Antivirals

Question 1

Where do we target with antivirals?

Answer 1

Reverse transcriptase (retrovirus)
Transcription and translation
Release (cell lysis)

Question 2

What are directly acting antivirals?

Answer 2

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

Question 3

What is the cellular response to infection?

Answer 3

Day 1-3: Innate- Early inflammatory mediators
Day 4-7: Cytokine release
Day 7-9: Acquired- T/ B cells

Question 4

What is immunomodulation?

Answer 4

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

Question 5

What are the limiting factors of antiviral therapy?

Answer 5

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

Question 6

How are herpesviruses classified?

Answer 6

Question 7

How does chicken pox extend?

Answer 7

Primary infection (eg chickenpox)

ØLatency (eg in dorsal root ganglia)

ØReactivation (eg zoster – shingles)

Question 8

What is chickenpox?

Answer 8

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

Question 9

What is reactivation of VZV?

Answer 9

• Reactivation of latent infection (dorsal root ganglia)
• Immunocompetent

oDermatomal distribution

oComplication: Post-herpetic neuralgia

•Immunocompromised

oCan experience multidermatomal or disseminated infection with severe complications

Question 10

What is a prodrug?

Answer 10

A prodrug is an inactive precursor of a drug, that is metabolized into the active form within the body.

Question 11

What antivirals are used for VZV/ HZV?

Answer 11

• 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

Question 12

What is the MOA of aciclovir?

Answer 12

Further elongation of the chain is impossible because acyclovir lacks the 3’ hydroxyl group necessary for the insertion of an additional nucleotide

Question 13

What is selective activity of guanosine analogues?

Answer 13

• 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

Question 14

What is HSV encephalitis?

Answer 14

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 *

Question 15

What is the indication for VZV treatment?

Answer 15

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

Question 16

What is CMV?

Answer 16

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…

Question 17

What are the CMV antiviral drugs?

Answer 17

Ganciclovir (IV)

Valganciclovir (PO)

Foscarnet (IV/ intravitreal)

Cidofovir (IV)

Letermovir

Question 18

What is Ganciclovir?

Answer 18

• 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)

Question 19

What is Foscarnet?

Answer 19

• 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

Question 20

What is Cidofovir?

Answer 20

• 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

Question 21

What is the management of CMV in transplant pts?

Answer 21

1. Treat established disease (ganciclovir & reduce immunosuppression) – high mortality in BMTs
2. 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

Question 22

What is maribavir?

Answer 22

• 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

Question 23

What is letermovir?

Answer 23

• 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!

Question 24

What is EBV?

Answer 24

• 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

Question 25

What is PTLD?

Answer 25

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 –

Question 26

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

Answer 26

IV aciclovir

Question 27

What is on the surface of Influenza?

Answer 27

Haemagluttinin Neuraminidase

Question 28

What are the neuraminidase inhibitors?

Answer 28

•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

Question 29

What is the treatment pathways for influenza?

Answer 29

Question 30

When are NI indicated?

Answer 30

Indicated in the community if all 3 apply (NICE guidance): 1. National surveillance indicates influenza is circulating 2. Patient is in a ‘risk-group’ \* 3. 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

Question 31

What is Peramivir?

Answer 31

* 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

Question 32

What is Baloxavir?

Answer 32

* 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

Question 33

What is the dual therapy?

Answer 33

Favipravir + oseltamivir ## Footnote * Favipravir: a viral RNA polymerase inhibitor prodrug. Available both iv and po * Combination may have synergistic action

Question 34

What is RSV?

Answer 34

* 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

Question 35

What is Ribavirin?

Answer 35

* 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

Question 36

What is IVIG?

Answer 36

* Derived from pooled donors * Often administered as an adjunct to treatment of viral pneumonitis in the immunocompromised

Question 37

What is Palivizumab?

Answer 37

* 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

Question 38

What is Nirsevimab?

Answer 38

* Extended half life mAb * Requires single IM injection to provide protection for the whole winter

Question 39

What do we use to treat SARS CoV 2?

Answer 39

* Antiviral drugs * Neutralising monoclonal antibodies(nMabs) * Immunomodulators

Question 40

What antivirals are used for COVID?

Answer 40

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).

Question 41

What are nMabs?

Answer 41

•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!

Question 42

What are immunomodulators for COVID?

Answer 42

* Steroids (eg dexamethasone) * Cytokine Release Syndrome (CRS): oTocilizumab: IL-6 receptor antagonist oSarilumab: IL-6 receptor antagonist oAnakinra: IL-1 receptor antagonist (+ Thromboprophylaxis – heparin)

Question 43

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

Answer 43

Oseltamivir directly inhibits the influenza neuraminidase

Question 44

What are the other viruses?

Answer 44

BK virus Adenovirus

Question 45

What is BK virus?

Answer 45

* 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

Question 46

What is the treatment of BK haemorrhagic cystitis?

Answer 46

* Bladder washouts * Reduce level of immunosuppression if possible * Cidofovir iv (+ probenicid) if significant morbidity * Intravesical cidofovir (5mg/kg/wk) an option if nephrotoxicity

Question 47

How do you treat BK nephropathy?

Answer 47

* Reduce level of immunosuppression if possible * Normal human immunoglobulin (~ IVIG)

Question 48

What is adenovirus?

Answer 48

* Paeds transplant recipients * Severe multi-organ involvement * Rx: Ribavirin Cidofovir iv IVIG

Question 49

What is Brincidofovir?

Answer 49

* 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…)

Question 50

What is cellular immunotherapy?

Answer 50

Adoptive immunotherapy / virus-specific cytotoxic T cells / donor lymphocyte infusion : beneficial for treatment of CMV, adenovirus, BK virus, EBV… in transplant recipients

Question 51

What may result in treatment failrue of antivirals?

Answer 51

•Patient oImmunocompromised oPoor treatment adherence: * Intolerance * Side effects * Drugs oPotency oAbsorption oPenetration oActivation / inactivation oInteractions •Virus oDrug resistance mutations

Question 52

What are the drug resistance mechanisms?

Answer 52

•Diversity Quasispecies, mutation / recombination •Selection Replication (eg in the presence of suboptimal drug concentrations)

Question 53

What are the implications of drug resistance?

Answer 53

* 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

Question 54

What is the prevention of drug resistance?

Answer 54

* 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…)

Question 55

When do you test for drug resistance?

Answer 55

* Treatment failure (choice of salvage Rx) * HIV: Baseline pre-Rx, on diagnosis (transmission of resistant strains)

Question 56

What are drug resistance assays?

Answer 56

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

Question 57

What is HSV drug resistance?

Answer 57

* 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

Question 58

What is CMV drug resistance?

Answer 58

•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

Question 59

What are immunoglobulin preparations?

Answer 59

* 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)

Question 60

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

Answer 60

Aciclovir resistance in HSV is most commonly mediated by mutations in the viral thymidine kinase