treatment of viruses

Question 1

why are viral infections increasing

Answer 1

Zoonosis – close human contact
Travel
Animal farming – animals close to each other, all same species, not getting best care

Climate suitability for transmission of virus
Time and change in Ro – Ro is rising – global warming

Question 2

when do the following need rx:
* covid
* chickenpox
* herpes
* viral hep
* monkey pox

Answer 2

COVID -> respiratory failure
Chickenpox -> varicella pneumonitis
Herpes -> encephalitis
Viral hepatitis -> chronic hep c
Monkeypox -> eye lesions

Question 3

aim of rx of viruses

Answer 3

Reduce deaths (mortality)

Reduce illness severity / duration (morbidity)

Prevent occurrence in those at risk (Pre / post exposure prophylaxis)

Reduce transmission from people infected (treatment as prevention)

Question 4

target of action against viruses

Answer 4

host - supportive care
virus
* genetic material in capsid
* prevent replication and cell damage
* Target transcription and translation by introducing analogues – takes space so cant transcribe the protein to make the virus and propahrate disease
upreg immune system - imiquimod for HPV because not good immune system in the mucosal folds - imiquimod damages skin - > immune response
down reg immune system - steroids for covid

Question 5

targetting viruses

Answer 5

can target any part of replication cycle

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

Antiviral drugs that inhibit viral replication include the nucleoside and nucleotide analogues (which inhibit viral polymerase activity), protease inhibitors, integrase inhibitors etc…

Question 6

immune modulators that can boost antiviral immune response

Answer 6

Rx for HBV,
IVIG for viral pneumonitis,
imiquimod for HPV,
steroids for HSE (?)
IL-6 receptor antagonist for COVID

Question 7

what are the limits of antivirals

Answer 7

need host immune response because drugs suppress virus but dont clear them ->
* (in transplant pts should reduce immune suppression, and in HIV give ART)

adherence
resistance
toxicity
interactions

Question 8

what type of virus are the human herpes viruses

Answer 8

DNA

Question 9

summarise the herpes viruses

Answer 9

Question 10

difference between DNA and RNA viruses

Answer 10

RNA -> acute infection that body can clear away

DNA -> CMV VZV EBV HSV – cause asx infection – find places to hide in body, never get rid of them – immune system keeps them under control, but if get stressed get flare

Question 11

when do you treat HSV

Answer 11

HSV – Disease
* Encephalitis - inflammation of the parenchyma – seizure, confusion, reduced consciousness CN abnormality
* Mucocutaneous (some)
* Genital lesions (most)

HSV Suppression (some)

HSV Prophylaxis (transplant)

Question 12

when do you treat VZV

Answer 12

VZV Disease
* Encephalitis
* Chickenpox (some)
* Shingles (some)

adults
immunocompromised patients
neonates
immunocompetent children if:
* potential for complications (eg ophthalmic zoster, or underlying chronic cutaneous or pulmonary disorders)
* Secondary cases in household contacts since these cases are usually more severe than primary cases

VZV Post exposure prophylaxis

Question 13

treatment of HSV and VSV

Answer 13

Viral DNA synthesis inhibitors

Aciclovir (IV or oral)
* guanosine analogue,
* Gets activated by viral thymidine kinase
* Treatment for encephalitis

Valaciclovir
* oral only,
* more expensive,
* fewer doses/day,
* prodrug - metabolised to acyclovir
* Use diff mech of activation – doint use tyhymidine kinase

2nd line (ACV resistance) - effective but more toxic:
* Foscarnet (DNA polymerase inhibitor)
* Cidofovir (cytidine analogue)

Question 14

SE of acyclovir

Answer 14

neurotoxicity, nephrotoxicity (precipitation in tubules, reversible)

Question 15

mode of action of acyclovir

Answer 15

ACV becomes incorporated into the DNA, -> DNA chain elongation is blocked because acyclovir lacks the 3’ hydroxyl group (sometimes referred to as chain terminators).

Specific targeting of viral components (as opposed to human cellular components) allows a reduced level of cytotoxic effects.

ACV specifically targets virus in 2 ways:

1. It requires activation by the viral enzyme TK, so that active drug is found predominantly in cells infected with the virus
2. Also ACV has much higher affinity for viral DNA polymerase than it does for host enzyme

Question 16

treatment of HSV encephalitis

Answer 16

empiric treatment immediately
with iv ACV 10mg/kg tds

If confirmed, treat for 14 - 21 days

delay -> permanent neuro sequlae

Question 17

sx of encephalitis

Answer 17

fever
confusion
seizures
and/or altered consciousness

Question 18

treatment for opthalmic zoster

Answer 18

Oral antiviral therapy

unless evidence of complicated disease (eg, acute retinal necrosis, encephalitis)

Question 19

when do you treat CMV

Answer 19

congenital

prophylaxis

CMV disease, not CMV infection - pre-emptive in high risk (BMT - monitor viral load so when see load go up you can treat because know they will go onto get disease)

Question 20

summarise CMV infection

Answer 20

Primary infection
* Latency in blood monocytes and dendritic cells
* Reactivation (eg following immunosuppression)

Colitis
Pneumonitis
Hepatitis
Retinitis
Bone marrow suppression
Encephalitis/ventriculitis
Nephritis
Cystitis
Myocarditis

Asymptomatic shedding in saliva, urine, semen and cervical secretions
MAJOR pathogen in the immunocompromised (including solid organ and bone marrow transplant patients)

Question 21

mx of CMV in transplant patients

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
   * issue is breakthrough virus may be resistant

Question 22

Answer 22

Examples of CMV disease and the typical histopathological appearance of owl’s eye inclusion bodies.

Florid retinal haemorrhages and exudates