A hybrid type 2 cluster randomized trial of an enhanced combined cognitive behavioral therapy and medication management algorithm for treatment of depression among youth living with HIV: study protocol

BACKGROUND: The treatment of depression is essential for improving both psychiatric and medical outcomes for youth with HIV (YWH). Previous studies have shown that the combination of a medication algorithm and CBT tailored for YWH (COMB) is efficacious for decreasing depressive symptoms and improving quality of life, but sustainability of effects remains difficult. Most recently, a cluster-randomized RCT found at Week 24 statistically significant improvement in the site-level mean number of depressive symptoms, the proportion of YWH with a treatment response, and the proportion in remission at COMB sites compared to treatment as usual (TAU) sites (6.7 vs. 10.6, 62% vs. 18%, 48% vs.17%, ps[Formula: see text]0.01, respectively). However, by Week 48, differences were no longer significant between arms for these outcomes. Additionally, viral suppression did not improve in COMB compared to TAU. These findings indicate a "voltage drop" of COMB's impact. To improve sustainability, we plan to enhance the combination treatment with five additional implementation strategies (COMBEX) suggested in our post-trial interviews from our efficacy study. This protocol paper describes a Hybrid Type 2 Cluster Randomized Trial in which COMBEX will be compared to COMB, with co-primary effectiveness and implementation aims guided by the Consolidated Framework for Sustainability Constructs in Healthcare. METHODS: Eligibility will include youth with HIV (15-24 years, n = 130) with a diagnosis of ongoing nonpsychotic depression at HIV clinic sites in the US. Using restricted randomization, sites (n = 8) will be assigned to either COMBEX (with its additional implementation strategies) or to COMB. Implementation outcomes of adoption, fidelity, and sustainability will be evaluated, as well as the impact of COMBEX compared to COMB in improving real-world effectiveness of reducing indices of depression (e.g., symptoms, treatment response, remission) and decreasing viral load over 72 weeks. Additionally, an explanatory, sequential, mixed-method approach will be used to evaluate the context of implementation for both COMB and COMBEX, guided by the sustainability framework with data from staff/clinicians (n = 64). Arm comparisons will use t-tests on site-level means. DISCUSSION: This study will inform the broader implementation of this efficacious approach to treatment of depression for youth with HIV by revealing strategies relevant to its sustainment. TRIAL REGISTRATION: NCT07211087 (registered October 7, 2025).