Antivirals

Antiviral therapy is harder than antibacterial therapy because a virus replicates inside the host cell, using much of the host’s own machinery. The central problem is therefore selectivity: blocking a step that belongs to the virus, or is used very differently by it, without poisoning the patient. The agents that succeed do so by targeting a viral enzyme or a viral process, the polymerase above all, but also the protease, entry and uncoating, integration, and assembly and release.

What a drug can achieve depends on the infection. Acute infections, such as influenza or herpes simplex encephalitis, are treated in short courses that limit damage if started early. Chronic infections divide into those that can only be suppressed while treatment continues, HIV and hepatitis B, because each keeps a stable reservoir the drugs cannot clear, and the one that can be cured in a few weeks, hepatitis C, which has no such reservoir. Resistance shadows all of it, and a drug’s genetic barrier, the number of mutations a virus needs to escape it, largely decides how durable it is.

Most antivirals are small molecules, but antibody-based agents (such as palivizumab and nirsevimab against respiratory syncytial virus) increasingly sit alongside them for prevention. The topic is treated in three articles.

→ See Antiherpesvirus Agents for the drugs that treat herpes simplex, varicella-zoster and cytomegalovirus: aciclovir and its prodrugs, ganciclovir, foscarnet, cidofovir, and the newer agents letermovir, maribavir and the helicase-primase inhibitors.

→ See Antivirals for Respiratory and Hepatitis Viruses for the influenza, SARS-CoV-2, hepatitis B and hepatitis C agents, and the broad-spectrum drug ribavirin.

→ See Antiretrovirals for the HIV drug classes, the largest part of the antiviral armamentarium.

Key terms

The vocabulary that recurs across the topic, grouped by theme.

Mechanism and selectivity:

Term	Definition
Selective toxicity	Harming the virus far more than the host, the central design problem of an antiviral drug.
Prodrug	An inactive form converted to the active drug in the body, used to improve absorption (valaciclovir, valganciclovir, oseltamivir, tenofovir).
Nucleoside or nucleotide analogue	A faulty building block incorporated into the growing viral nucleic acid; the largest antiviral class.
Chain terminator	An incorporated analogue that halts nucleic-acid synthesis, either obligate (stopping at once, as aciclovir does) or delayed (a few more bases add first, as with ganciclovir).
Pharmacoenhancement (boosting)	Co-administering a CYP3A inhibitor (ritonavir, cobicistat) to raise the active drug’s level, with no antiviral effect of its own.

Resistance:

Term	Definition
Genetic barrier to resistance	The number of mutations a virus needs to escape a drug; a high barrier (dolutegravir, the hepatitis C regimens) resists failure, a low barrier (the NNRTIs, the influenza M2 inhibitors) fails easily.
Resistance-associated substitution	A mutation that reduces susceptibility to a drug, such as influenza H275Y, hepatitis C NS5A Y93H, or cytomegalovirus UL97 mutations.
Cross-resistance	A single change reducing susceptibility to several drugs at once, often across a whole class.

Goals and strategies of use:

Term	Definition
Suppression versus cure	Whether therapy holds an infection in check while it continues (HIV, hepatitis B) or eradicates it (hepatitis C).
Prophylaxis versus pre-emptive therapy	Prophylaxis treats all at-risk patients for a set period; pre-emptive therapy waits for an early marker of infection before treating.
Pre-exposure prophylaxis (PrEP)	A drug taken before exposure to prevent infection, as for HIV.
Post-exposure prophylaxis (PEP)	A short course started after a discrete exposure to prevent infection (HIV, hepatitis B, rabies).
Empirical and off-licence use	Starting therapy before laboratory results are available, and using an agent outside its formally registered indication.

References and recommended reading

• Coen DM, Namchuk MN, Kuritzkes DR. Antiviral Agents. In: Fields Virology, 7th edition (Fundamentals), Chapter 14. Wolters Kluwer; 2022. The current reference for antiviral mechanism, selectivity and resistance across the drug classes.
• Gordon CL, Kubin CJ, Hammer SM. Antiherpesvirus Agents. In: Richman DD, Whitley RJ, Hayden FG, editors. Clinical Virology, 4th edition, Chapter 12. ASM Press; 2016. The reference for the antiherpesvirus agents and the principles of antiviral drug development.