Antiviral agents acting on DNA virus
Purine and pyrimidines analogs active against DNA viruses are aciclovir, valacyclovir, famciclovir, idoxuridine, trifluridine, vidarabine, ganciclovir and cidofovir. They are used for the treatment of the infections caused by viruses of the Herpes viridae family, Herpes simplex virus (HSV), Varicella-zoster virus (VZV) and cytomegaloviruses (CMV).
Aciclovir, also written acyclovir, is a guanine analog substituted by replacement of a hydrogen atom by an acyclic chain with an alcohol function. To be active, aciclovir must be phosphorylated to aciclovir triphosphate which enters in competition with deoxyguanosine triphosphate.
The activation of aciclovir depend on the presence of viral thymidine kinase inside the host cell: in absence of infection, aciclovir is not converted to aciclovir monophosphate and the later steps are thus not possible. In the presence of virus inside the cell, aciclovir is converted to aciclovir monophosphate which is then converted, by cellular enzymes, to aciclovir diphosphate and triphosphate. Aciclovir triphosphate inhibits the DNA polymerase and prevents the viral multiplication. Aciclovir triphosphate is present in infected cells but not in uninfected cells.
Metabolism and activation of aciclovir
Concerning pharmacokinetics, the bioavailability of aciclovir by oral route is low, 15 to 30%; its plasma half-life approximately two hours; its elimination is renal.
Its clinical uses are primarily the treatment of the infections due to Herpes simplex virus and Varicella-zoster virus. Aciclovir (Zovirax*) is given by intravenous route and by oral route but valacyclovir has a better oral bioavailability. Aciclovir is also used as cream for treating herpes labialis. Aciclovir did not show real efficacy in the treatment of infectious mononucleosis due to Epstein-Barr virus. Aciclovir is generally well tolerated.
Valacyclovir, (Zelitrex*, Valtrex*), molecule of aciclovir esterified by L-valine, has a bioavailability by oral route definitely more important than aciclovir. After absorption, it is hydrolyzed to aciclovir. It is used as a preventive treatment (prevention of pains and ophthalmic complications of herpes zoster infection, the treatment must be initiated early after the onset of the eruption) and as a curative treatment with the same indications as acyclovir.
Famciclovir (Famvir*) is administered by oral route and is the precursor of penciclovir, purine derivative with a chemical structure quite similar to that of aciclovir. It is used for the prevention of infections due to Herpes simplex virus and herpes zoster virus. It acts after transformation in penciclovir triphosphate.
Penciclovir itself is used in several countries in the form of cream for the local treatment of herpes labialis.
Ganciclovir has a chemical structure quite similar to that of aciclovir and is active after intracellular conversion to triphosphate derivative, but it is more active against cytomegaloviruses which constitute a sub-group of virus of the herpes type. It is used to treat the various cytomegalovirus infections, in particular the retinitis observed in patients with HIV infections.
Ganciclovir (Cymevene*, Cytovene*) exists under preparations for intravenous administration and local application. Its oral bioavailability is poor, approximately 6%, reaching about 20% when it is taken with food; it is generally replaced by valganciclovir.
The most common adverse effects of ganciclovir are haematological, neutropenia and thrombocytopenia. It is teratogenic. Used by intravenous route, it could induce sterility in men and women.
Valganciclovir is a prodrug which acts after transformation in ganciclovir. It is an ester of ganciclovir and valine, explaining its name. Valganciclovir has a bioavailability by oral route of about 60% whereas that of the ganciclovir is only about 6% when it is taken on an empty stomach. The esterification of ganciclovir by valine increases considerably its bioavailability by increasing its intestinal absorption, as a substrate of peptidic carrier PEPT1. In the body, after its intestinal absorption, valganciclovir is hydrolyzed into ganciclovir, the active product. Valganciclovir (Valcyte*) is used in the treatment of cytomegalovirus retinitis in immunocompromised patients.
Cidofovir (Vistide*) is a cytidine analog, active after phosphorylation against strains of human cytomegalovirus resistant to ganciclovir. It is prescribed for the treatment of cytomegalovirus retinitis in immunocompromised patients.
Adefovir is an analog of adenine having antiviral properties, in particular against hepatitis B virus. But adefovir is poorly absorbed after administration by oral route. To increase its digestive absorption, it is esterified by 2 substituents, from where the dipivoxyl term. The bioavailability to adefovir dipivoxyl (Hepsera*) reaches 60%. In the body adefovir dipivoxyl is hydrolyzed to adefovir, the active product. It is used in the treatment of chronic hepatitis B.
Idoxuridine or 5-iodo-2'-deoxyuridine is a thymidine structural analog: iodine replacing a methyl group. Idoxuridine, after conversion into triphosphate derivative, is incorporated in viral DNA and inhibits the virus replication in the host cells. It is inactive on RNA viruses. It was used in some countries as an ophthalmic solution for the treatment of the Herpes simplex virus keratitis.
Trifluridine, also called trifluorothymidine, after its conversion into trifluridine triphosphate, inhibits the replication of viral DNA in which it is incorporated. It is used in some countries as an ophthalmic solution (Virophta*) for the treatment of keratoconjunctivitis due to Herpes simplex virus.
Vidarabine, is a structural analog of adenosine, the ribose being replaced by its isomer arabinose. After phosphorylation, vidarabine inhibits the viral DNA polymerase, impairing virus replication. Vidarabine gel for local application was prescribed to accelerate the cicatrization of genital herpetic lesions.