Viral infections and antivirals

Question 1

Aciclovir

Answer 1

Anti-herpesvirus drug - high selective toxicity.

Question 2

Aciclovir is used to treat or prevent infection with what?

Answer 2

HSV1
HSV2
VZV

Question 3

What are some of the few side effects of Aciclovir?

Answer 3

Accumulation causes neurotoxicity.

Maintaining hydration and dose adjustment in renal dysfunction.

Question 4

Mechanism of action of Aciclovir?

Answer 4

Pro-drug, activated to a monophosphate by the viral thymidine kinase only in herpesvirus infected cells.

Host cell kinases then adds a second and third phosphate group.

Aciclovir triphosphate competitively inhibits herpesvirus specific DNA polymerases.

Further viral DNA synthesis is inhibited without affecting other normal cellular functions.

Question 5

For which herpesvirus infections is acyclovir useful?

Answer 5

Genital herpes (HSV1 or HSV2).

Herpes labialis/stomatitis (HSV1).

Disseminated herpes (HSV1 mucositis post chemo Rx).

Herpes keratitis - fluorescein stained cornea: dendritic ulcer.

Chickenpox and shingles.

Question 6

What is the new JCVI recommendation for Combination MMRV vaccine?

Answer 6

Given at 12 and 18 months, possible catch-up programme up to age 5.

Question 7

Explain the chickenpox burden.

Answer 7

Iceberg analogy.

Tip is those with complications:
- Secondary bacterial infection (Group A Strep)
- Encephalitis/pneumonitis/ stroke
- Babies under 4 weeks old/adults/immunocompromised/pregnant at greatest risk
- Adverse effects on foetus before first 20 weeks of pregnancy

Under the water part:
- 50% children have had it by the age of 4
- 90% children have had it by age of 10
- Clinically diagnosed
- Managed in community/supportive care/no anti-virals
- Care-giver working days lost ++
- Children lose 5 or more days from nursery or school

Question 8

How is chickenpox diagnosed?

Answer 8

Clinical diagnosis (Small, erythematous macules appear on the scalp, face, trunk, and proximal limbs, which progress over 12–14 hours to papules, clear vesicles (which are intensely itchy), and pustules.)

Laboratory diagnosis: PCR.

Question 9

Explain the pathophysiology of shingles:

Answer 9

Primary infection - widespread chickenpox.

Viral dormancy in dorsal root or cerebral ganglion.

Localised reactivation - dermatomal shingles around T6.

Question 10

Explain the shingles vaccination programme.

Answer 10

Offered to eligible cohorts.

Shingrix, non-live vaccine. 2 doses.
Over 60s.

Question 11

What are the red flags of Herpes Zoster infections?

Answer 11

Multiple dermatomes involved.

Haemorrhagic change.

Occular involvement.

Peripheral/unusual dermatomes affected.

Question 12

What is a disadvantage of oral acyclovir?

Answer 12

Poor oral bioavailability - necessitates frequent dosing.

Question 13

When is IV acyclovir used?

Answer 13

Severe herpes virus infections
Herpes virus encephalitis
Disseminated herpes (neonatal or congenital herpes)
Severe shingles/opthalmic zoster
Herpes viruses in immunocompromised patients
Extensive eczema herpeticum

Question 14

What is valaciclovir?

Answer 14

L-valyl ester; pro-drug of aciclovir.

Question 15

What are the benefits of Valaciclovir?

Answer 15

Better oral absorption.

Improves plasma concentration of acyclovir.

3/5x better bioavailability.

Dosing is 2/3x a day.

Question 16

What is the primary use of Ganciclovir (IV)?

Answer 16

To treat CMV infection.

Can be both treatment and prophylaxis (in immunocompromised: SOT=solid organ transplant).

Question 17

Ganciclovir is a potent inhibitor of

Answer 17

Most members of the herpesvirus family.

Question 18

Ganciclovir 5’triphosphate is a

Answer 18

Selective and potent inhibitor of viral DNA polymerase.

Question 19

What is the active form of Ganciclovir?

Answer 19

The triphosphate form.

Question 20

What are the 3 phosphorylation steps in Ganciclovir?

Answer 20

1. A deoxyguanosine kinase induced by CMV-infected cells (encoded by UL97 region).
2. Guanylate kinase (cellular).
3. Phosphoglycerate kinase (cellular) other nucleotide-metabolising enzymes may be involved as well.

Question 21

Valganciclovir is better because

Answer 21

VGCV has better absorption in the intestines and better oral bioavailability.

The valine side is cleaved by gut esterases = converted to GCV.

Question 22

If CMV is reactivated, it leads to

Answer 22

End organ disease.

Question 23

The benefits of GCV

Answer 23

Selective antiviral response.

Much stronger inhibition of viral DNA polymerases by GCV-TP than cellular DNA polymerase.

GCV-TP accumulates in CMV-infected cells.

Question 24

What are the side effects of GCV?

Answer 24

Myelosuppression= pancytopenia.

Haemolytic anaeamia.

Potential foetal toxicities.

Azoospermia/low fertility.

Resistance due to mutations in UL97 and UL54.

Question 25

Foscarnet

Answer 25

Inorganic structure mimics the anion pyrophosphate.

Selectively inhibits pyrophosphate binding site on DNA polymerase.

Inhibits all known human herpesviruses.

Does not require activation by thymidine kinase or other kinases.

Retains activity against HSV TK deficient mutants and CMV UL97 mutants

Combination of ganciclovir and foscarnet may have enhanced activity.

Question 26

Side effects of Foscarnet

Answer 26

Significant renal toxicity; monitor carefully maintain hydration, dose adjust.

Crystal induced nephropathy.

Marked plasma mineral and electrolyte disturbance, can lead to seizures if not recognised and corrected:
Hypomagnesaemia
Hypocalcaemia
Hypophosphataemia
Hyponatraemia

Acidosis, raised LDH raised Alk Phos.

Question 27

Rituximab

Answer 27

Post transplant EBV driven B cell proliferation (PTLD).

Greatest risk if EBV sero-negative donor received EBV positive tissue.

Monitor weekly quantitative EBV DNA post transplant.

Those with higher EBV loads are at greater risk of PTLD.

First step is reduction of immunosuppression. (balance risk of organ rejection).

Early pre-emptive use of rituximab reduces risk of malignant transformation;

Presents its challenges such as:
risk of reactivation of TB
risk of Hepatitis B infection in those with past resolved infection
Hypogammaglobulinaemia and bacterial infection risk.

Question 28

Describe measles

Answer 28

Highly infectious - R0=16-18 (4 days before onset and after onset of rash).

Question 29

What are the sign and symptoms of measles:

Answer 29

High fever
Morbilliform rash
Koplik spots
Coryza
Cough
Diarrhoea
Conjunctivitis

Question 30

Is measles a notifiable disease?

Answer 30

Yes!

Question 31

How are individuals exposed to measles managed?

Answer 31

Accurate contact tracing, prioritising pregnant or immunosuppressed individuals.

MMR vaccination history and immunity checks.

Prophylaxis for non-immune individuals.

Immunocompetent but non-immune:
MMR vaccination within 72 hours

Immunosuppressed but likely to maintain previous immunity:
Sero-status check and IVIG if non-immune

Profound immunosuppression:
Arrange IVIG regardless, don’t await serology.

Question 32

Ribavirin

Answer 32

Small molecule with a broad spectrum of activity.

Guanosine analogue, interferes with production of mRNA.

Question 33

How can Ribavirin delivered?

Answer 33

SPAG delivery for RSV respiratory illness (tiny snow particles hitting the face).

Oral formulation: Was used in combination with anti-Hep C drugs prior to availability of the more efficacious Directly Acting Antivirals for Hepatitis C (DAAs)
Re-birth: has activity against hepatitis E infection, improving clearance in those with persisting infections.

IV: treatment of Lassa Fever.

Question 34

What are the groups of treatment for CoVID-19?

Answer 34

Anti-virals and immune modulators.

Question 35

Anti-virals for CoVID-19:

Answer 35

Nirmatrelvir/ritonavir
BD dosing for 5 days
Recent onset CoVID
At risk of complications
Caution as long list of potential drug-drug interactions.

Sotrovimab
Anti-spike monoclonal antibody
Single infusion 500mg, benefit lasts 4 weeks
12 yrs over/more than 40kg
Recent onset CoVID, not hospitalized or requiring supplementary O2
One risk factor(s) for poorer outcome

Remdesivir: Antiviral, infusion for 3 consecutive days. Use in first 10 days of illness, moderate or severe immunosuppression, at risk of worst outcomes.

Question 36

Immune modulators for CoVID-19:

Answer 36

Dexamethasone
Glucocorticoid. For patients with symptomatic CoVID-19 who are admitted and require supplementary oxygen.

Baricitinib
Selectively and reversibly inhibits the Janus-associated tyrosine kinases JAK1 and JAK2.
For patients with rapidly increasing conventional oxygen needs and systemic inflammation, NIV.

Tocilizumab
When heading towards mechanical ventilation. Blocks IL-6 which is a key cytokine in lung inflammation.

Question 37

Immunoglobulin Post Exposure Prophylaxis

Answer 37

HNIG:
Human Normal Immunoglobulin is used for the treatment of certain diseases that are caused due to lack of antibodies in your blood.

VZIG:
VZIG prophylaxis is recommended for individuals who fulfil all of the following three criteria:
- Significant exposure to chickenpox (varicella) or shingles (zoster) during the infectious period
- At increased risk of severe chickenpox i.e. neonates and pregnant women exposed in the first 20 weeks of
pregnancy, ie up to and including 20+0 weeks.
- No antibodies to varicella-zoster virus (VZV). Urgent VZV antibody testing can be performed within 24 hours

HBIG: Provides ABs to fight Hep B infection.