Evolution of therapy for cytomegalovirus infection

Abstract

The first antiherpes agents discovered in the early 1960s were 2'-deoxy-5-iodouridine (idoxuridine; IUDR), beta-D-arabinofuranosylcytosine (cytarabine; ara-C), and 9-beta-D-arabinofuranosyladenine (vidarabine; ara-A), 2'-deoxy-5-fluorouridine (floxuridine; FUDR), and 2'-deoxy-5-trifluoromethyluridine (trifluridine; TFT). All of these drugs showed potency against herpes simplex virus (HSV) and cytomegalovirus (CMV) in vitro but had a narrow therapeutic margin. Although ribavirin, a nucleoside analogue synthesized in 1972, was much less toxic than earlier drugs, it proved ineffective against CMV. Phosphonoformic acid (PFA), a pyrophosphate analogue, has recently shown encouraging results for CMV infections in bone marrow and renal transplant recipients. Several interferons, alone or in combination with other antiviral agents, have proved clinically ineffective against CMV infections. Antiviral nucleoside analogues synthesized in the late 1970s generated much hope and enthusiasm, and acyclovir (9-[(2-hydroxyethoxy)methyl]guanine; ACV) has emerged as a safe and efficacious anti-HSV agent and has shown some promise in the treatment of CMV infection in transplant recipients. The most recent anti-CMV agent, ganciclovir (9-[(1,3-dihydroxy-2-propoxy)methyl]guanine; DHPG), is an analogue of 2'-deoxyguanosine. It was reported independently in 1982 by four laboratories. DHPG is a potent agent against all five human herpesviruses. Its toxicity, unfortunately, limits its clinical use at present to life- and sight-threatening CMV infections.