HIV reproduces very quickly, making billions of new viruses every day. Because it often makes errors while copying itself, each new generation of viruses differs slightly from the one before.

Some of these errors produce viruses which are defective and so cannot reproduce themselves well. Over time these 'less fit' viruses will die off. However, some changes to the structure of the virus can also improve its ability to reproduce despite high levels of anti-HIV drugs being present. Viruses which are able to reproduce while you are taking drugs are said to be resistant to those drugs.

Researchers estimate that every possible error that might appear in HIV's structure occurs once every day if virus production is not being suppressed. This means the seeds for a drug resistant crop of viruses are being sown every day, and these viruses will be the ones which grow best when you start taking anti-HIV treatment.

If you are not taking treatment, then the population of viruses in your body will be influenced only by which viruses are most 'fit' to reproduce themselves. Resistant viruses will form only a tiny part of this population. Starting a drug combination creates the conditions in which resistant viruses have an advantage over viruses which are sensitive to the drugs. These may have been present before the start of treatment, but could not grow as well as viruses without the mutations.

How does resistance affect treatment?

When you take anti-HIV drugs, HIV that is vulnerable to the drugs will be suppressed. This leaves behind viruses which can continue to reproduce despite the drugs' presence. Over time, the pool of HIV in the body changes to include fewer and fewer drug sensitive viruses and more and more resistant ones.

Resistance is an important reason why anti-HIV drugs may have only limited or short-term usefulness. Your viral load, which usually drops when you start anti-HIV treatment, may rebound if a resistant virus population emerges.

It is not clear how developing resistance will affect the risk of becoming ill in the future. It is important to remember that resistance is a sign that your current treatment has failed to keep viral load fully suppressed, but that any reduction in viral load is associated with a benefit in terms of improved health and survival.

Types of resistance

Researchers make a distinction between two types of resistance: genotypic and phenotypic resistance. HIV is said to have genotypic resistance to a drug if tests show that it has the particular mutations in its genetic make-up that have been associated with resistance to that drug. HIV is said to have phenotypic resistance to a drug if laboratory tests show that the virus is significantly less susceptible to the drugs anti-viral effects.

Cross-resistance

Resistance to one drug may cause some cross-resistance to other drugs within the same class. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) in particular are often highly cross-resistant. Cross-resistance also occurs within the nucleoside and nucleotide reverse transcriptase inhibitor (NRTI and NtRTI) and protease inhibitor classes.

Resistance mutations

Most resistance is caused by changes in the genetic material of HIV. Changes in the gene for reverse transcriptase inhibitors causes resistance to the reverse transcriptase inhibitors, while changes in the protease gene are responsible for protease inhibitor resistance.

Resistance mutations are usually referred to using a number, with or without letters either side. The number refers to the position along the gene where the mutation has taken place. This is also called the 'codon'. Each codon in the gene instructs the cell's machinery which 'amino acid' building block to insert at that position in the enzyme. There are twenty different amino acids, which are given single-letter codes. Changing just one amino acid can alter the shape of the full enzyme, thereby changing its physical and chemical properties and leading to the development of drug resistance.

The letter given before the codon number refers to the amino acid that is present in unmutated or 'wild type' HIV. The letter given after the codon number refers to the new amino acid that is inserted by the mutant HIV.

For example, M184V is a mutation in the reverse transcriptase gene that causes resistance to 3TC (lamivudine, Epivir). It is caused by a mutation at codon number 184 in the reverse transcriptase gene. This mutation means that the amino acid methionine (M) is replaced by valine (V) in the reverse transcriptase enzyme. This change in amino acid is responsible for the ability of HIV containing this mutation to replicate in the presence of 3TC.