The human immunodeficiency virus (HIV) protease inhibitors are a broad class of agents that are widely used in the therapy and prevention of HIV infection and the acquired immunodeficiency syndrome (AIDS). All of the currently available protease inhibitors have been associated with transient and usually asymptomatic elevations in serum aminotransferase levels, and several (atazanavir, indinavir) with mild-to-moderate elevations in indirect and total bilirubin concentration. The protease inhibitors are rare causes of clinically apparent, acute liver injury. In HBV or HCV coinfected patients, antiretroviral therapy with highly active antiretroviral therapy (HAART) including protease inhibitors may result in an exacerbation of the underlying chronic hepatitis B or C.
The antiretroviral protease inhibitors act by binding to the catalytic site of the HIV protease, thereby preventing the cleavage of viral polyprotein precursors into mature, functional proteins that are necessary for viral replication. Most of these agents were developed by rational drug design based upon chemical structures that would interact with the catalytic site of the HIV protease, based upon x-ray crystallographic studies defining the three-dimensional molecular structure of the protease. For these reasons, the protease inhibitors are heterogeneous molecules with little structural similarity, most of which are peptide-like and resemble the short peptide that is cleaved by the viral protease (usually the N terminal side of the middle proline residue is phenylalanine-proline-proline).
The initial HIV protease approved for use in the United States was ritonavir (1996), followed in short order by indinavir (1996), nelfinavir (1997), saquinavir (1997), amprenavir (1999), lopinavir/ritonavir (2000), atazanavir (2003), fosamprenavir (2003), tipranavir (2005), and darunivir (2006). The potencies of these agents are similar and the major reason for using one or the other relates to pharmacokinetics (whether they are taken once vs multiple times daily), tolerance and presence of antiviral resistance.