Antiviral Drugs Quiz

Antiviral Drugs

• Antibacterial and antifungal drugs have little to no effect on viral infections
• Compounds have been developed to treat some viral infections (e.g., HIV, influenza, and hepatitis)
• Antiviral drugs work in a variety of ways (e.g., prevent replication of viral nucleic acid; inhibit entry, uncoating, or release of virus)

Influenza

• 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, can shorten duration of illness in infected persons and prevent complications

Neuraminidase Inhibitors

• Reduce complications including otitis media (OM) and pneumonia (PNA)
• Drug therapy should be started as early as possible for any patient with confirmed or suspected influenza who is hospitalized, has severe illness, or is at higher risk of complications
• Most beneficial in reducing symptom severity and duration of illness if given < 3 days after 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

Prophylaxis

• 70-90% effective in preventing influenza, useful adjuncts to vaccines
• CDC recommended against prophylaxis because of risk of resistance
• Only prophylaxis, populations at risk of complications and control institutional outbreaks

Baloxavir Marboxil (Xofluza)

• Single dose PO treatment for influenza A and B
• First-in-class medication
• Unique mechanism of action (MOA) targets ribonuclease activity that affects transcription of viral RNA
• Approved in the US in 2018
• Potentially less side effects vs oseltamivir

Herpesviruses

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

Drugs for Herpesviruses

• Nucleoside analogues:
  • Acyclovir (Zovirax): IV acyclovir 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
  • Ganciclovir (Cytovene)
  • Trifluridine (Viroptic)
  • Valacyclovir (Valtrex): prodrug that gets rapidly converted to acyclovir by intestinal and hepatic enzymes, more completely absorbed (55%)
  • Famciclovir (Famvir): has the greatest bioavailability (80%)
• Other drugs:
  • Foscarnet (Foscavir)

Treating Genital Herpes

• When given orally for genital herpes, prevents replication of HSV and reduces pain and other symptoms of acute infection
• Shortens time to healing of lesions, reduces the amount of viral shedding
• Does not eliminate the virus, recurrent episodes are common (can be treated with lesser doses)

Treating Shingles

• When given orally for shingles, shortens duration of acute illness and pain and lowers incidence of postherpetic pain
• Famciclovir and valacyclovir are more effective than acyclovir
• Newer drugs have less frequent administration, higher serum levels
• A vaccine is now available (Zostavaz) that reduces the incidence and severity of herpes zoster infections in older adults

Human Immunodeficiency Virus (HIV)

• Many remarkable advancements have been made in treating HIV infection and AIDS
• Combined use of 2 or more drugs from different classes have been shown to markedly reduce viral load and improve survival
• Multidrug treatment called highly active antiretroviral therapy (HAART)

HAART

• Initially were complicated regimens requiring multiple doses of several drugs every day
• Recent emphasis on developing drug regimens that require only a few doses each day or even a single pill (like Atripla)
• Guidelines continue to evolve as new regimens are developed and testing

Pathophysiology of HIV

• Enters CD4 cells, viral RNA produced double-stranded DNA via reverse transcriptase
• Viral DNA enters host cell nucleus and gets incorporated into host genome via HIV integrase
• Eventually, the viral DNA gets transcribed/translated to produce polyproteins that get packed into immature virions
• HIV protease cleaves polyproteins into smaller functional proteins during viral maturation where virions get released into plasma

Drug Classes

• 1. Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
• 2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
• 3. Protease inhibitors (PIs)
• 4. Fusion and entry inhibitors
• 5. Integrase inhibitors

Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• Do not require metabolic activation and are not incorporated into viral DNA
• Efavirenz is the most potent NNRTI available, preferred for initial treatment of people with HIV because it can be taken qd
• Nevirapine is used in combo with two NRTIs
• Delaviridine, 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 sq bid
• 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