Sequencing antiretroviral drugs for long-lasting suppression of HIV replication.

The primary goal of antiretroviral sequencing is to extend maximal viral suppression for as long as possible by avoiding the selection of a multidrug-resistant virus. It is likely that lamivudine or emtricitabine will be an unavoidable component of any initial regimen because of their efficacy, tolerability and convenience of administration. The risk of selecting a nucleotide excision or the 65R mutations is minimised with abacavir plus lamivudine or tenofovir plus emtricitabine when they are combined with boosted protease inhibitors (PIs) or efavirenz. These dual-nucleoside reverse transcriptase inhibitor backbones (NRTIs) also have the major advantage of their low potential for mitochondrial toxicity, which may contribute to the long-lasting suppression of viral replication by avoiding treatment interruptions due to drug toxicity. Neither PIs nor non-NRTIs (NNRTIs) cause mitochondrial injury, but the initial use of boosted PIs has the advantages of avoiding the selection of class-resistant variants and reducing the risk of selecting for NRTI resistance, thus preserving a wider range of subsequent treatment options. Although the question is still controversial, NNRTIs may best be used as second-line options in both simplification and salvage regimens. The optimal timing for starting entry inhibitors during the course of HIV disease has not yet been fully elucidated.