CMV?
MAJOR pathogen in the immunocompromised (including solid organ and bone marrow transplant patients) – causes bone marrow suppression, retinitis, pneumonitis, hepatitis, colitis, encephalitis.
What are the treatments for CMV?
Ganciclovir - IV
Valganciclovir - PO
Foscarnet - IV/Intravitreal
Cidofovir - IV
+ Letermovir
Which viruses does Ganciclovir have activity against?
Activity against CMV
Also activity against HSV, VZV, EBV and HHV6, but seldom used
What are specific indications for ganciclovir?
CMV disease in immunocompromised (retinitis, pneumonitis), and neonates with congenital CMV.
Given together with IVIG for CMV pneumonitis.
What are side effects of ganciclovir?
Less easily tolerated than ACV.
Bone marrow toxicity (leukopenia, thrombocytopenia, anaemia, pancytopenia).
Renal and hepatic toxicity.
What are contraindications for ganciclovir?
Bone marrow suppression (neutropenia)
What is Foscarnet?
Non-competitive inhibitor of viral DNA polymerase
Does NOT require activation by phosphorylation
What viruses does Foscarnet have activity against?
Activity against CMV, and also occasionally used for HSV (eg if ACV-resistance).
Also activity against VZV, EBV and HHV6, but seldom used.
What are specific indications for Foscarnet?
CMV disease in patients in whom GCV is contraindicated – ie neutropenic patients (eg pre-engraftment post-BMT); GCV-resistant CMV; CMV retinitis (intravitreal implants).
What are side effects of Foscarnet?
Nephrotoxic: Keep well hydrated and monitor electrolytes
What is Cidofovir?
Nucleotide (cytidine) analogue.
Competitive inhibitor of viral DNA synthesis.
Does NOT require activation by phosphorylation.
What viruses does Cidofovir have activity on?
Activity against CMV, and also occasionally used for HSV (eg if ACV-resistance) and for other viruses (eg adenovirus, BK virus).
What are specific indications for Cidofovir?
Third line Rx of CMV disease in the immunocompromised
What are side effects of Cidofovir?
Nephrotoxic: Require hydration + probenicid
What are some new antivirals in trial?
Maribavir
Letermovir
What is Maribavir effective against?
Effective in vitro against CMV and EBV: Directly inhibits viral kinase (UL97).
Effective in vitro against GCV-resistant CMV strains.
Ongoing clinical trials for pre-emptive treatment in both SCT and solid organ transplant patients.
What are the side effects of Maribavir?
Relatively well tolerated
Mainly GI side effects
What is Letermovir useful against?
A CMV DNA terminase inhibitor.
Now licensed in the UK for CMV prophylaxis in CMV IgG+ HSCT recipients.
CMV specific!
What are the side effects of Letermovir?
Remains active against GCV-resistant strains.
Well tolerated and safe - Mainly GI side effects.
What are potential drug-drug interactions with Letermovir?
Drug interactions with immunosuppressants (eg cyclosporine, tacrolimus, sirolimus) - need to monitor drug levels of the above.
What is Epstein-Barr Virus?
Salivary transmission, infection common in childhood, usually minimally symptomatic and self-limiting.
Classical cause of infectious mononucleosis.
Lifelong infection – continuous low grade viral replication in B lymphocytes kept in check by cellular immune system (immunosurveillance).
Associated with lymphoproliferative disease in the immunocompromised.
What is Post-Transplant Lymphoproliferative Disease?
Associated with EBV infection.
Breakdown of immunosurveillance.
Latently infected B cells – polyclonal expansion.
Predispose to lymphoma.
How is Post-Transplant Lymphoproliferative Disease diagnosed?
EBV viral load in blood (> 105 c/ml), biopsy
What is the management of Post-Transplant Lymphoproliferative Disease?
Reduce immunosuppression (regression in < 50%).
Anti-CD20 monoclonal Ab therapy (B cell marker) – rituximab.
A 42-year-old lady is admitted with a 2 day history of fever and confusion and presents with new onset seizures. What antiviral medication should she receive as soon as possible?
A. Oral aciclovir
B. IV foscarnet
C. Oral valaciclovir
D. IV ganciclovir
E. IV aciclovir
E. IV aciclovir
What are examples of neuraminidase inhibitors?
Oseltamivir (Tamiflu, oral)
Zanamivir (Relenza, dry powder inhaler)
What are specific indications for neuraminidase inhibitors?
Indicated for all patients admitted to hospital due to influenza virus-related respiratory disease.
What is Baloxavir?
New antiviral in pipeline to treat influenza.
Approved for use in Japan and USA.
Inhibitor of endonuclease activity of the RNA polymerase complex required for viral gene transcription.
What is respiratory syncytial virus?
Commonest cause of severe respiratory tract illness and hospitalisation of infants worldwide (bronchiolitis).
Associated with subsequent wheeze and asthma diagnosis in later life.
Other risk groups: Elderly, chronic lung disease and the immunocompromised.
What is Ribavarin?
Guanosine analogue
How does Ribavarin work?
Inhibits viral RNA synthesis (exact mechanism unclear) – broad activity in vitro: effective for Lassa fever and HEV. Used in combination with other drugs for HCV.
What are adverse effects of Ribavarin?
Anaemia and possible teratogenicity.
Where is IVIg derived and what is it used for?
Derived from pooled donors.
Often administered as an adjunct to treatment of viral pneumonitis in the immunocompromised.
What is Palivizumab?
Monoclonal antibody against RSV
What are indications for Palivizumab?
For the prevention of serious lower respiratory tract disease caused by RSV in infants at high risk: eg born preterm and severe underlying heart or lung disease (such as bronchopulmonary dysplasia), SCID or long term ventilation.
What are antivirals which may be effective against SARS-CoV2?
Remdesevir: Broad spectrum adenosine nucleotide analogue pro-drug. iv.
Molnupiravir: Broad spectrum. induces viral RNA mutagenesis.
Paxlovid: Protease inhibitor nirmatrelvir (administered together with low dose ritonavir to increase drug t1/2).
What are neutralising monoclonal antibodies which can be used against SARS-CoV2?
Ronapreve: (Combination casirivimab + imdevimab), 2.4g iv once only.
Sotrovimab: 500mg iv once only.
Strategy to treat patients who have mild to moderate disease, but who are at high risk of severe disease. Administer as early in the disease process as possible!
What are immunomodulators which may be used against SARS-CoV2?
Steroids (e.g. dexamethasone)
Cytokine Release Syndrome (CRS):
- Tocilizumab: IL-6 receptor antagonist
- Sarilumab: IL-6 receptor antagonist
- Anakinra: IL-1 receptor antagonist
The following statements concern the antiviral drugs oseltamivir and zanamivir. Choose the best answer.
A. Oseltamivir directly inhibits the influenza neuraminidase
B. Zanamivir blocks binding of viral haemagglutinin to host cell sialic acid
C. Oseltamivir inhibits influenza virus uncoating
D. Zanamivir is usually given intravenously
E. Zanamivir is usually given by nebuliser
E. Zanamivir is usually given by nebuliser
What is BK virus?
Part of Polyomavirus family (related to JC virus).
Primary BK virus infection in childhood with minimal symptoms, but subsequent lifelong carriage in kidneys and urinary tract.
In which groups of patients does BK virus become problematic?
Immunocompromised
BMT: Haemorrhagic cystitis; Less commonly nephritis
Renal transplant: BK nephritis and ureteric stenosis
What is the treatment of BK haemorrhagic cystitis?
Bladder washouts.
Reduce level of immunosuppression if possible.
Cidofovir iv (+ probenicid) if significant morbidity.
Intravesical cidofovir (5mg/kg/wk) an option if nephrotoxicity.
What is the treatment of BK nephropathy?
Reduce level of immunosuppression if possible
Normal human immunoglobulin (~ IVIG)
In which group of patients do adenoviruses become problematic?
Paeds transplant recipients
Severe multi-organ involvement
What is the treatment for adenovirus?
Cidofovir IV
IVIG
What is Brincidofovir?
Lipid-conjugated oral prodrug of cidofovir.
Main potential is for treatment of adenovirus and of BK virus disease in the immunocompromised.
What are the side effects of Brincidofovir?
Less toxicity – mainly diarrhoea and mild transaminitis.
Not licensed in UK.
How does CMV become resistant to Ganciclovir?
In protein kinase gene (UL97) - most common
In the DNA polymerase gene (UL54) – rare
UL56 terminase gene (letermovir)
How does HSV become resistant to ACV?
Mutations usually in viral thymidine kinase (95%), and rarely in the viral DNA polymerase (5%).
