Drug resistance

Derek Thaczuk

HIV reproduces in the body very quickly, making billions of new viruses every day by replicating its genetic material. HIV is a retrovirus; retroviruses have an inherently high mutation rate, caused by copy errors during replication and the lack of a proof-reading function to correct those errors.

Naturally occurring strains of HIV are known as 'wild-type' virus and are the most susceptible to antiretroviral (ARV) drugs. Wild-type virus is normally the most powerful form of virus in the body and reproduces the best.

Perfect wild-type copies of the virus are produced as well as copies with errors, known as variants or mutated virus. Researchers estimate that every possible error in the wild-type structure of HIV occurs once every day if viral production is not suppressed with antiretroviral drugs. Some of these errors produce defective variants that cannot reproduce themselves well. Over time, these 'less fit' viruses will die off.

Other variants undergo certain changes, known as polymorphisms, which can actually improve the ability of virus to reproduce itself. Because of viral mutations, there is not one type of HIV virus, but rather a large population of mixed viruses called quasi-species, some of which are drug-resistant.

Viral resistance occurs when the drug levels in the bloodstream are not high enough to stop HIV from reproducing. Suboptimal drug levels can result from missed or incorrectly taken doses, ones that are not absorbed or metabolised properly, or because of interactions that may occur with other drugs or food.

Depending on the viral mutation, sometimes resistance to one drug can cause the virus population to become resistant to similar drugs in the same class (known as cross-resistance). It is possible for someone to be cross-resistant to a drug they have never taken. This happens frequently with the non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs efavirenz (Sustiva) and nevirapine (Viramune).

Resistance to several drugs from different drug classes in the ARV regimen is also possible. Most of the time, when a virus stops responding to one drug, it will still be susceptible to another. Resistance tests are very useful in guiding the selection of an ARV regimen.

There are basically two different types of resistance tests that can determine – in advance of treatment or during viral rebound – either the specific mutations present in someone's virus that cause resistance (known as genotypic testing) or that can test the amount of an ARV drug necessary to suppress virus replication (phenotypic testing).

Most assays in current clinical use will detect resistant virus only if that viral subpopulation makes up at least 10 to 20% of a person's total viral population.

In research settings, the role of low-frequency drug-resistant variants is being explored. Recent work indicates that standard HIV resistance testing may fail to detect HIV drug resistance in more than one-third of all treatment-naive patients, because hypersensitive tests are needed to detect minority populations of resistant virus.1

References

  1. Johnson JA et al. Minority HIV-1 drug resistance mutations are present in antiretroviral treatment-naïve populations and associate with reduced treatment efficacy. PLoS Med 5(7): e158, doi:10.1371/journal.pmed.0050158, 2008