Antiviral Drugs and Influenza

Antiviral Drugs

• Antibacterial and antifungal drugs have little to no effect on viral infections.
• Compounds have been developed to treat some viral infections, such as HIV, influenza, and hepatitis.
• Antiviral drugs work in various ways, including:
  • Preventing replication of viral nucleic acid.
  • Inhibiting entry, uncoating, or release of the virus.

Influenza Drugs

• Influenza is one of the most common causes of infectious disease-related deaths.
• Vaccines are the primary means of prevention.
• Neuraminidase inhibitors are useful for prophylaxis during outbreaks and can:
  • Shorten the duration of illness in infected persons.
  • Prevent complications.

Neuraminidase Inhibitors

• These drugs inhibit the enzyme neuraminidase in influenza A and B viruses.
• Neuraminidase catalyzes reactions that promote viral spreading and infection, including:
  • Enabling the release of virions from the surface of infected cells.
  • Inactivating respiratory tract mucous that would prevent the spreading of virions.
• Neuraminidase inhibitors:
  • Reduce complications, including otitis media (OM) and pneumonia (PNA).
  • Are most beneficial in reducing symptom severity and duration of illness if given within 3 days of onset, preferably within 48 hours.
  • May still provide benefit in reducing respiratory failure and death in pregnant women if started 3-4 days after onset.

Baloxavir Marboxil (Xofluza)

• Single-dose oral treatment for influenza A and B.
• First-in-class medication.
• Unique mechanism of action (MOA): prodrug gets converted to baloxavir acid (BXA), which targets ribonuclease activity affecting transcription of viral RNA.
• Approved in the US in 2018.
• Potentially has fewer side effects compared to oseltamivir.

Herpesvirus Infections

• Cytomegalovirus (CMV) infections in immunocompetent individuals are usually asymptomatic.
• CMV retinitis, esophagitis, and colitis are usually seen in immunocompromised patients.

Drugs for Herpesviruses

• Nucleoside analogues:
  • Acyclovir (Zovirax):
    • IV acyclovir is most effective for serious herpesvirus infections, including encephalitis and infections in immunocompromised patients.
    • Topical acyclovir can be used to treat genital herpes and mild mucocutaneous infections.
  • Valacyclovir (Valtrex):
    • Prodrug that gets rapidly converted to acyclovir by intestinal and hepatic enzymes.
    • More completely absorbed (55%) compared to acyclovir.
  • Famciclovir (Famvir):
    • Greatest bioavailability (80%).
    • Gets rapidly hydrolyzed to penciclovir after absorption.
• Other drugs:
  • Foscarney (Foscavir).
• Treating genital herpes:
  • When given orally, prevents replication of HSV and reduces pain and other symptoms of acute infection.
  • Shortens time to healing of lesions and reduces viral shedding.
  • Does not eliminate the virus; recurrent episodes are common (can be treated with lesser doses).
• Treating shingles:
  • When given orally, shortens duration of acute illness and pain and lowers incidence of postherpetic pain.
  • Famciclovir and valacyclovir are more effective than acyclovir.

Integrase Strand Transfer Inhibitors

• Reverse transcriptase inhibitors:
  • Nucleoside reverse transcriptase inhibitors (NRTIs).
  • Non-nucleoside reverse transcriptase inhibitors (NNRTIs).
• Nucleoside reverse transcriptase inhibitors (NRTIs):
  • First class of drugs developed for treating HIV+ individuals.
  • Included in almost all regimens.
  • Serve as antimetabolites for different purine and pyrimidine bases of DNA.
  • More effective when combined with other NRTIs.
  • Examples:
    • Zidovudine (AZT, ZDV) aka Retrovir.
    • Lamivudine (3TC) aka Epivir.
    • Emtricitabine (FTC) aka Emtriva.
    • Tenofovir disoproxil (TDF) aka Viread.

AZT/ZDV

• First NRTI to be developed, still one of the most widely used drugs in this class.
• Always combined with other drugs.
• In utero transmission:
  • AZT treatment significantly reduces in utero transmission of HIV from infected pregnant women to their offspring.

Initial Treatment of HIV

• Newer NRTIs are now recommended for initial treatment of HIV:
  • Tenofovir disoproxil fumarate (TDF).
  • Emtricitabine (FTC).
• Combo drug containing TDF, FTC, and efavirenz called Atripla is now available, once a day therapy with a single pill.

Non-Nucleoside RTIs (NNRTIs)

• Efavirenz is the most potent NNRTI available, preferred for initial treatment of people with HIV because it can be taken once daily.
• Nevirapine is used in combo with two NRTIs.
• Delaviridine is not recommended for most patients, has lower antiviral activity compared to others in this class.

Protease Inhibitors (PIs)

• HIV protease is responsible for maturation of the virus.
• Protease inhibitors bind to the active site of the enzyme and inhibit its activity, resulting in production of immature, non-infectious virus particles.
• First PI introduced in 1995, ushered in a new era of HIV treatment.
• Newer PIs like atazanavir are better tolerated and have improved pharmacokinetic properties.
• Atazanavir and darunavir are the preferred PIs for treating HIV today.

Fusion and Entry Inhibitors

• Enfuvirtide (Fuzeon, T-20):
  • Large peptide that binds to HIV glycoprotein 41 and blocks fusion process.
  • Not active when given orally, must be injected subcutaneously (sc) twice daily.
  • Often causes injection site reactions (ISRs), so change the injection site.
• Maraviroc (Selzentry):
  • Newer drugs that inhibit fusion and entry of HIV.
  • Active against HIV strains resistant to RTIs and PIs.
  • Approved to treat HIV infection caused by drug-resistant strains.

Integrase Inhibitors

• Integrase incorporates viral DNA formed by reverse transcriptase into DNA of CD4 cells.
• Raltegravir (Isentress) is the first integrase strand inhibitor approved to treat HIV.
• Works by preventing DNA strand transfer.
• Potent in vitro activity against wild-type and MDR HIV strains.
• Recent recommendations for initial treatment include a regimen containing raltegravir.