Efficacy, safety, bone and metabolic effects of HIV nucleoside reverse transcriptase inhibitor BMS-986001 (AI467003): a phase 2b randomised, controlled, partly blinded trial

Abstract

MethodsAI467003 was a Phase 2b, randomised, active-controlled, blinded-to-BMS-986001 dose trial.HIV-1-infected adults with plasma HIV-1 RNA greater than 5000 copies per mL and CD4+ T-cell counts greater than 200 cells/mm 3 were randomised 2:2:2:3 to three BMS-986001 arms (100, 200 or 400 mg once daily), or reference arm (TDF 300 mg once daily), each with efavirenz (600 mg once daily) and lamivudine (300 mg once daily). Both subjects and investigators remained blinded to BMS-986001 dose, but not allocation, through Week 48. Proportion of subjects with plasma HIV-1 RNA less than 50 copies per mL and safety (serious adverse events [SAEs] and AEs leading to discontinuation) through Week 24 were primary endpoints. Resistance analysis was a secondary endpoint, and additional safety parameters were exploratory endpoints.AI467003 is registered with ClinicalTrials.gov (NCT01489046). FindingsA total of 757 subjects were assessed for eligibility and 301 randomised. Randomised subjects were assigned to receive either BMS-986001 (n=67 for the 100 mg once-daily group, n=67 for the 200 mg once-daily group, n=66 for the 400 mg once-daily group) or TDF (n=101 In a Phase 2a, dose-escalating, monotherapy study conducted for 10 days in treatment-experienced, HIV-1-infected, subjects who were not exposed to any antiretroviral treatment in the previous 3months, BMS-986001 demonstrated a median decrease in HIV-1 RNA from baseline of at least 1 log10 copies per mL for all doses. 19 These findings were used to support the design of this dosefinding Phase 2b study, which assessed the efficacy and safety of three doses of BMS-986001 (100, 200, and 400 mg once daily) versus tenofovir disoproxil fumarate (TDF 300 mg once daily), when coadministered with efavirenz (EFV 600 mg once daily) and lamivudine (3TC 300 mg once daily) in treatment-naïve, HIV-1-infected subjects. A detailed assessment of bone, renal, metabolic and mitochondrial parameters was performed to assess the safety of BMS-986001. 6 METHODS Study designAI467003 was a Phase 2b, randomised, active-controlled, blinded-to-BMS-986001 dose trial carried out at 47 sites across South America, North America, South Africa, Australia, Asia, and Europe.This study was conducted in accordance with Good Clinical Practice (GCP), as defined by the ParticipantsEligible subjects were treatment-naïve (defined as no current or previous exposure to an antiretroviral drug for more than 1 week), HIV-1-infected adults aged at least 18 years with plasma HIV-1 RNA greater than 5,000 copies per mL and CD4+ T-cell counts greater than 200 cells/mm 3 at screening.Exclusion criteria included a history of phenotypic and/or genotypic drug resistance testing showing resistance to EFV, TDF, or 3TC, presence of hepatitis B surface antigen, hepatitis C virus antibody or RNA, history of abnormal liver transaminases (defined as greater than three times the upper limit of normal) at screening, and creatinine clearance less than 60 mL/min at screening. All subjects provided written informed consent in agreement wi...

The Effect of Tenofovir Disoproxil Fumarate on Bone Mineral Density: A Systematic Review and Meta-Analysis

“…Ultimately, we included 25 distinct papers for final data extraction (Figure 1). Of these, 10 investigated PrEP users [1,3,11,12,15–20] and were included in our primary analyses, while 15 investigated HIV [21–35]. We did not find any HBV studies or new relevant conference proceedings that had not already been published as one of our reviewed studies.…”

“…Nine studies [23,24,26–28,31–34] measured BMD changes over 1 year in people using TDF for HIV. As for the PrEP studies, all showed a larger decrease from baseline in TDF compared with non-TDF treated participants.…”

Structure of HIV‐1 reverse transcriptase/d4TTP complex: Novel DNA cross‐linking site and pH‐dependent conformational changes

“…Although d4T itself is being phased out as a treatment for HIV, chemically modified versions of d4T may yet find a place in the future. A 4′‐ethynyl derivative of d4T (BMS‐986001) in Phase 2 trials showed similar efficacy as tenofovir disoproxil fumarate; however, development was discontinued due to a lower resistance barrier and gains in both peripheral and central fat accumulation . Such modifications could add specificity while retaining the flat ring that may allow d4TTP to retain the same catalytic efficiency as dTTP, despite the absence of the 2′ hydroxyl.…”

C9orf72-Related Neurodegenerative Diseases: From Clinical Diagnosis to Therapeutic Strategies

“…An ongoing phase 2a study is evaluating the safety and tolerability of TPN-101 on a small sample (40 participants) of C9orf72 ALS/FTD patients (NCT04993755). TPN-101 (OBP-601, BMS-986001, festinavir, censavudine;Smith et al, 2015) is a thymidine analog NRTI (nucleoside reverse transcriptase inhibitor) that shows major efficacy against HIV-2 and HIV-1 (Gupta et al, 2016). The active form of TPN-101 (BMS-986001-5 -triphosphate) is a substrate for incorporation by HIV-1 reverse transcriptase, inducing the termination of viral DNA synthesis (Smith et al, 2015).…”