Research progress on second-generation integrase strand transfer inhibitor-based fixed-dose combination therapies

Defu Yuan; Fei Zhao; Shanshan Liu; Hongxia Yan; Lifeng Liu; Tong Zhang; Bei Wang; Bin Su

Abstract：Integrase Strand Transfer Inhibitors (INSTIs) have favorable safety and tolerability profiles, potent antiviral activity, and high resistance barriers, solving the limitations of previous antiretrovirals caused by resistant mutations. While first-generation INSTIs have exhibited emerging resistance challenges during extended clinical use, second-generation INSTIs provide enhanced resistance barriers and extended plasma half-lives relative to their predecessors. Optimized combination regimens incorporating these agents have substantially improved therapeutic convenience and long-term disease management in human immunodeficiency virus (HIV) care. Current investigations focus on multiple combination strategies employing second-generation INSTIs including dolutegravir (DTG) and bictegravir (BIC), with preliminary findings demonstrating substantial clinical benefits. The DTG/lamivudine (3TC) dual regimen in the GEMINI and TANGO studies achieved 92.1%-99.6% virologic suppression rates at week 48, maintaining efficacy through 144 weeks. The cabotegravir (CAB)/Rilpivirine (RPV) long-acting injectable combination in ATLAS trials demonstrated 92.5% suppression efficacy with validated every-two-month dosing intervals. The BIC/emtricitabine/tenofovir alafenamide triple regimen in studies 1489/1490 maintained >84% suppression at week 144 while retaining activity against resistant variants. Real-world data confirm that these regimens maintained a viral suppression rate of >90% in both treatment-naïve and -experienced patients, with treatment interruption rates of <5%. Recent advances include the US Food and Drug Administration's approval of DTG/3TC for use in adolescents ≥12 years old and adaptive studies of CAB/RPV in special populations. This article summarizes the research progress of current combination formulations based on second-generation INSTIs to provide new therapeutic options and clinical insights for the treatment of patients with HIV.