• Target part of the viral lifecycle:  Attachment and Entry
• Binds to the first heptad repeat in the gp41 subunit of the viral glycoprotein
• Prevents conformational changes required for viral and cellular membranes
• Injection site reactions
• Pneumonia
• Resistance:  substitutions in the aa's in the HIV gp41 envelope glycoprotein
• Indicated for the treatment of HIV-1 infection  -- treatment-experienced patients                  -- evidence of HIV-1 replication despite ongoing antiretroviral therapy

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• Target part of the viral lifecycle:  viral uncoating
• Prevents the release of infectious viral nucleic acid into the host cell
• Interferes with the influx of protons through a transmembrane domain of the viral M2 protein
• Reduces infection rates by 50% and illness rates by 60%
• CNS depression

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• Target part of viral lifecycle:  Genome Replication
• Guanosine analog (2 carbon atoms missing from ribose, no -OH for polymerase rxn)
• Selective phosphorylation
• Basis for selectivity of drug for virus infected cells
• 3000 fold greater concentration required to inhibit non-infected cell growth

Dosage Forms:

• Oral - prophylaxis and treatment primary and recurrent genital herpes; preventing reactivation in immunosupressed patients
• Ointment - symptomatic relief of recurrent herpes labialis
• IV - chronic and recurrent mucocutaneous HSV infections in immunocompromised patients

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Drug Resistance:

• Loss of viral thymidine kinase activity
• Elaboration of viral thymidine kinase with altered substrate specificity
• Expression of altered DNA polymerase activity
• REMEMBER: Resistance to acyclovir = resistance to valacyclovir***

Valacyclovir

Herpetic ginigvostomatitis, recurrent intraoral herpes simplex, herpes labialis, herpes zoster -- routinely treated with valacyclovir (=acyclovir + valine)

Bioavailability of Acyclovir: Poor 20% (Dose = 200 mg 5x/day)

Bioavailability of Valacyclovir:  Fair 54%

• Target part of viral lifecycle:  Genome Replication 
• Inhibits HSV polymerase competitively with deoxyguanosine triphospate
• Indicated for HSV-1 and HSV-1 (off-label: varicella zoster)

Dosage Form:

• Cream--apply every 2 hours while awake for 4 days.  Treatment should be started as early as possible (during the prodrome phase).

• Target part of viral lifecycle:  Genome Replication
• Same mechanism as acyclovir
• Same specificity for viral thymidine kinase
• Inhibits viral DNA polymerase
• More potent than acyclovir against HSV, CMV, and VZV
• Used for acyclovir resistant HSV infections (trying to save it for people with resistant HIV)

Adverse effects:

• aspermatogenesis
• carcinogenicity
• teratogenicity

Dosage Forms:

• Ganciclovir is always IV
• Valganciclovir come in an oral form

Acyclovir (or Valacyclovir) for HSV

Famciclovir for VZV

Ganciclovir (or Valganciclovir) for CMV

Zidovudine (AZT) for HIV

• Target part of viral lifecycle:  Genome Replication 
• Phosphorylated by cellular enzymes
• Incorporated in viral complementary DNA
• Terminates chain elongation
• HIV reverse transcriptase is 100 times more susceptible to inhibition than mammalian DNA polymerase
• Significantly reduces the incidence of neonatal infection

Post exposure prophylaxis:

• Controversial
• In a case controled study, the risk of infection in exposed health care workers decreased by 79%
• Guidelines:  4 week regimen of 2 drugs (maybe 3 now) that are nucleoside reverse transcriptase inhibitors

• Target part of viral lifecycle:  Genome Replication
• Non-nucleoside DNA polymerase inhibitor
• Indicated for HSV, CMV, and HIV
• Not a purine or pyrimidine analong
• Phosphonoformate analog
• Blocks the pyrophosphate binding site on viral DNA polymerase
• Treatment of acyclovir resistant HSV invections in AIDS patients
• CMV retinitis in immunocompromised patients
• Acyclovir resistant VZV
• HIV-1
• Toxic:  Renal impairment, CNS disturbance, leukopenia, liver dysfunction 

• Target part of viral lifecycle:  Genome Replication
• Non-nucleoside/nucleotide reverse transcriptase inhibitor
• Binds directly to reverse transcriptase and non-competitively inhibits DNA synthesis
• Metabolized by P450 3A
• Induces its own metabolism

• Target part of viral lifecycle:  Inhibition of Viral Maturation
• HIV Protease:  Cleavage of HIV polyproteins into enzymes and structural proteins required for the final assembly of new virons; has higher affinity for drug than the HIV polypeptides
• Saquinavir:  peptide-like substrate analogue; binds to the protease adctive site
• Inhibitor of and metabolized byr P450 3A

• Target part of viral lifecycle:  Inhibition of Viral Release
• Target: Neuraminidase (present on the surface of influenza virus particles; enables the virus to separate itself from cells

Uses:

• uncomplicated acute illness due to influenza A and B virus
• adults and pediatric patients 1 year of age and older
• symptomatic for no more than 2 days
• Prophylaxis
• Not Recommended in patients with underlying airway disease (asthma or COPD)

• For HIV
• "Drug Cocktails"
• triple drug combinations
• either a PI or and NnRtI with two NRTI anti-HIV drugs
• Lower doses, less toxicity
• Decrease emergence of resistance
• More efficacious:  greatly reduce disease progression and deaths in HIV + patients

Examples of Antivirals Approved in 2008

For the treatment experienced:  Aptivus, Selzentry

For the treatment naive: Reyataz, Prezista