Antiviral drug resistance

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Deenan Pillay (D.Pillay@bham.ac.uk), head of unita,
Maria Zambon, consultant medical virologistb

Public Health Laboratory Service Antiviral Susceptibility Reference Unit, Division of Immunity and Infection, University of Birmingham Medical School, Birmingham B15 2TT,
Enteric and Respiratory Virus Laboratory, Central Public Health Laboratory, London NW9 5HT

Correspondence to: Dr Pillay

The development of effective antiviral drugs is an important biomedical scientific achievement of the late 20th century. Highly potent drugs are now available against herpes viruses, HIV, hepatitis B virus, and influenza virus. This list will extend to papillomaviruses, respiratory viruses, enteroviruses, and hepatitis C virus over the next 5-10 years. Viruses that maintain latency (the herpes viruses) or persistence (HIV and hepatitis B virus) are not specifically cleared from the body by these drugs, but their replication can be effectively suppressed. Currently, 18 specific antiviral drugs (excluding interferons) are licensed in the United Kingdom, with many more in phase 3 clinical trials or available on expanded access. For the common viral infections, prescribing will shift into primary care, as has already occurred for shingles and herpes simplex infections.

Against this exciting background comes the news of drug resistance. Virally encoded drug resistance has been documented against nearly all compounds with antiviral activity, and the genetic basis of resistance is now known.

Summary points

Resistance has developed to nearly all specific and effective antiviral agents

Resistance has developed to all drugs against HIV, and treating hepatitis B with nucleoside analogue monotherapy gives rise to drug resistant variants

Resistance develops rapidly when viral replication is not maximally suppressed

Drug resistant viruses may be transmitted

Assays to measure drug resistance are available in specialised laboratories

Biological basis of resistance

Drug resistance is defined as a reduced susceptibility to a drug in a laboratory culture system and is expressed as an altered IC₅₀ or IC₉₀ (drug concentration required to inhibit viral growth by 50% or 90% respectively). This is termed the phenotype. This phenotype is determined by specific mutations in the viral genome (the genotype), which leads to alterations in the viral target protein (for example, HIV reverse transcriptase) or the viral drug activator (for example, herpes …