Category:Anti-herpesvirus agents

An anti-herpesvirus agent is a medicine used to treat infection by one of the eight human herpesviruses: herpes simplex virus 1 (HSV-1, principally oral and central-nervous-system disease), herpes simplex virus 2 (HSV-2, principally genital disease), varicella-zoster virus (VZV, primary varicella and reactivated zoster), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and the more recently characterised human herpesviruses 6, 7, and 8. The category falls within antivirals and consists predominantly of nucleoside analogues that exploit the viral thymidine kinase and the viral DNA polymerase, with a small set of mechanistically distinct agents for resistant or mechanistically separate indications.

The pharmacological history of the category is the founding chapter of the contemporary antiviral pharmacopoeia (described under antivirals). Idoxuridine in 1962 was the first clinically used systemic antiviral and was the first medicine of any kind to selectively inhibit a virus by a defined molecular mechanism: an iodinated thymidine analogue that the viral DNA polymerase incorporated preferentially over the host enzyme. Idoxuridine's systemic toxicity restricted it to topical ophthalmic use, but the medicine established the nucleoside-analogue principle that has dominated anti-herpesvirus pharmacology ever since.

The transformative agent was aciclovir (acyclovir), reported by Gertrude Elion and colleagues at Burroughs Wellcome in 1977. Acyclovir is an acyclic guanosine analogue that requires phosphorylation by the herpesvirus-encoded thymidine kinase to its monophosphate, then by cellular kinases to the active triphosphate; the triphosphate is a chain-terminator at the viral DNA polymerase. Because the host thymidine kinase phosphorylates the medicine at negligible rate, acyclovir is concentrated by orders of magnitude in herpes-infected cells over uninfected cells, giving extraordinary selectivity. The therapeutic index of acyclovir is one of the highest in antimicrobial pharmacology, and the medicine has remained the foundation of anti-herpesvirus therapy for nearly fifty years.^[1]

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 derivatives followed. 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. 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. 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 valganciclovir (Valcyte, 2001) provides oral bioavailability sufficient for routine outpatient CMV prophylaxis and pre-emptive therapy. The phosphonoformate 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, 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 maribavir (Livtencity, Takeda 2021), an inhibitor of the CMV UL97 kinase, is used for refractory CMV after transplantation.

By target:

• Acyclic guanosine analogues (HSV, VZV; thymidine-kinase-dependent activation):
  • Aciclovir (acyclovir) (Zovirax; intravenous, oral, topical)
  • Valaciclovir (Valtrex; L-valyl valyl ester of acyclovir)
  • 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):
  • Ganciclovir (Cytovene; intravenous and oral; CMV-active)
  • Valganciclovir (Valcyte; L-valyl L-valyl ester of ganciclovir)
• Acyclic phosphonates (no viral kinase needed; broader spectrum, more toxicity):
  • Cidofovir (Vistide; intravenous)
  • Brincidofovir (Tembexa; oral lipid-conjugated derivative of cidofovir; smallpox and selected anti-herpesvirus use)
• Pyrophosphate analogues:
  • Foscarnet (Foscavir; intravenous; for ganciclovir-resistant CMV and acyclovir-resistant HSV)
• CMV-specific small molecules:
  • Letermovir (Prevymis; terminase inhibitor; CMV prophylaxis post-HSCT)
  • Maribavir (Livtencity; UL97 kinase inhibitor; refractory CMV)
• Topical anti-herpesvirus:
  • Penciclovir cream, acyclovir cream and ointment, docosanol cream (Abreva; OTC)
  • Trifluridine ophthalmic, idoxuridine ophthalmic (mostly retired)
• Other:
  • Vidarabine (Vira-A, adenine arabinoside; largely retired, replaced by acyclovir)

The boundary of this category is "medicine active against one of the human herpesviruses and prescribed primarily for this indication." The vaccines for varicella (Varivax, ProQuad), zoster (Zostavax live, Shingrix recombinant adjuvanted), and the cytomegalovirus vaccines in trial are biologics rather than antiviral medicines and are listed under biologics. The Epstein-Barr-virus targeted CAR-T cell products and EBV-specific cytotoxic T lymphocyte preparations are cellular immunotherapies and are listed under immunomodulators. The medicines used for human herpesvirus 8 (HHV-8, Kaposi-sarcoma-associated herpesvirus) are largely the same nucleoside analogues plus the antiretroviral therapy for the underlying HIV when KS is HIV-associated; they are cross-listed under antineoplastics for the KS indication.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.