MICRO: Antivirals Flashcards
What are the main pathways targeted by antivirals?
- Reverse transcription
- Transcription and translation
- Release (cell lysis)
What is a virus?
- Obligate intracellular parasites
- Metabolically inert
- Rely on host cell for replication
What are some virally encoded proteins that can be targeted with DAAs?
- nucleic acid polymerases,
- proteases,
- integrase,
- CCR5,
- terminase
Viruses encode specific proteins required for cell entry, genomic replication or transcription, assembly and release of progeny virions.
What are small molecule inhibitors AKA? What is their MOA?
Small molecule inhibitors - directly-acting antivirals (DAAs)
Interfere with the function viral proteins and inhibit viral replication
What does immunomodulation depend on? Give 3 examples of immunomodulation.
Boosting the innate immune response e.g. by increasing the production of type 1 interferons (IFNs)
Examples:
- Interferon for HBV and HCV,
- IVIG for viral pneumonitis,
- Imiquimod for HPV,
- Steroids for HSE (?)
- IL-6 receptor antagonist for COVID
List the herpesviruses and their clinical syndromes. Which ones are rapid vs slow growing?
HSV1, HSV2 and VZV are rapid growing
CMV, HHV-6 and HHV-7 are slow growing
Name a complication of chickenpox and zoster in adults.
Chickenpox - Pneumonitis
Zoster - Post-herpetic neuralgia
Define prodrug.
A prodrug is an inactive precursor of a drug, that is metabolized into the active form within the body.
Which antivirals are used for HSV and VZV? What do they interfere with?
Interfere with viral DNA synthesis
1st line:
- Aciclovir (po or iv)
- Valaciclovir (prodrug of aciclovir, po, high bioavailability)
- Famciclovir
2nd line:
- Foscarnet or cidofovir for ACV-resistant virus
- Ganciclovir
What type of drug is aciclovir? What is its MOA?
Guanosine analogue
MOA - Analogue of guanosine but further elongation of the chain by the virus is impossible because acyclovir lacks the 3’ hydroxyl group necessary for the insertion of an additional nucleotide
What herpesviruses are guanosine analogues most selective for?
Susceptibility: HSV-1 > HSV-2 >> VZV
Why does aciclovir not incorporate into the host DNA?
Its affinity for herpesvirus DNA polymerase is 10- to 30- fold higher than for cellular (host) DNA polymerase for ACV-PPP
Which enzyme converts aciclovir into the active form?
- First monophosphorylated by viral thymidine kinase (TK)
- Then further phosphorylated by cellular kinases to teh active form (ACV-PPP)
IV aciclovir
What is the treatment for HSV encephalitis?
Immediate IV aciclovir 10mg/kg TDS (do not wait for test results)
Treat for 14-21days until PCR negative
Give 4 indications for treating VZV.
- Chickenpox in an adult (risk: pneumonitis)
- Zoster in >50yo (risk: post-herpetic neuralgia)
- Primary infection or reactivation in immunocompromised
- Neonatal chickenpox
The following statements concern the antiviral drugs oseltamivir and zanamivir. Choose the best answer
- Oseltamivir directly inhibits the influenza neuraminidase
- Zanamivir blocks binding of viral haemagglutinin to host cell sialic acid
- Oseltamivir inhibits influenza virus uncoating
- Zanamivir is usually given intravenously
- Zanamivir is usually given by nebuliser
1
The following statements concern resistance to antiviral drugs. Choose the best answer.
- Resistance of HSV to aciclovir is common in the immunocompetent
- Phenotypic resistance testing is routinely used to detect resistance of CMV to ganciclovir
- Aciclovir resistance in HSV is most commonly mediated by mutations in the viral thymidine kinase
- Aciclovir resistance in HSV is most commonly mediated by mutations in the viral DNA polymerase
- Antiviral drug resistance is most commonly associated with good adherence to treatment
3
Which cells does CMV lie latent in?
Monocytes
Dendritic cells
What are the symptoms of CMV infection in the immunocompromised?
e.g. post transplant:
- BM suppression,
- retinitis,
- pneumonitis,
- hepatitis,
- colitis,
- encephalitis
What antivirals are first line for CMV? What can be given alongside these in transplant patients with CMV pneumonitis?
1st line
- Ganciclovir GCV iv
- OR Valganciclovir (VGC) po – prodrug of ganciclovir
2nd line: Foscarnet IV/intravitreal (for retinitis)
3rd line: Cidofovir IV
Letermovir can also be used.
Transplant patients with CMV pneumonitis = add IVIG
What is the use of Letermovir in CMV?
Can be used as prophylaxis in CMV IgG+ HSCT recipients
GCV/cGCV can also be used prophylactically to prevent CMV especially in solid organ transplant patients
Which antiviral is only CMV specific (i.e. has no activity against other HHVs)? What is its MOA?
Letermovir
MOA: CMV DNA terminase* inhibitor
(* Cleavage and packaging of viral progeny DNA into capsids)
What are the side effects of Letermovir?
- Mainly safe
- GI disturbance
- Drug interactions e.g. with cyclosporine, tacrolimus, sirolimus
What is the management of SCT patients to prevent CMV?
Pre-emptive therapy used i.e. monitoring eg weekly blood CMV PCR and giving vGCV/GCV or foscarnet Rx when PCR +ve
What is the MOA of ganciclovir? What enzyme converts ganciclovir into its active form?
MOA: Guanosine analogue which inhibits viral DNA synthesis
Viral UL97 kinase
What are the side effects of GCV? How does it compare to ACV?
Less easily tolerated than ACV
- BM toxicity (leukopenia, thrombocytopenia, anaemia, pancytopenia) - contraindicated in those with BM suppression
- Renal and hepatic toxicity (renally excreted)
What antiviral would you give to a BM suppressed patient with CMV?
Foscarnet e.g. pre-engraftment post-BMT
Also indicated in: GCV resistance, and CMV retinitis (because intravitreal available)
What is the MOA of foscarnet?
MOA: Non-competitive inhibitor of viral DNA polymerase; does NOT require activation by phosphorylation
What is the main SE of foscarnet?
Nephrotoxic - keep well hydrated and monitor electrolytes
What is the MOA of cidofovir? What is its main SE? How is this avoided?
MOA: Nucleotide (cytidine) analogue; competitive inhibitor of viral DNA synthesis; does NOT require activation by phosphorylation
SE: nephrotoxic, requires hydration AND probenicid (which prevents its excretion)
Which experimental drug has a MOA which inhibits the viral kinase UL97?
Maribavir
What is the clinical course of EBV infection?
Salivary transmission
Asymptomatic infection (in childhood) OR infectious mononucleosis
Lifelong infection by low grade viral replication in B lymphocytes controlled by immunosurveillance
PTLD/lymphoproliferative disease in the immunosuppresed
Define PTLD.
Post-Transplant Lymphoproliferative Disease - EBV infection resulting in the breakdown of immunosurveillance, polyclonal expansion of infected B cells and predisposition to lymphoma.
Diagnosed by EBV viral load in blood (> 105 c/ml) or biopsy
What is the managament of PTLD?
Reduce immunosuppression (regression in < 50%)
Rituximab –anti-CD20 mAb
Which influenza virus enzyme is involved in releasing new virus into the airway?
Neuraminidase - releases new virus and propagates the infection
Name 2 neuraminidase inhibitors. What is first line for influenza treatment?
Effective for both influenza A and B and indicated for all patients in hospital due to influenza related respiratory disease.
- 1st line: Oseltamivir (Tamiflu PO)
- 2nd line: Zanamivir (Relenza powder INH or IV)
- Also:*
- Peramivir - Flu A only NB: resistance: H275Y mutation confers reduced susceptibility; not licensed in UK
Name the community criteria for neuraminidase inhibitor treatment.
All of the following must apply for community treatment:
- National surveillance indicates influenza is circulating
- Patient is in a ‘risk-group’ *
- Within 48 hours of symptom onset (36 hours for zanamivir)
*Risks:
- Aged ≥ 65 years
- Immunosuppressed
- Chronic respiratory disease
- Chronic heart disease
- Chronic liver disease
- Chronic neurological disease
- Diabetes mellitus
- Pregnant women
- Morbid obesity (BMI ≥ 40)
- Children < 6 months
What is the MAO of Baloxavir (use for influenza)?
MOA: Inhibitor of endonuclease activity of the RNA polymerase complex required for viral gene transcription
SE: diarrhoea, bronchitis
Only used in Japan and USA
What dual therapy can be used for synergistic action in influenza?
Favipravir + Oseltamivir
NB: Favipravir MOA: a viral RNA polymerase inhibitor prodrug.
True or false?
RSV bronchiolitis is associated with subsequent wheeze and asthma diagnosis in later life
True
What is the MOA of Ribavirin? What are the adverse effects?
MOA: Guanosine analogue; Inhibits viral RNA synthesis (exact mechanism unclear). Broad activity in vitro.
Oral only
SE: anaemia + teratogenicity
What is an effective treatment for RSV? When is it indicated?
Palivizumab - mAb against RSV
Use: RSV prevention in infants at high risk e.g. preterm, underlying cardiac/lung disease, SCID, ventilation
Also:
Nirsevimab - has an extended half life and only requires one IM injection for whole winter
NB: ribavirin has unknown clinical efficacy against RSV
Lust 3 types of treatment for SARS-CoV-2.
- Antiviral drugs
- Neutralising monoclonal antibodies(nMabs)
- Immunomodulators
Name an antiviral drug used for SARS-CoV2 and its MOA.
Remdesevir: Broad spectrum adenosine nucleotide analogue pro-drug. iv.
Other:
Molnupiravir: Broad spectrum. induces viral RNA mutagenesis
Paxlovid: Protease inhibitor nirmatrelvir (administered together with low dose ritonavir to increase drug t1/2).
Name a nMabs treatment for SARS-CoV2. What is the aim of nMabs use? What is the MOA?
Ronapreve: (combination casirivimab + imdevimab), 2.4g iv once only
Sotrovimab: 500mg iv once only
Aim: 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.
MOA: target the S protein to stoDp the virus interacting with ACE2 and entering.
Name 2 immunomodulator treatments (incl. to treat CRS) used in SARS-CoV2 and their MOA.
- Steroids (eg dexamethasone)
Cytokine Release Syndrome (CRS):
- Tocilizumab: IL-6 receptor antagonist
- Sarilumab: IL-6 receptor antagonist
- Anakinra: IL-1 receptor antagonist
Within how many days of symptom onset can remdesivir be given in SARS-CoV-2? Name a criterion for IL-6 inhibitor use.
Remdesivir - _<_10 days - given to all patients
IL-6 inhibitor - CRP >75mg/L AND sats of <92% or requiring supplemental oxygen
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
A - both oseltamivir and zanamivir are NA inhibitors
What family does BK virus belong to? What is its clinical course?
Polyomavirus family + related to JC virus
Primary infection in childhood with minimal symptoms, but subsequent lifelong carriage in kidneys and urinary tract
What are the complications of BK virus in the immunocompromised?
BM transplant –> haemorrhagic cystitis
Renal transplant –> BK nephritis and ureteric stenosis
What is the management of BK haemorrhagic cystitis? What is the first line antiviral?
- Bladder washout
- Reduce immunosuppression
1st line: Cidofovir iv (+ probenicid)
2nd line: Intravesical* cidofovir (5mg/kg/wk) in nephrotoxicity
What i sthe management of BK nephropathy?
- Reduce immunosuppression if possible
- IVIG
What is the treatment for adenovirus infection in paeds transplant recipients?
Adenovirus –> severe multi-organ involvement
- 1st line: Cidofovir iv
- IVIG – sometimes used; limited evidence
What is the benefit of using the oral prodrug form of cidofovir?
Brincidofovir = lipid-cojugated oral prodrug form of cidofovir
Benefits: milder toxicity (mainly diarrhoea and mild transaminitis)
BUT not licensed for used in UK. Potential use for adenovirus and BK virus.
What are the uses of cellular immunotherapy?
Cellular immunotherapy =
- adoptive
- virus-specific cytotoxic T cells
- infused from donors
Beneficial for:
- CMV
- Adenovirus
- BK virus
- EBV in transplants
Name and describe two drug resistance mechanisms to antvirals.
Diversity – e.g. presence of quasispecies, mutation / recombination
Selection - replication eg in the presence of suboptimal drug concentrations
Define quasispecies.
Quasispecies – when viruses are heterogenous rather than monoclonal
What is the problem with many second line antiviral treatments when resistance is found?
- Less effective
- More toxic
- Cross resistance* may be found
e.g. Foscarnet or cidofovir are required for GCV-resistant CMV, but nephrotoxicity can be a problem.
*Cross-resistance = when a resistant virus emerging under the selective pressure of one therapy but is also cross-resistant to a second antiviral agent.
What are two strategies to prevent drug resistance?
Combination treatment e.g. HAART
Improved adherence e.g. OD regimens, patient education
When should you test for viral drug resistance? How is this done?
When:
- HIV - done at baseline on diagnosis
- Other - when treatment fails
How: drug resistance assays
- Genotypic - e.g. for HIV drug resistance
- Phenotypic - i.e. cell culture or plaque reduction assays e.g. for HSC drug resistance testing
What are the two main HSV ACV resistance mechanisms? How is this managed?
Mutations;
- Viral thymidine kinase (95%) –> GCV resistance too
- Viral DNA polymerase (5%)
Management:
- Foscarnet or cidofovir
What are the most common CMV GCV resistance mechanisms? What is the management?
Resistance mechanisms:
- Protein kinase gene (UL97) - most common
- DNA polymerase gene (UL54) – rare
- UL56 terminase gene (letermovir)
Management:
- Foscarnet or cidofovir
What is a clinically important mutation conferring reistance to neuraminidase inhibitors?
In H1N1 = H275Y mutation
Name a prophylactic IVIG preparation and its use.
Prophylactic: palivizumab (RSV)
Name 3 post-exposure prophylaxis IVIG preparations and their uses.
Varicella zoster immunoglobulin - for immunocompromised / pregnant / neonates
Hepatitis B immunoglobulin- unvaccinated recipient exposed to HBV; non-responder to vaccine exposed to source of positive or unknown status
Human Rabies Immunoglobulin (HRIG)
Name 2 therapeutic IVIG preparations and their uses.
Human normal immunoglobulin (IVIG) = adjunctive treatment for viral pneumonitis (eg CMV)
Rituximab (anti-CD20) = for EBV-driven PTLD
Sotrovimab & ronapreve = neutralising mAbs for COVID Rx
The following statements concern resistance to antiviral drugs. Choose the best answer.
- a)Resistance of HSV to aciclovir is common in the immunocompetent
- b)Phenotypic resistance testing is routinely used to detect resistance of CMV to ganciclovir
- c)Aciclovir resistance in HSV is most commonly mediated by mutations in the viral thymidine kinase
- d)Aciclovir resistance in HSV is most commonly mediated by mutations in the viral DNA polymerase
- e)Antiviral drug resistance is most commonly associated with good adherence to treatment
a) Aciclovir resistance in HSV is most commonly mediated by mutations in the viral thymidine kinase
