• Infectious Disease Clinical Trials
• HIV & AIDS

• Infectious Disease Clinical Trials
• Infectious Disease
• HIV & AIDS

BMS-986001 is a novel nucleoside analog reverse-transcriptase inhibitor (NRTI) that, in higher doses, demonstrated comparable efficacy to tenofovir (TDF) in treatment-naïve HIV-1-infected subjects. Samir Gupta, MD, Indiana University School of Medicine, Indianapolis, Indiana, United States, presented the results of this phase 2b randomized dose trial (active controlled, blinded to BMS-986001) with worldwide recruitment.

BMS-986001 was developed to better target viral transcription and minimize the toxicities associated with current NRTIs, such as increased risk of osteoporotic fracture [Bedimo R et al. AIDS. 2012], renal dysfunction [Scherzer R et al. AIDS. 2012], and adverse metabolic outcomes [Hammond E et al. Clin Infect Dis. 2010]. It is active against some HIV-1 isolates with NRTI resistance-associated mutations, including the K65R and L74V substitutions and the Q151M constellation (without M184V) [Li Z et al. Antimicrob Agents Chemother. 2013]. In a previous study [Cotte L et al. J Acquir Immune Defic Syndr. 2013], BMS-986001 administration for 10 days led to substantial decreases in plasma HIV-1 RNA levels and was well tolerated.

In this study, the safety and efficacy of BMS-986001 (100, 200, and 400 mg QD) was compared with TDF (300 mg QD) in treatment-naïve subjects with HIV-1. All subjects also received 600 mg of efavirenz (EFV) plus 300 mg of lamivudine (3TC) QD. The primary study end points were the efficacy and safety of BMS-986001 at week 24, determined by measuring the proportions of subjects with plasma HIV-1 RNA < 50 counts/mL and the number of adverse events (AEs). Secondary end points included the efficacy and safety of BMS-986000 through week 48, change from baseline in CD4-positive T-cell count through weeks 24 and 48, and the number of subjects experiencing virologic failure with treatment-emergent resistance-associated mutations through weeks 24 and 48.

Patients were included in the study if they were ≥ 18 years of age and antiretroviral treatment naïve and if they had plasma HIV-1 RNA > 5000 counts/mL and a CD4-positive T-cell count > 200 cells/mm³. The exclusion criteria were resistance to 3TC, EFV, TDF, or protease inhibitors or a positive test for hepatitis B surface antigen or hepatitis C antibodies/RNA.

Baseline demographics and characteristics in the modified intent-to-treat population (received 1 dose of study drug) were similar among the 4 groups. Subjects age ranged between 29 and 34 years, and the majority were men (62% to 71%). HIV subtypes included AE, B, and C, reflecting the worldwide distribution of the subjects. Median HIV-1 RNA (log₁₀ counts/mL) was 4.4, with ∼ 18% having ≥ 100 000 counts/mL. Median CD4-positive T-cell count (cells/μL) was 312, with ∼ 8% having < 200 cells/μL.

The proportion of subjects achieving HIV-1 RNA < 50 counts/mL at weeks 24 and 48 was similar among treatment groups in the modified intent-to-treat population analysis. In the BMS-986000 group, these rates at weeks 24 and 48 were, respectively, 88% and 75% in the 100-mg arm, 81% and 81% for the 200-mg arm, and 95% and 89% for the 400-mg arm. In the TDF group, these rates at weeks 24 and 48 were 89% and 82%, respectively. The observed mean change in CD4-positive T-cell counts was similar from baseline through weeks 24 (about 100 to 150 cells/μL) and 48 (about 150 to 190 cells/μL).

Emergent resistance/reduced susceptibility to the study drug was higher in patients receiving BMS-986000, particularly with the 100-mg dose (14% vs 6% in the 200- and 400-mg dose groups and 1% in the TDF group). The occurrence of serious AEs was similar in the 4 groups. There were no noticeable trends for grade 2 to 4 related AEs or new/unexpected safety signals for TDF; 1 patient died (nonstudy related). Higher doses of BMS-986001 demonstrated comparable efficacy to TDF when combined with EFV + 3TC in treatment-naïve HIV-1-infected subjects.

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