Antiviral Drugs

Antiherpes Drugs

Antiretroviral Drugs

Nucleoside Reverse Transcriptase Inhibitors:

Class-Specific Properties

Non-Nucleoside Reverse Transcriptase Inhibitors

Class-Specific Properties

 

Antiretroviral Drugs:Protease Inhibitors

Class-Specific Properties

Other Antiviral Drugs

Introduction to Retroviral Biology

 

 

Acyclovir (Zovirax): Mechanism of Action
  • Acyclic guanosine derivative: clinical activity --herpes simplex virus -1,-2, Varicella-zoster virus.
  • In vitro activity against Epstein-Barr virus, cytomegalovirus, human herpes virus-6
  • requires three phosphorylation steps:
    • first to the monophosphate (requires viral kinase); Viral kinase requirement provides selectivity for infected cells.
    • selected activation results in triphosphate accumulation only in infected cells.
    • Acyclovir triphosphate accumulates in infected cells and inhibits viral DNA synthesis by: competitive inhibition of dGTP for the viral DNA polymerase and by binding to the DNA template and resulting in chain termination after incorporation into viral DNA

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Acyclovir Resistance
  • in HSV (Human Simplex Virus) or VZV (Varicella-zoster virus):
    •  alteration in viral thymidine kinase or viral DNA polymerase
    •  deficiency in thymidine kinase activity (cross resistance with valacyclovir (Valtrex), famciclovir (Famvir), penciclovir (Denavir) and ganciclovir)
  • Resistant HSV isolates in HIV-positive individuals associated with:
    •  progressive mucosal disease
    •  visceral involvement (earlier)
  • Resistant the us the strains in HIV-positive individuals associated with:
    •  chronic cutaneous lesions
    •  invasive disease (rarely)
  • Infections with acyclovir (Zovirax)-& penciclovir (Denavir)-resistant HSV or VZV: may respond to foscarnet (Foscavir).
  • other antiviral agents that do not depend on viral kinases and which would not the exhibit cross resistance: foscarnet (Foscavir), cidofovir (Vistide), or trifluridine (Viroptic).
  • Acyclovir: oral, IV, topical; cleared primarily by glomerular filtration and tubular secretion. Half life varies enormously dependent on renal function. Drug tissue levels are from 50 percent to 100 percent of serum levels

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Clinical Uses and Consideration
  • Overview:
    •  IV acyclovir (Zovirax): drug of choice for serious infections due to herpes simplex virus (HSV) or Varicella zoster virus (VZV)
    •  Oral use:-effective in managing primary HSV infections; less effective in managing recurrence
    •  Long-term oral acyclovir (Zovirax) -- chronic suppression and, reducing symptomatic recurrence of genital herpes and asymptomatic HSV shedding.
    •  Oral acyclovir (Zovirax) (initiated within one day after rash onset): reduces severity of Varicella; may be used to treat localized, ophthalmic or disseminated zoster.
  • Most widespread use: treatment of primary infection and recurrence of genital and labial herpes; shortens symptom duration; viral shedding time; time to lesion resolution.
  • failure of treatment to reduce the frequency of recurrences suggests that acyclovir does not eliminate latent infection.
  • IV acyclovir: treatment of choice for herpes simplex encephalitis and neonatal HSV infection
  • VZV -- less susceptible to acyclovir therapy then HSV
  • IV acyclovir in immunocompromised patients reduces likelihood of cutaneous and visceral dissemination.
  •  Adverse Reactions: generally few side effects, and occasional nausea, diarrhea, headache; no evidence of terratogenicity; most frequently encountered toxicity -- renal dysfunction; occasional CNS affects (tremors, lethargy).
    • IV administration:
      •  phlebitis/inflammation at infusion site (or site of extravasation)
      •  reversible kidney dysfunction due to crystalline nephropathy{risk increased by: rapid infusion, dehydration, high dosage, renal insufficiency}
      •  associated with encephalopathy {including tremors, hallucinations, seizure, coma}

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Valacyclovir
  • rapidly converted to acyclovir after oral administration
    • achieves 3 to 5 times higher serum levels then with acyclovir (similar serum levels to IV acyclovir administration).
  • Mechanism of action, resistance profile, and pharmacokinetics: identical to that seen with acyclovir (Zovirax).
  • Used in treatment of patients with recurrent genital herpes or herpes zoster. May be administered with less frequency then acyclovir, a possible benefit.
  • Generally well tolerated; low incidence of nausea diarrhea and headache.
  •  HIV patients receiving high-dosage valacyclovir (eight grams per day):
    • GI disturbances
    • FATAL thrombotic microangiopathies (thrombocytopenic purpura and hemolytic uremic syndrome).
    • accordingly should not be given to immunocompromised patients.*
*Fauci, A.S. and Lane, H.C., Human Immunodeficiency Virus (HIV) Disease: AIDS and Related Disorders:. In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 1836.

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Famcyclovir
  • rapidly converted to penciclovir following oral administration and first-pass effect.
  •  Penciclovir (Denavir), the active form of the drug, is similar to acyclovir (Zovirax).
  • Antiviral activity against HSV-1,HSV-2,VZV, EBV, and hepatitis B.
  • Drug activation requires a viral thymidine kinase.
  • Inhibition of DNA synthesis results from competitive inhibition of viral DNA polymerase.
  • Penciclovir triphosphate, the active drug form, achieves a higher intracellular concentration than acyclovir triphosphate. Cross resistance seen between famciclovir (Famvir) and acyclovir (Zovirax)
  • Oral administration only. Clearance is by renal mechanisms.
  • Clinical use: recurrent genital herpes, herpes zoster infection
  • adverse reactions: infrequent headache diarrhea and nausea.

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Ganciclovir (DHPG, Cytovene)
  • Requires tri-phosphorylation for activation
    • competitively inhibits viral DNA polymerase
    • in CMV-infected cells: first phosphorylation step catalyzed by viral specific protein kinase
    • in HSV-infected cells: first phosphorylation step catalyzed by thymidine kinase
  • Ganciclovir (DHPG, Cytovene) has activity against: HSV, VZV, CMV, and EBV
  • Activity against CMV much greater than that of acyclovir
  • Ganciclovir (DHPG, Cytovene) resistance due to either DNA polymerase mutations or protein kinase mutation
  • IV and oral route of administration
  • renal clearance varies in a manner proportional to creatinine clearance

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Ganciclovir: (DHPG, Cytovene):Clinical Use
  • IV ganciclovir indicated for CMV retinitis in HIV patients.
    • Intraocular implant releasing ganciclovir (Vitrasert) appears more effective then I'd be ganciclovir (DHPG, Cytovene) for the eye with the implant (not effective in the other eye or systemically)
      •  In AIDS patients not taking a protease inhibitor, using the implant plus high-dose oral drug decreases the risk of contralateral retinitis and extraocular CMV disease
  • Oral or IV ganciclovir (DHPG, Cytovene) followed by high-dose acyclovir (Zovirax) (oral) reduces CMV disease risk in patients who have orthotopic liver transplantation
    •  Oral ganciclovir (DHPG, Cytovene) (three months) is better then oral acyclovir (Zovirax) for CMV infection/disease prevention patients receiving seropositive kidney transplants
  • IV ganciclovir indicated for CMV pneumonitis in patients with compromised immune systems.
    •  Also used in other CMV-associated disease, including esophagogastrointestinal infection, hepatitis and "wasting" illness
  • IV ganciclovir may be used to treat CMV colitis and esophagitis
  • Oral ganciclovir may be used to prevent and/or in CMV disease in AIDS patients and for maintenance therapy of CMV retinitis
    •  Oral form less effective in maintenance treatment for AIDS patients with CMV retinitis, compared to IV form.

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Ganciclovir: (DHPG, Cytovene):Adverse Reactions 
  • Teratogenic, carcinogenic & mutagenic agent
  • Most common: myelosuppression, notably neutropenia: bone marrow suppression limits this drug's use in many patients.
    • granulocytopenia & thrombocytopenia: more common with IV formulation {typically reversible}
  • Severe myelosuppression may be seen in patients receiving ganciclovir (DHPG, Cytovene) along with
    • zidovudine (Retrovir, AZT, azidothymidine)
    • azathioprine (Imuran)
    • or mycophenolate mofetil.
    •  Ganciclovir (DHPG, Cytovene)-induced neutropenia may be treated with GM CSF; G-CSF [granulocyte-colony-stimulation factors]
  • Unusual CNS toxicity may include headache, seizures, altered mental status.
  •  Resistance:
    • ganciclovir (DHPG, Cytovene) resistance associated with:
      •  persistent diarrhea
      • progressive disease
      • approximately 20% of organ transplant recipients who fail oral ganciclovir (DHPG, Cytovene) prophylaxis excrete ganciclovir (DHPG, Cytovene)-resistant virus
    • Ganciclovir (DHPG, Cytovene)-resistant CMV strains may be responsive to cidofovir (Vistide) or foscarnet (Foscavir)

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Cidofovir (Vistide)
  • in vitro activity against HSV-1, HSV-to, VZV, CMV, EBV, adenovirus, human herpes virus strain 6 (HHV-6) and human papilloma virus.
  • Cidofovir (Vistide) phosphorylation to the active diphosphate form is viral independent.
  • IV cidofovir: effective in treating CMV retinitis.
  • Topical 1 % cidofovir may be useful in treating genital warts and for treating mucocutaneous herpes simplex infection.
  • Cleared by the kidney -- dosage modification required in real failure
  • Nephrotoxicity: major does limiting side effect for IV route of administration.
  • Nephrotoxicity may be prevented by administration of oral probenecid (prevents tubular secretion) and adequate saline hydration
  • Drug resistance: DNA polymerase gene mutation

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Foscarnet (Foscavir)
  •  inhibits viral DNA polymerase, RNA. polymerase, HIV reverse transcriptase. Phosphorylation step not required for drug activation.
  • In vitro activity against HSV, VZV, HIV, hepatitis B. virus, HHV-6,Epstein-Barr virus, and CMV.
  • Foscarnet resistance: DNA polymerase gene point mutation, typically following prolonged administration; mutations may also occur in HIV-1 reverse transcriptase
  • Only available by IV route of administration.
  • Clearance: primarily renal; dosage adjustment required based on creatinine clearance.

 Foscarnet (Foscavir): Clinical Use

  • CMV retinitis, acyclovir-resistant HSV;
  • Foscarnet is as effective as ganciclovir in treating CMV retinitis in patients with AIDS; however, patients survived longer, perhaps because of foscarnet's anti-HIV activity.
  • foscarnet superior to vidarabine in treatment of acyclovir-resistant human simplex viral infections

Forcarnet: Adverse Reactions 

  • Significant renal side effects: real insufficiency, hypocalcemia, hypercalcemia, hypophosphatemia, hyperphosphatemia, hypomagnesemia (these effects are due to foscarnet's ability to bind divalent ions).
  • Lack of hematologic abnormalities allows foscarnet use in combination with myelosuppressive agents such as zidovudine (Retrovir, AZT, azidothymidine).
  • Slow infusion rates and saline hydration protect against nephrotoxicity and electrolyte imbalances.
  • Genital ulcerations
  • CNS toxicities: headache, seizures, hallucinations
  • Coadministration with pentamidine (Pentam) increases hypocalcemia and real toxicity

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Idoxuridine (Herplex)
  • topical use only in treating herpes kerititis; too toxic for systemic administration.

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Trifluridine (Viroptic)
  • Trifluridine: inhibitor of viral DNA synthesis.
  • In vitro activity against: HSV-1,HSV-2,vaccinia, some adenoviruses.
  • Intracellularly phosphorylated by cellular kinases
  • phosphorylated-product competes with thymidine triphosphate for incorporation by viral polymerases.
  •  1% solution: effective for primary keratoconjunctivitis, recurrent epithelial kerititis due to herpes simplex virus
  • Topical application sometimes in conjunction with interferon-alpha: effective for treatment of acyclovir-resistant HSV infections

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Vidarabine (ara-A )
  • Vidarabine: (ara-A ): in vitro activity against human simplex virus, Varicella zoster virus, cytomegalovirus.
  • Intracellular phosphorylation results in the active drug, ara-ATP, at inhibitor of viral DNA polymerase.
  • Vidarabine triphosphate is incorporated both into both cellular and viral DNA.
  • Rapid metabolism reduces effective antiviral action, contributing to significant toxicity.

Vidarabine: Clinical Use

  • 3% ointment: effective in treating acute keratoconjunctivitis, recurrent epithelial kerititis, and superficial kerititis (HSV).
  • Vidarabine is clinically effective against Varicella and mucocutaneous HSV disease in immunocompromised patients; however, acyclovir is preferred because of ease of administration.
  • IV vidarabine effective in treating: HSV encephalitis, neonatal herpes, and VSV infection in immunocompromised individuals.
  • Ineffective in treatment of acyclovir-resistant HSV infections in AIDS patients.
  • Renal elimination with dosage reduction recommended if the patient has impaired renal function.

 Vidarabine: Adverse Effects

  • Toxicities include: GI intolerance, CNS effects (confusion, seizures, myoclonus), myelosuppression.
  • Hematopoietic side effects, particularly noted at higher doses (20 mg/kg per day), include anemia, leukopenia, and thrombocytopenia.
  • CNS toxicity has been noted at high doses and in patients with hepatic or renal insufficiency.

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Dolan, R., Antiviral Chemotherapy. In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 1076-1078.
Safrin, S. and Chambers, H. F Antiviral Agents, in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 788-801.
Drugs for non-HIV viral infection. The Medical Letter, 1999, vol. 41 (Issue 1067) December 3, 1999