Protease inhibitor resistance update: where are we now?

The introduction of protease inhibitors (PIs) and highly active antiretroviral therapy in the mid-1990s dramatically altered the treatment of HIV infection, enabling suppression of viral replication to undetectable levels and preventing disease progression. Most PIs present a strong barrier against viral resistance; the accumulation of multiple mutations is often required to produce resistance. However, there is variability of resistance within the PI class, as demonstrated by the fact that some PIs require fewer mutations to confer resistance compared with others. Resistance to individual PIs as well as the development of broad cross-resistance to multiple agents in this class remain major challenges in clinical practice. Resistance to PIs may involve primary or secondary mutations in the protease gene in addition to mutations outside of protease in the gag cleavage and noncleavage sites. Primary mutations may be sufficient to confer resistance to select PIs. Secondary mutations may be required to produce resistance with some PIs, whereas other mutations may be compensatory, restoring activity of the viral protease or increasing the replicative capacity of the virus. Specific resistance patterns associated with individual PIs have been identified. Strategies to prevent PI cross-resistance and to manage its occurrence involve rational sequencing of PIs, ritonavir boosting to maintain a strong barrier against viral resistance, the use of newer PIs with activity against resistant viruses or unique resistance profiles, avoidance of PI combinations with overlapping resistance patterns, and application of knowledge of mutations associated with hypersusceptibility to other agents in this class.