Antivirals Flashcards
Where do we target with antivirals?
Reverse transcriptase (retrovirus)
Transcription and translation
Release (cell lysis)
What are directly acting antivirals?
Viruses encode specific proteins required for cell entry, genomic replication or transcription, assembly and release of progeny virions
Virally-encoded proteins, e.g. nucleic acid polymerases, proteases, integrase, CCR5, terminase
Small molecule inhibitors - directly-acting antivirals (DAAs) – interfere with the function of the above and inhibit viral replication
What is the cellular response to infection?
Day 1-3: Innate- Early inflammatory mediators
Day 4-7: Cytokine release
Day 7-9: Acquired- T/ B cells
What is immunomodulation?
Viral replication detected by pattern-recognition receptors (PRRs, Toll-like receptors, RIG-like receptors )
Triggers innate immune responses leading to production of restriction factors such as type 1 interferons (IFNs)
Antiviral immune response can be boosted by exogenous immunomodulators
Examples:
Interferon Rx for HBV and HCV,
IVIG for viral pneumonitis,
imiquimod for HPV,
steroids for HSE (?)
IL-6 receptor antagonist for COVID
What are the limiting factors of antiviral therapy?
Host immune response is critical to achieve suppression of viral replication
Transplant patients: If possible reduce immunosuppressive Rx
HIV patients: Start antiretroviral Rx
Adherence to treatment / antiviral drug resistance
Drug toxicity
Drug interactions
How are herpesviruses classified?
How does chicken pox extend?
Primary infection (eg chickenpox)
ØLatency (eg in dorsal root ganglia)
ØReactivation (eg zoster – shingles)
What is chickenpox?
oCaused by primary infection with varicella-zoster virus (VZV)
oMajority uncomplicated in healthy children
oAdults at risk of complications including pneumonitis
oSevere disease in the immunocompromised
What is reactivation of VZV?
- Reactivation of latent infection (dorsal root ganglia)
- Immunocompetent
oDermatomal distribution
oComplication: Post-herpetic neuralgia
•Immunocompromised
oCan experience multidermatomal or disseminated infection with severe complications
What is a prodrug?
A prodrug is an inactive precursor of a drug, that is metabolized into the active form within the body.
What antivirals are used for VZV/ HZV?
- Aciclovir (po or iv)
- Valaciclovir (prodrug of aciclovir, po, high bioavailability)
- Famciclovir
- 2nd line: Foscarnet or cidofovir for ACV-resistant virus
- Ganciclovir
•
•Interfere with viral DNA synthesis
What is the MOA of aciclovir?
Further elongation of the chain is impossible because acyclovir lacks the 3’ hydroxyl group necessary for the insertion of an additional nucleotide
What is selective 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
- Susceptibility: HSV-1 > HSV-2 >> VZV
- VZV 10x less sensitive so higher doses required
What is HSV encephalitis?
If suspected clinically:
Start empiric treatment immediately
with iv ACV 10mg/kg tds
without waiting for test results
If confirmed, treat for 14 - 21 days *
What is the indication for VZV treatment?
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?
Primary infection
ØLatency in blood monocytes and dendritic cells
ØReactivation (eg following immunosuppression)
- Asymptomatic shedding in saliva, urine, semen and cervical secretions
- 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 CMV antiviral drugs?
Ganciclovir (IV)
Valganciclovir (PO)
Foscarnet (IV/ intravitreal)
Cidofovir (IV)
Letermovir
What is Ganciclovir?
- Guanosine analogue - Inhibits viral DNA synthesis
- Activity against CMV
- Also activity against HSV, VZV, EBV and HHV6, but seldom used
- GCV: SLOW IV infusion ; vGCV: oral pro-drug
- Renal excretion
- Indications: CMV disease in immunocompromised (retinitis, pneumonitis), and neonates with congenital CMV
oGiven together with IVIG for CMV pneumonitis in Tx patients
•S/E: Less easily tolerated than ACV
oBone marrow toxicity (leukopenia, thrombocytopenia, anaemia, pancytopenia)
oRenal and hepatic toxicity
•C/I: Bone marrow suppression (neutropenia)
What is Foscarnet?
- Non-competitive inhibitor of viral DNA polymerase
- Does NOT require activation by phosphorylation
- Activity against CMV, and also occasionally used for HSV (eg if ACV-resistance)
- Also activity against VZV, EBV and HHV6, but seldom used
- SLOW IV infusion, intravitreal implants
- Indications: CMV disease in patients in whom GCV is contraindicated – ie neutropenic patients (eg pre-engraftment post-BMT); GCV-resistant CMV; CMV retinitis (intravitreal implants).
- S/E: Nephrotoxic
oKeep well hydrated and monitor electrolytes
What is Cidofovir?
- Nucleotide (cytidine) analogue
- Competitive inhibitor of viral DNA synthesis
- Does NOT require activation by phosphorylation
- Activity against CMV, and also occasionally used for HSV (eg if ACV-resistance) …
…and for other viruses (eg adenovirus, BK virus…)
•Administration: iv infusion
(also local administration - cream)
- Indication: Third line Rx of CMV disease in the immunocompromised
- S/E: nephrotoxic
Require hydration + probenicid
What is the management of CMV in transplant pts?
- Treat established disease (ganciclovir & reduce immunosuppression) – high mortality in BMTs
- Prophylaxis with GCV/vGCV (or ACV/vACV)
- SEs include BM toxicity
- Mostly used for solid organ Tx (eg renal)
3.Pre-emptive therapy:
- Monitoring (eg weekly blood CMV PCR)
- vGCV/GCV or foscarnet Rx when PCR +ve
- Mostly used for stem cell transplant
What is maribavir?
- Po, bd
- Effective in vitro against CMV and EBV
- Directly inhibits viral kinase (UL97)
- Effective in vitro against GCV-resistant CMV strains
- Relatively well tolerated
- Mainly GI side effects
- Ongoing clinical trials for pre-emptive treatment in both SCT and solid organ transplant patients
What is letermovir?
- A CMV DNA terminase* inhibitor
- Now licensed in the UK for CMV prophylaxis in CMV IgG+ HSCT recipients
- 480mg od, available po and iv
- Remains active against GCV-resistant strains
- Well tolerated and safe - Mainly GI side effects
- Drug interactions with immunosuppressants (eg cyclosporine, tacrolimus, sirolimus) - need to monitor drug levels of the above.
- CMV-specific!
What is EBV?
- 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 PTLD?
Post-Transplant Lymphoproliferative Disease
oAssociated with EBV infection
oBreakdown of immunosurveillance
oLatently infected B cells – polyclonal expansion
oPredispose to lymphoma
oDiagnosis: EBV viral load in blood (> 105 c/ml), biopsy
oManagement:
- 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? Choose the best answer.
a) Oral aciclovir
b) IV foscarnet
c) Oral valaciclovir
d) IV ganciclovir
e) IV aciclovir
IV aciclovir
What is on the surface of Influenza?
Haemagluttinin
Neuraminidase
What are the neuraminidase inhibitors?
•Oseltamivir (Tamiflu, oral);
zanamivir (Relenza, dry powder inhaler)
- IV and nebulised formulations can also be obtained
- Effective for both influenza A and B
- Inpatients:
Indicated for all patients admitted to hospital due to influenza virus-related respiratory disease
What is the treatment pathways for influenza?
When are NI indicated?
Indicated in the community if all 3 apply (NICE guidance):
- National surveillance indicates influenza is circulating
- Patient is in a ‘risk-group’ *
- Within 48 hours of symptom onset (36 hours for zanamivir)
* Risk-groups:
- 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 Peramivir?
- Neuraminidase inhibitor licensed in US, but also available in UK
- 600mg IV od
- Evidence mainly for ‘flu A
- H275Y mutation confers reduced susceptibility -> avoid use with oseltamivir resistance
What is Baloxavir?
- Baloxavir marboxil tablets (Xoflusa)
- Approved for use in Japan and USA
- Inhibitor of endonuclease activity of the RNA polymerase complex required for viral gene transcription
- Single dose po
- SEs: diarrhoea, bronchitis
- Emergence of resistance seen in 2-10% of patients treated – but reduced viral fitness
What is the dual therapy?
Favipravir + oseltamivir
- Favipravir: a viral RNA polymerase inhibitor prodrug. Available both iv and po
- Combination may have synergistic action
What is RSV?
- 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 Ribavirin?
- Guanosine analogue
- Administer po or iv nebulised
- 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.
- Clinical efficacy for RSV is unclear – Lack of good evidence for RSV!
- Adverse effects include anaemia and possible teratogenicity
What is IVIG?
- Derived from pooled donors
- Often administered as an adjunct to treatment of viral pneumonitis in the immunocompromised
What is Palivizumab?
- Palivizumab is a monoclonal antibody against RSV
- Indication: 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
- Monthly administration by im injection
What is Nirsevimab?
- Extended half life mAb
- Requires single IM injection to provide protection for the whole winter
What do we use to treat SARS CoV 2?
- Antiviral drugs
- Neutralising monoclonal antibodies(nMabs)
- Immunomodulators
What antivirals are used for COVID?
oRemdesevir: Broad spectrum adenosine nucleotide analogue pro-drug. iv.
oMolnupiravir: Broad spectrum. induces viral RNA mutagenesis
oPaxlovid: Protease inhibitor nirmatrelvir (administered together with low dose ritonavir to increase drug t1/2).
What are nMabs?
•Neutralising monoclonal Abs - “nMabs”:
oRonapreve: (combination casirivimab + imdevimab), 2.4g iv once only
oSotrovimab: 500mg iv once only
oStrategy to treat patients who have mild to moderate disease, but who are at high risk of severe disease.
oAdminister as early in the disease process as possible!
What are immunomodulators for COVID?
- Steroids (eg dexamethasone)
- Cytokine Release Syndrome (CRS):
oTocilizumab: IL-6 receptor antagonist
oSarilumab: IL-6 receptor antagonist
oAnakinra: IL-1 receptor antagonist
(+ Thromboprophylaxis – heparin)
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
Oseltamivir directly inhibits the influenza neuraminidase
What are the other viruses?
BK virus
Adenovirus
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
- Only becomes problematic in the immunocompromised:
oBMT: Haemorrhagic cystitis
Less commonly nephritis
oRenal 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
How do you treat BK nephropathy?
- Reduce level of immunosuppression if possible
- Normal human immunoglobulin (~ IVIG)
What is adenovirus?
- Paeds transplant recipients
- Severe multi-organ involvement
- Rx: Ribavirin
Cidofovir iv
IVIG
What is Brincidofovir?
- Lipid-conjugated oral prodrug of cidofovir
- 100mg twice a week
- Less toxicity – mainly diarrhoea and mild transaminitis
- Not licensed in UK
- Main potential is for treatment of adenovirus and of BK virus disease in the immunocompromised
- (NB orthopox viruses…)
What is cellular immunotherapy?
Adoptive immunotherapy / virus-specific cytotoxic T cells / donor lymphocyte infusion :
beneficial for treatment of CMV, adenovirus, BK virus, EBV…
in transplant recipients
What may result in treatment failrue of antivirals?
•Patient
oImmunocompromised
oPoor treatment adherence:
- Intolerance
- Side effects
- Drugs
oPotency
oAbsorption
oPenetration
oActivation / inactivation
oInteractions
•Virus
oDrug resistance mutations
What are the drug resistance mechanisms?
•Diversity
Quasispecies, mutation / recombination
•Selection
Replication (eg in the presence of suboptimal drug concentrations)
What are the implications of drug resistance?
- Treatment failure
- Change to 2nd line drugs:
- Less effective
- More toxic
Example:
Foscarnet or cidofovir are required for GCV-resistant CMV, but nephrotoxicity can be a problem.
•Cross resistance
What is the prevention of drug resistance?
- Use potent drug regimens to achieve maximal suppression of viral replication (combination Rx / HAART)
- Increase adherence to treatment
(low drug burden, once-daily regimens,
patient education…)
When do you test for drug resistance?
- Treatment failure (choice of salvage Rx)
- HIV: Baseline pre-Rx, on diagnosis (transmission of resistant strains)
What are drug resistance assays?
Genotypic: Sequencing / resistance mutations
Example: HIV drug resistance
Also used for HBV, HCV & CMV drug resistance
Phenotypic: Cell culture
Plaque reduction assay
Routinely used for HSV drug resistance testing
What is HSV drug resistance?
- Mutations usually in viral thymidine kinase (95%), and rarely in the viral DNA polymerase (5%)
- The former mediates cross-resistance to GCV
- Resistance strains selected out by drug treatment
- Nearly always occurs in the context of immunosuppression – TK-deficient strains less virulent
- Suspect if lesions fail to resolve despite adequate antiviral therapy
- Treat ACV-resistant HSV with FOS or CDV
- Virus tends to revert to wild type upon cessation of Rx
What is CMV drug resistance?
•CMV genetic mutations:
oIn protein kinase gene (UL97) - most common
oIn the DNA polymerase gene (UL54) – rare
oUL56 terminase gene (letermovir)
- Most likely to occur in context of prolonged therapy in immunocompromised
- Suspect if clinical or virological failure despite appropriate therapy and reduction of immune suppression
- 2nd line for CMV is foscarnet or cidofovir
What are immunoglobulin preparations?
- Prophylactic: palivizumab (RSV)
- Post-exposure prophylaxis:
oVaricella zoster immunoglobulin
•Immunocompromised / pregnant / neonates
oHepatitis B immunoglobulin
- Unvaccinated recipient exposed to hepatitis B-positive source
- Non-responder to vaccine exposed to source of positive or unknown status
oHuman Rabies Immunoglobulin (HRIG)
•Therapeutic:
oHuman normal immunoglobulin (IVIG) as adjunctive treatment for viral pneumonitis (eg CMV)
oRituximab (anti-CD20) for EBV-driven PTLD
oSotrovimab & 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
Aciclovir resistance in HSV is most commonly mediated by mutations in the viral thymidine kinase
