C.5

Question 1

Agents to treat Herpes simplex (HSV), Varicalla-zoster virus (VZV), cytomegalovirus (CMV). Anti-influenza agents, Drugs against Corona- and other viruses

Answer 1

1. HSV1/2, VZV: (val)acyclovir
2. CMV, EBV, HHV6/8: (val)gancyclovir, Foscarnet, Letermovir
3. Influenza: Oseltamivir
4. RSV: Ribavirin, Palivizumab
5. COVID: Remdesivir, Molnupiravir, Nirmatrelvir

Question 2

(val)acyclovir

Answer 2

MOA: Guanosine analogs, Acyclovir is converted to its triphosphate form (ACV-TP)→ inhibits viral DNA-polymerase.
Valcyclovir is valyl-ester prodrug;
IND: HSV and VZV infections. herpes encephalitis, neonatal herpes (i.v). genital herpes, disseminated and ophthalmic VZV, prophylaxis during immunosuppression (valacyclovir);
ROA: I.V, p.o, topical;
Kinetics: Valacyclovir has better BA p.o and better penetration, penetration to scrotum and CNS, eliminated via renal filtration, T1/2: 2.5-3h;
SEs: well-tolerated, hydration is important to prevent crystalluria, non-teratogenic-recommended to prevent vertical transmission;
Resistance: viral TK or DNA-polymerase mutations, 3.5-10% in immunocompromised patients, up to 25% in BM transplanted

Question 3

(val)gancyclovir

Answer 3

MOA: deoxy-guanosine analogs, mechanism similar to acyclovir;
IND: broad spectrum, 1st line against CMV, EBV, HHV6, HHV8, CMV retinitis, CMV pneumonia, oesophagitis, colitis in immunocompromised;
SEs: more toxic than acyclovir, neutropenia, teratogenic;
Kinetics: given mainly I.V, Gancyclovir- poorly absorbed from GI, valgancyclovir well absorbed from GI, good penetration in tissues and CNS, Renal elimination

Question 4

Foscarnet

Answer 4

MOA: Pyrophosphate analog, non-competitive inhibitor of DNA-polymerases;
IND: CMV retinitis (for GCV resistants), in AIDS. Mucocutaneous Acyclovir resistant HSV infections, 2nd line. Active but not indicated against HSVs, less effective against HBV, HIV;
Kinetics: i.v for 2-3w, then maintenance, CNS penetration, accumulates in bone, excreted in urine;
SEs: nephrotoxicity, bone alterations, decreased hemoglobin level;
Extra: synergistic with gancyclovir

Question 5

Letermovir

Answer 5

MOA: Inhibits CMV terminase complex (cleavage of DNA after replication);
IND: prophylaxis in BM transplantees, CMV specific;
SEs: well-tolerated, only headache, malaise, and mild cardiovascular SEs;
ROA: p.o and i.v;
Extra: No cross-resistance

Question 6

Oseltamivir

Answer 6

MOA: Neuraminidase inhibitor- prevents the release of virion from the cell;
IND: influenza A and B; Kinetics: prodrug, given p.o, most effective in the first few days of the infection;
SEs: GI disturbances (diarrhea, vomiting, dyspepsia); Extra: uncommon cross-resistance

Question 7

Ribavirin

Answer 7

MOA: guanosine analog, RNA -polymerase inhibitor;
IND: Broad spectrum, HCV, RSV, Lassa, Hanta, Crimean-Kongo fever;
Kinetics: administered p.o or i.v;. HCV- 12-48 weeks p.o as adjunct therapy in patients with decompensated cirrhosis and in genotype 4;
SEs: malaise, insomnia, coughing, itching, hemolytic anemia, BM suppression, possibly teratogenic and carcinogenic;
Contra-IND: pregnancy (can lead to birth defects)

Question 8

Palivizumab

Answer 8

MOA: monoclonal Ab against RSV;
ROA: i.m, monthly;
IND: for immunocompromised children in the RSV season, for prevention

Question 9

Remdesivir

Answer 9

MOA: RNA-dependant RNA polymerase inhibitor nucleotide;
IND: developed against Ebola, as orphan drug in the EU, then HepC. used for hospitalized medium-severity patients, where no cytokine storm has developed, can be given with Dexamethasone for patients requiring at least high-flow oxygen delivery ;
ROA: i.v

Question 10

Molnupiravir

Answer 10

MOA: RNA-dependant RNA polymerase inhibitor, nucleoside analog;
ROA: p.o;
IND: for not yet hospitalized low-to-medium severity patients with high risk progression

Question 11

Nirmatrelvir

Answer 11

MOA: 3C-like protease inhibitor;
ROA: p.o with ritonavir booster;
IND: for adults and pediatric patients with severe ARDS and high risk for progression

Question 12

Resistance to antiviral agents

Answer 12

1. Mutations are frequent
2. “Viral fitness”
3. “Antiviral potency”
4. “Genetic barrier”

Question 13

2. “Viral fitness”

Answer 13

• Most mutant viruses can replicate slower than wild-type
• The agent can select the mutant
• Another mutation can restore the fitness

Question 14

3. “Antiviral potency”

Answer 14

• Low potency agent: minimal pressure, no resistance
• High potency agent: blocks multiplication, no mutations, resistance
• Modest potency: problematic

Question 15

4. “Genetic barrier”

Answer 15

• How many mutations needed for resistance

Question 16

Targets of anti-viral agents

Answer 16

1. Entry inhibitors
2. Uncoating inhibitor
3. DNA/RNA synthesis inhibition
4. Other viral enzyme inhibitors
5. Immunological agents