Adult AIDS Clinical Trials Group 5043 examined pharmacokinetic (PK) interactions between amprenavir (APV) and efavirenz (EFV) both by themselves and when nelfinavir (NFV), indinavir (IDV), ritonavir (RTV), or saquinavir (SQV) is added. A PK study was conducted after the administration of single doses of APV (day 0). Subjects (n ؍ 56) received 600 mg of EFV every 24 h (q24h) for 10 days and restarted APV with EFV for days 11 to 13 with a PK study on day 14. A second protease inhibitor (PI) (NFV, 1,250 mg, q12h; IDV, 1,200 mg, q12h; RTV, 100 mg, q12h; or SQV, 1,600 mg, q12h) was added to APV and EFV on day 15, and a PK study was conducted on day 21. Controls continued APV and EFV without a second PI. Among subjects, the APV areas under the curve (AUCs) on days 0, 14, and 21 were compared using the Wilcoxon signed-rank test. Ninety-percent confidence intervals around the geometric mean ratios (GMR) were calculated. APV AUCs were 46% to 61% lower (median percentage of AUC) with EFV (day 14 versus day 0; P values of <0.05). In the NFV, IDV, and RTV groups, day 21 APV AUCs with EFV were higher than AUCs for EFV alone. Ninety-percent confidence intervals around the GMR were 3.5 to 5.3 for NFV (P < 0.001), 2.8 to 4.5 for IDV (P < 0.001), and 7.8 to 11.5 for RTV (P ؍ 0.004). Saquinavir modestly increased the APV AUCs (GMR, 1.0 to 1.4; P ؍ 0.106). Control group AUCs were lower on day 21 compared to those on day 14 (GMR, 0.7 to 1.0; P ؍ 0.042). African-American non-Hispanics had higher day 14 efavirenz AUCs than white non-Hispanics. We conclude that EFV lowered APV AUCs, but nelfinavir, indinavir, or ritonavir compensated for EFV induction.The clinical use of antiretroviral regimens containing combinations of nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleotide reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PI) has become the accepted approach to therapy for human immunodeficiency virus (HIV) infection, especially for patients with multiple prior antiretroviral regimens (1,29). This has led to the development of new antiretroviral treatments and clinical studies of three-and four-drug combinations as salvage regimens for antiviral-experienced patients. While these combination regimens are often guided by HIV-1 resistance assays, there are often incomplete pharmacokinetic (PK) data available to guide optimal dosing of dual protease inhibitors in an NNRTI-containing regimen.Due to the complex nature of drug interactions (metabolic induction versus inhibition, efflux transporter interactions) and the desire to understand mechanisms underlying these drug interactions, Adult AIDS Clinical Trials Group (ACTG) protocol A5043 was developed to examine these interactions. At the time A5043 was developed, the routine use of low-dose ritonavir (RTV) was not considered to be the standard of care, and the optimal approach to combining two PIs with efavirenz (EFV) was under investigation in ACTG 398. ACTG 398 utilized NNRTI-PI combinations similar to those of ACTG 5043 along with nucleoside ana...