Category:Anti-herpesvirus agents: Difference between revisions

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The clinical indications of acyclovir map to its activity spectrum. HSV-1 and HSV-2 are highly sensitive; the medicine is used for primary genital herpes (200 mg five times daily or 400 mg three times daily for 7 to 10 days), for recurrent episodes (3 to 5 days at the same dose), and for chronic suppressive therapy (400 mg twice daily) in patients with frequent recurrences. Varicella-zoster virus is approximately ten-fold less sensitive and requires higher doses (800 mg five times daily for 7 days for shingles; 800 mg four times daily for varicella). Epstein-Barr virus is variably sensitive at higher doses and is not a standard acyclovir indication. Cytomegalovirus is essentially insensitive at clinically achievable doses and requires the related but distinct ganciclovir.

The improved-bioavailability acyclovir ~~prodrugs~~ followed. [[Valacyclovir|Valaciclovir]] (Valtrex, 1995, the L-valyl ester) is converted to acyclovir on first pass and provides three-to-five-fold higher oral bioavailability, allowing once- or twice-daily dosing for most indications. [[wikipedia:Famciclovir|Famciclovir]] (Famvir, 1994, the diacetyl ~~prodrug~~ of penciclovir) provides similar oral bioavailability through a closely related guanosine analogue. The acyclic phosphonate cidofovir (Vistide, 1996), administered intravenously with concurrent probenecid and saline diuresis, retains activity against acyclovir-resistant HSV and against CMV, but at the cost of substantial dose-related nephrotoxicity; brincidofovir, the lipid-conjugated oral ~~prodrug~~ of cidofovir, was approved in 2021 for smallpox and may extend cidofovir's anti-herpesvirus use.

The improved-bioavailability acyclovir derivatives followed. [[Valacyclovir|Valaciclovir]] (Valtrex, 1995, the L-valyl ester) is converted to acyclovir on first pass and provides three-to-five-fold higher oral bioavailability, allowing once- or twice-daily dosing for most indications. [[wikipedia:Famciclovir|Famciclovir]] (Famvir, 1994, the diacetyl ester of penciclovir, hydrolysed in vivo to the active compound) provides similar oral bioavailability through a closely related guanosine analogue. The acyclic phosphonate cidofovir (Vistide, 1996), administered intravenously with concurrent probenecid and saline diuresis, retains activity against acyclovir-resistant HSV and against CMV, but at the cost of substantial dose-related nephrotoxicity; brincidofovir, the lipid-conjugated oral derivative of cidofovir, was approved in 2021 for smallpox and may extend cidofovir's anti-herpesvirus use.

The cytomegalovirus medicines complete the contemporary category. [[wikipedia:Ganciclovir|Ganciclovir]] (Cytovene, Roche 1989) is a guanosine analogue similar in structure to acyclovir but phosphorylated by the CMV-encoded UL97 kinase rather than by HSV thymidine kinase; it is the standard treatment of CMV retinitis, CMV pneumonitis, CMV colitis, and prophylaxis in transplantation. Its myelosuppression limits chronic use. The ~~oral prodrug~~ [[wikipedia:Valganciclovir|valganciclovir]] (Valcyte, 2001~~, the L-valyl ester~~) provides oral bioavailability sufficient for routine outpatient CMV prophylaxis and pre-emptive therapy. The phosphonoformate [[wikipedia:Foscarnet|foscarnet]] (Foscavir, 1991) is used for ganciclovir-resistant CMV and for acyclovir-resistant HSV, particularly in immunocompromised hosts; its nephrotoxicity, electrolyte derangement (hypocalcemia, hypomagnesemia, hypophosphatemia, hyperphosphatemia), and genital ulceration limit its use. The most recent CMV-specific medicine, [[wikipedia:Letermovir|letermovir]] (Prevymis, Merck 2017), inhibits the CMV terminase complex (a target absent from human cells) and is used as primary CMV prophylaxis in adult hematopoietic-cell transplant recipients; its CMV-specific mechanism gives it a favourable safety profile compared to the older agents. The newer [[wikipedia:Maribavir|maribavir]] (Livtencity, Takeda 2021), an inhibitor of the CMV UL97 kinase, is used for refractory CMV after transplantation.

The cytomegalovirus medicines complete the contemporary category. [[wikipedia:Ganciclovir|Ganciclovir]] (Cytovene, Roche 1989) is a guanosine analogue similar in structure to acyclovir but phosphorylated by the CMV-encoded UL97 kinase rather than by HSV thymidine kinase; it is the standard treatment of CMV retinitis, CMV pneumonitis, CMV colitis, and prophylaxis in transplantation. Its myelosuppression limits chronic use. The orally bioavailable L-valyl ester [[wikipedia:Valganciclovir|valganciclovir]] (Valcyte, 2001) provides oral bioavailability sufficient for routine outpatient CMV prophylaxis and pre-emptive therapy. The phosphonoformate [[wikipedia:Foscarnet|foscarnet]] (Foscavir, 1991) is used for ganciclovir-resistant CMV and for acyclovir-resistant HSV, particularly in immunocompromised hosts; its nephrotoxicity, electrolyte derangement (hypocalcemia, hypomagnesemia, hypophosphatemia, hyperphosphatemia), and genital ulceration limit its use. The most recent CMV-specific medicine, [[wikipedia:Letermovir|letermovir]] (Prevymis, Merck 2017), inhibits the CMV terminase complex (a target absent from human cells) and is used as primary CMV prophylaxis in adult hematopoietic-cell transplant recipients; its CMV-specific mechanism gives it a favourable safety profile compared to the older agents. The newer [[wikipedia:Maribavir|maribavir]] (Livtencity, Takeda 2021), an inhibitor of the CMV UL97 kinase, is used for refractory CMV after transplantation.

== Classes indexed ==

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* '''Acyclic guanosine analogues''' (HSV, VZV; thymidine-kinase-dependent activation):

** [[Acyclovir|Aciclovir (acyclovir)]] (Zovirax; intravenous, oral, topical)

** [[Valacyclovir|Valaciclovir]] (Valtrex; L-valyl ~~prodrug~~ of acyclovir)

** [[Valacyclovir|Valaciclovir]] (Valtrex; L-valyl valyl ester of acyclovir)

** [[wikipedia:Famciclovir|Famciclovir]] (Famvir; diacetyl ~~prodrug~~ of penciclovir)

** [[wikipedia:Famciclovir|Famciclovir]] (Famvir; diacetyl diacetyl ester of penciclovir)

** Penciclovir (Denavir; topical only)

** Trifluridine (Viroptic; topical ophthalmic only, also used in oncology as trifluridine-tipiracil for colorectal cancer)

* '''Acyclic guanosine analogues with broader spectrum''' (HSV, VZV, CMV, EBV):

** [[wikipedia:Ganciclovir|Ganciclovir]] (Cytovene; intravenous and oral; CMV-active)

** [[wikipedia:Valganciclovir|Valganciclovir]] (Valcyte; L-valyl ~~prodrug~~ of ganciclovir)

** [[wikipedia:Valganciclovir|Valganciclovir]] (Valcyte; L-valyl L-valyl ester of ganciclovir)

* '''Acyclic phosphonates''' (no viral kinase needed; broader spectrum, more toxicity):

** [[wikipedia:Cidofovir|Cidofovir]] (Vistide; intravenous)

** Brincidofovir (Tembexa; oral lipid-conjugated ~~prodrug~~; smallpox and selected anti-herpesvirus use)

** Brincidofovir (Tembexa; oral lipid-conjugated derivative of cidofovir; smallpox and selected anti-herpesvirus use)

* '''Pyrophosphate analogues''':

** [[wikipedia:Foscarnet|Foscarnet]] (Foscavir; intravenous; for ganciclovir-resistant CMV and acyclovir-resistant HSV)

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