PHASE-I STUDY OF ATEVIRDINE MESYLATE (U-87201E) MONOTHERAPY IN HIV-1-INFECTED PATIENTS

The safety, tolerability, and antiviral activity of atevirdine (ATV), a nonnucleoside reverse transcriptase inhibitor, were studied in a pha se I/II clinical trial (ACTG 187) of patients with CD4 counts less tha n or equal to 500/mm(3). In all, 34 HIV-1-infected patients were rando mized to receive ATV for 12 weeks in doses chosen to achieve one of th ree serum trough levels: 5 to 13 mu M, 14 to 22 mu M, or 23 to 31 mu M Rash was the most common adverse event, with a grade 3 or 4 rash occu rring in 4 patients. No significant change from baseline in HIV-1 plas ma RNA mean copy number was detected at week 4 (+0.09 log(10) copies/m l, p = .30). However, some evidence indicated moderate antiviral activ ity at week 4, based on median changes in CD4 count (+23/mm(3);p = .05 ), and viral peripheral blood mononuclear cell (PBMC) titer (-0.68 log (10) copies/ml; p = .03). In addition, 2 of 4 patients with detectable baseline serum p24 antigen showed declines of >50%. HIV-1 resistance to ATV was detected in 41% of patients and was most commonly associate d with RT mutations K103N and Y181C. In contrast, the Y181C mutation w as not detected in ATV-resistant isolates obtained from patients enrol led in ACTG 199, a study of ATV given in combination with zidovudine. Under the conditions of this study, ATV failed to demonstrate signific ant antiretroviral activity. However, transient in vivo activity might have been obscured by rapid development of resistance coupled with in adequate sampling at early time points following initiation of ATV the rapy.