Viruses are obligate intracellular parasites; their replication depends primarily on synthetic processes of the host cell. Therefore, to be effective, antiviral agents must either block viral entry into or exit from the cell or be active inside the host cell. As a corollary, nonselective inhibitors of virus replication may interfere with host cell function and result in toxicity.
Progress in antiviral chemotherapy began in the early 1950s, when the search for anti-cancer drugs generated several new compounds capable of inhibiting viral DNA synthesis. The two first-generation antiviral agents, 5-iododeoxyuridine and trifluorothymidine, had poor specificity (ie, they inhibited host cell DNA as well as viral DNA) that rendered them too toxic for systemic use. However, both agents are effective when used topically for the treatment of herpes keratitis.
Knowledge of the mechanisms of viral replication has provided insights into critical steps in the viral life cycle that can serve as potential targets for antiviral therapy. Recent research has focused on identifying agents with greater selectivity, higher potency, in vivo stability, and reduced toxicity. Antiviral therapy is now available for herpes simplex virus (HSV), cytomegalovirus (CMV), varicella zoster virus (VZV), hepatitis C virus (HCV), hepatitis B virus (HBV), influenza, human immunodeficiency virus (HIV), and respiratory syncytial virus (RSV). Antiviral drugs share the common property of being virustatic; they are active only against replicating viruses and do not affect latent virus. Whereas some infections require monotherapy for brief periods of time (eg, HSV, influenza), others require multiple drug therapy for indefinite periods (HIV). In chronic illnesses such as viral hepatitis and HIV infection, potent inhibition of viral replication is crucial in limiting the extent of systemic damage.
Viral replication requires several steps (see Figure 49–1). Antiviral agents can potentially target any of these steps.
Three oral nucleoside analogs are licensed for the treatment of HSV and VZV infections: acyclovir, valacyclovir, and famciclovir. They have similar mechanisms of action and comparable indications for clinical use (see Table 49–1); all are well tolerated.
Comparative trials have demonstrated similar efficacies of these three agents for the treatment of HSV, with shortening of the duration of symptoms by approximately 2 days, the time to lesion healing by 4 days, and the duration of viral shedding by 7 days in first episodes of genital herpes and shortening of the overall time course by 1–2 days in recurrent genital herpes. Treatment of first-episode genital herpes does not alter the frequency or severity of recurrent outbreaks. Long-term suppression with antiherpes agents in patients with frequent recurrences of genital herpes decreases the frequency of symptomatic recurrences and of asymptomatic viral shedding, thus decreasing the rate of sexual transmission. However, outbreaks may resume upon discontinuation of suppression. The efficacy of the anti-herpes agents in orolabial herpes is generally less than that in anogenital herpes.
Integration (retroviruses) Transcription Blocked by INSTIs (HIV) Blocked by PIs (HIV, HCV) Blocked by NRTIs, NNRTIs (HIV), Nucleoside/nucleotide analogs (HSV, HBV) Viral attachment and entry Viral release Uncoating Nucleic acid synthesis Viral protein synthesis Packaging and assembly MammaliancellBlocked by amantadine, rimantadine (influenza) Blocked by enfuvirtide (HIV); docosanol (HSV), maraviroc (HIV), palivizumab (RSV) Blocked by neuraminidase inhibitors (influenza) Penetration Blocked by interferon-alfa (HBV, HCV)