Second-generation non-nucleosidic reverse transcriptase inhibitor HBY097 and HIV-1 viral load

to –1·38 log10) (table). In one of five patients who received 250 mg and two of five patients on 750 mg, viral load went below detection. In the high-dose cohorts, the mean viral load stayed below the value at entry after a 7-day washout period (–0·22 to –0·27 log10), in contrast with placebo treated patients, who had +0·25 and +0·58 log10 increase in viral load. In order to evaluate the generation of resistant viruses under short-term monotherapy, half maximum inhibition values by the drug in cell culture (IC50) were determined from viruses isolated from the patients before and after therapy. IC50 values at entry were between 0·1 and 3 nmoL, except for patient 6 in the 750 mg group, who had a resistant virus at entry with an IC50 of 160 nmoL, containing a NNRTI resistance mutation as well as a zidovudineresistance mutation in virions derived from plasma and in cultured virus. Development of a less sensitive virus after treatment was seen in only one patient in the 750 mg study and one patient in the 1000 mg study. No correlation was seen between initial viral load and the probability for development of a less sensitive virus (data not shown). The elevations in IC50 values were moderate (15 and 2·2 nmoL, respectively) and correlated with a partial or full mutation at position 103 of the reverse transcriptase. In studies with nevirapine, resistant virus replaced wild type within 2–4 weeks in all patients. These data suggest that HBY097 and related compounds are promising second-generation NNRTIs, which could be included in first-line combination therapies.