*Antiviral Chemotherapy 3

Question 1

NNIs (HCV)

Answer 1

Different classes of the HCV polymerase are under investigation
Large molecules- do not fit rule of 5

Question 2

NS5A inhibitors

Answer 2

Multi-functional homodimeric protein essential for HCV replication
Modulates NS5B polymerase activity, regulates HCV replication, assembly and release, interferes with the host immune response mechanisms (viral escape)
Due to its multiple essential roles for HCV life cycle, several inhibitors of this protein have been developed and have been approved

Question 3

Influenza

Answer 3

Hemagglutinin and neuraminidase proteins are important for mechanism of action and developing the vaccine
Could have one protein from human virus and one protein from animal virus

Question 4

Favipiravir

Answer 4

Approved in 2014 in Japan for influenza pandemics
Orally administered pro-drug, active form believed to act as polymerase inhibitor
Active against several RNA viruses, including yellow fever, Chikungunya, Zika and Ebola

Question 5

Amantadine

Answer 5

Early antiviral (no longer recommended), approved both vs influenza A and as anti-Parkinson's
Very narrow spectrum of activity as antiviral: influenza A and C and some herpes zoster activity. No flu type B activity. 
Works best if taken early in infection, or before infection (prophylaxis), not very potent
Acts early in the viral replication, by inhibiting the viral particles uncoating, possibly blocking the virus M2 protein (ion channel)

Question 6

Amantadine modification

Answer 6

Little structural modification is permitted in amantadine, few alternative structures are active
Amine substitution by other groups, or substitution within the carbocycle, reduces or removes antiviral activity

Question 7

Herpes viruses

Answer 7

There are ca. 30 different forms of herpes virus, but only 6 are of significance to man. Their infections can range in severity from minor aliments to death
VZV: chicken pox, shingles
CMV: infectious mononucleosis, congenital infection
EBV: infectious mononucleosis
HSV: cold sores, genital herpes
Herpes B virus: ascending myelitis

Question 8

Herpes viral particles

Answer 8

Despite the wide range of clinical presentations, the causative herpes viral particles are all very similar in nature
There is a core of double stranded DNA. Surrounding this is a rigid protein coat, composed of about 160 identical capsomers (proteins)
And outside this is the fluid lipoprotein envelope, which is about 150nm in diameter
Different antivirals are approved to treat herpes viruses infections: most are nucleoside inhibitors of the viral polymerase

Question 9

Herpes simplex treatment

Answer 9

Mild HSV1 (mouth, lips and eyes) and HSV2 (genitals): topical antiviral
Severe infection, neonatal or immunocompromised patients: systemic antiviral

Question 10

Varicella zoster

Answer 10

Chicken pox in neonates, immunocompromised: parenteral antiviral
Chicken pox in children 1 month-12 years: no antiviral usually required
Chicken pox in adolescents/adults: systemic/parenteral antiviral
Shingles: systemic/parenteral antiviral to reduce pain and complications
Vaccine available (not part of routine childhood vaccination schedule)

Question 11

Cytomegalovirus (HCMV)

Answer 11

Can be life threatening in immunocompromised patients: parenteral antiviral
Ganciclovir: more potent than acyclovir but more toxic, prevention of CMV during immunosuppressive therapy, treatment of HCMV in immunocompromised only
Valganciclovir: only for cytomegalovirus retinitis in patients with AIDs, prevention of CMV disease following organ transplant from CMV positive patient
Valaciclovir: prevention of CMV after organ transplant when others cannot be used

Question 12

Herpes viruses- additional treatments

Answer 12

Inosine acedoben dimepranol: for mucocutaneous HSV only, indirect antiviral action- immunostimulant
Foscarnet: early antiviral, low potency, acts as DNA polymerase inhibitor, mucocutaneous HSV, cytomegalovirus treatment

Question 13

Influenza virus treatment

Answer 13

Vaccination remains the preferred strategy
For management of pandemics, treatment and post exposure prophylaxis: neuraminidase inhibitors, systemic
Oseltamivir: prevention and treatment of flu, effective against A and B, oral administration
Zanamivir: post exposure prophylaxis, prevention during epidemics, treatment of flu A and B, inhalation of powder
Use of amantadine for prophylaxis and treatment no longer recommended

Question 14

Chronic hepatitis C

Answer 14

Previous therapy: pegylated interferon-a and ribavirin
Non specific for HCV, only effective on 30-50% of patients with the most common HCV genotyoe
IFNs do not act directly on the virus, the virus can quickly replicate to overcome ribavirin
IFN is administered as subcutaneous injection, not preferred by patients
Several side effects

Question 15

Ribavirin

Answer 15

Synthesized in 1972
Broad spectrum of antiviral activity (active against RNA and DNA virsues)
Used for the first time in the mid 80s to treat respiratory syncytial virus in children
Used as monotherapy at the beginning of hepatitis C treatment
Acts through different mechanisms
Direct: direct inhibition of the viral replication (multiple viral targets)
Indirect: immunomodulation, mutagenesis and error catastrophe

Question 16

Chronic hepatitis C- combination treatments

Answer 16

HCV treatment has been revolutionised with the introduction of direct acting antivirals
Using these agents in combination therapies, the viral infection can now be cured in most patients
To overcome resistance and eradicate the virus, multiple direct acting antivirals acting on different targets are co-administered. With or without ribavirin, all-oral regimen, genotypes 1 and 4

Question 17

Chronic hepatitis B

Answer 17

Vaccination is the main strategy
A definitive cure for the infection is not available
Infection becomes a chronic condition: can be controlled with antivirals

Question 18

Chronic hepatitis B treatment options

Answer 18

Peginterferon alfa: monotherapy, subcutaneous injection three times a week, limited response, frequent relapse
Entecavir: polymerase inhibitor, oral monotherapy
Telbivudine: polymerase inhibitor (l-nuc), oral monotherapy
Adefovir: reverse transcriptase inhibitor, oral monotherapy
Lamivudine: reverse transcriptase inhibitor, oral monotherapy
Tenofovir: reverse transcriptase inhibitor, oral monotherapy

Question 19

HIV treatment

Answer 19

Not possible to eradicate the virus from the host cells (integrated in the host genome): definitive cure not available
The virus replication can be controlled: HIV has become a chronic condition
HAART includes a combination of RT and or protease inhibitors, aims to reduce the insurgence of resistance and to reduce toxicity
Combination has caused viral levels to drop so much they cannot be detected

Question 20

HAART

Answer 20

Highly Active AntiRetrovial Therapy
Decreases HIV total levels, maintains the functions of the immune system, prevents opportunistic infections that used to lead to death, progression of the infection to AIDs has become increasingly rare
Most common combinations: three drugs from at least two drug classes: 2 NRTIs and 1 PI/NNRTI/INSTI
Often combined together into one single pill (fixed dose combinations)
PrEP: Pre-exposure prophylaxis to reduce the risk of sexually acquired HIV1