Use of viral resistance patterns to antiretroviral drugs in optimising selection of drug combinations and sequences.

High rates of viral replication throughout HIV infection, and the frequency of mutation occurring during each replication cycle due to the inaccuracy of reverse transcriptase, drive the potential for drug-resistant viral variants to appear under the selective pressure of antiretroviral therapy. Loss of antiviral effect with a variety of antiretroviral agents has been reported to coincide with the appearance of viral mutants with reduced drug sensitivity. Additionally, the presence of both phenotypic and genotypic zidovudine resistance is associated with an increased risk of clinical disease progression and death, independent of a change of therapy to didanosine. The patterns of resistance to and cross-resistance between antiretroviral agents are increasingly well characterised, and represent an important consideration when deciding how to combine and/or sequence antiretrovirals to achieve optimal antiviral effects. Given the limited number of antiretrovirals currently available or in advanced development, it is important not to potentially limit future therapeutic options by using, early in the treatment sequence, therapies which may select for cross-resistant viral variants and hence potentially reduce the additional therapeutic response when treatment is changed to another member of that drug class.