77. Antiviral drugs against herpes and hepatitis viruses

Antivirals against HSV, VZV and CMV

We can classify the antivirals against herpes viruses according to the mechanism of action:

• Guanosine analogues activated by thymidine kinase
  • Acyclovir
  • Valacyclovir – prodrug of acyclovir
  • Penciclovir
  • Famciclovir – prodrug of penciclovir
• Guanosine analogues activated by UL97 kinase
  • Ganciclovir
  • Valganciclovir – prodrug of ganciclovir
• Direct viral DNA/RNA polymerase inhibitor
  • Foscarnet
• Cytidine analogues
  • Cidofovir

Indications

Acyclovir, penciclovir and their prodrugs are only active against active infections with active, replicated viruses. They’re not effective against latent infections. They’re used to treat HSV, VSV and EBV. They’re used topically to treat labial herpes.

Ganciclovir and its prodrug valganciclovir are used to treat or as prophylaxis for CMV infections in AIDS patients and organ transplant patients.

Foscarnet is used to treat ganciclovir-resistant CMV infections and acyclovir-resistant herpes infections.

Cidofovir is used to treat CMV retinitis and acyclovir- resistant herpes infections.

Mechanism of action

Acyclovir and penciclovir are guanosine analogues. They are originally inactive but are activated intracellularly by virally encoded thymidine kinase into an active, monophosphorylated form. The active form will competitively inhibit DNA polymerase and cause chain termination. Because these drugs must be activated by virally encoded proteins, they’re specific for cells which are infected by the virus.

Ganciclovir is also a guanosine analogue. It is also activated intracellularly but by another kinase called UL97 kinase. The active form will then competitively inhibit DNA polymerase and cause chain termination. Ganciclovir is less specific for infected cells than the aforementioned drugs.

Foscarnet is a pyrophosphate analogue. It directly inhibits viral DNA polymerase by binding to the pyrophosphate binding site of DNA polymerase. No enzymatic activation is required.

Cidofovir is a cytidine analogue. Like the other analogue antivirals, it is activated intracellularly into an active form which competitively inhibits DNA polymerase.

Mechanism of resistance

Acyclovir and penciclovir depend on viral thymidine kinase for activation. Ganciclovir depends on viral UL97 kinase for activation. Mutation in these proteins can cause resistance.

Foscarnet and cidofovir act directly on viral DNA polymerase. Mutations in viral DNA polymerase can cause resistance.

Pharmacokinetics and dosing

Acyclovir has poor oral bioavailability, only 20%. Valacyclovir, the ester prodrug of acyclovir, has around 60%. Their serum half-life is only 3 hours, but the intracellular half-life (which is the most important) is even shorter. Both can be given IV, PO or topically. Because of the poor oral bioavailability acyclovir must be given in large doses, and because of the low half-life it must be given often. The oral dosing for acyclovir is 800 mg 5 times daily. For valacyclovir the dosing is 1000 mg 3 times daily.

Penciclovir is not absorbed orally and can only be used topically. Its ester prodrug famciclovir is orally absorbed.

Ganciclovir is not absorbed orally and can only be used topically. Its ester prodrug valganciclovir is orally absorbed. For retinitis these drugs can be given intravitreally.

Foscarnet and cidofovir are not absorbed orally and must be given IV. An active metabolite of cidofovir has very long half-lives, allowing cidofovir to be dosed only every two weeks.

The ester prodrugs are hydrolysed into their active form in the liver. The elimination of all mentioned antivirals is renal. Co-administration of probenecid, a uricosuric drug, delays the renal elimination of cidofovir.

Adverse effects

• Acyclovir, valacyclovir, penciclovir, famciclovir
  • Acute kidney injury – only for acyclovir
    • Due to acyclovir crystallizing in the kidney
    • Adequate hydration is important to prevent
  • Generally well tolerated drugs, few adverse effects
• Ganciclovir, valganciclovir
  • Side effects severe and common!
  • Pancytopaenia
    • Especially when given with NRTIs like zidovudine
  • CNS toxicity
• Foscarnet
  • Side effects severe and common!
  • Nephrotoxic
  • GI toxicity
  • CNS toxicity
  • Anaemia
• Cidofovir
  • Nephrotoxicity
    • Reduced by co-administration of probenecid and fluids

Antivirals against hepatitis B

• Antivirals against HBV and HCV
  • Interferon-alpha
  • Pegylated interferon-alpha
• Antivirals against HBV
  • Tenofovir
  • Entecavir
  • Lamivudine
  • Telbivudine
  • Adefovir

Indications

Acute hepatitis B doesn’t require antiviral treatment. Antiviral treatment should be initiated in people with chronic active hepatitis B with evidence of liver inflammation. Entecavir and tenofovir are the first-line choices in most cases.

Interferon alpha is used primarily to treat young patients who don’t want the life-long treatment of the other antivirals. However, it has more adverse effects.

Lamivudine is cheaper and safer than entecavir and tenofovir, but HBV rapidly develops resistance to it and so it’s not preferred anymore. Telbivudine also has a higher risk of drug resistance and adverse effects than the first-line drugs. Adefovir is less potent than the first-line drugs and has higher risk of drug resistance.

Mechanism of action

Interferon-α (IFN-α) has a complex mechanism of action. It inhibits viral protein synthesis, promotes the breakdown of viral RNA and induces the expression of MHC I molecules on infected cells, plus more. The pegylated form has longer half-life and is preferred over regular IFN-α in all cases.

Tenofovir and adefovir are nucleotide analogues. They are activated in hepatocytes where they bind to viral DNA polymerase and interfere with DNA transcription.

Entecavir, lamivudine and telbivudine are nucleoside analogues. They inhibit the enzyme reverse transcriptase.

Adverse effects

Interferon alpha causes flu-like symptoms in 90% of patients. It can also suppress the bone marrow and the CNS and induce the production of antibodies. These antibodies can give the patient an autoimmune disease or worsen an already present one.

Adefovir causes GI symptoms and dose-dependent nephrotoxicity. It can also cause exacerbation of hepatitis during treatment and after discontinuation. These symptoms are much rarer with tenofovir.

Lamivudine and entecavir rarely cause side effects. Telbivudine has a high risk for myopathy and peripheral neuropathy.

Antivirals against hepatitis C

• Antivirals against HBV and HCV
  • Interferon-alpha
  • Pegylated interferon-alpha
• Antivirals against HCV
  • Ribavirin
  • Direct-acting antivirals
    • Protease inhibitors
      • Simeprevir
      • Grazoprevir
    • NS5B RNA polymerase inhibitors
      • Sofosbuvir
      • Dasabuvir
    • NS5A replication complex inhibitors
      • Velpatasvir
      • Ledipasvir

Indications

Not long ago, curing hepatitis C was very difficult and time-consuming, and the involved drugs had serious side effects. Nowadays curing hep C is much simpler thanks to the introduction of newer antivirals.

For acute hepatitis C peg-interferon-α for 6 months cures the condition in 95% of cases.

For chronic hepatitis C the exact drug of choice depends on the genotype of the HCV which caused the infection. The best regimens are ribavirin-free and interferon-free and consist of 12 weeks of two direct-acting antivirals, one NS5B inhibitor and one NS5A inhibitor. The most common regimens are ledipasvir + sofosbuvir or velpatasvir + sofosbuvir.

Mechanism of action

Ribavirin is a guanosine analogue. It competitively inhibits IMP dehydrogenase, thereby preventing synthesis of guanine nucleoside.

Simeprevir and grazoprevir are protease inhibitors. They inhibit a protease called NS3/4A which is required for viral replication.

Sofosbuvir and dasabuvir are NS5B protein inhibitors. NS5B is an RNA polymerase, which is required for viral replication.

Velpatasvir and ledipasvir are NS5A protein inhibitors. The NS5A protein is important in viral replication, but the exact mechanism is not known.

Adverse effects

Ribavirin causes haemolytic anaemia in up to 30% of patients. Other symptoms include nausea and cough. Because of ribavirin’s adverse effects it’s no longer a first-line drug in the treatment of chronic HCV.

The direct acting antivirals most commonly cause benign side effects like fatigue and GI symptoms.