Rational approaches to resistance: nucleoside analogues

To review knowledge of drug-resistance patterns to nucleoside HIV reverse transcriptase inhibitors and how this can be used to advantage in patient management.

The speed of emergence of HIV-1 drug resistance is dependent on host, viral and drug factors. Resistance to zidovudine develops over months to years, and is associated with mutations in HIV reverse transcriptase at positions 41, 67, 70, 215 and 219. Reductions in susceptibility to didanosine, zalcitabine and stavudine develop more slowly and are lower than those seen with zidovudine. Resistance to lamivudine develops rapidly, in weeks to months; selection of a pre-existing mutated viral strain results in a 1000-fold reduction in susceptibility. There is some cross-resistance between nucleoside antiretroviral agents, particularly among didanosine, zalcitabine and lamivudine.

Some agents induce mutations that reverse or suppress zidovudine resistance; combination therapy with these drugs may delay the emergence of multidrug-resistance, but the mutational flexibility of the HIV-1 virus means that drug resistant isolates will eventually develop. Combining HIV protease inhibitors that strongly suppress viral replication with nucleoside inhibitors also delays the emergence of resistance.

Widespread use of nucleoside HIV reverse transcriptase inhibitors that incompletely suppress viral replication has led to the emergence of resistant viral strains, with a consequent risk of transmission of drug-resistant virus. Combinations of protease inhibitors and reverse transcriptase inhibitors may slow viral replication sufficiently to prevent generation of resistant virus, to extend the duration of antiviral activity and increase the benefit to patients.