HIV-1 chemotherapy and drug resistance

Background: Therapy with inhibitors of human immunodeficiency virus type 1 (HIV-1) replication has had only transient clinical benefit to date. It has been speculated that drug-resistant virus mutants may contribute to therapeutic failure. Objective: To extrapolate from the biology of drug-resistant HIV-1 to improve antiretroviral chemotherapeutic strategies. Study design: The literature was reviewed in regard to clinical and virologic correlates of HIV-1 drug resistance, methodology for detection of resistant virus, and chemotherapeutic strategies for prolonging suppression of virus replication. Results: HIV-1 isolates resistant to different nucleoside reverse transcriptase (RT) inhibitors, nonnucleoside RT inhibitors, and protease inhibitors have been implicated to different extents with virologic or clinical failure of therapeutic effectiveness. The in vivo antiviral effect of certain nonnucleoside RT inhibitors as monotherapy is lost coincident with emergence of a dominant population of resistant virus. Disease progression is more rapid among patients at advanced stages of HIV-1 disease with highly zidovudine (AZT)-resistant virus (50% inhibitory concentration ≤ 1.0 μM AZT) and is not attributable to effects of other baseline predictors of progression studied to date. However, there is no definitive evidence that high level AZT resistance causes the loss of therapeutic benefit of AZT. Several of the research methods used for detection of drug-resistant mutants could be developed for future use as screening assays in clinical virology laboratories. Conclusions: Strategies for individualizing therapy based on switching, or adding, drugs at first detection of drug-resistant HIV-1 aim to minimize replication of viruses that are drug-resistant, as well as those that remain susceptible to the drug. If clinical investigation reveals that such approaches extend duration of antiretroviral therapeutic benefit, HIV-1 drug-resistance assessment may be increasingly requested from clinical virology laboratories. Monitoring antiviral suppression by quantifying plasma HIV-1 RNA appears more practical at present, however. Different combination regimens are also being studied to see if some regimens delay emergence of resistant virus longer than others. In the future, sequential empiric changes to new combination regimens every few months may also bear investigation to attempt to "pre-empt" HIV-1 resistance development.