• Drug-Drug Interactions in HIV Infections
  Slide Session 421
  Authored by S. C. Piscitelli

Drug interactions in the treatment of HIV infection was the focus of several presentations on Sunday. Steve Piscitelli provided a concise overview of the subject, noting that many medications are metabolized by or induce the expression of the P450 cytochromes, especially the 3A4 isozyme. Prominent among these are several of the protease inhibitors (PIs) and non-nucleoside RT inhibitors. He noted that there is a paucity of studies that address this subject, and that most only evaluate the effect of two drugs at a time. However, since most persons receiving HIV therapy take three or more medications, and that these drugs may each have different effects on CYP3A4, further studies are needed to delineate how physicians should dose complex combinations of medications.

Piscitelli noted that both efavirenz and nevirapine are inducers of CYP3A4; therefore inducers of the metabolism of several protease inhibitors. This induction causes reduction in the level of co-administered protease inhibitors (when used as single PIs). Both efavirenz and nevirapine reduce steady-state levels of indinavir by about 30%; efavirenz lowers the levels of saquinavir by 45%, amprenavir by 43%.

The use of ritonavir to inhibit CYP3A4 can increase the drug levels of CPY3A4 substrates, reducing pill burden and possibly increasing the therapeutic effectiveness of other drugs in patients who receive these PIs in combination with ritonavir. A key question is how ritonavir-combined PIs are affected by the simultaneous use of the non-nucleosides.

When ritonavir is used in high dose (400 mg twice daily), there appears to be no significant decrease in the levels of saquinavir when efavirenz is used; this dose protects saquinavir from the efavirenz-induced reduction of saquinavir. Similar results are seen with 200-mg twice-daily ritonavir. For example, when amprenavir (1200 or 450 mg twice daily) is administered with 200 mg ritonavir, there is no change in amprenavir levels after efavirenz is given.

Low dose ritonavir (100 mg twice daily) is being used with increasing frequency to "boost" the levels of other PIs. How does this dose stand up with regards to blocking the non-nuke effect? Piscitelli reviewed recent data that showed that nevirapine decreased the levels of both indinavir (given 800 mg twice daily) and ritonavir (100 mg twice daily). In this study, indinavir trough concentrations decreased by 68% and ritonavir trough decreased by 72%.