Antiretroviral Therapy
(Part XXIV)

HIV-1 Resistance: A Primer

The development of viral resistance to antiretroviral agents is complex, often involving complicated mutational patterns. To appreciate the significance of many of the following presentations, a basic understanding of HIV-1 resistance is necessary.

HIV-1 Resistance Testing

In vitro, viral resistance can be detected using genotypic and phenotypic assays. Phenotypic resistance refers to an increased ability of HIV to replicate in cell culture in the presence of a drug. Phenotypic resistance is usually reported in terms of the inhibitory concentration of the drug required to reduce viral replication 50% or 90% (the IC50 or the IC90). Currently, these assays are time consuming, expensive and require specialized laboratory facilities. They are therefore unlikely to become widely available clinical assays in the near future.

Genotypic Assays

Genotypic resistance refers to the specific nucleic acid changes which are associated with phenotypic resistance. For example, a mutation at position 30 of the protease gene is associated with high level phenotypic resistance to nelfinavir (Viracept). Typically, an aspartic acid (D) amino acid to asparagine (N) substitution occurs. This mutation is therefore referred to as D30N.

Several genotypic assays are currently in development. Some assays, such as the high-density oligonucleotide sequencing technique (Affymetrix) can rapidly sequence the entire reverse transcriptase and protease genes. These assays are generally limited by their inability to detect minor variants. Other assays, such as the differential hybridization technique, focus on specific mutations, and are able to detect variants present at low frequencies.

Mutations Associated with Resistance to Antiretroviral Drugs