uk-453-061 and efavirenz

A 96-week clinical study was planned to estimate the antiviral activity and safety of lersivirine in treatment-naive HIV-1-infected patients.. This ongoing international, multicenter, double-blind, randomized, Phase IIb exploratory study evaluates the efficacy and safety of 2 doses of lersivirine or 1 of efavirenz, each combined with tenofovir disoproxil fumarate/emtricitabine. Patients were randomized 1:1:1 to receive lersivirine (500 or 750 mg once daily) or efavirenz (600 mg once daily), each administered with tenofovir disoproxil fumarate/emtricitabine (300 mg/200 mg, once daily). The primary endpoint is the proportion of patients with HIV-1 RNA <50 copies per milliliter (missing/discontinuation = failure) at week 48.. For the 193 patients in the study, baseline mean plasma HIV-1 RNA was 4.7 log10 copies per milliliter, and median CD4 cell count was 312 cells per cubic millimeter. At week 48, the percentage of patients with HIV-1 RNA <50 copies per milliliter was 78.5% (51/65), 78.5% (51/65), and 85.7% (54/63) in the lersivirine 500 mg, 750 mg, and efavirenz groups, respectively. CD4 cell count changes from baseline were similar across groups. Virologic failure occurred in 7 patients (11%) in each of the lersivirine groups and 3 patients (5%) in the efavirenz group. The pattern of lersivirine resistance was distinct from other nonnucleoside reverse transcriptase inhibitors. Overall incidences of all-causality treatment-related or grade 3/4 adverse events (AEs) or AE-related discontinuations were lower with lersivirine than with efavirenz, and serious AEs occurred at similar rates across treatment groups.. Both lersivirine doses showed broadly comparable efficacy to efavirenz over 48 weeks in treatment-naive patients, with different AE profiles from efavirenz.

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Deoxycytidine; Double-Blind Method; Drug Resistance, Viral; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Intention to Treat Analysis; Male; Middle Aged; Mutation; Nitriles; Organophosphonates; Pyrazoles; Reverse Transcriptase Inhibitors; RNA, Viral; Tenofovir; Young Adult

Lersivirine is a nonnucleoside reverse transcriptase inhibitor undergoing clinical development for the treatment of HIV-1.. The goal of this study was to investigate the safety and tolerability of multiple oral doses of lersivirine administered to healthy male subjects to assist in the planning of longer term studies.. This was a randomized, double-blind, double-dummy, placebo-controlled, parallel-group, multicenter, Phase I clinical study in fasting, healthy male volunteers. Subjects were randomly assigned in a ratio of 7:7:4:4 to receive lersivirine 500 mg BID, lersivirine 750 mg once daily, efavirenz 600 mg once daily, or placebo once daily for 28 days. Safety and tolerability were assessed throughout the study by continuous collection of adverse events (AEs), including adverse drug reactions, illnesses with onset during the study, exacerbation of previous illnesses, and clinically significant changes in physical examination findings. Vital sign measurements and ECGs were performed at screening; on day 1 (predose and 2, 3, and 4 hours postdose); on days 7, 14, 21, and 28 (predose); at discharge; and at follow-up. Safety laboratory tests (including hematology, chemistry, and urinalysis) were performed at screening; days 0, 7, 14, 21, and 27; and at follow-up.. Of the 66 healthy male subjects enrolled (age range, 21-51 years; body mass index, 18.1-29.9 kg/m(2)), 40 were white, 22 were Asian, 3 were black, and 1 was of mixed race. There were no clinically significant laboratory abnormalities, including changes in lipid profile, liver or renal function test results, or ECG findings. Overall, 86% (18/21) of subjects in the lersivirine 500-mg BID group, 81% (17/21) in the lersivirine 750-mg once-daily group, 92% (11/12) in the efavirenz 600-mg once-daily group, and 92% (11/12) in the placebo group experienced at least one treatment-related AE. Eight subjects were permanently discontinued from the study; 4 subjects in the efavirenz group (3 of whom participated in the trial at the Brussels study center) were permanently discontinued due to AEs considered to be treatment related. No subjects receiving lersivirine permanently discontinued the study due to treatment-related AEs, although one subject temporarily discontinued treatment. In addition, 4 subjects withdrew consent (2 subjects [1 of whom was at the Brussels study center] receiving lersivirine 750 mg once daily and 2 subjects [1 of whom was at the Brussels study center] receiving efavirenz). There were no deaths or serious AEs in any of the study groups.. Lersivirine appeared to be well tolerated after 28 days of continuous dosing in this small, selected group of young, healthy male volunteers.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Male; Middle Aged; Nitriles; Pyrazoles; Reverse Transcriptase Inhibitors; Young Adult